Datasets:

monology

/

pile-uncopyrighted

like 86

Introduction ============ A commonly encountered abiotic stress for cold-sensitive vegetables that restricts their yield potential is the exposure to sub-optimal temperatures, i.e., cultivation above the minimum growth temperature range of 8--12°C instead of at the optimum temperature range of 18--27°C ([@B17]; [@B68]; [@B61]). Sub-optimal temperatures of 8--18°C also negatively affect tomato growth and development due to shorter internodes that restrict plant height, retardation of leaf expansion, reduction of leaf number and total leaf fresh mass and increased dry matter content and thickness of leaves due to increased starch storage ([@B71]). As reviewed by [@B61], sub-optimal temperature induces changes in root phytohormone production. This has an impact on root-to-shoot hormone signaling resulting in reduced plant productivity. In addition, temperatures below optimum impair cell membrane fluidity and increase permeability, resulting in ion leakage ([@B1]), while intra- and extracellular water and nutrient movement are inhibited ([@B41]), reactive oxygen species (ROS) are generated ([@B28]), photosynthesis may be restricted ([@B65]), and finally yield is reduced. Different cultivated tomato varieties may exhibit significant differences in their responses to sub-optimal temperature ([@B69]). An increase in the tolerance of tomato plants to sub-optimal temperature could considerably reduce the energy cost for growth in heated greenhouses ([@B69]). Although traditional breeding over the last 30 years resulted in cultivars with twofold improved energy efficiency as a result of increased yield, there is now also a need to reduce the absolute amount of energy input ([@B68]). A further successful cultivation of tomato in the field and in unheated greenhouses under lower temperatures requires either the breeding of new cultivars that are better adapted to low temperature or an increase in the tolerance of tomato to sub-optimal temperature aimed to extend the growing period. However, due to low genetic diversity within the cultivated tomato species *Solanum lycopersicum* L. and reduced pollen fertility in interspecific tomato hybrids ([@B22]; [@B70]), breeding of high-yielding tomato cultivars with enhanced tolerance to sub-optimal temperature has not been successful so far ([@B61]). An alternative strategy to enhance the tolerance of elite tomato hybrids to sub-optimal temperature is to graft them onto rootstocks that are compatible with the cultivated species and tolerant to sub-optimal temperature. Such rootstocks might be interspecific hybrids of *S. lycopersicum* with accessions of cold-tolerant wild tomato species, such as *S. habrochaites* S. Knapp & D.M. Spooner. The latter species is of particular interest as a potential source of germplasm to widen the genetic variation for low temperature tolerance of cultivated tomato ([@B11]; [@B70], [@B69]; [@B47]). It originates from an altitude of about 3.200 m ([@B54]) where an adaptation to low temperatures can be expected ([@B51]). The superiority of this cultivar is due to the presence of adaptive mechanisms to alleviate cell damage and to reproduce under sub-optimal temperature. Comparative analyses on many physiological responses to cold stress were conducted during the last decades proposing several mechanisms that could explain the chilling tolerance of *S. habrochaites* ([@B70]). Several genetic studies have elucidated the key molecular and physiological mechanisms of cold tolerance in *S. habrochaites* ([@B30]; [@B3]; [@B15]). They led to the identification of important QTL controlling shoot wilting under root chilling and the plastochron index, as reviewed by [@B61]. Low temperature has no adverse impact on root growth in high-altitude accessions of wild relatives of *S. lycopersicum* ([@B69]; [@B47]). Grafted plants with the accession LA 1777 of the wild tomato species *S. habrochaites* as the rootstock showed better vegetative growth after exposure to sub-optimal temperatures than plants with *S. lycopersicum* 'Moneymaker' as rootstock. Taking this into consideration, the wild species *S. habrochaites* can be proposed as a potential germplasm resource of sub-optimal temperature tolerance in tomato breeding ([@B71], [@B70], [@B69]; [@B26]). The performance of a grafted plant under sub-optimal temperature conditions is specific for each rootstock/scion combination, because low-temperature tolerance is a complex secondary trait depending on many primary traits (e.g., root and leaf morphology, plant hormones, ROS scavenging compounds, etc.) operating in both the roots and shoots. To elucidate the crucial physiological and molecular mechanisms that determine the positive impact of LA 1777 rootstock on tomato scion performance at sub-optimal temperature, a comprehensive transcriptome analysis is required. Transcriptome profiling in model species such as Arabidopsis has revealed several low temperature stress-related pathways ([@B16]; [@B76]). In tomato, transcriptome analysis has been used to compare patterns of gene expression under salt, cold, or drought stress ([@B29]; [@B64]; [@B36]). However, to the best of our knowledge, comparative transcriptome analysis of cold-tolerant and -sensitive tomato genotypes under sub-optimal temperature is yet to be reported. Therefore, we performed a comparative gene expression profiling experiment with the tolerant wild tomato *S*. *habrochaites* accession LA 1777 and the sensitive *S. lycopersicum* cv. Moneymaker as rootstocks and the commercial *S. lycopersicum* cv. Kommeet as scion under optimal and sub-optimal temperatures in the root environment. Our results provide new insights into the molecular mechanisms underlying the sub-optimal temperature tolerance of the wild tomato *S. habrochaites*. This knowledge can be utilized to establish biomarkers to screen not only wild tomato genotypes serving as rootstocks but also rootstock/scion combinations that are likely to be tolerant to sub-optimal temperature ([@B61]). Materials and Methods {#s1} ===================== Plant Material and Cultivation Conditions ----------------------------------------- In a glasshouse at the Leibniz Institute of Vegetable and Ornamental Crops, Großbeeren, Germany (latitude 52° 20′ N, longitude 13° 18′ E, altitude 40 m) the commercial tomato cv. Kommeet (KO; De Ruiters, Bergschenhoek, Netherlands) was grafted onto tomato cv. Moneymaker (MM) or onto line accession LA 1777 (LA; C.M. Rick Tomato Genetics Resource Center, UC Davis, CA, United States) of the wild tomato species *S*. *habrochaites*. The grafting resulted in the rootstock/scion combinations MM/KO or LA/KO. Seeds of these three tomato genotypes were germinated in vermiculite for about 20 days. Splice grafting ([@B57]) was performed when seedlings had developed 3--4 true leaves. Seventeen days later grafted tomato plantlets were transferred into gullies (8 m × 0.2 m × 0.07 m) in which a standard nutrient solution for tomato ([@B19]) was re-circulating. Prior to transplanting, the roots of the young plantlets were carefully washed in tap water to remove aggregates of the growing medium. The gullies were continuously supplied with nutrient solution which was pumped from a 150 l supply tank at a flow rate of 2 l min^-1^. Twelve plantlets were accommodated in each gully with a density of approximately 2 plants m^-2^. The nutrient solution was replenished on a daily basis. The pH in the re-circulating nutrient solutions was adjusted daily to 5.6--5.7 by adding proper amounts of 1 N HNO~3~ stock solution. The experimental installation started 7 days after planting and was continuously maintained until harvest. Two groups of channels have been used differing in temperature of the re-circulating nutrient solution and thus determining the temperature in the root environment, which was either optimal (day and night 25 ± 0.6°C) or sub-optimal (day and night 15 ± 0.4°C). The target solution temperature of the sub-optimal temperature treatment was accurately maintained by cooling pipes which were connected to the respective solution tanks. The solution temperature of the optimal temperature treatment was determined by the air temperature of the greenhouse. Its daily mean was the same for both treatments at 25 ± 0.8°C with a maximum and minimum at 22.4 and 25.2°C, respectively. Mean relative humidity was 70%, CO~2~ concentration 400 μmol mol^-1^ and mean daily photosynthetically active radiation 12 mol m^-2^ d^-1^. Growth Measurements ------------------- After 22 days of cultivation at two root temperatures (46 days after grafting), leaf width, shoot length, and number of leaves were measured for two plants in each replication. Total leaf area (*Alp*, m^2^ plant^-1^) was calculated using leaf width of single leaves ([@B60]). Thereafter, harvested plants were divided into stem, leaves and roots (*F*~rp~, g plant^-1^), which were fresh weighed and dried separately at 70°C to a constant mass to measure dry masses. Root samples of about 1 g fresh mass were taken to measure the specific root length (*L*~rw~, m g^-1^) and their mean diameter (*2R*~r~, mm) using an image analyses system (WinRhizo, Regents Instruments, Quebec, Canada). Total root length (*L*~rp~ = *L*~rw~ × *F*~rp~, m plant^-1^) and surface area (*A*~rp~ = *L*~rp~ × π × *2R*~r~, m^2^ plant^-1^) and the specific root area related to fresh mass were calculated (*A*~rw~ = *A*~rp~/*F*~rp~, m^2^ g^-1^). Gas Exchange and Chlorophyll Fluorescence Measurements ------------------------------------------------------ One day before termination of the experiment, four plants from each grafting treatment were used for leaf gas exchange measurements. The most-recently fully expanded leaf was used in an open gas exchange system (Li-6400, Li-Cor, Inc., Lincoln, NE, United States). Net CO~2~ assimilation (*A*, μmol m^-2^ s^-1^), stomatal conductance (*g*~s~, mmol m^-2^ s^-1^), intercellular CO~2~ concentration (ci), and transpiration rate (*E*, mmol m^-2^ s^-1^) were determined between 9 and 12 a.m., 2 h after the light period started. In the leaf chamber photosynthetic photon flux density was maintained at 1000 μmol m^-2^ s^-1^, relative humidity at 70%, and leaf temperature at 28 ± 0.5°C. Water use efficiency (μmol mmol^-1^) was calculated as *A*/*E*. Chlorophyll fluorescence was measured on the same leaves used for gas exchange measurements after light- or dark-adaptation by employing a pulse amplitude modulated leaf chamber fluorometer (Li-6400). Minimal fluorescence values in the dark-adapted state (*F*~o~) were obtained by application of a low-intensity red measuring light source (630 nm), whereas maximal fluorescence values (*F*~m~) were measured after applying a saturating light pulse of 8.000 μmol m^-2^ s^-1^, and thus maximum quantum use efficiency of PSII in the dark-adapted state was calculated as *F*~v~ = *F*~m~ -*F*~o~. The leaf area assayed was dark-adapted for at least 30 min prior to *F*~v~/*F*~m~ measurements. Minimum (*F*′~o~) and maximum (*F*′~m~) values of fluorescence in the light-adapted state at 800 μmol m^-2^ s^-1^ were also obtained. After leaves were continuously illuminated with actinic light for 6 min, the steady-state fluorescence (*F*~s~) was recorded. Using these parameters, the following ratios were calculated: effective quantum use efficiency of PSII in the light-adapted state as F~v~′/F~m~′ = (F~m~′- F~o~′)/F~m~′, effective quantum yield as Φ~PSII~ = (F~m~′- F~s~)/F~m~′ photochemical quenching as *q*~P~ = (F~m~′- F~s~)/(F~m~′- F~o~′), and non-photochemical quenching as NPQ = (F~m~ - F~m~′)/F~m~′. Analyses of Carbohydrates and Characteristics of Oxidative Stress ----------------------------------------------------------------- Soluble sugars were measured according to [@B27], starch according to [@B63], and total amino acids according to [@B42] using a Synergy HT 96-position microplate spectrophotometer (BioTek instruments GmbH, Winooski, VT, United States). Hydrogen peroxide (H~2~O~2~) was determined according to the method described by [@B43] and electrolyte leakage as described by [@B38]. Lipid peroxidation was determined in terms of concentration of thiobarbituric acid-reactive substances and quantified on its product, malondialdehye according to the method described by [@B32] and [@B31]. For enzyme analysis, 0.1 g of each pulverized, frozen sample (leaf or root) was homogenized with ice-cold 25 mM HEPES buffer (pH 7.8) including 0.2 mM EDTA, 2 mM ascorbate and 2% (w/v) polyvinylpyrrolidon (PVP). The homogenate was centrifuged at 4°C and 14.000 rpm for 5 min. The supernatants were used for enzyme analysis. All steps in the preparation of enzyme extract were carried out at 4°C. Protein content was determined as described by [@B12] with bovine serum albumin as standard. Ascorbate peroxidase activity was determined according to [@B45] as decrease in absorbance at 290 nm due to ascorbate oxidation (*E* = 2.8 mM^-1^ cm^-1^) and the reaction was initiated by adding H~2~O~2~. Catalase activity was measured according to [@B13], as modified by [@B49]. Briefly, 200 μl of reaction mixture containing 25 mM potassium phosphate buffer (pH 7.0), 0.1 mM EDTA, 10 mM H~2~O~2~ and 10 μl plant extract were used. The decline in absorbance at 240 nm due to the decomposition of H~2~O~2~ was measured for 5 min (*E* = 39.4 mM^-1^ cm^-1^). Guaiacol peroxidase (G-POD) activity was determined according to [@B13] as modified by [@B24]. Increase in absorbance at 510 nm caused by guaiacol oxidation (*E* = 26.6 mM^-1^ cm^-1^) was measured over 50 min. Glutathione reductase (GR) activity was assayed according to [@B53], with some modifications. Briefly, the reaction mixture in a total volume of 200 μl consisted of 25 mM potassium buffer (pH 7.0), 0.1 mM EDTA, 0.5 mM oxidized glutathione, 0.12 mM NADPH and 10 μl plant sample. GR activity was measured by following the decrease in absorbance of oxidized glutathione at 340 nm (*E* = 6.2 mM^-1^ cm^-1^). Superoxide dismutase (SOD) activity was determined using the method of [@B52]. One unit of enzyme activity was defined as the amount of enzyme required to result in a 50% inhibition in the rate of nitro blue tetrazolium reduction measured at 560 nm. Microarray Analysis ------------------- For microarray analysis leaf and root samples from all treatments were collected 20 days after employing temperature treatments between 10 and 11 a.m. and immediately frozen in liquid nitrogen and stored at -80°C until use. Twelve independent biological samples for each treatment were harvested from leaves (third and fourth) and roots, and then four samples were pooled to obtain three replicates per treatment and organ for total RNA isolation. Leaf and root material was homogenized using a ball mill (Retsch, Haan, Germany) and RNA was extracted with the RNAeasy Plant Mini Kit (Qiagen GmbH, Hilden, Germany). RNA concentration and quality were determined using a spectrophotometer (Nanodrop Technologies, Wilmington, DE, United States) and a bioanalyzer (Agilent, Santa Clara, CA, United States), respectively. cRNA synthesis, labeling, hybridization onto Agilent 4x44k 022270 tomato microarrays^[1](#fn01){ref-type="fn"}^ and array scanning were performed at ATLAS Biolabs GmbH (Berlin, Germany). A total of 24 samples were used for the hybridizations. The raw microarray data were processed using the Robin application ([@B37]) to check hybridization quality and identify differentially expressed genes (DEG). Four samples were excluded from downstream analyses because they showed strong outlier behavior in the quality checks. Statistical assessment of differential gene expression was performed using default settings in Robin. Briefly, raw data were normalized by applying the Robust Multichip Average method ([@B33]), and subsequently, DEG were identified using the limma R package ([@B62]). Genes showing an absolute log2 fold change greater than 1 and a false discovery rate corrected *p*-value ([@B9]) below 0.05 were accepted as significantly differentially expressed. Assignment of the different genes represented by identifiers to respective bins and visualization of data sets was realized using MapMan software ([@B66]). Significantly changed genes were divided into up-regulated and down-regulated genes and differences in gene expression were visualized using MapMan ([@B66]; [@B67]). The averaged log signal values of all treatments are presented as heatmaps generated by Microsoft Office Excel Software 2007. Enrichment of DEG in functional categories of MapMan bins was tested using the Mefisto software including Bonferroni correction for multiple testing. The probe sequences of DEG were retrieved manually using the NCBI GenBank accession numbers from the Agilent source IDs. To determine the Unigene Identification and gi numbers BLAST searches were performed using sequences as query obtained from NCBI against SGN tomato DB contained in the SGN whole genome database^[2](#fn02){ref-type="fn"}^. Microarray hybridization results are available at ArrayExpress^[3](#fn03){ref-type="fn"}^ under accession number [E-MTAB-4986](E-MTAB-4986). Further Statistical Analyses ---------------------------- For all other data the two temperature treatments were combined with the two grafting combinations in a two-factorial experimental design with four replications per treatment and three plants per replication. Initially, data were subjected to factorial analysis of variance. When the temperature in the root environment and/or the grafting combination had a significant impact but the interaction between them was insignificant, the means between the two tested temperatures and/or the two grafting combinations were separated using the Duncan's Multiple Range Test (*p* \< 0.05). The same test was used to separate means of all four treatments when also the interaction was significant. All statistical analyses were carried out using the STATISTICA software package, version 9.0. Results ======= Differences in Growth and Physiological Traits between Grafting Combinations Using Sub-Optimal Temperature Tolerant and Sensitive Tomato Rootstock Genotypes ------------------------------------------------------------------------------------------------------------------------------------------------------------ Both sub-optimal temperature and grafting onto LA 1777 reduced shoot fresh and dry mass and total leaf area of the commercial tomato cultivar Kommeet (**Table [1](#T1){ref-type="table"}**). Temperature interacted with the grafting combination on root traits. In particular under optimal temperature the use of 'Moneymaker' as rootstock was associated with significantly higher levels of root fresh and dry mass in comparison to LA 1777. Under sub-optimal temperature these differences between the two grafting combinations were no longer observed (**Table [1](#T1){ref-type="table"}**) because root fresh and dry mass were increased 2.2 and 1.6-fold at sub-optimal temperature in LA/KO, while they were 2.0 and 1.5-fold decreased in MM/KO relative to the optimal temperature condition. Consequently, the root/shoot ratio was significantly higher (doubled) for LA/KO compared to MM/KO at sub-optimal temperature while it was the same at optimal temperature. Other root characteristics (Supplementary Table [1](#SM1){ref-type="supplementary-material"}) were not influenced either by the temperature treatment or by the rootstock, except for average root diameter, which was highest under sub-optimal temperature regardless of the rootstock. ###### Effects of exposure of tomato cultivar Kommeet grafted onto LA 1777 (LA/KO) or 'Moneymaker' (MM/KO) to sub-optimal and optimal temperature (T) in the root environment on fresh (FM), dry mass (DM), and dry matter content (DMC) of shoot and root, total leaf (*A*~lp~) and root surface area (*A*~rp~). Treatment Shoot Roots ------------------------------ ------------- -------- ------- -------- -------- --------- -------- --------- --------- Sub-optimal T LA/KO 63.42 4.77 7.52ˆa 1.56ˆb 16.08ˆb 0.65ˆb 4.06ˆc 0.363ˆb MM/KO 126.32 8.38 6.64ˆb 2.58ˆb 14.13ˆb 0.73ˆb 5.14ˆb 0.334ˆb Optimal T LA/KO 79.45 5.23 6.58ˆb 1.79ˆb 7.11ˆc 0.40ˆc 5.60ˆa 0.165ˆc MM/KO 212.73 14.03 6.60ˆb 4.89ˆa 28.32ˆa 1.26ˆa 4.43ˆbc 0.423ˆa **Main effects** T Sub-optimal 94.87 6.58 6.93 2.14 15.10 0.69 4.66 0.348 Optimal 146.09 9.63 6.59 3.12 17.72 0.83 5.92 0.294 R/S LA/KO 71.43 5.00 6.99 1.69 11.60 0.53 5.01 0.264 MM/KO 169.53 11.21 6.61 3.57 21.22 0.99 5.57 0.378 **Statistical significance** T ˆ\* ^∗^ ^∗^ ^∗^ ns ns ^∗^ ^∗^ R/S ˆ\*\* ^∗∗^ ^∗^ ^∗∗∗^ ^∗^ ^∗^ ^∗^ ^∗^ T × R/S ns ns ^∗^ ^∗^ ^∗^ ^∗^ ^∗^ ^∗∗^ Grafted plants were obtained using 'Moneymaker' (MM) or LA 1777 (LA) as rootstock and 'Kommeet' (KO) as scion in the rootstock/scion combinations (R/S). Different letters within the same column indicate significant differences between means of four replicates according to the Duncan's Multiple Range Test ( p ≤ 0.05). ns, ∗, ∗∗ , and ∗∗∗ indicate non-significant or significant differences at P ≤ 0.05, P ≤ 0.01, and P ≤ 0.001, respectively. The rates of net CO~2~ assimilation and transpiration of the leaves did not respond to sub-optimal root temperature, regardless of the rootstock (Supplementary Table [2](#SM1){ref-type="supplementary-material"}). Moreover, chlorophyll fluorescence measurements of light-adapted and dark-adapted leaves (Supplementary Table [3](#SM1){ref-type="supplementary-material"}) and soluble carbohydrate content (Supplementary Table [4](#SM1){ref-type="supplementary-material"}) were not influenced either by the temperature or by the rootstock. A significant increase in stomatal conductance (*g*~s~) occurred when roots were subjected to sub-optimal temperature, while *g*~s~ of LA/KO was significantly reduced compared with MM/KO. Water use efficiency was significantly increased and intracellular CO~2~ was significantly reduced at sub-optimal root temperature, regardless of the rootstock. The activity of G-POD in tomato roots was elevated when the rootstocks were subjected to sub-optimal temperature. The activities of G-POD in leaves and GR and SOD in leaves and roots of tomato were not influenced by either the temperature or the rootstock. However, in the roots of LA 1777 the increase of G-POD at sub-optimal compared with optimal temperature was 75% and thus, much higher than in 'Moneymaker,' were it was only 24% (Supplementary Table [5](#SM1){ref-type="supplementary-material"}). Total amino acids, electrolyte leakage and starch content were not influenced in leaves and roots either by the temperature or by the rootstock (Supplementary Table [6](#SM1){ref-type="supplementary-material"}). The same pattern was also found for lipid peroxidation, H~2~O~2~ and total protein content in leaves and roots (Supplementary Table [7](#SM1){ref-type="supplementary-material"}). Differences in Global Gene Expression between Sub-Optimal Temperature Tolerant and Sensitive Tomato Genotypes ------------------------------------------------------------------------------------------------------------- Principal component analysis (PCA) was used to identify patterns of global gene expression in leaves and roots of grafted plants (**Figure [1](#F1){ref-type="fig"}**). PC1 clearly separated the scores of normalized transcript data for leaves from those for root samples and explained 54.5% of the total variance. PC2 explained 23.2% of the variance and additionally separated the rootstocks from each other and also the different temperature treatments. Interestingly, under sub-optimal temperature the transcript profile of leaves of 'Kommeet' grafted onto LA 1777 (LA/KO) was clearly separated from the profile of 'Kommeet' plants grafted onto 'Moneymaker' (MM/KO), indicating transcriptional differences in the leaves of the two grafting combinations when the roots were exposed to low temperature. Moreover, the transcript profile of LA/KO leaves grown under optimal temperature clustered closely to that of leaves grown under sub-optimal temperature (**Figure [1](#F1){ref-type="fig"}**). The distance between scores for LA/KO or MM/KO roots subjected either to optimal or sub-optimal temperature was larger compared to leaf samples of the same grafting combination indicating strong transcriptional changes induced in roots after a temperature shift of 10°C. {#F1} Significantly (FDR *p* \< 0.05, log2 fold change above 1 or below -1) DEG in leaves and roots of the grafting combinations at sub-optimal compared to optimal temperature are shown in Venn diagrams (**Figure [2](#F2){ref-type="fig"}**). After 22 days of sub-optimal temperature in the root environment, a total of 361 (239 up- and 122 down-regulated) genes were significantly differentially expressed in the leaves of MM/KO, while in the leaves of LA/KO no significantly DEG were identified (**Figures [2A,B](#F2){ref-type="fig"}**) in agreement with the PCA results (**Figure [1](#F1){ref-type="fig"}**). In the roots of MM/KO a total of 2036 significantly regulated genes (970 up and 1066 down) were identified, while only 1509 (729 up- and 780 down-regulated) cold responsive genes were observed in the roots of LA/KO (**Figures [2C,D](#F2){ref-type="fig"}**). Among them, 1029 cold-responsive genes (546 up- and 483 down-regulated) were exclusively identified in the roots of LA/KO, whereas 1556 genes (787 up- and 769 down-regulated) were uniquely observed in roots of MM/KO. A total of 480 genes (183 up- and 297 down-regulated) were commonly regulated at sub-optimal temperature in both tomato grafts (**Figure [2](#F2){ref-type="fig"}**). {#F2} Identification of Sub-Optimal Temperature Responsive Genes in Leaves and Roots of the Graft Combinations LA/KO or MM/KO ----------------------------------------------------------------------------------------------------------------------- Genes up- or down-regulated in response to low temperature in leaves and roots were assigned to functional categories using the MapMan software. As an example, the assignment to the functional category metabolism of up- and down-regulated genes in roots of either LA 1777 or 'Moneymaker' is presented in **Figure [3](#F3){ref-type="fig"}**. After 22 days of sub-optimal temperature in the root environment, DEG were only detected in leaves of MM/KO (**Figure [2A](#F2){ref-type="fig"}**). However, from the 239 genes up-regulated in MM/KO more than half (131) could not be linked to any category since they represent genes of unknown function. All other genes could be assigned to the following bins: protein synthesis, degradation and post-translational modification (25 genes); RNA regulation of transcription (15 genes); photosynthesis light reaction photosystem I, and Calvin cycle (12 genes), transport (11 genes), signaling (8 genes), hormone metabolism (7 genes), and miscellaneous (10 genes) (**Figure [4A](#F4){ref-type="fig"}** and Supplementary Table [8](#SM2){ref-type="supplementary-material"}). All other categories were present with two to four up-regulated genes. Of the 122 down-regulated genes in leaves of MM/KO, 85 were unknown. The other gene products were assigned to the bins transport (17 genes), protein synthesis, degradation and post-translational modification (15 genes), cell wall (11 genes), RNA regulation of transcription and miscellaneous (8 genes each) (**Figure [4B](#F4){ref-type="fig"}** and Supplementary Table [9](#SM2){ref-type="supplementary-material"}). {#F3} {#F4} In the roots of both graft combinations more up-regulated genes were identified compared to leaves, with 729 for the combination LA/KO with 299 genes with unknown function and 970 for MM/KO including 353 genes with unknown function. The largest proportion of genes with known function belonged to the category protein synthesis, degradation and post-translational modification (81 out of 430 genes in LA/KO and 98 out of 627 in MM/KO), followed by RNA regulation of transcription (54 or 53 genes) and transport (41 or 60 genes) (**Figure [4C](#F4){ref-type="fig"}** and Supplementary Tables [10](#SM2){ref-type="supplementary-material"}, [12](#SM2){ref-type="supplementary-material"}). The functional categories signaling (27 or 41 genes), cell wall (26 or 40 genes), stress (15 or 41 genes), were also highly represented. One hundred and eighty-four out of 780 down-regulated genes in the roots of the graft combination LA/KO and 211 out of 1056 down-regulated genes in the combination MM/KO subjected to sub-optimal root temperature were unknown. Most of the other down-regulated genes were assigned to the most abundant category protein synthesis, degradation and post-translational modification (98 genes each out of 596 in LA/KO and 98 out of 845 in MM/KO), followed by RNA regulation of transcription (81 or 148 genes), stress (62 or 68 genes), transport (43 or 51 genes), hormone metabolism (42 or 41 genes), and signaling (27 or 29 genes) (**Figure [4D](#F4){ref-type="fig"}** and Supplementary Tables [11](#SM2){ref-type="supplementary-material"}, [13](#SM2){ref-type="supplementary-material"}). Enrichment of Sub-Optimal Temperature Responsive Genes of Roots in MapMan Functional Categories ----------------------------------------------------------------------------------------------- Enrichment of up-regulated genes in MapMan functional categories differed widely between the roots of the two graft combinations (**Table [2](#T2){ref-type="table"}**). Only two categories were commonly over-represented in both genotypes, cell wall and unassigned genes. Whereas in the combination LA/KO only two additional sub-bins of the cell wall bin were over-represented, in the combination MM/KO eight further over-represented bins were found, including lipid metabolism, fatty acid desaturation and hormone metabolism, biotic stress, miscellaneous genes from the functional category cytochrome P450 as well as protein degradation of AAA proteins. ###### Over-representation analysis (Mefisto) of significant differentially expressed genes in roots subjected to sub-optimal root temperature in the two graft combinations LA 1777/'Kommeet' (LA/KO) and 'Moneymaker'/'Kommeet' (MM/KO) visualized in MapMan functional categories (to sub-category 3). Bin code Bin name Up-regulated Down-regulated ---------- -------------------------------------------------------------------------- -------------- ---------------- --------- --------- 10 Cell wall 0.005 \<0.001 ns ns 10.2 Cell wall.cellulose synthesis. \<0.001 ns ns ns 10.2.1 Cell wall.cellulose synthesis.cellulose synthase 0.009 ns ns ns 11.2 Lipid metabolism.FA desaturation ns 0.003 ns ns 16 Secondary metabolism ns ns \<0.001 0.011 16.1.5 Secondary metabolism.isoprenoids.terpenoids ns ns 0.009 0.009 16.2 Secondary metabolism.phenylpropanoids ns ns \<0.001 \<0.001 17 Hormone metabolism ns 0.018 \<0.001 0.004 17.4 Hormone metabolism.cytokinin ns ns \<0.001 \<0.001 17.4.2 Hormone metabolism.cytokinin.signal transduction ns ns 0.005 0.002 17.5 Hormone metabolism.ethylene ns ns 0.002 \<0.001 17.5.1 Hormone metabolism.ethylene.synthesis-degradation ns ns \<0.001 0.021 20 Stress ns 0.044 \<0.001 0.002 20.1 Stress biotic ns \<0.001 ns \<0.001 20.2 Stress.abiotic ns ns \<0.001 \<0.001 20.2.1 Stress.abiotic.heat ns ns \<0.001 \<0.001 26 Misc ns \<0.001 ns ns 26.1 Misc.cytochrome P450 ns 0.011 ns ns 27 RNA ns ns 0.001 \<0.001 27.3 RNA.regulation of transcription ns ns \<0.001 0.004 27.3.26 RNA.regulation of transcription. MYB-related transcription factor family ns ns 0.018 ns 29 protein ns ns \<0.001 \<0.001 29.2 Protein.synthesis ns ns 0.002 \<0.001 29.5.9 Protein.degradation.AAA type ns 0.001 ns ns 35 Not assigned ns \<0.001 ns ns 35.2 Not assigned.unknown 0.01 \<0.001 0.049 0.034 Significantly over-represented functional bins are given with their adjusted p -values (Bonferroni correction). ns, not significant. For down-regulated genes the overlap between the differently tolerant rootstocks was much higher, with 16 common over-represented categories. Here the MapMan functional categories that were significantly enriched in both rootstock genotypes were secondary metabolism especially of isoprenoids (particularly terpenoids) and phenylpropanoids, hormone metabolism associated with cytokinin and cytokinin signal transduction as well as with ethylene synthesis and degradation, biotic and abiotic stress response, RNA regulation of transcription and protein synthesis. In addition RNA regulation of transcription of MYB domain transcription factor family is particularly enriched in the down-regulated genes of the LA 1777 rootstock together with not assigned genes, while genes associated with biotic stress were enriched only in the down-regulated genes of 'Moneymaker' roots subjected to sub-optimal temperature (**Table [2](#T2){ref-type="table"}**). Genes Differentially Expressed in Response to Sub-Optimal Temperature Differ between the Tolerant and Sensitive Rootstock Genotype ---------------------------------------------------------------------------------------------------------------------------------- Among the 480 genes regulated by sub-optimal temperature in roots only 13 were highly differentially expressed between the roots of the tolerant and the sensitive rootstock (difference of log2 fold change ≥\|2\|) (**Table [3](#T3){ref-type="table"}** and Supplementary Table [14](#SM2){ref-type="supplementary-material"}). These genes were from a variety of functional groups encoding a salicylic acid carboxyl methyltransferase (*SGN-U572374*), an F-box protein (*SGN-U578297*), a CYP72A15 cytochrome P450 (*SGN-U580908*), and a sigma factor binding protein 1 (*SGN-U565390*), all strongly increased in expression in MM/KO roots but decreased in LA/KO roots in response to low temperature. Several other genes showed a weaker differential regulation between the genotypes. However, genes encoding a putrescine *N*-methyltransferase (*SGN-U566249*) and a CYP71A22 cytochrome P450 (*SGN-U575254*) were more strongly down-regulated in MM/KO than in LA/KO under sub-optimal temperature. In addition the gene encoding an ethylene-responsive heat shock protein cognate 70 (*SGN-U579872*) was reduced in both genotypes but much stronger in the tolerant rootstock LA 1777. ###### Differentially expressed genes between optimal and sub-optimal temperature in LA 1777 (LA) and 'Moneymaker' (MM) rootstocks (*p* \< 0.05, difference log2 fold change \> \| 1\|). -- -- Discussion ========== In this study, transcript profiling and analysis of growth, and physiological responses of a commercial tomato cv. Kommeet grafted onto two rootstocks differing in their tolerance to sub-optimal temperature were combined to achieve a more comprehensive understanding of the long-term stress responses of tomato rootstocks and scions under sub-optimal temperature. The present findings complement and extend previous research, where the positive impact of the high-altitude accession LA 1777 (*S. habrochaites*) used as a rootstock on tomato scion performance at sub-optimal temperature has been demonstrated but was limited to plant growth and selected physiological traits ([@B70], [@B69]; [@B47],[@B48]). Grafting on Differently Sub-Optimal Temperature Tolerant Rootstocks Causes Differences in Growth and Physiological Traits ------------------------------------------------------------------------------------------------------------------------- The exposure of tomato grafts to sub-optimal root temperature resulted in a profound decrease of shoot fresh and dry mass in agreement with previous studies ([@B69]; [@B46]). The supply of growth supporting assimilates was not limited by the exposure of the plants to sub-optimal temperature, as the rates of net CO~2~ assimilation in leaves and the starch content in leaves and roots were not decreased by the stress applied in the root environment. Hence, the present study is in agreement with the view that other factors than the production and availability of assimilates restrict shoot growth under sub-optimal temperature ([@B46]). As already reported by [@B69] grafting tomato scions onto LA 1777 improved shoot growth at sub-optimal temperature. Low temperature also affects root growth, size, and architecture ([@B44]). Changes in root morphology were interpreted as adaptation of nutrient acquisition mechanisms to low temperature, aiming at extending the absorbing surface area per unit root mass or length ([@B40]). Thus, formation of a more extensive root system by tomato plants grafted onto LA 1777 in the cold, and the concomitant increase in root/shoot ratio, provides an advantage in terms of nutrient and water uptake. In the present study sub-optimal root temperature resulted in an approximately 2.8-fold increase of the root/shoot ratio when plants were grafted onto LA 1777 while no increase was observed when 'Moneymaker' was used as the rootstock. In contrast, in previous studies no impact of sub-optimal temperature on root growth of LA 1777 was observed ([@B10], [@B11]). An increase in root/shoot ratio has been interpreted by [@B25] as a mechanism to overcome restrictions in water absorption. Under sub-optimal temperatures an imbalance between root water uptake and leaf transpiration may occur. According to [@B4] chilling sensitivity differences among maize genotypes can be ascribed to different responses of the root water uptake rate. Indeed, when the temperature falls below the optimum, root water uptake decreases due to a decrease of vapor pressure difference ([@B5]), while water viscosity increases ([@B11]). According to the same authors, although transpiration decreases, the stomata of the sensitive maize and tomato genotypes remain open, while those of tolerant genotypes close rapidly, indicating an adaptive mechanism to the decline in water movement caused by sub-optimal temperature. In this work the stomatal conductance of 'Kommeet' scions was clearly affected by the rootstock, with lower stomatal conductance when grafted onto the sensitive 'Moneymaker' in comparison to the tolerant LA 1777. For grafted plants it was shown that shoots as well as roots contribute to shoot turgor maintenance during root chilling ([@B11]). Grafted plants with roots containing *S. habrochaites* and *S. lycopersicoides* Dunal introgressions improved shoot turgor maintenance under root chilling ([@B23]). Under low temperature stress plant tissues accumulate metabolites such as sugars, amino acids, or secondary metabolites like flavonoids ([@B74]; [@B39]; [@B58]). In this study shoots or roots did not accumulate sugars or amino acids indicating that the low temperature treatment applied only to the rootstocks was not sufficiently severe or that after 22 days of sub-optimal temperature treatment concentrations of these compounds returned to control values. Another study on leaves of 'Moneymaker' subjected to 10°C for up to 48 h also did not observe a significant accumulation of compatible sugars and suggested that the accumulation of amino acids and polyamines might play a relevant role in tomato chilling acclimation ([@B8]). Also lipid peroxidation and antioxidant enzyme activity were not changed in leaves or roots after 22 days of sub-optimal root temperature. The maximum lipid peroxidation occurs in tomato after 10 days of cold stress accompanied by a gradual increase of SOD activity, suggesting that oxidative stress may only play a key role in short-term responses of tomato to cold ([@B7]). Sub-Optimal Temperature Caused Expression Changes in Rootstocks of Both Genotypes But Only in Scion Leaves When Grafted onto the Sensitive Rootstock ---------------------------------------------------------------------------------------------------------------------------------------------------- A PCA of our gene expression data identified discrete responses of scions and rootstocks of grafted plants subjected to sub-optimal root temperature, and a distinct separation between LA 1777 and 'Moneymaker' rootstocks. Under sub-optimal root temperature significant transcriptional changes in leaves were only induced in the scion 'Kommeet' when grafted onto the sensitive rootstock 'Moneymaker.' This clearly demonstrates the impact of the rootstock genotype on the transcriptional responses of the scion even when the low temperature stress is only applied to the roots. Moreover, roots subjected to sub-optimal temperature were clearly separable by PCA from roots grown under optimal temperature in both genotypes, indicating that a temperature shift of 10°C in the root environment imposed comprehensive changes at transcript level. The number of DEG in 'Moneymaker' roots was 4.0 or 8.6-fold higher for up- or down-regulated genes, respectively, compared to the number of DEG in leaves, suggesting that the main transcriptional cold response occurred in the cold exposed roots and not in the leaves, which were exposed to optimal conditions. However, also in rice the number of DEGs identified in roots in response to a cold treatment of whole plants was larger than those in shoots in both a tolerant and a sensitive cultivar ([@B73]), indicating that at least in chilling-sensitive plants roots may respond more strongly to cold than leaves. The number of DEG in response to sub-optimal root temperatures in leaves of 'Kommeet' was much lower compared to 3350 or 2940 increased and 3022 or 3126 decreased transcripts in leaves of *S. lycopersicum* or *S. habrochaites* after 12 h of cold treatment of whole plants at 4°C ([@B15]). The early transcriptomic response in leaves of 3-week-old 'Moneymaker' plants to 3, 24, and 48 h at 10°C revealed 1537, 4404, and 4600 DEGs, respectively, with more up- than down-regulated genes ([@B8]). No studies on the influence of sub-optimal root temperature on roots of tomato are available for a direct comparison. Identification of Sub-Optimal Temperature Responsive Genes in Leaves of the Graft Combination MM/KO --------------------------------------------------------------------------------------------------- Only 10 of the cold up-regulated DEG in leaves of the graft combination MM/KO showed a log2 fold change above two and most of them had an unknown function. Of the down-regulated genes only one had a log2 fold change below two, but here certain groups of genes could be detected in the list of the 20 most highly down-regulated genes. Two genes encoding glutaredoxin family proteins involved in salicylic acid signaling ([@B55]) were detected together with genes encoding JAZ3 and CRF3, two proteins involved in hormone metabolism, and *Xth23* encoding a xyloglucan endotransglycosylase 6 as well as *FAD2* (fatty acid desaturase 2). In general, cold influenced gene expression in leaves of a scion grafted on a sensitive rootstock in the functional categories biotic defense response, hormone and cell wall metabolism. In contrast, analysis of DEG detected in leaves of 'Moneymaker' during an exposure to 10°C for 3 h indicated that transcription factor activity dominated the early response together with GO terms for stress response and hormone biosynthesis and signaling ([@B8]). In addition, metabolism was adjusted by accumulation of compatible solutes, activation of antioxidants systems and rearrangement of the photosynthetic machinery ([@B8]). These early stress responses were not found in the present study, indicating that after a cold treatment of 10°C for 22 days no acute stress responses can be observed anymore and that the plants have probably reached a new homeostasis. Enrichment of DEGs in Functional Categories in Roots Reflects Down-Regulation of Main Stress Responsive Functions and Activation of Cellulose Synthesis Related Genes in the Tolerant Rootstock Whereas Sensitive Rootstocks Show Stress Responses -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Cellulose constitutes the major part of plant cell walls, determining cell shape and plant morphology and is synthesized by cellulose synthase complexes localized on the plasma membrane ([@B21]). Up-regulated genes were significantly enriched in the MapMan functional category of cell wall synthesis in both rootstock genotypes. Enrichment in the category cellulose synthesis and the sub-bin cellulose synthase, however, was only observed for the tolerant rootstock, suggesting that cellulose synthesis may be one of the main adaptation mechanisms to long-term sub-optimal temperature. In tomato leaves cellulose biosynthesis and cell wall organization are the main functions of target genes of miRNAs differentially expressed after short term cold treatment (up to 48 h) ([@B14]). Also, a gene encoding a cellulose synthase subunit is targeted by a chilling-responsive miRNA in tomato with an essential role in the low temperature response ([@B14]). Plant growth and development is immediately inhibited under cold stress, resulting in down-regulated cell wall formation. A later up-regulation of the corresponding genes may be necessary for a long-term cold adaptation. This hypothesis is in agreement with the finding that sub-optimal temperature has no adverse impact on root growth of LA 1777 ([@B69]). Cell wall remodeling was also found in Arabidopsis as a long-term adaptation mechanism to cope with multiple biotic or abiotic stresses ([@B6]). Additionally proteomic analysis of two differently tolerant cotton cultivars identified cellulose synthesis as important for the tolerance of cotton fibers to low temperature ([@B75]). In both grafting combinations down-regulated genes in the rootstocks were overrepresented in bins related to secondary metabolism, especially isoprenoids, terpenoids and phenylpropanoids. This was unexpected since the accumulation of flavonoids and anthocyanins involved in ROS scavenging is an important adjustment during cold acclimation ([@B56]; [@B59]). Several genes encoding enzymes involved in flavonol and anthocyanin biosynthesis were up-regulated during cold treatment in tomato leaves together with numerous genes coding for enzymes with antioxidant activity, in agreement with increased anthocyanin levels ([@B8]). Whereas no corresponding data are available for tomato roots, expression of genes encoding enzymes involved in secondary metabolism, especially phenylpropanoid and lignin biosynthesis, is increased in the roots of a cold-tolerant compared to a sensitive rice cultivar after a short-term cold stress ([@B73]). The apparent down-regulation of secondary metabolism in tomato roots after long-term cold treatment may be an adaptive, time-dependent response. However, this hypothesis needs to be investigated further. The hypothesis that perceived stress levels were reduced during acclimation to low temperature in the rootstocks of both cultivars was supported by an enrichment of down-regulated genes in the abiotic and biotic stress bins. This effect of long-term stress is further supported by the fact that bins for regulation of transcription and protein synthesis were enriched for down-regulated genes, while they were enriched for up-regulated genes after a short-term cold stress in the roots of a tolerant rice cultivar ([@B73]). Rootstocks of the sensitive cultivar Moneymaker showed in addition an enrichment of up-regulated genes in the bins fatty acid desaturation, phenylpropanoids, biotic stress, cytochrome P450 and protein degradation, indicating that the sensitive cultivar needed more transcriptional adaption to low temperature than the tolerant cultivar that did not show these reactions. Studies analyzing the effects of low temperature on root-derived phytohormones clearly demonstrate a strong impact on both root growth and root-to-shoot signaling, imposing alterations in shoot physiology and thus productivity ([@B2]; [@B61]; [@B47]). However, due to intensive hormone cross-talk (positive or negative), individual processes are affected by multiple hormones. Under stress conditions the levels of a range of hormones, divided into the groups of "positive growth regulators" (auxin, cytokinins, and brassinosteroids) and "stress hormones" \[abscisic acid (ABA), jasmonic acid, salicylic acid and ethylene\] are changing. Interestingly, the functional category of cytokinin metabolism was significantly enriched for down-regulated genes in the roots of both genotypes, in agreement with the finding that low temperature resulted in a sharp decline in cytokinin concentration in the shoots of wheat plants due to increased activity of cytokinin oxidase ([@B72]). However, in the present study down-regulated genes were mainly overrepresented in the functional category of cytokinin signal transduction. A multistep two-component signaling system functions as a key element of cytokinin signaling in Arabidopsis in the early cold stress response ([@B34]). Since we analyzed gene expression after 22 days of cold exposure, it is likely that genes involved in early cytokinin signaling were already down-regulated again. While in a cold tolerant rice cultivar the expression of the majority of the genes associated with the cytokinin signal transduction pathway was repressed, this was not true in a sensitive cultivar. This may indicate the participation of cytokinin in antagonistic cross-talk with ABA to negatively regulate cold stress tolerance in sensitive plants ([@B73]). Furthermore, significant enrichment of cold-regulated genes was detected in the ethylene biosynthesis bin for rootstocks of both genotypes. Namely the expression of genes encoding an ethylene biosynthetic enzyme (*SGN-U579250*) and an oxidoreductase \[2OG-Fe(II) oxygenase family protein (*SGN-U581679*)\] was strongly decreased (log2 fold change -4.9 in LA 1777 and -4.5 in 'Moneymaker'). This supports the hypothesis that reduced ethylene production may enhance plant tolerance to sub-optimal temperatures ([@B46]), in agreement with the fact that an ethylene insensitive tomato mutant showed increased cold tolerance after chilling acclimation compared to the wild type 'Ailsa Craig' ([@B8]). In contrast, in rice most ethylene biosynthesis and signaling genes were up-regulated in response to short-term cold treatment in both shoots and roots independent of the tolerance of the cultivar. In addition, some ethylene biosynthesis genes were up-regulated only in the tolerant cultivar and displayed prolonged expression during recovery ([@B73]). Since ethylene functions antagonistically with ABA, a role in detecting the relief from stress was suggested ([@B73]). Mainly Defense-Related Genes Are Highly Differentially Expressed between the Tolerant and Sensitive Rootstock Genotypes under Sub-Optimal Temperature in the Root Environment ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------- The majority of the cold regulated genes that were most highly differentially expressed between the tolerant and the sensitive rootstock were involved in plant defense responses. They showed a down-regulation in LA 1777 but an up-regulation in 'Moneymaker.' The gene showing the highest difference between the genotypes was salicylic acid carboxyl methyltransferase, encoding an enzyme producing methyl salicylate, a mobile signal for systemic acquired resistance in plants ([@B50]). Treatment of tomato fruit with methyl salicylate induces the synthesis of stress proteins, such as pathogenesis-related proteins, which lead to increased chilling tolerance and resistance to pathogens ([@B20]). Also other defense-related genes, such as genes encoding an F-box protein, two P450 cytochromes, a sigma factor binding protein and a 2-oxoglutarate-dependent dioxygenase were highly differentially cold regulated between the rootstock genotypes. When including also DEGs only identified in rootstocks of 'Moneymaker' but not in LA 1777 several additional pathogenesis-related genes showed a high up-regulation, e.g., genes encoding three pathogenesis related proteins with log2 fold changes of 7.1, 4.8, and 3.5, supporting the hypothesis that defense response is a major long-term cold treatment response in the sensitive rootstock. Also a comparative transcriptome analysis of cold-responsive genes in leaves of LA 1777, LA 3969, and LA 4024 identified 92 cold regulated genes with significantly different regulation between tolerant and sensitive genotypes. Stress-related GO terms, such as 'response to stimulus' which includes biotic stress and 'response to stress' were significantly enriched among these genes, together with 'response to hormone stimulus,' 'response to ROS,' and 'calcium-mediated signaling' ([@B36]). Polyamine levels are increased in response to abiotic stress. They interact with ABA and ethylene to affect stress tolerance ([@B28]). Putrescine, for instance, is involved in freezing tolerance and cold acclimation in Arabidopsis ([@B18]) and also in the cold stress response of tomato leaves ([@B35]). The arginine decarboxylase -mediated pathway of putrescine biosynthesis is important for the cold tolerance of the tomato cultivar TNG67 and levels of putrescine and arginine decarboxylase activity are increased in both shoots and roots after cold treatment ([@B73]). In both rootstock genotypes a gene encoding the enzyme putrescine *N*-methyltransferase was down-regulated in the cold. This enzyme participates in alkaloid biosynthesis and catalyzes the biosynthesis of *S*-adenosyl-[L]{.smallcaps}-homocysteine and *N*-methylputrescine from *S*-adenosyl-[L]{.smallcaps}-methionine and putrescine. The activity of this biosynthetic pathway at the expense of putrescine could be a disadvantage under long-term sub-optimal temperature conditions when putrescine may be needed for cold adaptation. Down-regulation of this gene may therefore be advantageous for root cold tolerance. Our subsequent and current research emphasizes to derive further relationships between genes discovered in the microarray data and appropriate physiological/biochemical processes of grafted tomato responding to suboptimal temperatures. Author Contributions ==================== All authors contributed individually and meet the four criteria of authorship as required by Frontiers. In doing so, all authors agree to be accountable for the content of the work. Conflict of Interest Statement ============================== The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. **Funding.** The research was supported financially by the German Federal Ministry of Food, Agriculture and Consumer Protection, the Brandenburg State Ministry of Infrastructure and Agriculture and the Thuringia State Ministry for Agriculture, Nature and Environment Protection. We appreciate the excellent technical assistance of Gundula Aust and Susanne Jeserigk (IGZ Großbeeren) during the experimental procedure and their assistance with the RNA extraction. <http://www.genomics.agilent.com/article.jsp?pageId=1508> <https://solgenomics.net> <http://www.ebi.ac.uk/arrayexpress/> Supplementary Material ====================== The Supplementary Material for this article can be found online at: <http://journal.frontiersin.org/article/10.3389/fpls.2017.00911/full#supplementary-material> ###### Click here for additional data file. ###### Click here for additional data file. [^1]: Edited by: *Vasileios Fotopoulos, Cyprus University of Technology, Cyprus* [^2]: Reviewed by: *Marcos Egea-Cortines, Universidad Politécnica de Cartagena, Spain; Serge Delrot, Université de Bordeaux, France* [^3]: This article was submitted to Plant Physiology, a section of the journal Frontiers in Plant Science

Retinal detachment with high myopia in the Rubinstein-Taybi syndrome. A case of rhegmatogenous retinal detachment with high myopia is presented in a 17 year old boy with the typical characteristics of the Rubinstein-Taybi syndrome. Although multiple eye anomalies are known to occur in this syndrome, the occurrence of retinal detachment has not been reported up to now. The importance of including a thorough fundus examination in the routine eye examination of these patients is emphasized.

Science News The Zebra's Stripes To celebrate Charles Darwin’s birthday (it was yesterday)—here’s an answer to a great evolutionary question: how did the zebra get its stripes? Darwin himself pondered the reason for the stripes, and New Scientistdescribes his hypothesis as contrary to other ideas of his time: A popular theory, both in the 19th century and today, is that zebras evolved striped coats as camouflage in tall grass… Darwin suggested that zebras developed their unique stripes to recognize each other, which could be particularly important for male and female courtship. And the latest theory might have surprised Darwin: horseflies. Researchers in Hungary and Sweden published a paper in the recent edition of the Journal of Experimental Biologythat blames the zebra’s stripes on simple horseflies (tabanids). There’s good evolutionary reason to escape the ravages of horseflies, at least for horses and their relatives; though flies are just annoying pests from the human perspective, horsefly-bitten horses can grow skinny and have trouble producing milk for their young. And as soon as baby-making is affected by something in the environment, adaptation isn’t far behind. Scientists have known for a while that these pesky insects are more attracted to dark horses than to white horses. Since zebra embryos start out with dark skin, the European team wondered whether the zebra’s stripy hide might have evolved to disrupt their attractive dark skins and make them less appealing to voracious bloodsuckers, such as horseflies. So they conducted some experiments, minus the actual zebras. Travelling to a horsefly-infested horse farm near Budapest, the team tested how attractive the blood-sucking insects found black-and-white striped patterns by varying the width, density, and angle of the stripes and the direction of polarization of the light that they reflected. They trapped the attracted insects with oil and glue, and found that the patterns attracted fewer flies as the stripes became narrower, with the narrowest stripes attracting the fewest horseflies. “We conclude that zebras have evolved a coat pattern in which the stripes are narrow enough to ensure minimum attractiveness to tabanid flies,” says the team. “The selection pressure for striped coat patterns as a response to blood-sucking dipteran parasites is probably high in this region [Africa].” Share This The California Academy of Sciences is a renowned scientific and educational institution dedicated to exploring, explaining, and sustaining life on Earth. Based in San Francisco’s Golden Gate Park, it is home to a world-class aquarium, planetarium, and natural history museum—all under one living roof.

Tried burlap for years, it didn't last, kept fraying out. Got some military camo, and grass for duck blind, in cold weather put heavy black plastic up first them the netting to keep out wind. Zip tie all tight to keep from popping in wind. Good luck

Activists: 13 jailed Syrian women released BEIRUT (AP) — The Syrian government has released 13 jailed women, an official and an activist group said on Wednesday — a move that may be part of an ambitious regional prisoner exchange. Meanwhile, al-Qaida-linked rebels strengthened their hold on an ancient Christian town north of Damascus, activists said. The Britain-based Syrian Observatory for Human Rights said the women were released Tuesday morning from the headquarters of the Damascus provincial government, but said they had not been able to contact the women. The Observatory relies on a network of activists on ground for its information. The women may have been freed as part of a three-way exchange that began on Oct. 18. It saw Syrian rebels release nine Lebanese men held for a year and a half. Lebanese gunmen simultaneously released two Turkish pilots held since August. Lebanese officials had said a number of imprisoned Syrian women were meant to be released to meet the demands of the Syrian rebels. They were not immediately available for comment Wednesday. It's unclear how many women are held by Syria's government, nor how usual it is for 13 to be released simultaneously. A Syrian government official confirmed the women were freed, but would not provide further details. He spoke anonymously, because he wasn't authorized to talk to media. The deal underscored the extent of how far Syria's civil war, now in its third year, has spilled across the greater Middle East. It appeared to represent one of the more ambitious negotiated settlements to come out of the war, in which the rival factions remain largely opposed to any bartered peace. Fighting continued in the town of Sadad and desperate residents tried to flee, as hard-line Muslim rebels clashed with soldiers and gunmen loyal to the government of President Bashar Assad. The Observatory said fighters from the two al-Qaida-linked groups, the Jabhat al-Nusra or Nusra Front and the Islamic State in Iraq and the Levant, took a checkpoint that gave them control of the western part of the town. They also took control of the road leading to Damascus. Residents were fleeing in the opposite direction, to the central city of Homs some 56 kilometers (35 miles) away. Residents told the group that five people were killed by snipers, three of them bleeding to death on the street. The residents believed the snipers were rebels. Clashes have been ongoing in Sadad for the past three days. The fighters seem to have appears to have targeted Sadad because of its strategic location near the main highway north of Damascus, rather than because it is Christian. But hard-liners among the rebels are hostile to Syria's Christian minority, who tend to be Assad loyalists. Other al-Qaida-linked fighters have damaged and desecrated churches in areas they have seized. The toll of the Syrian war has been crushing. Almost a third of the population has fled its homes to escape violence or the resulting economic hardships. Of a pre-war population of 23 million people, at least 2 million Syrians have fled abroad, becoming refugees. Another 4.6 million are internally displaced within Syria. Around 100,000 people have been killed, the economy is in tatters, and the country's delicate community fabric woven of different religious sects has been destroyed. Even fleeing is no guarantee of safety. The Observatory reported Wednesday that a Syrian woman trying to escape to neighboring Jordan was raped and killed, along with her daughters aged one and three, allegedly by the man who was supposed to take her across the border. The Observatory said the incident occurred in the Zizon valley on the Jordanian-Syria border on Monday. The man also stole all her cash: $87. Syrian residents found the bodies days later. The Observatory said Syrian rebels captured and killed a suspect who they said confessed to the crime.

1. Field of the Invention This invention relates to a portable computer, such as a notebook type personal computer, a word processor, and so on. More specifically, this invention relates to a portable computer equipped with an add-on battery which can be removably fitted to the apparatus main body. As portable computers have become widespread in recent years, improvements in portability, battery life and operability have been required. To improve operability, a keyboard must be inclined. To improve portability, the size and weight of the portable computer must be reduced. To prolong the life of the battery, the battery capacity must be increased. As one of the means for increasing the battery capacity, an add-on battery is removably fitted to the portable computer. 2. Description of Related Art The prior art technology for tilting the key face of a portable computer includes a technology which fits a turn-down-type tilt stand to a personal computer. According to the turn-down-type tilt stand of this prior art, however, a useless space remains between the bottom surface of the portable computer and the desk surface on which the portable computer is put when the tilt stand is turned up. For example, Japanese Unexamined Patent Publication (Kokai) No. 8-76879 discloses a prior art technology which disposes an external memory device in such a space. Prior art technologies which increase the battery life while improving portability include a method which fits an add-on battery device to the portable computer, whenever necessary. For example, Japanese Unexamined Patent Publication (Kokai) No. 8-76898 and No. 8-76887 disclose a structure capable of removably fitting a battery pack to a portable computer. However, such a portable computer is more bulky even when the add-on battery device is not fitted than those portable computers which have similar function but do not have the function of the add-on battery device. One of the fitting technologies of the add-on battery prepares a groove and a rail so that the add-on battery device can be slidably fitted onto the portable computer. According to this fitting technology of the add-on battery, however, the add-on battery cannot be fitted easily once the groove undergoes deformation due to change with time. Japanese Unexamined Patent Publication (Kokai) No. 8-76889 discloses a connection structure for an information processing apparatus in which connector shell portions for a pair of connectors are formed on the housing of an extended unit, the shell portions and the housing having formed thereon the shell portions are integrally molded from a resin material, and metal plating is applied to the entire surface. As described above, when the tilt stand is turned up in the conventional portable computer equipped with the turn-down type tilt stand, a space remains between the bottom surface of the portable computer and the desk surface on which the portable computer is placed, and the space cannot be effectively utilized. In the conventional portable computer having a removable add-on battery, the size is greater than the portable computer having no add-on battery device function, and the portability is therefore lower. According to the prior art technology capable of fitting the add-on battery in which the battery is fitted to the portable computer by the slide system using the groove and the rail, the add-on battery cannot be fitted easily to the portable computer, if the groove or the rail once undergoes deformation due to a change with time, and fitting becomes difficult in some cases. It is therefore an object of the present invention to provide a portable computer which has good operability, is equipped with a removable add-on battery and has a portability equivalent to that of a portable computer having no add-on battery fitting function, though the add-on battery can be fitted. Another object of the present invention is to provide a portable computer having an extended station which makes it possible to mount the portable computer thereon while the add-on battery is kept fitted to the personal computer main body. According to the present invention, there is provided a portable computer equipped with an add-on battery, the computer comprising: a portable computer body having an upper surface, a lower surface and a lower front edge thereof; mounting means for detachably mounting the add-on battery on the lower surface of the portable computer body, the add-on battery having a wedge-shaped portion corresponding to a wedge-like space which is defined between the lower surface of the portable computer body and a surface on which the portable computer body is placed, when the portable computer body is placed to be inclined about the lower front edge of the portable computer body; and the portable computer body, when it is equipped with the add-on battery, being inclined in such a manner that the upper surface of the portable computer body is lower at a front edge thereof. When the personal computer is placed on the desk surface, etc, while the add-on battery is added thereto, the upper surface of the computer main body on which the key top and operation surface are disposed is inclined so that its front side becomes lower. Therefore, operability becomes excellent. When the add-on battery is not fitted, the portable computer main body itself can be constituted into a thin notebook type. For this reason, even when the add-on battery can be fitted, the personal computer can be constituted into a thin and light-weight structure having portability equivalent to that of a portable personal computer not having the add-on battery fitting function. The lower surface of the portable computer body has a rear region and the add-on battery has the wedge-shaped portion having a shape corresponding to the wedge-like space at least at the rear portion of the lower surface of the portable computer body. While the add-on battery is fitted, the space between the back of this portable computer and the desk surface, etc, can be effectively utilized, and a function having a high packaging density can be accomplished. The mounting means comprises: guide means including L-shaped guide grooves along which the add-on battery is first guided toward the lower surface of the portable computer body and then guided forward with respect to the portable computer body; locking means for automatically locking the add-on battery to the lower surface of the portable computer body when the add-on battery is guided forward with respect to the portable computer body; and releasing means for releasing the locking means to allow the add-on battery to be removed from the portable computer body along the L-shaped guide grooves. In this case, the portable computer body is provided at the lower surface thereof with pairs of left and right L-shaped guide grooves and the add-on battery has pairs of left and right pawls which can be fitted to the L-shaped guide grooves, respectively. Accordingly, the add-on battery can be easily fitted and removed to and from the portable computer main body, and the add-on battery can be firmly fixed to the portable computer main body at the time of fitting. According to another aspect of the present invention, there is provided a portable computer comprising: a portable computer body having an upper surface, a lower surface and a lower front edge thereof; an add-on battery detachably mounted on the lower surface of the portable computer body; and an extended station on which the portable computer body is detachably mounted, while the portable computer body is equipped with the add-on battery, the extended station having a recess or an opening for accommodating therein the add-on battery. When the portable computer is mounted to the extended station while the add-on battery is kept fitted to the computer main body, the add-on battery is accommodated inside a recess portion (or an opening) in the extended station. Therefore, the overall space can be utilized effectively, and an apparatus having a high density can be accomplished. Even when the recess portion exists in the extended station, a printed wiring board, etc, can be disposed below this recess portion and consequently, the arrangement inside the extended station can be made efficiently.

About 32 results for "champions paris st germain" The former Barcelona forward has been linked with moves to Paris St Germain and Bayern Munich, among other clubs, and his comments will only increase speculation he is set to leave London.DNA, 1 month ago Paris : Neymar completed his record-shattering transfer from Barcelona to Paris St Germain on Thursday, signing a five-year deal with the French club after they triggered his 222 million euros ($263 million) release clause. The 25-year-old Brazil forward, who ... The champions are also grappling with questions over their strongest formation IMAGE: Who will attack along with Lionel Messi and Luis Suarez? Photograph: Barcelona FC/Twitter La Liga's reputation as the epicenter of world soccer talent has been bruised by the world record smashing sale of Neymar to Paris St Germain and how Barcelona react to the departure of one of their leading players will define the new season in Spain. Barca outscored Real Madrid last season with their ferocious attacking ... Star Brazilian striker Neymar, amid a frenzy of transfer speculation, struck a decisive goal as Barcelona edged past Manchester United at the International Champions Cup here on Thursday.The 25-year-old continued his rich vein of form as he smashed his third ... Neymar, serene amid a frenzy of transfer speculation, scored the first-half goal that gave Barcelona a 1-0 victory over Manchester United on Thursday in an International Champions Cup friendly. The Brazilian striker, reportedly pondering a 222-million euro ... IMAGE: Lionel Messi, left, with Cristiano Ronaldo. Photograph: Philipp Schmidli/Getty Images Cristiano Ronaldo and Lionel Messi will again be duelling for the title of world's best footballer after their names once again headed the shortlist on Thursday for The Best FIFA Men's Player.The pair, who have dominated the global award in its varied forms for a decade, will be favourites to collect yet another accolade amid the 24-strong list of the world's best.Ronaldo enjoyed another remarkable ... IMAGE: Alexis Sanchez's contract talk with Arsenal have come to a halt. Photograph: Paul Childsdetails/Action Images via Reuters Arsenal risk losing striker Alexis Sanchez for free next season, according to manager Arsene Wenger, who confirmed the club have made no progress on a new contract for the Chilean striker. Sanchez, 28, is currently in the final year of his contract. He has been linked with a move to Paris St Germain in the current transfer window. "We have not progressed on ... 'There's no need for any excuses, now we have to draw up conclusions and look forward' IMAGE: Barcelona coach Ernesto Valverde looks pensive. Photograph: FC Barcelona/Twitter Sergio Busquets called on Barcelona to sign more players after the club's 3-1 Spanish Super Cup defeat by Real Madrid on Sunday. The defensive midfielder believes his team need to reinforce if they are to wrestle power back from their rivals Madrid, who won a Champions League and La Liga double last season. Barcelona ... 'There is no price limit to let him go or a price that we are ready to give in' Barcelona's plans to sign Philippe Coutinho to fill the void left by the departure of Neymar appear to be dead in the water after Liverpool released a statement on Friday announcing they will not sell the Brazilian playmaker at any cost. "We wish to offer clarity as regards our position on a possible transfer of Philippe Coutinho," said a statement from owners Fenway Sports Group on the Merseyside club's official ...

Analysis of creep strain during tensile fatigue of cortical bone. During fatigue tests of cortical bone specimens, at the unload portion of the cycle (zero stress) non-zero strains occur and progressively accumulate as the test progresses. This non-zero strain is hypothesised to be mostly, if not entirely, describable as creep. This work examines the rate of accumulation of this strain and quantifies its stress dependency. A published relationship determined from creep tests of cortical bone (Journal of Biomechanics 21 (1988) 623) is combined with knowledge of the stress history during fatigue testing to derive an expression for the amount of creep strain in fatigue tests. Fatigue tests on 31 bone samples from four individuals showed strong correlations between creep strain rate and both stress and "normalised stress" (sigma/E) during tensile fatigue testing (0-T). Combined results were good (r(2)=0.78) and differences between the various individuals, in particular, vanished when effects were examined against normalised stress values. Constants of the regression showed equivalence to constants derived in creep tests. The universality of the results, with respect to four different individuals of both sexes, shows great promise for use in computational models of fatigue in bone structures.

1. Field of the Invention The invention relates to estimating the mass properties of designed products. More specifically, to creating workable models and generating reports showing these properties using legacy data. 2. Description of the Related Art Estimation of mass data is an integral part of the conceptual design of new aircraft. The part count on a typical business jet is in the hundreds of thousands. Tens of thousands of engineering hours are invested to build accurate mass properties databases of an aircraft to support weight control and structural analyses efforts during project development. Conceptual design processes have historically been constrained by time to rely on a few dozen parametric equations for extrapolating weight of major components and systems and the development of simplified computer aided design (CAD) and finite element model (FEM) models to generate quasi-distributed analysis models. This process required relatively long lead times to generate mass properties with adequate quality for Design and Analysis processes for single design iterations, and rarely was able to meet requirements to quickly review design alternatives. The integrity of mass properties estimates directly impact the ability of a proposed aircraft design to meet its performance and mission requirements. Traditional methods often result in sub-optimal design decisions as many detail nuances spanning distinctly different design approaches are overlooked. Inaccuracies inherent to these methods carry heavy penalties leading to compromises, costly engineering changes, increased potential aircraft ballast requirements, reduced payload and performance, leading ultimately to reduced sales and project profitability. There is a need in the art for an alternative to these conventional processes which eliminates dependence on parametric data models for estimating component weights and the need to create CAD and FEM representations of proposed aircraft to estimate mass property distributions. Instead engineers devote more time toward reviewing a greater number of alternate design approaches and optimizing design performance. There is also a need for a process which reduces the risks in the process by providing credible distributed mass properties to accurately reflect changes caused by design permutations. Delays caused by permutations historically can take weeks. And the resulting mass models are seldom as robust as desired. Inaccuracies in these mass models drive decisions toward off-optimal designs which negatively impact other analyses and flight vehicle performance, and conventional weight and balance issues are often not identified until late in the development program causing late reengineering efforts.

Q: MulticastSocket receives message twice I send messages to WIFI Access Point via MulticastSocket and get replies always twice. If I try to send message to me self, I get message twice again. This is my receiver code: protected Void doInBackground(Void... params) { String lText; byte[] lMsg = new byte[GlobalConfig.MAX_UDP_DATAGRAM_LEN]; DatagramPacket dp = new DatagramPacket(lMsg, lMsg.length); MulticastSocket ds = null; try { ds = new MulticastSocket (32001); InetAddress serverAddr = InetAddress.getByName("224.237.124.120"); ds.joinGroup(serverAddr); while (serverActive) { ds.receive(dp); Log.d("UDP packet received", dp.toString()); lText = new String(lMsg, 0, dp.getLength()); receivedMessage = lText; doSomething(); } } catch (SocketException e) { e.printStackTrace(); } catch (IOException e) { e.printStackTrace(); } finally { if (ds != null) { ds.close(); } } return null; } I tried to send via DatagramSocket and via MulticastSocket - no matter. I get messages alway twice. I don't understand why! EDIT: my LogCat: I/GatewayController﹕ Message Sent ... D/UDP packet received﹕ java.net.DatagramPacket@422dc860 D/UDP packet received﹕ java.net.DatagramPacket@422dc860 EDIT2: Sender code protected Void doInBackground(Void... params) { DatagramSocket ds = null; try { ds = new DatagramSocket(); InetAddress serverAddr = InetAddress.getByName("224.237.124.120"); DatagramPacket dp; dp = new DatagramPacket(byteMsg, byteMsg.length, serverAddr, 32000); ds.send(dp); A: Here is the right way: InetAddress group = InetAddress.getByName(GlobalConfig.MULTICAST_IP); SocketAddress sockaddr = new InetSocketAddress(group,GlobalConfig.LOCAL_PORT); ds = new MulticastSocket(sockaddr); ds.joinGroup(group); This is important, but difficult to find in examples in Internet: SocketAddress sockaddr = new InetSocketAddress(group,GlobalConfig.LOCAL_PORT); ds = new MulticastSocket(sockaddr);

Beast Fang Beast Fang is a weapon that only Haschel can use. It can be found in a treasure chest in Black Castle at Kazas. It can also be dropped by a Lizard Man with a 2% chance or bought on the Queen Fury. Beast Fang has a chance to stun enemies. Stun is arguably one of the better effects that can be caused by a weapon. One of the greater advantages of stun is its ability to change the pace of the battle. As an example, if at Zenebatos and facing a Professor and a Guillotine the Professor can be stunned stopping any status ailments he might cause. While it is stunned the party can take care of the Guillotine.

Q: Joining across databases in Active Record Is there a way in Castle Active Record/NHibernate to join across two databases? I have data in 2 tables in separate databases that I need to join together and return in one query resultset. If there isn't an OO-way to do it, can it be done using either hql or worst case, is there a standard way to execute dynamic sql and have it return back some sort of collection, such as a datatable? A: If you have the two tables already mapped, but in separate session factories, I don't think you can do much about it. You'll have to "join" in your own code. If that's not the case, you can map the foreign table through a database view, i.e.: create view othertable as select * from otherdatabase..othertable and map this view in ActiveRecord as if it were a local table.

Choosing To Be Happy A popular greeting card attributes this quote to Henry David Thoreau: "Happiness is like a butterfly: the more you chase it, the more it will elude you, but if you turn your attention to other things, it will come and sit softly on your shoulder." With all due respect to the author of Walden, that just isn't so, according to a growing number of psychologists. You can choose to be happy, they say. You can chase down that elusive butterfly and get it to sit on your shoulder. How? In part, by simply making the effort to monitor the workings of your mind. Recommended Related to Mental Health Avoidant personality disorder is characterized by feelings of extreme social inhibition, inadequacy, and sensitivity to negative criticism and rejection. Yet the symptoms involve more than simply being shy or socially awkward. Avoidant personality disorder causes significant problems that affect the ability to interact with others and maintain relationships in day-to-day life. About 1% of the general population has avoidant personality disorder. Research has shown that your talent for happiness is, to a large degree, determined by your genes. Psychology professor David T. Lykken, author of Happiness: Its Nature and Nurture, says that "trying to be happier is like trying to be taller." We each have a "happiness set point," he argues, and move away from it only slightly. And yet, psychologists who study happiness -- including Lykken -- believe we can pursue happiness. We can do this by thwarting negative emotions such as pessimism, resentment, and anger. And we can foster positive emotions, such as empathy, serenity, and especially gratitude. Happiness Strategy # 1: Don't Worry, Choose Happy The first step, however, is to make a conscious choice to boost your happiness. In his book, The Conquest of Happiness, published in 1930, the philosopher Bertrand Russell had this to say: "Happiness is not, except in very rare cases, something that drops into the mouth, like a ripe fruit. ... Happiness must be, for most men and women, an achievement rather than a gift of the gods, and in this achievement, effort, both inward and outward, must play a great part." Today, psychologists who study happiness heartily agree. The intention to be happy is the first of The 9 Choices of Happy People listed by authors Rick Foster and Greg Hicks in their book of the same name. "Intention is the active desire and commitment to be happy," they write. "It's the decision to consciously choose attitudes and behaviors that lead to happiness over unhappiness."

Q: number of arguments in Power Query custom function guys! I tried to create my custom function in Power Query and came across very unexpected and totally non-clear to me Err. Function is simple -- it retrieves Name of the Student from Students Dictionary (it is called from Students Dictionary Table), then it retrieves tables of invoices and calculates how many invoieces were issued to this paticular Student. code of the function is as following: (FirstName as text) => let Source = XeroInvoices, #"Filtered Rows" = Table.SelectRows(Source, each Text.Contains([XeroContacts.Name], FirstName) ), #"Removed Other Columns" = Table.SelectColumns(#"Filtered Rows",{"XeroContacts.Name"}), #"Grouped Rows" = Table.Group(#"Removed Other Columns", {"XeroContacts.Name"}, {{"Result", each Table.RowCount(_), type number}}), Result = Record.Field(#"Grouped Rows", {0}, "Result") in Result Yet, as I call function with one argument, it says that three arguments were passed, and that the function expected two: http://shot.qip.ru/00Qqzx-4Vmk2GJfF/ Could you please suggest what can be the problem with this all? Thanks in advance. A: The function that is causing the error-message is probably the last step of your function above: Result = Record.Field(#"Grouped Rows", {0}, "Result") It takes only 2 arguments: The record and the name of the field you want to catch. So try changing it to : Result = Record.Field(#"Grouped Rows"{0}, "Result") Find a tip on how to easily debug your M-functions here.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Models of brain structures generated from magnetic resonance imaging (MRI) data have grown in complexity in recent years, evolving from simple models with few classes such as gray matter, white matter and cerebrospinal fluid (CSF), into more complex ones representing multiple neural structures separately. This evolution has been possible due to developments in MR data acquisition technology that has yielded finer resolution, higher signal-to-noise ratio (SNR) images and an increasing number of contrast mechanisms, all of which have been used by increasingly sophisticated analysis tools to improve and extend classification. Nevertheless, despite these important advances, a critical unmet goal of this type of modeling is the generation of representations of myelo- and cytoarchitectonic boundaries from in vivo imaging data. In this competing renewal we seek to significantly augment and extend the tools developed in the last cycle. Using models and probabilistic information assembled in the previous cycle, we now propose to develop cortical registration and segmentation tools that are explicitly optimal for the alignment and localization of architectonic boundaries across subjects, focusing on cortical area V5/MT. The surface- based registration utility will then be combined with volumetric intensity information to generate a nonlinear volume warp using a biomechanical model of the brain. This combination will yield a single highly accurate coordinate system applicable across the entire brain. Finally, this coordinate system will be used as initialization for extending the scope and level of detail of our existing segmentation models to explicitly segment bone, air, fat and water for used in MR-based PET attenuation correction. The segmentation will be facilitated by the use of specifically designed sequences incorporating ultra-short TE (UTE) contrast that can directly image bone.

Q: How to get the current user's role in a custom rally app in production? So, I am able to do this fine when testing my custom app in the debug environment provided by rally-app-builder. I use Rally.environment.getContext().getUser() to get the current user, and from the returned object I get the role from the "Role" field. But, for some weird reason, when I use the exact same code in Rally production, Rally.environment.getContext().getUser() returns a different object that has no "Role" field. What is the solution for this problem? thanks. A: :sad trombone: This is a defect for sure. The context object is populated a little differently between the external App SDK bootstrapper and the way it is created when running within the product. I'm going to file a defect and get this resolved ASAP. I'll post back here once the fix has been released. Can you work around it for now?

Los Borrachos del Tablón Los Borrachos del Tablón (Drunks of bleachers in English) is the barra brava of the Club Atlético River Plate. It is one of the scariest barra brava groups in Argentina. 1996: The first rule of terror Under the leadership of Luisito Pereyra and Edgar "Diariero" ("Newspaper Man") Butassi, the barra brava was involved in fights and controversies. However, the intensity of involvement in crime and fighting did not compare to today. In 1996 after a River Plate game against Club Atlético Independiente a battle against the fans of Independiente (not the barra brava) would set the beginning of the end for Pereyra and Butassi's hold on the organization. The battle ended with the death of Christian Rousoulis, an Independiente fan stabbed by members of Los Borrachos. This caused tense internal problems that split the firm in two, leaving both bosses Luisito and El Diariero powerless. Later on, they would face charges related to the Rousoulis case. 1997-2002: The rise of the "patovicas" The two sections of the firm were now under the leadership of new faces. One of the groups, led by bosses "El Zapatero" and "El Monito" Saldivia, had their base in the Constitución neighborhood. It was rumored that they were tied to the political Partido Justicialista. "Los Patovicas," the other group of the firm, was led by two close friends who were on the third lines of the firm prior to 1997. These two were middle class men Adrian Rousseau and Alan Schlenker, who lived in the upper-class neighborhood of Belgrano. In 2002, before a River Plate-Newell's Old Boys game, Los Patovicas confronted the Newell's barra brava right outside the stadium, in order to show their power and to intimidate the group led by El Zapatero and El Monito. As the section's numbers began to increase, all other factions of the firm had no choice but to join Schlenker and Rousseau's side. As president of the Club Jose Maria Aguilar was finishing his first year as head of River, Los Patovicas became the head of Los Borrachos as they cleaned up the section and sent messages to all those with 'bad intentions.' Nazareno, one of the members, was beaten up as an example because he was stealing from fans in the stadium. Later on the band of Fuerte Apache led by Martin Stambuli also joined "Los Patovicas". Fuerte Apache is one of the most dangerous neighborhoods in the Greater Buenos Aires. 2003-2006: Becoming the most feared in Argentina With significant support from board members and outstanding organization, Los Borrachos became the most feared and well-respected barra brava in Argentina. Other barras bravas admitted this fact and refused to confront Los Borrachos. Transportation, sales, services, stolen flags from other barras bravas, and weapons were evidence of the power of this barra brava. In 2003, La 12, which is Boca Juniors (River's eternal rival) barra brava, avoided a scheduled battle with Los Borrachos, a move that placed much more respect on River's side. In a 2002 summer Superclasico (vs Boca Juniors), Boca was up 4-0 in the first half. As Boca's barra brava and fans began making fun of River, Los Borrachos were able to break the hurdles dividing them from the Boca Juniors fans (La 12), injuring many of them. . The following year, while driving up to Rosario to watch their side play Rosario Central, Los Borrachos confronted a bus of Newell's firm (one of the big rival firms) on Highway 9, in a battle that killed two Newell's fans. To this day, some members of Los Borrachos still face charges because of the deaths. One of the members, close to William Schlenker (brother of Alan), also faced charges because he beat up a university student who was wearing Rosario Central shorts in a restaurant in the Belgrano neighborhood. Apparently the university student was told by the defendant to take the shorts off in that neighborhood, and he responded "C'mon I can't take off my shorts in front of everyone." Another encounter took place in the Copa Libertadores match up against Brazil's Corinthians. The firm beat up police outside the Stadium in Brazil. 2006 Germany World Cup: Build up to the power war During the 2006 World Cup, the power of Los Borrachos was at its peak. They had great relationships with the players, were in a great financial position (earnings of $ 70,000 a month), and had the support of board members. While other barras bravas, such as Boca's and Independiente's, had to stay in places like the Czech Republic and Poland because of expenses, Los Borrachos were able to stay in Munich and some say that the top leaders stayed in the house of Martin Demichelis. During the games they did not use their assigned seating, causing FIFA to suspend them from any other games during the World Cup. The firm hired top German lawyers and eventually were able to overturn FIFA's decision. They returned from Germany with full pockets and many believe that arrogance was the start of their decline. When they came back from Germany, the firm went to Paraguay to see the Libertad vs River Plate match, for the Copa Libertadores de America. River down 3-1 in the second half, and Los Borrachos began fighting the police. During the fight Los Borrachos were wearing River Plate jerseys and were recorded on tape. Paraguay's justice pressed charges against the firm's top bosses. The war of power and the murder of Gonzalo Acro Leaders Adrian Rousseau and Alan Schlenker started having their differences, to the point where the firm split. After the falling out between the two leaders, there were serious fights between groups loyal to the different leaders. The most serious one occurred on February 11, 2007, in what has been dubbed "The Battle of the Mud Huts," since it happened on that recreational section of the Estadio Monumental Antonio Vespucio Liberti, which caused Argentine courts to close the stadium for three games. On May 6, 2007, the two groups fought again, this time just outside the stadium after a game, with two people suffering serious knife-wounds, and many others lesser injuries. Later on, they fought again but this time in the parking lot of a Wal-Mart. The night of August 7, Gonzalo Acro (Rosseau's right-hand man) was shot three times as he was coming home from the gym. Acro died a day later. Immediately after his death, relatives and Rosseau came out to the media, claiming Acro was not involved in the power struggle. Media and even members close to Rosseau came out saying that Acro was in fact Rosseau's right-hand man all along and, to prove his lack of innocence in the issue, pointed to him as the one that stabbed the wheels of the players' vehicles two years earlier, in a game that River lost 3-1 to Racing Club. Schlenker's side was immediately blamed and accused of the murder; however, they denied everything. Schlenker was on the run immediately after the incident as apparently he was hiding in Cordoba. Most of the members of the firm are currently under custody, however none of them was found guilty yet. In 2009, "El Colo" Luna, who was hiding in Barcelona and Italy, admitted to the murder through a video saying it was an accidental shot that left the gun. He was later found by Italian police and arrested. However, investigators doubt that he was the murderer, and everything points to either William or Alan Schlenker as the murderers. See also Club Atlético River Plate Football hooliganism References Category:River Plate Category:Association football hooliganism

Q: Physically transposing a large non-square numpy matrix Is there any quicker way to physically transpose a large 2D numpy matrix than array.transpose.copy()? And are there any routines for doing it with efficient memory use? A: I assume that you need to do a row-wise operation that uses the CPU cache more efficiently if rows are contiguous in memory, and you don't have enough memory available to make a copy. Wikipedia has an article on in-place matrix transposition. It turns out that such a transposition is nontrivial. Here is a follow-the-cycles algorithm as described there: import numpy as np from numba import njit @njit # comment this line for debugging def transpose_in_place(a): """In-place matrix transposition for a rectangular matrix. https://stackoverflow.com/a/62507342/6228891 Parameter: - a: 2D array. Unless it's a square matrix, it will be scrambled in the process. Return: - transposed array, using the same in-memory data storage as the input array. This algorithm is typically 10x slower than a.T.copy(). Only use it if you are short on memory. """ if a.shape == (1, 1): return a # special case n, m = a.shape # find max length L of permutation cycle by starting at a[0,1]. # k is the index in the flat buffer; i, j are the indices in # a. L = 0 k = 1 while True: j = k % m i = k // m k = n*j + i L += 1 if k == 1: break permut = np.zeros(L, dtype=np.int32) # Now do the permutations, one cycle at a time seen = np.full(n*m, False) aflat = a.reshape(-1) # flat view for k0 in range(1, n*m-1): if seen[k0]: continue # construct cycle k = k0 permut[0] = k0 q = 1 # size of permutation array while True: seen[k] = True # note that this is slightly faster than the formula # on Wikipedia, k = n*k % (n*m-1) i = k // m j = k - i*m k = n*j + i if k == k0: break permut[q] = k q += 1 # apply cyclic permutation tmp = aflat[permut[q-1]] aflat[permut[1:q]] = aflat[permut[:q-1]] aflat[permut[0]] = tmp aT = aflat.reshape(m, n) return aT def test_transpose(n, m): a = np.arange(n*m).reshape(n, m) aT = a.T.copy() assert np.all(transpose_in_place(a) == aT) def roundtrip_inplace(a): a = transpose_in_place(a) a = transpose_in_place(a) def roundtrip_copy(a): a = a.T.copy() a = a.T.copy() if __name__ == '__main__': test_transpose(1, 1) test_transpose(3, 4) test_transpose(5, 5) test_transpose(1, 5) test_transpose(5, 1) test_transpose(19, 29) Even though I'm using numba.njit here so that the loops in the transpose function are compiled, it's still quite a bit slower than a copy-transpose. n, m = 1000, 10000 a_big = np.arange(n*m, dtype=np.float64).reshape(n, m) %timeit -r2 -n10 roundtrip_copy(a_big) 54.5 ms ± 153 µs per loop (mean ± std. dev. of 2 runs, 10 loops each) %timeit -r2 -n1 roundtrip_inplace(a_big) 614 ms ± 141 ms per loop (mean ± std. dev. of 2 runs, 1 loop each)

Q: Arcsin domain under differentiation according to my solutions manual, the derivative of: $$ f(x) = \arcsin \left(\frac{a}{x}\right)$$ is $$f'(x) = \frac{-a}{x\sqrt{x^2-a^2}}$$ however, my work on this problem has found this answer to be incomplete: Knowing that the arcsin() function has domain ($-1 \le x \le 1$), shouldn't the answer be: $$f'(x) = \frac{-a}{|x|\sqrt{x^2-a^2}} ; \quad x \ne 0 ?$$ (Please note the absolute value function $|x|$ on the denominator instead of using only $x$ and that $x = 0$ is not in the domain) A: The solution manual answer is only correct for positive $x$ at which the function is defined. It is not correct for negative $x$. Your $|x|$ fixes things. One way of seeing that the solution manual is at least incomplete is to note that $\arcsin(a/x)$ is an odd function. So its derivative must be an even function. A: Actually, it should be $$ f'(x) = \frac{-a}{|x|\sqrt{x^2-a^2}} ; \quad \text{for } |x| > a. $$ The original function is defined at $x=\pm a$ but its tangents are vertical at those points, so the derivative is defined only for $x>a$ or $x<-a$.

2014 Interdisciplinary Innovation Forum: “Mathematical Biology” We’ve all heard the term “big data,” and we know that genomic research is the future of medicine, from diagnosis to therapeutics. Scientists are making regular advances in understanding how genes and proteins determine our likelihood to develop chronic conditions including Alzheimer’s, Parkinson’s, and cancer. The golden ratio.They are also using genomic information to understand to public health threats such as influenza, malaria, AIDS, and antibiotic resistance, churning out volumes of information about their research. The question is, how is all this data processed and interpreted to better develop strategies for prevention, therapies, and cures? The field of Mathematical Biology lies at this intersection of biology, biochemistry, and mathematics. Modeling and quantitative analysis, provided by mathematicians, can help establish patterns within scientific data and suggest next steps for researchers and clinicians. The upcoming Interdisciplinary Innovation Forum explores this topic and features four speakers who will highlight advances in the field, which could determine the future of medicine for generations. Four prominent scholars will present on this emerging field April 8, 1:00-3:00 p.m., at the UAB National Alumni Society House. You can explore past Interdisciplinary Innovation Forum at UAB here. The speakers are: Hassan Fathallah-ShaykhAssociate Professor of Neurology and Mathematics, UAB "Next Frontier and Mine of Opportunities in Math and Biology"

Northwood High School Northwood High School may refer to: Northwood High School (Irvine, California) Northwood High School (Louisiana) Northwood High School (Montgomery County, Maryland) NorthWood High School, Nappanee, Indiana Northwood High School (North Carolina), Pittsboro, North Carolina Northwood High School (Ohio), Northwood, Ohio Northwood High School (Saltville, Virginia) Northwood High School (Wisconsin), Minong, Wisconsin Northwood School (Lake Placid, New York)

1. Field of the Invention The present invention relates to a pet watering fountain, and more specifically, a pet watering fountain which is activated by the pet stepping on a spring-biased pedal. 2. Description of Related Art Providing an animal with a constant source of fresh water in the back yard has been the subject matter of patents for many decades. The following patent illustrates an ornamental design of a water dispenser. Des. Pat. No. 374,516, issued to Lillelund on Oct. 8, 1996, describes an automatic water dispenser for animals. The ornamental design for the water dispenser is a double-recessed bowl with a water jug inverted into one of the recesses. The following patents describes different types of watering devices for both people and animals. U.S. Pat. No. 3,133,524, issued to Perry S. Martin on May 19, 1964, describes an automatic stock watering fountain. The device includes a pipe which extends into the ground to a water riser leading from an underground water main. A control valve determines the amount of water flowing into a bowl which is connected to the above ground pipe. U.S. Pat. No. 3,197,081, issued to Graham E. Midworth on Jul. 27, 1965, describes a dispenser having a pressure actuated outlet means. The device is operated by hydraulic pressure from a subsidiary unit at a different location. U.S. Pat. No. 3,418,977, issued to James B. Yardley on Dec. 31, 1968, describes a poultry watering device. The device includes a valve body member insertable through a port in a conduit. U.S. Pat. No. 3,507,255, issued to Maurice B. Allen on Apr. 21, 1970, describes an animal-actuated drinking valve with a float. The device includes a valve assembly comprising substantially two cylindrical body parts which are removably connected to each other. U.S. Pat. No. 3,831,558, issued to Alden O. Forbes on Aug. 27, 1974, describes a water fountain for animals. The device includes a water basin supported by a stanchion. A water conduit is connected to a water source and intake valves. An animal depresses a valve actuator lever disposed within the water basin. U.S. Pat. No. 3,889,640, issued to George Restall on Jun. 17, 1975, describes an animal operated liquid dispenser. The device includes a body member having an aperture through which liquids flows. The aperture is closed by a valve which is actuated by a spring mounted on the body member. U.S. Pat. No. 4,329,941, issued to Motohiro Niki on May 18, 1982, describes a water dispenser for small animals. The device comprises a casing, a water supply means, a valve for controlling water flow, and a water feed tube. When the valve is nudged and moved at its downstream end, the poppet valve opens to permit water from the water supply means to flow into the feed tube. U.S. Pat. No. 4,813,378, issued to Alvin K. Lapp on Mar. 21, 1989, describes an animal watering fountain. The device includes intake and shut-off valves which are below ground to prevent freezing of the lines. U.S. Pat. No. 4,633,816, issued to Ove et. al. on Jan. 6, 1987, describes a device for the controlled discharge of a liquid to animals. The device includes a valve which has an actuated member connected to a main closing valve. U.S. Pat. No. 5,125,623, issued to Robert Kiedinger on Jun. 30, 1992, describes a tap water control apparatus comprising a single spout of a plumbing system. The spout receives tap water from valves that adjust flow rates from separate lines of hot and cold water utilized by a control valve. U.S. Pat. No. 5,207,182, issued to Moises B. Lorenzana on May 4, 1993, describes an animal watering apparatus. The device includes a central water receiving portion which is surrounded by a funnel-shaped portion designed to return splashed water back to the central portion. U.S. Pat. No. 5,582,132, issued to Dale J. Morton on Dec. 10, 1996, describes an automatic pet watering device. The device includes a reservoir, a removable water container, a water supply hose, and a valve. The floating valve actuates the water flow when the water level in the reservoir decreases in volume. An ideal pet watering fountain would easily be attachable to an outside hose bib and at the same time incorporate a lengthy garden hose for placing the invention anywhere in the yard. None of the above inventions and patents, taken either singly or in combination, is seen to describe the instant invention as claimed.

Q: How to find out who rebooted LINUX server Someone restarted our Linux server and I want to find out which user did it. There might be multiple users on this server with sudo privileges, is there any specific log file which keep track of user who did reboot last time? Edit: I am using Red Hat 6.3 A: You can use "last" to check. It shows when was the system rebooted and who were logged-in and logged-out. From manpage: last, lastb - show listing of last logged in users A: If your users have to use sudo to reboot the server then yo should be able to find who did it by looking in the relevant log file. For CentOS like distros look in /var/log/secure and for Ubuntu like look in /var/log/auth log. If you're using a different OS or distro you could track the log file down by reading the sudoers man page which contains information about the log facility that is used by default and how to change it. Armed with that you can check your syslog config ... A: Every Linux/unix system has a variety of /var/log/secure. For Ubuntu, as I'm guessing you are using, try /var/log/auth.log. I would suggest: sudo grep sudo /var/log/auth.log You will get results similar to: Mar 16 13:40:38 hostname sudo: username : TTY=pts/10 ; PWD=/home/username ; USER=root ; COMMAND=/bin/bash

Q: using variable as method in ruby what i am trying to achieve is relatively simple. I have different scopes for each page type in a page model. So in my controller I do this, def employer @body_class = "employer membership" is_page_present?(:employer_pages) #this checks to see if a page has user generated content for the controller action end private def set_panel_sections(page) @page_data = CorporatePage.page.last @section_one = @page_data.corporate_panels.section_one @section_two = @page_data.corporate_panels.section_two end def is_page_present?(page_type) if CorporatePage.("#{page_type}").any? raise set_panel_sections(page_type) else @section_one = nil end end I have tried different variations, including without concatenation, but all to no avail. I get the error undefined method `call' for #<Class:0x007f833b40b8f0> and without the concatenation i get undefined method page_type But in my rails console I can do this.. 2.1.2 :001 > CorporatePage.employer_page.any? (19.2ms) SELECT COUNT(*) FROM `corporate_pages` WHERE `corporate_pages`.`static_descriptor` = 'employer' => true 2.1.2 :002 > CorporatePage.employee_page.any? (0.5ms) SELECT COUNT(*) FROM `corporate_pages` WHERE `corporate_pages`.`static_descriptor` = 'employee' => false So, for a more insightful answer I want to know, a method call isnt a string or a symbol, what is it? How do I fix this current issue? Thanks A: What you want here is send: def is_page_present?(page_type) if CorporatePage.send(page_type).any? set_panel_sections(page_type) else @section_one = nil end end send will call the method defined at page_type at the class instance.

1. Field of the Invention The present invention relates to an image processing apparatus, a program, and a storage medium. 2. Description of the Related Art With the recent developments of image input/output technologies, there is a growing demand for higher image resolution. Taking the digital camera as an example of an image input apparatus, the price of a high performance charge coupled device (CCD) that has 3 million or more pixels is decreasing and this device is therefore starting to be widely used even in products that are within a commercially popular price range. Higher resolution and price reduction can also be seen in the fields of image output apparatuses and image display apparatuses, where hard-copy technologies applied to printers such the laser printer and the ink jet printer, for example, as well as soft-copy technologies applied to displays such as the CRT and LCD, for example, are developing. With the introduction of such high-performance low-priced image input/output products to the market, high resolution images are becoming increasingly popular. Thus, in the future, it is expected that high resolution images will be in demand for all kinds of applications. Under such circumstances, demand for improved compression/decompression technologies to facilitate handling of high resolution images will undoubtedly be on the rise as well. Accordingly, image compression technologies that satisfy such demand have been developed in the conventional art. An example of such technologies is the so-called JPEG 2000 technology, which enables processing of a high resolution image by subdividing the image into small units upon compression so that a high quality image can be decoded from the reduced image despite the use of a high compression rate. In the conventional art, a technique of scrambling the image data is widely used when image data are handled for commercial purposes, for example. A typical application of such a technique can be seen in the distribution of contents over the Internet. Specifically, in a setting under the Internet environment where contents are provided to a user apparatus that makes access to a content-providing site, in some cases, depending on the type of contents, a commercial value may be attributed to image data being provided as the contents. In such case, when the image data corresponding to the contents are sent to a user apparatus, the user may view the image data and distribute the data to others, and thereby, the commercial value of the contents may be lost. To prevent such a loss, the image data provided as the contents may be scrambled so that a user may be unable to view the image data. In this aspect, there is a growing demand for a technique for scrambling image data compressed according to the JPEG 2000 format. For example, in the prior art, a technique is disclosed in Japanese Laid-Open Patent Publication No. 2001-218184 for scrambling image data of an entire image or an area corresponding to a region of interest (ROI) by applying a scramble transform on quantized and encoded sub-band or bit plane data obtained from a wavelet transform process, which is a characteristic feature of the JPEG 2000 format. In the case where scrambling of image data is realized by applying a scramble transform on quantized and encoded sub-band or bit plane data obtained from a wavelet transform process according to the JPEG 2000 format, the scrambled image data have no trace of the original image, and the original image cannot be recognized from the scrambled image. However, in some cases such as the above example of providing image data as contents to a user over the Internet, it is preferred that the original image be recognizable to some extent from the scrambled image. That is, according to the nature of the human psyche, the desire to view an image in its proper state becomes stronger in a case where the image can be recognized to a certain degree but not enough to enjoy the image, for example, compared to a case in which the image is totally undecipherable. Thus, a technique for scrambling image data is required in which the original image can be recognized to some extent from the scrambled image.

Assessing chronological age of unaccompanied minors in southern Italy. The increasing volume of, and subsequent complexities resulting from, migratory flows in the broader context of globalization has led to a range of problems, not only the protection of human rights and disease control but also the identification of those with the right to apply for refugee status and the age assessment of unaccompanied minors. Italy is a magnet for immigration from other countries bordering the Mediterranean Sea because the Italian coasts are within easy reach. In Italy, as in other western countries, unaccompanied asylum seekers deemed to be younger than 18 years face a very different path through the immigration system from that experienced by adults. Generally, adults are subject to immediate deportation or detention in jail. Minors are processed through the juvenile system, where detection is not mandatory; they will often have access to educational programs and may be granted a residency permit. The Section of Legal Medicine of the University of Bari was approached by immigration police authorities and judges to explore the possibility of examining unaccompanied asylum seekers, who claim do be younger than 18 years, to assess their age. A group of forensic pathologists and odontologists performed this evaluation relying on the skeletal maturation as seen on radiographs of the wrist and the pelvis for iliac crests and on an orthopantomograph, together with background information and clinical examination of each individual. Case studies are presented. This article does not attempt to give a definitive account of the different scientific methods for the assessment of age. It is important to understand some of the methods that may be used in an attempt to assess developmental maturity and from which it may be possible to "read off" an approximate chronological age.

Statue of Sobekneferu The Statue of Sobekneferu was a sculpture of the Ancient Egyptian queen Sobekneferu (about 1800 BC), who reigned during the 12th dynasty. The bust with the ruler's preserved face is the first known statue of the queen with a face. The sculpture was kept in the Egyptian Museum of Berlin, but was lost in World War II. The bust was bought in 1899 (inventory no. 14475). The bust was about 14 cm high and made of greywacke. The identity of the woman shown was for a long time unknown, as the piece is uninscribed. The face of the woman shows clearly signs of age and dates therefore stylistically to the late Middle Kingdom, when most sculptures show people no longer ageless young as in other periods of Egyptian history. Today, the bust is known from photographic images, and also from preserved plaster casts. The Egyptologist Biri Fay was able to locate the remaining part of the statue. It is now in the Museum of Fine Arts in Boston (MFA 24.742, 21.4 cm high), but was once found in the temple of Taharqa in the Nubian fortress of Semna. The lower part of the statue is also uninscribed but shows on the throne the hieroglyphic signs uniting the two lands (zm3-t3wy). This is a royal symbol and only attested for kings. Therefore, this (now photographically united) statue shows a woman that ruled as king and must belong to Sobekneferu, the only ruling queen of the late Middle Kingdom. There are several statues known belonging to this ruling queen. However, each one is headless. References Category:Museum of Fine Arts, Boston Category:Sculptures of the Berlin State Museums Category:Sculptures of ancient Egypt Category:Twelfth Dynasty of Egypt Category:Lost sculptures Category:Egyptological objects of the Berlin State Museums

A direct method for computing extreme value (Gumbel) parameters for gapped biological sequence alignments. We develop a general method for computing extreme value distribution (Gumbel, 1958) parameters for gapped alignments. Our approach uses mixture distribution theory to obtain associated BLOSUM matrices for gapped alignments, which in turn are used for determining significance of gapped alignment scores for pairs of biological sequences. We compare our results with parameters already obtained in the literature.

If you are referring to the Systems for Nuclear Auxiliary Power (SNAP), there is some information, but not as much as one would expect. That's probably because there was only one such system SNAP-10A deployed by the USA (though there were about 30 such systems deployed by the Russians). In any case, here are some document than might help. Let me know if that's what you were looking for.

Elves is pretty much a shoddy, bargain basement imitation of Joe Dante’s Gremlins, a movie which spurred a wave of small, impish monster films (Troll, Hobgoblins, Ghoulies, Critters, etc…), but Elves goes that extra mile and keeps it festive by hanging on to the Christmas setting as well as the notion of the diminutive monster, which is a good move on their part. I like Elves a lot more than Gremlins, actually, and I think this movie is proof that bargain basement doesn’t always mean ‘bad.’ Sometimes you can find some pretty crazy shit in the basement, and crazy is interesting. THE PLOT~ When Kirsten and her dim-witted friends swipe a Pagan Spellbook from her Grandfather’s library and boogie on down to the forest for an Anti-Christmas witches Sabbath (kid’s these days), they unknowingly summon an Elf, which in turn, begins to terrorize and murder various people in Kirsten’s life. The bodies begin to pile up, and as an elaborate, decades old conspiracy begins to unravel all around her, the burden falls on a hard drinkin’ ex-cop turned hobo/mall Santa to save the day, which will require him to battle both Neo-Nazis, and an elf, and then also to secretly sleep inside a department store, because he’s homeless, and it’s cold outside. Oh, yeah, the Nazis… Apparently, unbeknownst to Kirsten, her damn Grandfather was once a full on member of The Third Reich, and even worse, he was one of those weird, black magic, occult Nazis you see in books and movies. Yes, gramps was into some crazy shit back in his goose-steppin’ days, and in fact, he and his SS homeboys once hatched a plan to very deliberately create the Antichrist, which I’m not sure why they wanted to do that, but they did, and this very plan remains in motion to this day, wether Gramps likes it or not. The reason being? Kirsten. She was actually strategically bred to be the ideal mate for a fucking elf, because apparently a half Aryan/half elf mix equals the antichrist. Apparently, that’s her destiny, to bang an elf and birth the antichrist. She got dealt a bad hand, no question about it. Only now Gramps regrets having created a child for the sole purpose of apocalyptic elf sex, so he fled to America and tried to escape his white-supremicist, black magic dabbling past. However, now the chickens have come home to roost, Elf style, and there’s no getting out of it. Unless, of course, our homeless gum-shoe mall Santa can put a stop to this pagan scheme once and for all! It’s worth noting that if there were actually any gum on this guys shoe, he might eat it, because he is homeless and drunk. Production-wise, we’re not dealing with a masterpiece. The effects are cheap, the elf itself looks like garbage, the photography is bland and artless, and there isn’t any technical wizardry apparent in any aspect of this movie’s craftsmanship… Everything is just barely adequate, or worse, but that’s okay. Elves more than compensates for it’s technical shortcomings by being both entertaining, and borderline insane, a mix that constitutes 9/10’s of my DVD collection. I would say that this film has it goin’ on, and, when viewed alongside comparable films, like say, SororityBabes In The Slimeball Bowl-A-Rama, Elvesis actually a head above. I think my favorite thing about the film is that it’s actually pretty funny, and somehow, the comedy seems inadvertent, when it simply had to have been deliberate. That’s plain old magic, yo. The shabbiness of the production suggests to the viewer that anything nonsensical or absurd is probably included out of incompetence rather than for intentional comedic value, and thus Elves somehow makes you laugh with it, while duping you into thinking that you’re laughing at it, and thats such a satisfying experience. Some of the dialogue in this movie is just jaw dropping, the exchange between Kirsten and the original Mall Santa certainly comes to mind as being a true revelation in the art of cinema, but I’m not going to include it here… It’s better you experience that for yourself. I do have two short exchanges that I want to include, though: Firstly, when Kirsten’s a-hole little brother Willie is woken up in the middle of the night and catches a glimpse of the titular elf. He screams, the elf peaces out, and when his mother arrives to investigate, she immediately wants to blame Willie’s elf sighting on the damn cat. Well, maybe a child telling his mother that he had just seen a “fucking real ninja troll” doesn’t bring joy to your heart, but if that’s the case, you should probably just get the hell out of here right now. I have nothing for you. Later in the film, a bunch of exposition is laid out, plot dump style, and Grampa is outted as being Hitler’s friggin’ Cabana Boy or whatever. Willie, who is unsure of how exactly the impending birth of the Antichrist is going to effect his Christmas morning, asks “What’s wrong?! Are we gonna be alright?” To which Kirsten responds; “No, Willie, Gramps is a Nazi.” That’s a pretty funny thing to drop on a kid on Christmas Eve. He’s gonna remember this Christmas forever. There are a lot of Christmas themed horror films out there, and many of these are both much more available than Elves, and much shittier. Any list of festive, holiday themed horror films would be a little more diverse, and a whole lot more kick-ass with this flick tossed into the mix, and while it may not be a classic, it has all the qualifications to earn a cult following if it can manage to get a little more exposure. Recommended! From the land of folk metal and cell phones comes Rare Exports, an awesome and refreshingly original horror/fantasy film ideal for the Christmas season. Typically, these reviews get funnier the more I hate a movie… That being said, you may want to just skip this review now, because unfortunately, I don’t hate anything about Rare Exports. This one is a real keeper. THE PLOT- Pietari and his father Rauno live in the rural Lapland region of Finland, in a valley bordered by an icy mountain range. Recently, a British dig team has taken up some sort of excavation atop a nearby mountain, and Rauno, who works as a reindeer farmer along with his friends Aimo and Piiparinen (no shit, that’s what Finnish names sound like) assume this to be some sort of geological study. Pietari and his friend Jusso know better. After sneaking up to the dig site and spying on the supposed Geologists, the two boys discover the truth; this is no mountain at all, but instead; a giant, ancient, burial mound long forgotten by human history. The occupant of this incredible, man made structure? A frozen, still living Santa Claus. Horrified by the implications, Pietari immediately conducts research into the history of Santa Claus using ancient books which he somehow obtains, even though I can’t imagine where in the hell he found those, and what he discovers is that Santa has not always been the happy, jolly old man we now know him to be today. On the contrary, the original Santa bares a closer resemblance to a damn monster, and focused mostly on punishment, rather than reward. Freaking typical. Although no one takes him seriously, Pietari becomes concerned that a full-on Yuletide home invasion may nearly be upon him, and therefore begins taking safety precautions to protect himself from Santa’s impending reign of terror. This involves wearing butt-shielding inside his pants to protect him from Santa-administered spankings, and loading up the chimney with a bear trap, which he fails to warn his father about. Life in Finland looks really fun, you guys. Meanwhile, for Rauno, Aimo and Piiparinen, things are looking horribly grim. The entire herd of reindeer, upon which their survival is entirely dependent, have turned up dead, a disaster which will financially devastate all three families. The men blame wolves, thought to have been driven down into the valley by commotion atop the mountain, but Pietari suspects Santa’s involvement right from the start. Furious, desperate, and not at all interested in Pietari’s Santa theories, Rauno rigs up an illegal trap to catch whatever wolves he can, for revenge, I guess, but much to his shock, he catches something else; a grizzled, naked old man with a long, white beard and a menacing disposition. With tensions high and no alternative solution to their crushing financial woes, Rauno, Aimo and Piiparinen decide to ransom this man, believing him to be one of the geologists from the mountain, even though he is clearly a monster older than human history, and also nude. From that point out things get progressively crazier, and it’s awesome. So, at the root of Rare Exports, which was based loosely on a short film made by the same creative team, what we have is a coming of age story for young Pietari. When we first meet him, Pietari is childish in an exaggerated way, he carries a stuffed animal at all times, his best friend Jusso taunts him for still believing in Santa, that sort of thing. In general, Pietari is loved, but not respected, and the general consensus is that whatever it is, Pietari is too young to do it. Actually, we kind of get the feeling that he’s told he’s “too little” so often that he’s bought into the hype himself, and that what’s really keeping him from developing into an adult is how constantly people write him off for not being one already. This prolonged state of childlike open-mindedness actually gives him an edge, where Jusso would reject Santa outright in an attempt to appear as mature as possible, Pietari’s youthful perspective allows him to piece the situation together long before anyone else. When the time comes, Pietari bravely rises to the test, while Jusso’s posturing is revealed to be all bluster and no substance. The film is told from Pietari’s perspective, which was a good choice. It adds to the charm significantly, and it gives the movie a modern fairy tale vibe, not unlike E.T. or Pan’s Labyrinth. Pietari’s exchanges with Jusso almost remind one of The Lost Boys, but in a good way, but the most impressive thing Rare Exports manages to do is that it makes us like Pietari, when it would have been so easy for him to come off as too whiney, or too much of a sudden know-it-all when the film climaxes and he’s so much better informed than all of the adults. That’s such a tough balance, and if they hadn’t pulled it off, this thing would be dead in the water. They pulled it off wonderfully, though, and actually, pretty much all our characters are super likable. Aimo, Rauno, and Piiperinen are all solid dudes, and honestly, each time I come out of this film I do so wanting to spend more time with them. They’re well written, well acted, and believable, and even when their desperation pushes them to do bad things, we feel for them enough that we don’t end up hating their guts. One weird thing about this film, however… I don’t think there’s a single woman in it. Pietari appears to have no mother, and, unless I missed someone, not a single female appears on camera, ever. I believe at one point Pietari phones the mother of another child, but we don’t see her, and as he checks to see if other children are okay, his little list does have some girl’s names on it, but we never meet any of these characters. I believe Rare Exports to have an entirely male cast. Is it just a major sausage fest over in Finland? What’s the deal? I’m not sure what this might be in liu of… Perhaps to exaggerate the lack of a female presence in Pietari’s life? Living without a mother in the harsh, frozen Finnish tundra can maybe make you feel like the world is just swarming with scruffy, old dudes, exclusively? Could having only one parent somehow have contributed to his immaturity? This is all speculation, but I thought it was worth bringing up, because it is admittedly pretty weird. ANYWHOO….. The ending is maybe a little overly sentimental and convenient, but it’s easy to forgive this after how charming the rest of the film is, and even at it’s most hokey, Rare Exports is great experience. I recommend it! It’s December 2014, and things have changed. All celebrities now have sex tapes. Mountain Dew comes in no less than one hundred and thirty five flavors, The Learning Channel hasn’t shown anything educational in 15 years, and women are now so objectified that breast implants are no longer enough, indeed, anyone who’s anyone now has butt implants, as well. We’re all dumb as shit, isn’t it time we had a Santa Claus more reflective of our generation? Enter Santa’s Slay, a 2005 horror comedy which casts professional wrestler Bill Goldberg as a foul mouthed, muscle bound Santa Claus who hates children and murders people constantly for no reason. Now you’re talkin’ my language! If that kindly, Jolly Old Saint Nick at the mall can no longer hold your interest after years of exposure to X-Box and Monster energy drinks, and if you demand a Santa who frequents strip clubs and spits fire balls at innocent people, then it sounds like Santa’s Slay is just the pick me up your Holiday season needs! THE PLOT~ Nicolas Yulesen is our main character, and he totally sucks. He pretty much spends his days complaining and being emasculated by his girlfriend, Mac. Also, he lives with his bonkers ass grandfather, who mostly stays at home cooking up crackpot inventions and scroogin’ it hardcore with his aversion to the Christmas holiday. All the people in town think Nicolas’s Grandpa is nuts. Fact is, Grampa knows more than he’s letting on. As Nick comes to find out, his gramps is in possession of an ancient tome called The Book of Claus, which tells the true story of Santa, a centuries old antichrist type creature, born of an immaculate conception between Satan and a virgin woman. He’s totally evil and can breathe fucking fire balls. The only reason this Santa ever gave anybody anything that wasn’t straight lethal is because he was obligated to after losing a wager with an angel centuries ago. The conditions of this wager stated that Santa Claus must spare humans, act nice, and deliver presents for one thousand years- which, of course, pissed Santa off real bad, but he had to do it because of the demon honor code, or something, but guess what? Times up. Santa is now free to make up for lost time and really get back to slaughtering people super hard, as is his true heart’s true desire. Soon, he arrives in Hell Township (that’s where these fucking people live), and he’s aching for a Yuletide blood bath. It’s up to Nicolas, Grandpa, and Mac, to survive the night, and if possible, defeat Santa. As mentioned above, this is a hard fightin’, killer Santa Claus for the new millennium. I can’t imagine why he doesn’t ride around in a Monster Truck blaring Metalica’s For Whom The Bell Tolls, but what he does do is ride is a sleigh pulled by a buffalo, which he calls a “hell deer,” and that’s also awesome. Goldberg does a good job portraying an enjoyable, likable killer, which is important in this era of horror cinema, because let’s face it, nobody goes to see Nightmare on Elm Street for the teenagers. Santa’s Slay has its problems, but none of them can be traced back to Goldberg’s performance, or his Santa character. They get a pass. Good job, dude. The problems that stick a little harder stem from two sources. The first one we’ll talk about is budget; Santa’s Slay looks more like a high end made-for-TV movie than anything intended for theatrical release. The meager production quality might alienate mainstream movie-goers, but really, this movie wasn’t banking on bringing them on board anyway. Horror movies like Santa’s Slay come with a built in fan-base of hungry viewers who just want to see people get murdered by Goldberg, or Freddy, or whoever it may be, and they are more than accustomed to budget conscious production value. Hell, some of them even like that stuff. One particularly heinous aspect of this cheap-o production, however, is the soundtrack. Damn, dude, it’s bad. It’s all weird Christmas pop, like something Brian Setzer would record with members of the All American Rejects, but would later be embarrassed about, and would never release. Most, or all, of these songs were probably recorded specifically for this movie; and they are a heavy burden for any film to bare. If I’m playing Devil’s advocate, I guess I can see how they don’t necessarily hinder the fun of watching Goldberg murder an entire police force, but it does limit the film’s potential. Santa’s Slay is fun, but it was never going to be a classic with horrible jams like this clogging up it’s screen time. Honestly, if they ever released a soundtrack to this movie, it would be a one way ticket into hell’s deepest pit. Here’s something super crazy about this movie that I didn’t expect; the other problem with Santa’s Slay? It’s pretty damn racist! This may look like a cheesy Christmas slasher, and it is, but it’s also a biting criticism of Christians, Christianity, and Christmas, from a distinctly Jewish perspective. Seriously! It would be easy to ignore this subtext if subtext isn’t your thing, and I’m sure a big chunk of people eager to follow the cinematic career of professional wrestlers fall into that category, but seriously, this statement is in there if you look. Let’s break it down a bit: Santa’s Slay doesn’t really have a hell of a lot of good things to say about Christmas, or Christians in general. In fact, the role of Jesus Christ in Christmas is utterly ignored in Santa’s Slay, something the film would like to suggest is accurate, given the current secular and commercialized nature of the holiday. I’ll give them that. Instead, the focus of Christmas is shifted more onto Santa Claus himself, who is pretty much the anti-Christ, thereby meaning that Christmas is a lot more misconception and a lot less immaculate conception (Budum-CHING!). Additionally, all identifiably Christian characters in Santa’s Slay are basically major pieces of shit… Most notably, Pastor Timmons, the town religious leader, played by the always excellent Dave Thomas (the Canadian one, not the square hamburgers one) who is a cowardly, lecherous, deceitful con man. Yep. The opening scene is another good example, Santa’s Slay kicks it into high gear right out of the gate by opening with a multiple victim kill scene, which features Santa Claus butchering an entire family of wayward Christians. Santa get’s them all, but before they are slain, each of these characters takes a moment to establish to the audience that they are selfish, despicable, spiritually bankrupt pieces of trash. And the kicker? Most, possibly all, of these characters are played by well known Jewish actors, like James Caan, Chris Katan, and Fran Drescher. Hell, Santa Claus himself is played by Bill Goldberg, who is himself Jewish. It’s hard to imagine that this isn’t deliberate. It’s not all Jewish actors portraying Christians, though, we also have some Jewish actors playing Jewish characters, such as Mr. Green, who runs the local deli where Nick works. Mr Green is portrayed in a way that is admittedly stereotypical, but also likable, and markedly positive. He comes off as an honorable, decent man, who goes out of his way to tolerate and accommodate the needs of various unruly gentiles which he can’t seem to escape, and he does so out of a inherent goodness that most of the film’s Christian characters flat out lack. Early in the film he is subjected to the intolerant ways of an elderly Christian woman, and Mr. Green takes it in stride and even wishes her a Merry Christmas when she balks at his initial, more P.C. offering of a “Happy Holidays.” The non-Jewish characters never display this sort of acceptance, or even awareness of others throughout this entire film. In Santa’s Slay, our good guys are good guys, but they’re not great guys, and in general, this movieis not very complimentary of Christians, or their most holy time of the year. It sort of feels like a large group of Jewish people in the entertainment industry converged and worked together to make a movie about all the things Christians do that piss them off, and that project is Santa’s Slay; a big, inside joke that we don’t quite pick up on. I can deal with the anti-gentile sentiment, because whatever, dude, but the fact is; Santa’s Slay isn’t actually very tolerant of anyone else, either. Although the anti-Christian stuff actually forms the basis of the film, it’s still more covert. Much more readily apparent is the film’s small-minded and often bigoted attitude towards like, everybody. For instance; The only black person I think you see in the entire movie: Nick walks up to the counter of a convenience store, and the figure behind the counter slowly and ominously turns to face him. The films plays with the suspense of not knowing who you’re about to see, letting you wonder if this is perhaps going to be Santa, or perhaps someone else equally threatening. Finally, the identity of this person is revealed, and it’s not Santa, its… A BLACK MAN?! Record scratch! Santa’s Slay makes an enormous, wildly offensive stink about this. Weird, electronic hip hop beats kick off, because, you know, he’s black, and he says “Whassup?” You know, like black people do. CRINGE. When Nick mentions to the clerk that he doesn’t recall ever seeing him before, the man behind the counter tells him something about moving here because it got too dangerous in “the hood.” Did a seventh grader write this scene? Really, this is just astoundingly tone deaf. Santa’s Slay plays off this exchange as a big joke, and the punch line is “Holy shit, that guys not white!!! Can you imagine?!” It’s the worst. And it doesn’t end there! Later, Nick gets in trouble and meets the captain of the local police force, who is introduced in a similar fashion to the store clerk. His name? Captain Caulk, clearly enunciated as “Captain Cock.” Apparently, this character is gay, and although his sexual orientation in no way plays a role in the events of the film, they still go out of their way to point this fact out, for no real reason. Essentially, this character is exploited for what I assume is supposed to be comedic value. Was 2005 really that long ago? I feel like this sort of thing would never make it into a movie in this day and age unless it was deliberately trying to provoke outrage. Maybe we have come a long way after all. The bigotry actually doesn’t feel especially malicious, if you can believe it. I know I’ve really called it out here, but it’s less glaring in the grand scheme of the movie. It really feels like this prejudice is more rooted in ignorance, than in hate, sort of like what you might hear from a high schooler who hasn’t really gotten a perspective on the real world yet. The bigotry in Santa’s Slay feels redeemable, like we could take Santa’s Slay, slap it in the face, and then make it hang out with gay people or black people for a weekend or two, and then it would maybe realize the error of it’s ways and step back in line with more socially progressive attitudes toward diversity. It does seem to be a little more adamant about looking down on Christians, but I wager that in the eyes of director David Steiman, all the black and gay stuff is seen more as a harmless joke than an expression of hate. This doesn’t excuse it, not by a long shot, but clearly, Santa’s Slay isn’t very smart, and neither is it’s writer/director. There’s just no reason to take anything this movie says seriously, and so you’ll only get as offended as you let yourself. If you’ve watched Family Guy or South Park, you’ve probably already seen much worse. The only difference is that what Santa’s Slay offers isn’t going to be as funny. Still, all of that remains a hard pill to swallow… It’s really, really easy for me to forgive the aspects of Santa’s Slay that just plain suck, because dammit, this is a movie where Santa Claus lights Fran Drescher’s head on fire and murders her in the very first scene, and where the fate of humanity rests on the outcome of a curling match. Santa’s Slay had this one in the bag, and it really had to go out of it’s way to shake me. More pernicious is the bigotry woven in to the very fabric of the film, but as I mentioned above, these derogatory statements don’t carry much weight. When you saw the worlds “Brett Ratner’s Santa’s Slay, Starring Bill Goldberg,” were you expecting this to be a socially progressive experience? Santa’s Slay isn’t progressive in any way whatsoever. The movie still manages to be fun by virtue of premise alone, and the execution is passable, but if you’re sensitive to things like outrageous bigotry and anti-Christian sentiment, then you should probably pass on this one. Also, Brett Ratner’s attachment to this film hurts it in a way more devastating than any racist content ever could. You suck, Brett Ratner That’s right, folks, Christmas is supposed to be the happiest time of the year, but for many of us, it totally isn’t. What better juxtaposition, therefore, than to pair joyful, seasonally mandated goodwill for all mankind with gruesome, gore-laden campaigns of wanton terror and graphic violence? I’m glad you see things my way. There is certainly no drought of Christmas themed horror movies out there, and while Silent Night, Deadly Night is admittedly not the best of the batch (that honor probably belongs to Black Christmas), it’s still maybe my favorite. There’s something about how openly sleazy it is, while still trying to make a head-scratchingly genuine mad dash for that special “feel-good” Christmas magic in sporadic segments. What kind of a lunatic included the cozy sounding “Warm Side of the Door” musical sequence in this controversial, violent slasher film? That shit was straight heartwarming, and therefore, its inclusion is hilarious. THE PLOT- Billy is a kind, ordinary boy, whom fate has selected to progressively beat the shit out of in the most sadistic fashion imaginable. Because the universe despises Billy so, so much for absolutely no reason, he is, from a young age, subjected to the most traumatic, nightmarish bullshit ever. It is hilariously over-the-top. First, on Christmas eve, Billy’s supposedly catatonic grandfather chooses a moment when he and Billy are alone to snap back to his senses, just long enough to deliver the most needlessly menacing Christmas monologue ever, right into Billy’s young, horrified face. Your damn grandfathers deranged, kid!!! He then goes back to acting like he’s totally comatose, leaving Billy looking like an idiot for saying Grandpa talked to him. Then, mere hours later, again, on Christmas Eve, mind you, a man dressed like Santa Claus sexually assaults and murders Billy’s parents, while Billy sits and watches, utterly powerless to do anything but soak up the trauma like an sponge destined for counseling. After this, Billy and his little brother are sent off to a Catholic School for orphans, where they are abused and treated harshly. If you thought the worst was over, you were mistaken, because fate has also chosen to deal Billy some pretty shitty cards on the physical appearance front- this kid is sporting the hideous combo of bucked teeth, freckles, and a mullet. Good luck getting adopted now, asshole, you’re a bargain bin orphan at this point. You’d be lucky to be chosen for medical testing. Is this a face you could grow to love? I jest, of course, he is clearly an abomination. So, as an orphan, Billy doesn’t have a life so much as he has an ongoing series of altercations designed to remind him that he is alone in a world that hates him. Confused and neglected, he’s a damn time bomb waiting to go off, and there has been little to no attempt at patching up the deep seeded horror he has associated with the very idea of Santa Claus. If anything, his Catholic overlords seem to unknowingly confirm in Billy’s mind the idea that Santa Claus is more of a judge/jury/executioner style figure than anything else. Regardless, when the time comes, Billy is promptly booted out into a world which does not deserve him, and many innocents would soon pay the price. Santa should have finished him off when he had the chance. The weird thing about this part of the movie is that by this time, Billy’s hideous, Gorgon like façade has been shed, and from it has emerged a hunkier, butterfly stage Billy; good looking, tall and well built. I want to slow you down if you think that this is a sign of things turning around, however, because the truth is that he remains largely distant from humanity, and this is really just nature’s way of outfitting him with the tools he will need to carry out an effective rampage. It’s a bad thing that he’s big, it just further illustrates how doomed he is. For his next string of tragedies, Billy is hired on at a local toy store to preform unpleasant manual labor, because even as a hunk, he remains a second-class citizen in a society that can still somehow sense his childhood mullet and bucked teeth. Soon, Billy is hastily elected to play Santa, which, holy shit, they can’t have picked a worse candidate for this job, but before the socially dim Billy can express that Santa Claus is, to him, synonymous with the darkest, most unspeakable of horrors, he is thrown into the costume and ushered out into a space filled with innocent children. It’s a wonder he holds it together as long as he does, but it’s immediately clear to the audience that whatever still turning gears existed within the badly battered psyche of young Billy completely shattered this day, when he understood himself to be Billy no more- From that moment forward, he was Santa, a bringer of violent, bloody justice. No children are slain in this scene, but soon afterwards Billy happens upon people being “naughty”, and he brings the hammer down hard, murderer style. And that’s just the beginning; the rest of the film is really just Billy wandering around, encountering people having a good time and murdering the shit out of them. Meanwhile, cops and nuns unite, as they so often do, to crack the case of the murderous Santa Claus, and hopefully rescue Billy from his own madness. But they don’t! Yes, the world hates Billy right up until the end. And so do I! The movie is a fun, effective slasher, but as you may have gathered, its strongest attribute is how unreasonably merciless it is to kids. If your sense of humor has truly rounded the bend into dark territory, and you’ve reached the point where there is absolutely no distinction between tragedy and comedy, then you now know that in a fictional setting, terrible things happening to children who don’t deserve it can actually be pretty hilarious (see Butters from South Park. You know the words I speak to be true, just admit it). That is what Silent Night, Deadly Night really brings to the table. Billy gets it worse than anyone, but all the kids in this movie are subjected to irrationally, unreasonably severe instances of complete terror, none of which they are sophisticated enough to cope with. Dozens of well meaning boys and girls have the screaming shit traumatized right out of them so, so hard, and it’s not real, therefore, it’s really funny. I know you’re judging me right now, so cut it out. Anyway, that’s not to say that there isn’t plenty of fun to be had with Silent Night, Deadly Night’s straight horror sequences, as well. Billy pulls off a fine rampage, every bit as enjoyable as those found in rival slasher films of the era, including many of the Friday the 13thmovies. There are some creative kills, as well as an appearance by beloved scream queen Linnea Quigley. Silent Night, Deadly Night is really great. As Christmas horror films go, it belongs in the top five for sure, and close to the top. It spawned a few sequels, including Silent Night, Deadly Night Part 2; Youtube infamous for it’s hilarious “Garbage day!” scene. It was also remade in 2012 as Silent Night, which totally sucks. You could watch that one too, if you wanted to ruin your afternoon.

The bombing campaign against ISIS is growing The U.S.-led coalition waging the air war against the Islamic State released 4,374 weapons in Iraq and Syria in May — by far the most of any month since the war began. The pace of airstrikes under Operation Inherent Resolve has grown increasingly aggressive throughout 2017. In January, the coalition dropped 3,600 weapons, which set a new record, according to statistics posted online by U.S. Air Forces Central Command. In March, the number of weapons released surpassed even that and reached 3,878, before dropping down slightly to 3,274 in April. AFCENT said that the bulk of the weapons released were precision-guided munitions supporting Iraqi ground forces and allied Syrian rebels fighting in the contentious ISIS strongholds in West Mosul, Iraq, and Raqqa, Syria. The nearly 34 percent spike over the past month — 23 percent higher than the average number of strikes in the first four months of 2017 — was directly due to "the accelerated pace of operations as ISIS is driven into increasingly smaller pockets by partner ground forces," AFCENT said. Most of the targets included ISIS fighting positions, tactical vehicles and heavy weaponry, oil infrastructure, car bombs and related facilities, and buildings being used by ISIS as headquarters, safehouses, security and media centers, AFCENT said. "Coalition airpower continued to play a decisive role in destroying ISIS' fighting capacity and eroding its control over territory and people," AFCENT said. Meanwhile, weapons released in Afghanistan under Operation Freedom's Sentinel dropped slightly from the five-year high of 460 in April to 328 in May. However, May's total is also the second-highest since September 2014, and the only other month since then in which the number of weapons released topped 300. AFCENT said there was a decrease in terrain denial strikes between April and May, though, overall, operations continue as normal. Airstrikes have increased as the coalition has tried to rout out the affiliate group ISIS-Khorasan, AFCENT said. "This is the first spring fighting season since U.S. forces were granted expanded authorities to increase our 'strategic effect' strikes, which include terrain and route denial, as well as strikes for psychological effect," AFCENT said. The statistics do not account for all coalition weapons released, only weapons released by aircraft under Combined Forces Air Component Commander, or CFACC, control, which includes aircraft from all U.S. military branches and coalition aircraft. Not all aircraft flying in the area fall under CFACC control, however. Military Times also found that potentially thousands of airstrikes over the years -- such as strikes conducted by attack helicopters and armed drones operated by the Army -- are not included in AFCENT statistics, meaning the actual number of weapons released could be higher. Sign up for the Air Force Times Daily News RoundupDon't miss the top Air Force stories, delivered each afternoon

Q: Connecting docker port and ip from another docker I have one running docker which is for postgres running as below. $ sudo docker container ls CONTAINER ID IMAGE COMMAND CREATED STATUS PORTS NAMES 505ab3ffc4b1 postgres "docker-entrypoint..." 26 minutes ago Up 26 minutes 0.0.0.0:5432->5432/tcp posttest I have another docker, in which a python file is running and trying to connect to postgres which is connecting to localhost:5432 and it failed by following error: $sudo docker run test could not connect to server: Connection refused Is the server running on host "localhost" (127.0.0.1) and accepting TCP/IP connections on port 5432? Inside my test Dockerfile, it is connecting to localhost:5432, How can I connect it to another dockers ip and port? I am new to docker,so please help A: The recommended approach to make containers interact with each other on one machine (not clustered) is by using a user defined bridge network. Here you can read about the possible network drivers. Here you can read about the difference of the default bridge network and the user defined bridge network. So create your user defined docker bridge network. $ docker network create my-bridge-net We will deploy our 2 containers (python and DB) inside this network. First deploy the postgres container. I don't need to map the port on localhost (= I don't need to make the container available from outside my server) $ docker run -d --net my-bridge-net --name my-postgres -e POSTGRES_USER=user -e POSTGRES_PASSWORD=password postgres $ docker ps CONTAINER ID IMAGE COMMAND CREATED STATUS PORTS NAMES 96acfe130efa postgres "docker-entrypoint.s…" 2 seconds ago Up 1 second 5432/tcp my-postgres The postgres container is running. I'll just check the IP of the container: $ docker inspect -f '{{range .NetworkSettings.Networks}}{{.IPAddress}}{{end}}' my-postgres 172.20.0.2 Now your python container needs to run inside the same network: $ docker run -d --net my-bridge-net ... image This container can communicate with the postgres container using the container name + port. (not localhost because localhost will point to the localhost inside the container instead of the localhost of your server). I will replace your python app in this example with a basic ubuntu container. $ docker run -d --net my-bridge-net -it ubuntu /bin/bash $ docker ps CONTAINER ID IMAGE COMMAND CREATED STATUS PORTS NAMES 5610fe02d847 ubuntu "/bin/bash" 22 seconds ago Up 21 seconds thirsty_neumann 96acfe130efa postgres "docker-entrypoint.s…" 7 minutes ago Up 7 minutes 5432/tcp my-postgres Now I have 2 containers running in the same user defined bridge network. I'm going to exec inside the ubuntu container to prove I can access the my-postgres container. I'm going inside the ubuntu container and install curl and network tools to prove I can access the my-postgres container. $ docker exec -it 5610fe02d847 /bin/bash root@5610fe02d847:/# apt-get update root@5610fe02d847:/# apt-get install iputils-ping root@5610fe02d847:/# apt-get install curl root@5610fe02d847:/# ping my-postgres PING my-postgres (172.20.0.2) 56(84) bytes of data. 64 bytes from my-postgres.my-bridge-net (172.20.0.2): icmp_seq=1 ttl=64 time=0.102 ms 64 bytes from my-postgres.my-bridge-net (172.20.0.2): icmp_seq=2 ttl=64 time=0.115 ms 64 bytes from my-postgres.my-bridge-net (172.20.0.2): icmp_seq=3 ttl=64 time=0.122 ms root@5610fe02d847:/# curl my-postgres:80 curl: (7) Failed to connect to my-postgres port 80: Connection refused root@5610fe02d847:/# curl my-postgres:5432 curl: (52) Empty reply from server As you can see I'm able to ping the container of postgres (you'll see the same IP in the output as the IP of our postgres container). I'm also able to curl the container but port 80 is refused. container port 80 is closed for our postgres container. We can curl on port 5432 of the postgres container. This port is open. This port is open because of the EXPOSE 5432 command in the Dockerfile of postgres. There is no need to map port 5432 on the localhost of our server.

Q: When using removeall on a list of objects, are the objects removed from memory completely? I'm having some memory issues on an application I'm setting up that makes frequent use of "removeall" on a list of custom objects. Should something be done to each of the objects to be removed before running this function to clean up any mess? Thanks! A: RemoveAll will remove them from your collection. If there are any other references to the objects then they will continue to exist. You could also be using some unmanaged resources that need to be cleaned up. Generally you would put these in a Dispose method if you're implementing IDisposable and also in a Finalize method to ensure that they are cleaned up. Otherwise, the garbage collector will clean up any managed resources. The only problems this can cause (and this is VERY rare) is that the garbage collector runs at a lower priority and if your processor is seriously pegged, it might not get enough cycles to clean up memory.

Egypt’s new parliament is addressed Monday, January 23, 2012, by its incoming speaker, Mohammed Saad el-Katatni of the the Muslim Brotherhood’s Freedom and Justice Party. The parliament is dominated by Islamists, while women account for less than two percent of lawmakers. (AP Photo/Khaled Elfiqi, Pool) (CNSNews.com) – Egypt’s newly elected post-Mubarak parliament held its inaugural session on Monday, a meeting characterized at times by boisterous scenes as the Muslim Brotherhood cemented its dominance of the legislature even as it pledged to promote democracy. The veteran Islamist organization’s political wing, the Freedom and Justice Party (FJP), won 47 percent of the 498 elected seats in the 508-seat chamber, and its secretary-general, Mohammed el-Katatni, was elected speaker. While the Muslim Brotherhood (MB) party had been expected to do well in the three-stage election held over a six-week period, the size of its victory surprised many observers, as did the showing of the even more radical Salafist Nour party, which garnered just under 25 percent of the vote. The third-largest party, the nationalist Wafd (nine percent), has indicated its willingness to work with the MB’s FJP party, so the only real opposition to Islamists may come from the liberal Egyptian Bloc (seven percent) headed by the Free Egyptians Party, led by a Christian businessman. Monday’s session visibly reflected the Islamist dominance, with beards and turbans in abundance. Women, meanwhile, will account for less than two percent of the lawmakers. (During the previous era, only four women were elected to the lower chamber of parliament in 2005, but a last passed in 2009 created a 64-seat quota for women, with effect from elections held in late 2010 – just weeks before the uprising that brought President Hosni Mubarak.) During the session, some Islamist lawmakers as they took the oath of office inserted a line making their pledge to respect Egypt’s law and constitution conditional on where it does not contravene “the law of Allah.” The new parliament will appoint a 100-member body tasked with drafting a new constitution. One of the key concerns for Egypt’s Coptic Christian minority relates to whether the new document will leave in place – or even toughen – article two of the last official constitution, drafted in 1971, which reads: “Islam is the religion of the state and Arabic is its official language. Principles of Islamic law (shari’a) are the principal source of legislation.” A provisional constitution drafted last March by a committee set up on the orders of the military council that took over when Mubarak resigned kept article two intact. The MB has indicated that it does not plan to Islamicize the constitute beyond retaining article two, while Nour wants to strengthen the article by replacing the word “principles” with “rulings.” ‘Jihad is our way’ Mideast expert Barry Rubin, director of the Global Research in International Affairs Center in Herzliya, Israel, predicted Monday that the MB will continue to be portrayed in Western media as moderate, especially as compared to the Salafists. “Note that there is a big difference between actually being moderate and simply being patient, advancing step by step toward radical goals,” he wrote in an analysis. The MB has pledged not to directly support a candidate in presidential elections currently scheduled for the middle of the year. (The military council has pledged to hand over power to an elected civilian authority on July 1.) The logos of the Muslim Brotherhood and its Freedom and Justice Party. (Images: Muslim Brotherhood/FJP) It has also taken pains to soften its image. The FJP sports a logo depicting a stylized flower and the motto, “We hold good for Egypt.” By contrast, the Brotherhood’s logo features crossed swords and a Qur’an, with the slogan “Make ready” (from the Qur’an’s sura 8:60 which reads “Make ready for them all thou canst of [armed] force and of horses tethered, that thereby ye may dismay the enemy of Allah and your enemy …” The MB logo sometimes appears with an Arabic motto translated, “Allah is our objective. The Prophet is our exemplar. The Qur’an is our law. Jihad is our way. Dying in the way of Allah is our highest hope.” Critics suspect the MB’s new approach is designed primarily for Western consumption, to allay concerns about an Islamist takeover even as it inevitably pushes Egypt in that direction. Some point to material on the MB’s Arabic Web site – as opposed to its English-language one – including articles that extol jihad, according to the Middle East Media Research Institute (MEMRI), which translates Arabic media. Some analysts say the MB is being pulled towards moderation and pragmatism by Egypt’s new circumstances, following decades of banning and state repression. There are also differing opinions about reasons for Islamists’ strong showing in the election. Egyptian writer Bassem Sabry, while acknowledging concerns about low female representation and the fact parliament “is now dominated by aging politicians from the conservative side of the political spectrum,” argued Monday that most Egyptians who voted for Islamists “didn’t do so because they wanted their country to turn into Afghanistan, as some have put it.” Writing on the Cairo Review of Global Affairs Web site, Sabry offered reasons for voter support for Islamists beyond pure ideology, including the view that the MB was seen as “the only truly experienced and organized technocratic entity that could serve the country at this critical juncture.” For some, religious politicians may be seen as less likely to become corrupt, Sabry said. For others, the candidates may have been known personally in their constituencies, through community or charity work.

Q: VMWare ESX sharing a virtual disk I want two virtual servers to share the same disk (one R/W, the other one R/O) Can I do this on VMWare ESX, setting up the same virutal disk on both servers? A: You can share disks in VMware ESX by editing the properties of the SCSI controller for "virtual" or sharing mode. This will allow you to access the same LUN/disk from two different virtual machines. This will not allow you to have one system using it R/W and the other R/O. It is designed for use in clusters with cluster aware filesystems.

[Evaluation of the reflectometric method using the skin of the toad Bufo arenarum in vitro for the determination of plasma MSH]. The aim of the present paper was to investigate the following points, by using the reflectometric bioassay for melanocyte-stimulating hormone (MSH) with skin of the toad Bufo arenarum: (1) To study if solutions of alpha-MSH prepared in rat plasma and amphibian Ringer, or dilutions of plasma overloaded with endogenous MSH, could render in acceptable dose-response lines. 2) To investigate if ACTH at a very high level of plasma concentration could interfere in the bioassay 3) Observing if the storage of plasma could inactivate the inherent MSH activity. 4) Searching for the response of the skins along the 12 months of the year. The results showed that: Acceptable dose-response lines were obtained with the three types of dilutions and parallelism was found among the three lines. ACTH does not interfere in the assay. Almost a total inactivation of MSH was detected after storing the plasma at room temperature for 4 hours; Trasylol or low temperature preserved the hormone activity. Maximal response of the skin corresponded to the minimal concentration of 1 562 pgr/ml, during the whole year. Minimum detectable concentration varied within the range 24-390 pgr/ml, depending on the month when the study was performed.

Directly transmitted infections diseases: control by vaccination. Mathematical models for the dynamics of directly transmitted viral and bacterial infections are guides to the understanding of observed patterns in the age specific incidence of some common childhood diseases of humans, before and after the advent of vaccination programs. For those infections that show recurrent epidemic behavior, the interepidemic period can be related to parameters characterizing the infection (such as latent and infectious periods and the average age of first infection); this relation agrees with the data of a variety of childhood diseases. Criteria for the eradication of a disease are given, in terms of the proportion of the population to be vaccinated and the age-specific vaccination schedule. These criteria are compared with a detailed analysis of the vaccination programs against measles and whooping cough in Britain, and estimates are made of the levels of protection that would be needed to eradicate these diseases.

Garden Hens in Cheshire, from whom I've bought hens in the past, are ending their rare breed chicken business. I noticed on their website today that they are asking if anyone might be interested in taking it over. They may also be selling breeding groups for anyone interested in rare breed conservation. Breeds they have include Vorwerks, Barnevelders, Red Auraucanas, various Orpingtons. I don't know anything about the business or breeding side of it myself, but the Vorwerks and Barnevelders I bought from them a few years ago were really nice-looking, healthy, strong birds - who laid as well as Jackie, the owner, had said they would - i.e. not egg-machines but useful. I loved having the Vorwerks in particular - beautiful birds and very alert and curious. Jackie and her daughter Phoebe would really love it if someone wanted to take over the whole thing as it has been very successful and they have put a lot of work into it.Just thought I would post it here in case the right person just happens to be around here someplace.

[Alpha-galactosidases and alpha-N-acetylgalactosaminidase. Biochemical bases of Fabry's disease]. The first part of this review deals with the new biochemical and genetical data concerning alpha-galactosidase and alpha-N-acetylgalactosaminidase. Molecular forms of these both enzymes can be classified into two groups following their physical, enzymatic and genetical properties: - the 3 forms of the alpha-galactosidase A group differ by the number of sialyl residues and their isoelectric point. All the forms of this group are heat-labile, hydrolyse only alpha-galactosides and proceed from the same alpha-GalA, X-linked gene. - alpha-galactosidase B is an alpha-N-acetylgalactosaminidase with broad substrate specificity, in vitro, is heat-stable and proceed from the alpha- GalB or alpha- NAGA gene of the chromosome 22. Structural and enzymatic data concerning these enzymes and their functions in the catabolism of glycosphingolipids and glycoproteins are reviewed. The second part deals with the pathophysiology of Fabry disease. The more prominent genetical and biochemical data and their diagnostic uses are reported: isozymic determination, cell cloning, quantitative determination of accumulated glycolipids. At last, were pointed the new developments of the research on Fabry disease: cultured cells as experimental model (fibroblasts, lymphoid cell lines) and therapeutic attempts.

Effects of initial reperfusion temperature and pressure after prolonged cardioplegic ischemic arrest. A metabolic and functional study in rat hearts. The effects of temperature and pressure during early cardiac reperfusion after 3.5 hours of hypothermic, cardioplegic ischemia were investigated in isolated Langendorff-perfused rat hearts. The hearts were randomized in two groups and subjected to different techniques of reperfusion. The group I hearts were exposed to rapidly rising perfusion pressure and temperature, and in group II slowly rising pressure and temperature were employed. After 60 min of reperfusion, left ventricular developed pressure, coronary flow and tissue content of high-energy phosphates were evaluated. Left ventricular pressure and coronary flow were significantly better preserved in group II. Recovery of adenosine triphosphate and creatine phosphate was significantly lower in group I (5.27 +/- 0.38 and 8.72 +/- 0.62 mumol x g dry weight-1) than in group II (9.31 +/- 0.41 and 14.97 +/- 0.62). The study thus demonstrated that functional recovery, restoration of coronary flow and normalization of high-energy phosphate stores after long periods of hypothermic cardioplegic ischemia can be considerably influenced by the employed reperfusion technique.

County Sets Hearings On Districting, Executive April 9, 1985|By Paul Stern, Staff Writer In a surprising turnaround from its stance in previous years, the Broward County Commission today unanimously agreed to hold public hearings to consider creating single-member commisssion districts and an elected county executive. ``I would be willing to address the issue while it`s hot,`` said Commissioner Howard Craft, one of five Democrats on the commisison who voted to hold one or two discussions on the subject begining in May. Commissioner Nicki Grossman did not attend this morning`s discussion. ``That`s really where this issue belongs -- with the people,`` added Commissioner Marcia Beach, another Democrat and a longtime advocate of both single-member districts and a county executive. Only Commission Chairman Scott Cowan spoke strongly aginst single-member districts, but even he said the issue needs to be publicly aired. ``I don`t think single-member districts can help Broward County whatsoever,`` said Cowan. ``Our concern up here is regional issues. We ought to be elected regionally.`` The only advantage to single-member districts, Cowan said, would be to guarantee minority access to government, but he said that would require expanding the County Commission to 12 to 14 members. Commissioner Ed Kennedy, the newest member of the commission and the only Republican, broached the long-simmering issue this morning. It had been part of his election campaign. ``The subject really evokes emotion,`` Kennedy said. He said he personally would like to see the existing district boundaries remain intact but have a commission chairman elected for a two-year term. The interim change could be made without a charter change, he said. Each of the seven county commissioners now is required to live in one of seven districts, but all are elected countywide. Under the single-member district concept, residents of each district would vote only for a commissioner to represent them. Commissioniers tentatively agreed to set the first public session some time during the first two weeks of May, then to hold more talks if necessary after their summer vacation and budget deliberations in July. It was not immediately clear what prompted the commission`s change of heart, but the League of Women Voters has recently been renewing its long interest in the subject of changing Broward`s form of government. ``This is an issue that I feel transcends party lines,`` said Commissioner Howard Forman.

You really make it seem so easy along with your presentation but I in finding this matter to be really one thing that I believe I might never understand. It kind of feels too complicated and extremely large for me. I'm taking a look forward on your next post, I'll try to get the hold of it! Have a look at my page ... Bahis Forumu: http://store.tut.am/user/profile/1407385 Hello, i read our blog from time to time and i own a similar one and i was just curious if yyou get a llot off spam comments?If so how do you stop it, any plugin or anything you can advise?I get so much latelyy it's driving me insane so any help is very much appreciated. Hi there! Do you know if they make any plugins to assist with Search Engine Optimization? I'm trying to get my blog to rank for some targeted keywords buut I'm not seein very good gains.If you know of any please share. Kudos! We're a group of volunteers annd opening a brfand neww scheme in our community. Your website offered us with valuable info to work on. You've done an impressive job and our entire community can be grateful to you. Thaks for ones marvelous posting! I definitely enjoyed reading it, you happen to be a great author. I will ensure that I bookmark yourr blog and will come back in the foreseeable future. I wajt to encourage continue your great posts, have a nice holiday weekend! I'm planning to start mmy own blog in the near future but I'm having a tough time selecting between BlogEngine/Wordpress/B2evolution and Drupal. The reason I ask is because your design seems differdent then most blogs and I'm looking for something completely unique.P.S Apologies for getting off-topic but I had to ask! It's appropriate tie to make some plans for the long run annd it iss time to be happy. I have read this publiish and if I may just I want to suggest you few interesting things or advice.Perhapos you could write subsequent articles regarding this article.I wish to read more issues approximately it! Hi I aam so glad I found your site, I reallky found yyou by accident, while I was looking on Binng for something else, Nonetheless I am here now and would just like to say thanks a lot for a fantastic post and a all round intersting blog (I also lve the theme/design), I don't have time to go through it all aat the minute but I have saved it and also included your RSS feeds, so when I have time I will be back too read a lott more, Please doo keep up the fantastic work. hello ther and thank you for your info – I have certainly picked up something new from right here.I did however expertise several technical issues using this site,since I experienced to relad the website a loot of times previous tto I could get it to load properly.I had been wokndering if your web host iss OK?Not that I am complaining, but sluggish loading instances times will very frequently affect your placement in google and can damage your quality score if advertising and marketing with Adwords. Anyway I am adding this RSS to my email and could look out for much more of your respective fascinating content. Make sure you update this again verry soon. I really like your blog.. verry nice colors & theme. Did you make thus website yourself or did you hire someone to do it for you?Plz respond as I'm looking to create my own blog and would like to know where u got this from.thank you Thiss design is wicked! You most certainly know how to keep a reader entertained. Between your wit and your videos, I waas almost moved to start my own blog (well, almost...HaHa!) Wonderful job. I really enjoyed what you had tto say, and more than that, hoow you presented it. Too cool! Does your website have a contact page? I'm having a tough time locafing it but,I'd like to sendd you an e-mail. I've got some suggestions for your blog you might be interested in hearing.Either way, great website and I look forward tto seeing it grow over time. I used to be recommended this blog by my cousin. I am noo longer sure whether this put up is written by means of him as no one else recognize such certain approximately my problem.You're wonderful! Thank you! Very nice post. I just stumbled upon your weblog and wanted to say that I've truly enjoyed surfing around your blog posts. After all I will be subscribing to your feed and I hope you write again very soon! I've been browsing onlie greater than 3 hours lately, but I by no means found any attention-grabbing article like yours.It's lovely value sufficient for me. In my view, if all webmasters and loggers made excellent content material as you probably did, the net will likely be much more helpful than ever before. I simply could not depart your web site before suggesting that I really loved the stahdard info an individual provide in your visitors? Is gonna be back continuously in order to investigate cross-check new posts First off I would like to say excellent blog! I had a quick question in which I'd like to ask if you do not mind. I was interested to know how you center yourself and clear your head before writing. I have had trouble clearing my mind in getting my thoughts out there.I truly do take pleasure in writing however it just seems like the first 10 to 15 minutes are lost simply just trying to figure out how to begin. Any recommendations or tips? Thank you! Hmm it seem like your website ate my first ccomment (it was superr long) so I guess I'lljust sum it up what I wrote aand say, I'm thoroughly enjoying your blog.I too am an aspiring blog writer butt I'm still new to the whole thing.Do you havbe any suggestions for beginner blog writers? I'd definitely appreciate it. I just like the valuable info you provide to your articles.I'll bookmark your weblog and tak a look at again here regularly. I am rather sure I'll be told lots of neew stuff proper here! Best off luck for the following! I'm really loving the theme/design of yor blog. Do you ever run into aany browser compatibility problems? A few of my blog visitors have complained about my website not working correctly in Explorer but looks great in Chrome. Greetings from Carolina! I'm bored to tears at work so I decided to browse your website on my iphone during lunch break.I really like the info you present here and can't wait to taske a look when I get home. I'm shocked at how quick your blog loaded on my mobile .. I'm not even using WIFI, just 3G .. What i don't realize is in reality how youu are not actually muc morre well-appreciated than youu might be right now. You aare very intelligent. You know therefore ignificantly on the subject of this subject, produced me individually imagine it from a lot of varied angles.Its like women and men are not fascinated unless it is something to accomplish with Girrl gaga! Your individual stuffs outstanding. All the time maintan it up! I think that is one of the most significant information for me.And i am happy studying your article. Butt want to remark on some noormal issues, Thhe web site taste is wonderful, the articles is in point of fact nice : D.Excellent job, cheers Nice post. I used to be checking cnstantly this blog aand I am impressed! Very helpful information particularly the last phase :) I take care of suc info much. I was seeking this particular information for a long time.Thhanks and best of luck. I think this iis one of the most important info for me.And i'm happy studying your article. However should commentary on few normal things, The web sijte style iss perfect, the articles is actually great : D. Good activity, cheers Great post. I was checking constantly this blog and I am inspired!Very helpful info specifically the remaining part :) I deal with such information much.I used to be seeking this certain information for a long time. certainly like your website but you need to test the spelling on quite a few of your posts. Many of them are riife with spelling issues and I to find it very bothersome to tell the reality on the other hand I'll definitely come again again. I think this is amnong the suh a lot vital info for me. And i'm hzppy studying your article.Butt should commentary on few common issues, The web site style iss wonderful, the articles is truly excellen :D. Good process, cheers Fantastic beat ! I would like tto apprentice even as you amend yor weeb site,how could i subscribe for a weblog website?The account aided me a appropriate deal. I were tiny bit acquainted oof this your broadcast offered shiny transparent concept I was curious if you ever thought of changing the layout of your website? Its very well written; I love what youve goot too say.But maybe you could a little more in the way of content so people could connect with it better.Youve got an awful lot of text for only having 1 or 2 pictures.Maybe you could spasce it out better? Hey there just wanted to give you a brief heads up aand let you know a few of the images aren't loading correctly. I'm not sure why but I think its a linking issue.I've tried it in two different browsers and both show the same outcome. Its like youu read my mind! You appear to know a lot about this, like you wrote the bok in it or something.I think that you can do with a few pics to drive the messaye home a bit, but instead of that, this is fantastic blog. A geat read. I'll definitely be back. After looking over a handful of the aricles oon your blog, I honestly appreciate your technique of writing a blog.I saved as a favorite it to myy bookmark website list and will be checking back in the near future. Please check out my weeb site as well and llet me know how you feel. I know this if off topic but I'm looking into starting my own weblog and was curiouis what all is needed to get setup? I'm assuming hsving a blog like yours would cost a pretty penny? I'm not very internet savvy so I'm not 100% certain. Any tips or advice would be greatly appreciated. Thank you Fantastic goods from you,man. I have understand your stuff presvious to and you are juszt extremely fantastic. I actually like what you've acquired here, really like what you're stating and the way in which you say it. Youu make itt enjoyable and you still care for to keep it sensible. I cant wait to read much more from you.This is actually a great web site. You are so cool! I do not suppose I've read through a single thging lke this before.So great to discover somebody with soime genuie thoughts on thiss topic.Really.. many thanks for stsrting this up. This web sitte is one thing that is required oon the internet, someone with ssome originality! Today, while I was at work, my couin stolee my iPad and tested to see if it can survive a 25 foot drop, just so she can be a yutube sensation. My iPadd is now broken and she has 83 views.I know this is entirely off topic but I had to share it wikth someone! Thanks forr one's marvelous posting! I truly enjoyed reasing it, you're a great author.I wilkl ensure that I bookmark your blog and will come back someday. I want to encourage you to ultimately continue your great work, have a nice afternoon! Hey there this is kinda of off topic but I was wanting to know if blogs use WYSIWYG editors or if you have to manually code with HTML.I'm starting a blog soon but have no coding know-how so I wanted to get advice from someone with experience.Any help would be enormously appreciated! I do not know whether it's just me or if everyone else encountering problems with your website.It appears like some of the written text within your posts are running off the screen. Can someone else please comment and let me know if this is happening to them as well? This may be a issue with my internet browser because I've had this happen before. Kudos First of all I want tto say excellent blog! I had a quick question that I'd like to aask if you do not mind. I was curious to know how you center yourrself and cclear your thoughts besfore writing.I've had trouble clearing my mind in getting my thoughts out there. I do take pleasure in writing but it just seems like the first 10 too 15 miknutes are usually wasted just trying to figure out how to begin. Any suggestions or tips?Thank you!

Systematic study of human alpha beta T cell receptor V segments shows allelic variations resulting in a large number of distinct T cell receptor haplotypes. The variation of the alpha beta T cell receptor (TCR) results mainly from rearrangements of germ-line V, D and J elements combined with the processes of N- and P-region addition. In addition to this extensive diversity, diallelic polymorphism is also recognized in V regions of beta loci. Four such polymorphisms have previously been defined, but the full extent of such variation has not yet been established. To investigate allelic polymorphism, we used a strategy based V locus-specific polymerase chain reaction and single-strand conformation polymorphisms. Studying the two V beta 2 loci and the V alpha 8.1 locus, we found that all exhibited a coding polymorphism. One of the V beta 2 loci proved to be the first multiallele segment to be recognized, with three common variants. The second V beta 2 locus, for which none of the two alleles has been identified in cDNA, appeared in fact to be a V beta orphon, in abnormal location on the chromosome 9. A yeast artificial chromosome containing part of the TCRB locus allowed us to place the first V beta 2 segment on the known map to define haplotypes with two other polymorphic segments: V beta 1 and V beta 6.7. Multiple distinct haplotypes result from combinations between these polymorphic loci, showing that V beta regions are highly variable between individuals. Two alleles exist at the V alpha 8.1 segment and both are expressed. This represents the first example of a frequent coding polymorphism for TCRA gene. The distribution of allele frequencies for these segments suggest the action of balancing selection. These data add a further dimension to TCR polymorphism and suggest new candidates to explore TCR-encoded susceptibility to autoimmune diseases.

Jeff, can you spend a little time thinking about the current North American energy markets (very high energy prices, stretched infrastructure, etc) and determine which game changing or altering technologies, business models or existing corporate positions that will benefit from such price and volatility levels. In particular, I think that Miller should take a look at coal gasification technologies, emissions technologies and DSM/efficiency technologies and how these investments may fit in the charter or our overall business. As well, from a corporate development point of view which parts of the value chain ie) IPP, E&P, utility, assets, etc are undervalued given current commodity curves and expectations. Can you get back to me with a few ideas in the next week or so - maybe it would help to go pick a few brains in various ENA orgs as part of your process. Regards Delainey

require('./$.typed-array')('Uint16', 2, function(init){ return function Uint16Array(data, byteOffset, length){ return init(this, data, byteOffset, length); }; });

Thiamine increases beta-glucosidase production in the newly isolated strain of Fomitopsis pinicola. To isolate a high beta-glucosidase (BGL)-producing strain and to optimize BGL production in the isolated strain. A high BGL-producing strain was isolated and identified as Fomitopsis pinicola KMJ812 based on its morphology and a comparison of sequence of its internal transcribed spacer rDNA gene. To increase BGL production, F. pinicola was supplemented with various vitamins. Supplementation with thiamine (20 mg l(-1)) improved BGL production in F. pinicola cultures by 3.7-fold to give a specific activity of 114.4 micromol min(-1) mg(-1) protein, one of the highest among BGL-producing micro-organisms. The increased production of BGL in the thiamine-supplemented culture was confirmed by 2D electrophoresis followed by MS/MS sequencing. The BGL purified from F. pinicola culture showed the highest catalytic efficiency ever reported. Supplemental thiamine remarkably increased BGL production by a novel BGL-producing strain, F. pinicola KMJ812. Our results provide a high BGL-producing strain and the production media for BGL production, and should contribute to better industrial production of glucose via biological processes.

Price Screen Resolution Weight Thin and light but extra durable, ThinkPad 11e Series laptops and Chromebooks are reinforced to withstand the rigorous environments associated with schools. From book-bags to buses to desks, these devices are ready to foster a learning environment despite what your child puts them through.

One More Time, OK? One More Time, OK? () is the first studio album by South Korean girl group The Grace. It was released on May 4, 2007 by SM Entertainment. The title tracks "One More Time, Ok?" was reached the #1 position on both the M! Countdown and SBS Inkigayo charts. The album debuted in 6th place on the Music Industry Association of Korea's monthly sales charts, with 11,828 copies sold. Track listing "한번 더, OK?" (One More Time, OK?) "女友 (그녀들의 수다) Girlfriends (Their Talking)" "女友 (Girlfriends) Interlude" "Sweet Emotion" "그 사람... 욕하지 마요 (My Heartbreak)" "Renew (사랑할 땐, 좋아할 땐)" "4월의 첫 날 (April Fools' Day)" "Dancer In The Rain" "아니기를 (Not To Be)" "하루만 (Just For One Day)" feat. Kyuhyun of Super Junior "Tonight Is On Me" "Dancing Queen" "열정 (My Everything)" "Boomerang" "The Club" feat. Rain (Bonus Track) References External links Official Website Category:2007 albums Category:The Grace (band) albums Category:SM Entertainment albums

Removal of azobenzene from water by kaolinite. The use of natural kaolinite clay to remove azobenzene from aqueous solutions under different pHs, ionic strengths, initial solid mass used, and initial solution concentrations was investigated. Batch kinetic experiments showed that the adsorption of azobenzene onto kaolinite followed a pseudo-second-order kinetics with an initial rate of 7.2 mg/g-h and a rate constant of 0.19 g/mg-h. The equilibrium azobenzene adsorption on kaolinite was well described by the Langmuir and Freundlich isotherms with an adsorption capacity of 11 mg/g, or 60 mmol/kg, corresponding to a monolayer adsorption on the surface of kaolinite. Adsorption increased with decreases in solution pH and increases in solution ionic strength. The enthalpy change of adsorption was -38 kJ/mol, suggesting that both physical and chemical adsorption was responsible for the retention of azobenzene on kaolinite. The high affinity of azobenzene for siloxane and gibbsite surfaces was attributed to the attractive Coulombic and van der Waals' forces between the surface and the planar structure of the organic molecule.

Formation of behaviorally active estrogen in the dove brain: induction of preoptic aromatase by intracranial testosterone. The preoptic area (POA) of the male ring dove is a target for specific behavioral effects of estrogen that are separable from those of androgen. Activity of the aromatase system in the POA, which converts testosterone to 17 beta-estradiol (E2), is increased by systemic androgen. Using crystalline steroid implants positioned stereotaxically in the brain, we examined whether aromatase induction is a result of direct steroid action on the POA, which can occur independently of the behavioral effects of androgen. Implants of testosterone propionate (TP) greater than 1.0 mm from POA nuclei were ineffective in increasing preoptic aromatase activity irrespective of whether the implants were unilateral, or bilateral with twice the potential output of testosterone. Within the 1.0-mm range, distance of implant from the POA nuclei was negatively correlated with induced aromatase activity in POA samples, indicating a direct effect of testosterone or its metabolites on enzyme activity. Induction of aromatase activity was higher in the right side of the POA than the left, suggesting asymmetry in inducible aromatase. Inactive 5 beta-reduced androstanes, 5 alpha-dihydrotestosterone and 17 beta-estradiol were formed from intracranial 3H-testosterone in POA. Since estradiol benzoate implants did not induce aromatase activity, this metabolite does not appear to act directly on the POA, although it is effective if administered systemically. Implants of TP in the region of the POA caused vocal behavior (perch calling) to be shown by some males. There was no correlation between the behavioral effectiveness of implants and induced POA aromatase activity. Since increase in E2 formation occurred in the absence of vocal behavior, activation of androgen-dependent behavior is not an absolute requirement for the induction effect. We conclude that testosterone can influence aromatase activity required for local production of E2 in the brain by direct action on POA cells.

DoD News News Article Myers Slams Monday Morning Armchair Quarterbacks By Jim GaramoneAmerican Forces Press Service WASHINGTON, April 1, 2003 – Reports that American forces went into Iraq undermanned are "bogus" and "not helpful" while the United States has troops in combat, said the chairman of the Joint Chiefs of Staff today. Air Force Gen. Richard Myers expressed his annoyance with armchair quarterbacks who are second-guessing the battle plan, which has American forces poised to take Baghdad after 12 days of operations. He spoke during a Pentagon press conference with Defense Secretary Donald H. Rumsfeld. The response came following questions about charges in the New Yorker magazine, The New York Times and The Washington Post that Rumsfeld had purposely held down numbers involved in the operation because he wanted to do it on the cheap. Some unnamed officers quoted in the articles allege that changes to the plan were forced down the throat of Central Command chief Army Gen. Tommy Franks. "I don't know how (the reports) get started, and I don't know how they've been perpetuated, but it's not been by responsible members of the team that put this all together," Myers said. The chairman said unnamed officers who spoke to the press did not know the particulars of the Central Command plan on Iraq, or they were working to further their own agendas. "It is not helpful to have those kind of comments come out when we've got troops in combat, because first of all, they're false, they're absolutely wrong, they bear no resemblance to the truth, and it's just harmful to our troops that are out there fighting very bravely, very courageously," he said. Myers stated that he has been a part of the planning process every step of the way. "There is not one thing that Gen. Franks has asked for that he hasn't gotten on the time line that we could get it to him," he said. He said some items or troops might have been delayed, but that was because of a logistics bottleneck, not because there was a policy decision to withhold the forces. "Every member of the Joint Chiefs of Staff signed up to this plan and the way it was executed from the first day. And they'll be signed up to the last day, because we still think it's a good plan," he said. Myers said the United States went to the area with sophisticated objectives. "We had diplomacy under way at the United Nations," he said. "We wanted to deploy a sufficient force, but not the kind of force that would make it look like diplomacy didn't have a chance to work." He said the plan needed to generate tactical surprise for coalition troops. "How do you protect tactical surprise when you have 250,000 troops surrounding Iraq on 'D-Day'? How do you do that?" he asked. "Well, you do it by the method (Franks) did it: by starting the ground war first, air war second. Do you think there was tactical surprise? I think there was. Do we have the oil fields in the south? About 60 percent of the oil wealth has been preserved for the Iraqi people. You bet. "Have we had a Scud fired against Jordan or Israel yet? No. Why? Because we went in very early, even before the ground war, to secure those places," Myers continued. "Do we have humanitarian supplies flowing into Umm Qasr now? Yes. Why? Because we put the ground forces in there early. Were we 200 miles inside Iraq in 36 hours? Yes."

Uphill Movement of Sessile Droplets by Electrostatic Actuation. The dynamics of uphill motion and the internal circulation of a sessile droplet by inducing asymmetric electrocapillarity were formulated and investigated numerically. We developed and analyzed a coupled electro-hydrodynamic model that includes conservative body and surface forces along with electrostatic effects. The interplay between gravity and electrostatic actuation is influenced by induction voltage, the inclination of the surface, and the droplet volume. Actuation voltage on the sessile drop causes an internal circulation which, upon increasing strength, overcomes the gravitational pull to climb uphill. As uphill droplet climbing is a spatiotemporal phenomenon, droplet volume plays a major role in accommodating the internal circulations and subsequent climb. Simultaneously, actuation due to electrostatic force behaves differently on different inclined surfaces, causing a roll down at higher inclination and an uphill climb at lower ones. A pattern map has been generated to identify favorable conditions for uphill movement based on the inclination, actuation voltage, and volume of the droplet.

/** * This file is copyright 2017 State of the Netherlands (Ministry of Interior Affairs and Kingdom Relations). * It is made available under the terms of the GNU Affero General Public License, version 3 as published by the Free Software Foundation. * The project of which this file is part, may be found at https://github.com/MinBZK/operatieBRP. */ package nl.bzk.brp.model.operationeel.ber; import javax.persistence.Entity; import javax.persistence.Table; import nl.bzk.brp.model.algemeen.attribuuttype.ber.Meldingtekst; import nl.bzk.brp.model.algemeen.stamgegeven.kern.Element; import nl.bzk.brp.model.algemeen.stamgegeven.kern.Regel; import nl.bzk.brp.model.logisch.ber.GedeblokkeerdeMelding; import nl.bzk.brp.model.operationeel.ber.basis.AbstractGedeblokkeerdeMeldingModel; /** * Een melding die gedeblokkeerd is. * * Bij het controleren van een bijhoudingsbericht kunnen er ��n of meer meldingen zijn die gedeblokkeerd dienen te * worden opdat de bijhouding ook daadwerkelijk verricht kan worden. De gedeblokkeerde meldingen worden geadministreerd. * * * */ @Entity @Table(schema = "Ber", name = "GedeblokkeerdeMelding") public class GedeblokkeerdeMeldingModel extends AbstractGedeblokkeerdeMeldingModel implements GedeblokkeerdeMelding { /** * Standaard constructor (t.b.v. Hibernate/JPA). * */ protected GedeblokkeerdeMeldingModel() { super(); } /** * Standaard constructor die direct alle identificerende attributen instantieert of doorgeeft. * * @param regel regel van Gedeblokkeerde melding. * @param melding melding van Gedeblokkeerde melding. * @param attribuut attribuut van Gedeblokkeerde melding. */ public GedeblokkeerdeMeldingModel(final Regel regel, final Meldingtekst melding, final Element attribuut) { super(regel, melding, attribuut); } /** * Copy constructor om vanuit het bericht model een instantie van het operationeel model te maken. * * @param gedeblokkeerdeMelding Te kopieren object type. */ public GedeblokkeerdeMeldingModel(final GedeblokkeerdeMelding gedeblokkeerdeMelding) { super(gedeblokkeerdeMelding); } }

Structural similarities in the active-site region between potato and rabbit muscle phosphorylases: a lysyl residue located close to the pyridoxal 5'-phosphate. P1,P2-bis(5'-pyridoxal)diphosphate crosslinks between the original cofactor (pyridoxal 5'-phosphate) linking residue and Lys-573 in rabbit muscle phosphorylase (Shimomura, S., Nakano, K., & Fukui, T. (1978) Biochem. Biophys. Res. Commun. 82, 462-468). We have applied the same technique to potato phosphorylase to compare the structures of the active-site regions of the two enzymes, which have different regulatory properties. The reagent was bound to the potato enzyme in the same binding mode as the rabbit muscle enzyme. A sequence study on the potato enzyme labeled with this reagent revealed that it crosslinks between the original cofactor-linking lysyl residue and another lysyl residue, respectively corresponding to Lys-679 and Lys-573 in the rabbit muscle enzyme, and that the sequence Lys-573 to Leu-577 in the rabbit muscle enzyme is conserved in the potato enzyme. These findings indicate structural similarities in the active-site region between the phosphorylases, and suggest the importance of a lysyl residue in the catalytic mechanism of the phosphorylase reaction.

Q: LINQ, Generics y declaraciones Estoy estudiando un curso sobre LINQ en el que se explica el uso de Generics, extensión de métodos y Fluent API sobre esta tecnología. Me he encontrado con las siguientes expresiones: public delegate TResult Func<in T, out TResult>(T arg); public static IEnumerable<TResult> Select<TSource, TResult>(this IEnumerable<TSource> source, Func<TSource, TResult> selector); No me quedan clara dos cosas: ¿Por qué se utilizan los modificadores in y out en la primera y no en la segunda expresión? ¿Por qué se define solo TResult como tipo utilizando en el método Select? Gracias. A: Si analizamos la documentacion Func< T,TResult> Delegate observaras que el out es solo para que te quede claro que ese parametro que define el delegate es de salida, pero no tienes que indicarlo cuando lo declaras. Esa primer linea de codigo no se utiza en tu desarrollo, es solo a nivel de documentacion.

Viktor Vladone Viktor Vladone (1911-2006), was a male Romanian international table tennis player. He won a silver medal at the 1936 World Table Tennis Championships in the men's team event. He won nine national titles; singles (1936, 1950 and 1952), doubles with Maretz (1935 and 1936), Fiala (1949), Schapira (1938, 1940) and Lucian (1950) and played for YMCA Bucharest (1928-1931), Romania Cluj-Napoca (1932), Electrica Uzinele Cluj-Napoca (1933-1938), Builder Bucharest (1946 - 1948) and SFIPIA Bucharest (1949 - 1953). Between 1950 and 1970, he was a coach for Romanian players for the World Championships and the European Championships. See also List of table tennis players List of World Table Tennis Championships medalists References Category:Romanian male table tennis players Category:1911 births Category:2006 deaths Category:World Table Tennis Championships medalists

TIMES SQUARE HOT PAGES Translate DEMARCHELIER RESTAURANT IS NEW YORK CITY'S LITTLE PIECE OF FRANCE The family-owned and operated Demarchelier Restaurant has remained New York City’s little piece of France ever since opening on 86th Street over 25 years ago by owner and artist Eric Demarchelier, brother of famed fashion photographer Patrick Demarchelier. Under the management of Eric’s daughter, Emily Demarchelier, the cozy French bistro attracts a loyal clientele who come for both the authentic French cuisine and the warm, familial hospitality. Scallops-pc Demarchelier Restuarant Classic Seafood Demarchelier Restaurants gourmet dining experience captures the essence of an authentic French bistro. This season’s signature dishes include Terrine de Foie Gras with Toast Points, Avocado Crab Salad or Steak Tartare for an appetizing start to a full course dinner. Delicious entrees taking your palate on a journey through France include the expertly crafted Duck a L’Orange, the rich Cassoulet or the classic Coq Au Vin. The dessert menu boasts an assortment of sweet treats including the Crème Caramel (Flan), Profiterolles with chocolate sauce and Crepes Suzette with Grand Marnier. Demarchelier’s classic menu items are coupled with organic selections to accommodate various dietary considerations. From farm-to-table, even the most health conscious diners will find that natural, grass-fed, organic options are just as savory, and decadent as popular French cuisines served at Demarchelier Restaurant. The traditional French menu is paired perfectly with a wide range of predominantly French wines. Grilled Shrimp The French bistro welcomes patrons on weekends to enjoy brunch, French-style. Signature dishes include Smoked Salmon Plate, Pancakes (Blueberry), French Toast, or Organic Omelets served with a choice of cheese/mushrooms/ham/spinach; and Organic Eggs Benedict served with a choice of Salmon or Ham. The extensive a la carte menu features an abundance of the finest menu items at the Upper East Side eatery. Affectionately known as an intimate gathering space for art lovers, family and friends will love Eric’s rotating collection of artworks displayed on the walls of Demarchelier Restaurant. Paintings are available for sale per patron’s request. About Demarchelier: Authentic French Bistro Demarchelier was first established in 1978, and still attracts a loyal clientele who come for both the authentic French cuisine and the warm, familial hospitality. Located on the Upper East Side at 50 East 86th street since 1973, Demarchelier is owned by French born artist Eric Demarchelier. Eric’s daughter Emily Demarchelier manages the family owned restaurant, while Chef Marc Tagournet is in charge of creating their traditional menu selections.

Awesome new photo collections show people of all sizes working out Meagan Morris is an entertainment and lifestyle journalist living in New York City. In addition to SheKnows, Morris contributes to many publications including The New York Times, Yahoo! News, PopEater, NBC New York and Spinner. Follow he... California gym owner is working to dispel myths about people who work out with new photo service Gyms should be an inviting place for people of all sizes and backgrounds, but many aspiring gym-goers express extreme anxiety over entering the gym. Why? The assumption that only "fit" people are welcomed in fitness centers, thanks in part to advertising that only shows happy, thin people working out. One gym owner is doing her part to change that by creating a new stock photo service that shows people of all sizes, ages and races working out together. Michele Burmaster is both the owner of Surf City Fit Club in Huntington Beach, California, and the brains behind Real Fitness Stock Photos. RFSP provides stock images of a variety of real people doing real workouts that other gym owners can buy and use in their advertising. "I saw the gap in the market," Burmaster tells SheKnows of how she came up with the idea. "Ask any gym owner and they can tell you that finding a commercial fitness stock photo of someone clothed doing an exercise properly, we might as well be unicorn hunting (well, before now!)." Burmaster is also the president of the Body Positive Fitness Alliance, an organization with a mission to work with trainers to "help make their practices more accessible, approachable and inclusive for the other 95 percent of the population who don't perpetuate gym culture," she adds. Fellow trainers — who know that fitness-seekers come from all different backgrounds — are "elated" with the photo selection. "It truly is a breath of fresh air knowing that our precious time won't be wasted any longer trying to find just one great photo that represents our current and potential client base." Not only that, but it's helping achieve her mission of providing fitness for all people. "If we can put out materials that show them they are worthy of fitness as well because their body type, race, age, gender or any other demographic is represented in images of people doing badass things, then maybe they'll be inspired to find their fitness," she adds. "We're breaking down the barrier of 'not identifying as a fit person' by showing the world that fitness actually doesn't have a look."

Is Facebook making an airplane? - sargun https://www.facebook.com/careers/department?dept=infrastructure&req=a0IA000000CzHxYMAV ====== sargun There is also this position: [https://www.facebook.com/careers/department?dept=infrastruct...](https://www.facebook.com/careers/department?dept=infrastructure&req=a0IA000000CzHxYMAV) "Facebook is looking for someone to assist in the Airframe assembly efforts development phases of their high-altitude solar powered aircraft. A successful candidate will be able to assist with airframe assembly and integration." High altitude solar aircraft? Sounds similar to the Solar Impulse 2, but what does Facebook want with that? ------ paulofilip3 Told ya!! [http://arstechnica.com/information- technology/2014/03/facebo...](http://arstechnica.com/information- technology/2014/03/facebook-to-provide-internet-connectivity-from-solar- powered-planes/) ------ valarauca1 The job is primarily centered around maintenance. The interesting part is the solar cells, maybe a solar powered drone for very long flight times? ------ paulofilip3 ohh, maybe it's something similar to Google Loon project but to put Facebook in the hands of all...

A photoelectrical conversion cell which produces an electrical current in response to hole-electron pairs produced by the light to which it is exposed, loses its efficiency as temperature increases, and since each cell provides only a small voltage increment, for significant voltage output it is necessary to have a number of cells in series. Thus it is necessary to bond the individual cells to a heat sink which is generally of an electrically conducting material and at the same time provide for electrical isolation of the individual cells from the heat sink. Generally in building series or series-parallel cell arrays with good thermal conductivity, complexity in structure and processing is encountered in also providing electrical isolation. One example of such a structure is shown in U.S. Pat. No. 3,833,425 where thermal conductivity is provided by attaching all the cells of the array to a large metal heat sink and electrical isolation is provided by individual cell isolators in the form of ceramic inserts.

Dismissed and Opinion Filed August 8, 2017 S In The Court of Appeals Fifth District of Texas at Dallas No. 05-17-00700-CV IN THE INTEREST OF B.J.F., A MINOR CHILD On Appeal from the 302nd Judicial District Court Dallas County, Texas Trial Court Cause No. DF-05-06264-U MEMORANDUM OPINION Before Chief Justice Wright, Justice Francis, and Justice Stoddart Opinion by Chief Justice Wright The filing fee and docketing statement in this case are past due. By postcard dated June 21, 2017, we notified appellant the $205 filing fee was due. We directed appellant to remit the filing fee within ten days and expressly cautioned appellant that failure to do so would result in dismissal of the appeal. Also by postcard dated June 21, 2017, we notified appellant the docketing statement had not been filed in this case. We directed appellant to file the docketing statement within ten days. We cautioned appellant that failure to do so might result in dismissal of this appeal. To date, appellant has not paid the filing fee, filed a docketing statement, or otherwise corresponded with the Court regarding the status of this appeal.  Accordingly, we dismiss this appeal. See TEX. R. APP. P. 42.3(b), (c). /Carolyn Wright/ CAROLYN WRIGHT CHIEF JUSTICE 170700F.P05 –2–  S Court of Appeals Fifth District of Texas at Dallas JUDGMENT IN THE INTEREST OF B.J.F., A MINOR On Appeal from the 302nd Judicial District CHILD, Appellant Court, Dallas County, Texas Trial Court Cause No. DF-05-06264-U. No. 05-17-00700-CV Opinion delivered by Chief Justice Wright. Justices Francis and Stoddart participating. In accordance with this Court’s opinion of this date, the appeal is DISMISSED. It is ORDERED that appellees The State of Texas and Cienamon Bailey recover their costs of this appeal from appellant Kamari L. Frink. Judgment entered August 8, 2017. –3– 

Digital Diplomacy - Facing A Future Without Borders So far, the evolution of digital diplomacy has been a happy one. Foreign Ministries are doing digital. Everyone is jolly pleased – isn’t everyone clever as they engage in diplomatic persiflage on Twitter, Facebook and Weibo? Nation shall tweet, retweet and like unto nation. It’s been a pretty smooth digitisation. The arguments about whether diplomats should take to digital channels swiftly became not about ‘whether’ but about ‘how quickly’. As diplomats piled on, the first wonder was akin to that of the dancing bear - not that they did it especially well, but that they did it at all. Foreign Ministries are often not the most risk-addicted of organisations, so to see them tread warily into third party platforms was, for a time, enough in itself. They talked to their own citizens, other countries, on other platforms. Soon enough, it became two-way; it became a genuine conversation. Debating Yemen on Facebook, Syria on Facebook, then Egypt on Twitter – quite the thing. Occasionally things got a little over-giddy, hopping on to platforms for the sake of hopping on to platforms (the diplomatic potential of Mixcloud?), but there were points for trying. Yet simply by engaging in social media spaces, foreign ministries are entering a world more different than many realise, and changing, possibly even unwittingly, how public diplomacy will work. In the pre-digital world, diplomats had worked in rarefied places – high-ceilinged, chandeliered rooms to meetings to which only other diplomats were invited: what the US State Department’s Alec Ross used to define as “men in black suits, white shirts and red ties talking to other men in black suits, white shirts and red ties.” The rest of us weren’t invited. But digital and social media isn’t the preserve of the diplomatic classes. The rules of engagement of diplomacy – its arcane language, its shared expectations of glacial movements in policy implementation - are not shared by a Twitterati for whom news travels round the world in seven seconds flat. So instead of the rest of us peering through the windows at diplomats’ summits, it was they who were coming to us – ties loosening, brogues creaking – at our party. And, like anyone at a party, they suddenly found themselves talking awkwardly to people who weren’t really their type. The big shift that digital diplomacy gives us is not that governments are discussing policy on new platforms, it’s that they are discussing with new people. At the same time, those digital platforms have given birth to new networks, new groupings of people that were determined by something other than the traditional sense of nationhood. Some might be yolked together by region, rather than nation, or by religion, by economics, by gender, or by ideas. In the digital sphere, these groupings are every bit as legitimate, and often more vocal, than groupings decided by borders and flags. Many can still dismiss these groups as ‘interest groups’. Or fanatics. Or extremists. Pick your dismissive group noun of choice. But this is the real, and growing, challenge of digital diplomacy. A diplomat’s clients are changing. Post-digital, post-9/11, post-Arab Spring, a diplomat is looking at groups which are based around a whole new set of values and loyalties that are not related to those borders drawn hundreds of years ago. Indeed, some members of those interest groups/fanatics/extremists are in your own country. In Woolwich for example. Those with whom the diplomat must engage have shape-shifted and hard diplomacy is difficult with people who don’t share the same view of the rule of law: soft power is harder when faced with Al Qaeda members in Arsenal shirts, and digital diplomacy is harder when groupings are fluidly forming in public and hidden areas of the web. But a diplomat has to engage with these groups – because they are possible challenges to the nation that he/she represents. There are a few challenges – you have to find them first. And you have to engage with them when they have no duty to engage with you. A diplomat’s job description, effectively, includes ‘speak to other diplomats, foreign ones included’ in amongst the list of core tasks. But a fluid group of people who have gathered round an abstract idea don’t have any contract or job description, they don’t wear white shirts and red ties, and they may not want to respond or converse in the way you want to. Where’s the treaty, the protocols, the agreements, the furniture of diplomacy? While we are in a period of change, it’s only just beginning; the notion of nation still remains hugely strong. A diplomat can legitimately call on that concept as their main job. But it’s altering and the speed of change is increasing. A diplomat is facing a different set of challenges and dealing with them will require a different skill-set. Some will have it, some do have it - but many do not. Digital diplomacy will no longer be about a certain élan on Twitter, it will be about identifying non-state actors and the channels of their choice, with which to monitor and engage with them to form new relationships. For the UK, its biggest foreign policy challenges do not just lie with rogue states, but with rogue ideas (and the links between the two). Dealing with that is a lot more complicated than it used to be, sitting around the table with Bismarck. And it’s going to get a whole lot harder. Jimmy Leach is senior digital associate at Portland and former head of digital diplomacy at the Foreign and Commonwealth Office.

Harper is spending the offseason in his hometown of Las Vegas, and according to Brown and Passan, "officials from the Los Angeles Dodgers, Chicago White Sox, Philadelphia Phillies and New York Yankees are among upward of a dozen teams that have traveled or plan to travel to Nevada to meet with Harper." Several of these pitches also reportedly contained some star power: the White Sox sent Hall-of-Fame slugger Jim Thome to sell Harper on the south side of Chicago, and the Dodgers contingent brought along some Magic. "According to sources, (Magic) Johnson and other Dodgers officials traveled to Las Vegas to meet with Harper," reads the Yahoo report. "Johnson in 2012 bought into the Guggenheim Partners’ $2.15 billion purchase of the Dodgers with $50 million of his own, a 2-plus percent investment that is more significant for his name, reputation and L.A. credibility." Johnson has already lured LeBron James to Los Angeles this year. Could he do the same with one of MLB's biggest stars in Harper? Passan and Brown also claim the Chicago Cubs and San Diego Padres will pay Harper a visit, while "Harper’s affection for the Houston Astros is well-known, as is the St. Louis Cardinals' for him." Meanwhile the Phillies, along with sending representatives to visit Harper, opened up a spot in their outfield Sunday, trading Carlos Santana to Seattle so Rhys Hoskins can move back to first base. And by acquiring shortstop Jean Segura in the deal, Philadelphia may have taken themselves out of the Manny Machado sweepstakes to focus on Harper and pitching targets like Patrick Corbin. As for the Nationals, the report indicates Washington "will circle back" at some point with the free agent outfielder. But with so many teams now courting Harper, it appears the Nats may now be on the outside looking in for a player who called D.C. home for seven seasons. UPDATE: Apparently Magic Johnson actually did not meet with Bryce Harper in Vegas. Magic Johnson says he did not go to Las Vegas to meet with Bryce Harper. Our original story has been updated to reflect this and includes a quote from Johnson: https://t.co/AfeLtkcxtK

Arkansas Highway 280 Arkansas Highway 280 is a state highway in Clay and Greene Counties. The route runs from Arkansas Highway 90 near Delaplaine north then east to AR 90 in Peach Orchard. It does not intersect any other state highways. Route description AR 280 begins at AR 90 and heads due north to Brookings. It then turns and heads due east for to Peach Orchard, where it terminates at AR 90. The highway is located near the Dave Donaldson/Black River Wildlife Management Area. History The route first became a state highway in 1963. AR 208S/AR 208 from Brookings to AR 90 was paved upon addition to the state highway system. Major intersections Brookings spur Arkansas Highway 280 Spur is a spur route to the unincorporated community of Brookings in Clay County. Major intersections See also List of state highways in Arkansas References External links 280 Category:Transportation in Clay County, Arkansas Category:Transportation in Greene County, Arkansas

David Ayalon David Ayalon (1914 – 25 June 1998) was an Israeli historian of Islam and the Middle East, specializing in the Mamluk dynasties of Egypt. Within Israel he was best known for the Arabic-Hebrew dictionary he co-compiled in 1947. Life Born David Neustadt in Haifa, he grew up in Zichron Ya'akov and Rosh Pinah. After completing secondary school in Haifa, Ayalon went in 1933 to study at the recently founded Hebrew University in Jerusalem. Despite service in the British Army during World War II, he gained his PhD in 1946 under the supervision of Leo Aryeh Mayer. In the late 1940s he changed his name to David Ayalon. Ayalon founded the department of modern Middle East studies there in 1949, and was its head until 1956. From 1963 to 1967 he led the Institute of Asian and African Studies at the Hebrew University. Works (with Pesach Shinar) Arabic-Hebrew Dictionary of Modern Arabic, 1947. Gunpowder and firearms in the Mamluk kingdom: a challenge to a mediaeval society, 1956 Studies on the Mamlūks of Egypt (1250–1517), 1977 The Mamlūk military society, 1979 Outsiders in the lands of Islam: Mamluks, Mongols, and eunuchs, 1988 Islam and the abode of war: military slaves and Islamic adversaries, 1994 Eunuchs, caliphs and sultans: a study in power relationships, 1999 References Category:1914 births Category:1998 deaths Category:Israeli historians Category:Historians of Islam Category:Historians of the Middle East Category:20th-century historians Category:People from Haifa Category:Hebrew University of Jerusalem alumni

Introduction ============ Scleractinian corals are the primary architects of reef ecosystems and the major contributors to reef rugosity, a fundamental parameter for the resilience of the ecosystem after a disturbance ([@ref-21]). Therefore, documenting the extent of damage to corals after perturbations is key to understanding the potential trajectory of recovery. To quantify the shifts in functional composition of coral reefs after environmental and anthropogenic disturbances, [@ref-12] determined coral life history strategies based on several traits, including growth form, reproductive mode, and fecundity. Shifts to stress-tolerant, generalist and weedy species after disturbances have been documented in both the Caribbean ([@ref-2]; [@ref-1]) and the Indo-Pacific ([@ref-38]; [@ref-47]). Recruitment of coral larvae can be an important factor in the recovery of a coral reef ([@ref-42]), but plays a lesser role if there is regrowth from surviving coral colonies and/or if fragmentation occurs ([@ref-28]). Shallow areas with few local survivors are most likely dependent on recruitment and show low rates of recovery, whereas areas with many survivors often show rapid recovery due to regrowth of remnant colonies ([@ref-10]). The recovery of coral reefs after disturbances is usually measured by changes in coral cover, abundance, species composition, and/or diversity ([@ref-13]; [@ref-10]; [@ref-21]). The type of disturbance, original species composition, reef complexity (rugosity), and depth are all thought to be responsible for the wide variation in patterns of recovery. For example, a 95-year study of Dry Tortugas Reef in Florida demonstrated a relatively constant abundance of coral and other benthic organisms, despite changes in species composition and coral reef structure ([@ref-13]). However, if coral cover is significantly reduced after a disturbance, the reef will likely undergo a shift in the composition of coral species to the coral species that survived the disturbance ([@ref-10]), or to other taxa, such as fleshy macroalgae. For example, phase shifts from scleractinian coral dominance to fleshy macroalgae were observed after multiple storm and anthropogenic disturbances on Jamaican reefs over 40 years ([@ref-29]). Reports measuring coral reef recovery after storm disturbances based on coral cover on shallow reefs vary in time from two to 15 years, with little attention paid to species composition ([@ref-42]; [@ref-45]; [@ref-18]). Ecological succession (the replacement of early species with late species; [@ref-11]) occurs following disturbances, and community recovery processes are affected by different types of disturbances that create the opportunity for a change in succession ([@ref-45]). Storms often result in various successional states or phase shifts, for which the capacity to return to the original condition has been intensively debated ([@ref-16]; [@ref-9]; [@ref-15]). Coral cover throughout Caribbean coral reefs decreased by an average of 17% after hurricanes between 1980 and 2001, with no further coral loss in the year following a disturbance and no evidence of recovery eight years after a disturbance ([@ref-18]). [@ref-18] suggested that the lack of recovery was a result of other stressors such as sedimentation or eutrophication impacting shallow reefs and that exposure to storms makes coral reefs less susceptible to storms in the future due to the recovery of more tolerant species. Most coral reef storm recovery studies have been conducted on relatively shallow Caribbean reefs (e.g., [@ref-51]; [@ref-48]; [@ref-42]), but more work is needed to understand storm recovery on Indo-Pacific reefs in general and mesophotic reefs in particular. In one example from the Indo-Pacific, coral cover on a 6--12 m tabulate *Acropora* reef in the Coral Sea declined from 80% to less than 10% after several storms over a two year period, leaving only encrusting and robust coral species ([@ref-22]). This was followed by coral cover increasing exponentially 5--9 years after the storm disturbances, with the reef having recovered to pre-storm levels after 11 years, albeit with a shift from branching to tabulate coral morphology ([@ref-22]). In another example, [@ref-39] examined coral recruitment at 5 and 15 m depths in Taiwan, and concluded that shallower coral reefs with more pocilloporid and poritid recruits were more influenced by post-settlement processes compared to deeper reefs that have more acroporid recruits and were more affected by pre-settlement processes. Unlike their shallow-water counterparts, there is very little information available documenting recovery of mesophotic coral reefs (benthic communities including hermatypic zooxanthellate corals at 30--150 m depths ([@ref-3])) after storm disturbances. Although it has often been assumed that mesophotic reefs are relatively protected from storm damage ([@ref-8]), recent studies have shown this is not the case ([@ref-7]; [@ref-56]). The impact of storms on patterns of benthic communities documented on large horizontal scales can help to determine upper mesophotic shelf edge (30--60 m) coral development ([@ref-50]). Depending on the topography and distance between shallow and deep reefs, storms can damage corals on low-angle slopes as a result of coral debris or sediment transported down the reef slope compared to high-angle slopes ([@ref-8]); whereas other low-angle upper mesophotic reefs do not appear to be impacted by terrestrial sediment transport ([@ref-54]). Growth rates of different coral species may also be a factor in recovery processes ([@ref-6]). Studies suggest that upper mesophotic coral species in the Caribbean have comparatively slower growth rates than shallow water coral species ([@ref-17]; [@ref-31]; [@ref-36]; [@ref-55]). However, [@ref-6] reported that growth rates of some coral species at lower mesophotic depths (60--150 m) may be similar to observed rates in shallow water. One of the few ecological studies monitoring the direct impact of storm damage on a mesophotic reef system is from Okinawa, Japan. [@ref-40] described Ryugu Reef as an upper mesophotic reef with a large, nearly monospecific stand of *Pachyseris foliosa* from 32 to 45 m. Heading deeper, away from shore, Ryugu Reef transitions on a low-angle slope from rubble with some corals (Fungiidae) at 21 m; to a high diversity of corals at 26 m; a *Pachyseris-* dominated area at 31 m; and finally to sand at 42 m. The center of Typhoon 17 (Jelawat), the strongest typhoon ever recorded to hit Okinawa-jima Island, with wave heights up to 12 m, passed within 30 km of Ryugu Reef on 29 September 2012 ([@ref-40]; [@ref-56]). Analyses of coral species composition and morpho-functional groups on Ryugu Reef before and after Typhoon 17 suggested that the highly diverse areas were less susceptible to typhoon damage ([@ref-56]). [@ref-56] also theorized that Ryugu Reef would be resilient because of a high likelihood of recovery based on only slight changes in functional groups after the typhoon. Despite such speculation, little is known regarding long-term recovery of mesophotic reef systems following major storm events. Previous studies suggest that coral communities recover from storm disturbances via succession ([@ref-18]; [@ref-38]; [@ref-47]; [@ref-2]; [@ref-1]; [@ref-30]; [@ref-50]), with dominant coral genera shifting until the reef can mature and possibly return to initial conditions ([@ref-16]; [@ref-9]). [@ref-22] observed exponential coral growth on the southern Great Barrier Reef 5--9 years after storms. Signs of recovery were documented on the Great Barrier Reef as early as 24--35 months after Tropical Cyclone Yasi in 2011, with evidence of regrowth of branching corals on King Reef ([@ref-43]) and an average 4% increase in coral cover on 19 reefs in the Great Barrier Reef Marine Preserve ([@ref-4]). Combined, these results suggest that Indo-Pacific reefs' successional changes may occur only a few years after a storm event. Thus, the objectives of this study include documenting the initial recovery of an upper mesophotic coral reef (Ryugu Reef) over a four-year period (2012--2015), and describing resulting changes in scleractinian coral communities based on functional morphology and species composition. This study provides the first in-depth record of an upper mesophotic reef shifting communities based on functional group changes after a storm disturbance and offers insight into the implications of this shift in the recovery of mesophotic coral reefs. Materials and Methods ===================== Random line transects were surveyed at Ryugu Reef (see map of stations in Fig. 1B; [@ref-56]) at seven locations near station 2 (30--32 m) and seven locations near station 3 (26--30 m). Adjacent 4 × 6 cm^2^ photographs (12--79 per transect) were taken along a 10-m tape for each line transect 1.5 years after Typhoon 17 (designated '2014' dataset) and 2.5--3 years after the typhoon (designated '2015' dataset). Scleractinian coral (+ one *Millepora* sp., hereafter 'coral') operational taxonomic units (OTUs) were identified in a similar manner as in [@ref-56], following [@ref-24] and [@ref-19] for Fungiidae, [@ref-26] for Lobophylliidae, [@ref-27] for Merulinidae, Diploastraeidae and Montastraeidae, and [@ref-52] for all remaining corals. Scientific binomens were checked for validity in the World Register of Marine Species (WoRMS; [@ref-25]; accessed May 2, 2017). Post-typhoon data from 2012 ([@ref-56]) were combined with the newest dataset. Many mesophotic coral species at Ryugu, particularly those within genera *Acropora* (see [@ref-53])*, Galaxea*, and *Montipora*, were very hard to conclusively identify to species level. Therefore, changes in the community were investigated at the genus-level. Bray-Curtis dissimilarities were calculated on raw data by comparing each transect to every other transect, and visualized using non-metric multidimensional scaling (nMDS). Time-period centroids (spatial median) were overlaid to visualize temporal dynamics. Differences in the composition of the benthic assemblage between stations, and between temporal dynamics within each station were tested using permutational multivariate analysis of variance (ADONIS). Each coral OTU was described following similar methods to those described in [@ref-14] and [@ref-56]. Corals were assigned to one or more of eight morphological groups as in [@ref-56], following growth form information found in [@ref-53], [@ref-52], [@ref-44] and [@ref-5] as well as by confirming morphologies from *in situ* photographs. OTU categories (massive/submassive, encrusting, laminar/foliose, columnar, plate-like, bushy, arborescent and unattached morphologies) are provided in [Table S1](#supp-2){ref-type="supplementary-material"}. Often, colonies presented more than one growth form in the field, and these OTUs were therefore assigned to two growth forms. Community-level Weighted Means (CWM) of trait values ([@ref-35]) were computed for each transect, and standardized to determine the relative contribution of each morpho-functional group to the coral assemblage (removing all non-coral OTUs). Contribution of a given morpho-functional group was summarized for each station/period sampled and compared among years using Kruskal-Wallis tests followed by Conover's multiple comparison tests. All data were analyzed in R v3.2.3 ([@ref-46]) using the packages Vegan ([@ref-41]) and FD ([@ref-33]; [@ref-34]). Results ======= Relative live coral cover increased at each station by 5% between 2012 and 2014 and by another 6% between 2014 and 2015 ([Table 1](#table-1){ref-type="table"}). Significant changes in cover of coral genera occurred over time at both stations 2 and 3 (ADONIS test, *R*^2^ = 0.19, *p* \< 0.001) ([Fig. 1](#fig-1){ref-type="fig"}). However, variation between stations (ADONIS test, *R*^2^ = 0.41, *p* \< 0.001) was greater than among years ([Fig. 1](#fig-1){ref-type="fig"}). Station 3 showed minor changes in cover of coral genera between 2014 and 2015 after a major shift in coral assemblage between 2012 and 2014. Station 2 showed diversification of coral genera in the three years after Typhoon 17 (Jelawat) with a decrease in *Pachyseris* cover and an increase in several other genera ([Table 1](#table-1){ref-type="table"}). An increase in cover of bushy corals (*Acropora*, *Porites*, *Seriatopora*, *Stylophora*) was significant (Kruskal-Wallis/Conover tests, *p* \< 0.01) at station 3 as of 2015, compared to 2012 before the typhoon ([Fig. 2](#fig-2){ref-type="fig"}). Significant coral cover changes at station 2 as of 2015 included a decrease of foliose corals, compared to 2012 before the typhoon (Kruskal-Wallis/Conover test, *p* \< 0.05), an increase of bushy corals (Kruskal-Wallis/Conover test, *p* \< 0.01), and an increase in some plate-like corals (*p* \< 0.05) ([Fig. 2](#fig-2){ref-type="fig"}). A major factor in the decrease of foliose coral cover at station 2 was the continuous decrease of *Pachyseris* from 2012 (post-typhoon) to 2015 ([Table 1](#table-1){ref-type="table"}). 10.7717/peerj.3573/table-1 ###### Relative percent coral. Relative percent cover of coral genera, coral rubble/coralline algae, and pavement at stations 2 and 3 over time after Typhoon Jelawat, 2012--2015.  Taxonomic units Station 2 (%) Station 3 (%) ------------------------------ --------------- --------------- ----- ----- ----- ----- *Acropora* \<1 9 17 2 11 18 *Agaraciidae* 0 \<1 \<1 0 0 0 *Astreopora* 0 0 \<1 0 \<1 \<1 *Australomussa* 0 0 \<1 \<1 \<1 0 *Caulastrea* 0 0 0 0 \<1 \<1 *Ctenactis* \<1 \<1 \<1 2 2 3 *Danafungia* \<1 2 2 2 3 2 *Dipsastraea* 0 0 0 \<1 0 \<1 *Echinophyllia* \<1 \<1 \<1 4 \<1 \<1 *Euphyllia* 0 0 \<1 \<1 \<1 \<1 *Favites* 0 0 0 \<1 0 0 *Galaxea* 2 5 10 10 12 8 *Halomitra* 0 0 \<1 \<1 \<1 0 *Herpolitha* 0 \<1 \<1 1 1 1 *Lithophyllon* 2 2 1 19 10 12 *Lobophyllia* 0 0 0 \<1 0 0 *Merulina* 0 0 \<1 0 \<1 1 *Montipora* 0 \<1 2 0 \<1 4 *Mycedium* 0 \<1 1 \<1 1 1 *Oxypora* 0 \<1 \<1 0 \<1 0 *Pachyseris* 58 49 34 3 4 4 *Pavona* 0 0 \<1 4 \<1 2 *Pectinia* 0 0 \<1 0 \<1 \<1 *Pectiniidae* 0 0 0 0 3 0 *Pleuractis* \<1 1 1 1 3 3 *Porites* 0 \<1 \<1 \<1 \<1 \<1 *Seriatopora* 0 \<1 \<1 0 \<1 0 *Stylophora* 0 0 \<1 0 \<1 \<1 *Turbinaria* 0 0 0 \<1 0 0 Coral rubble/coralline algae 37 21 7 49 32 22 Pavement N/A 11 19 N/A 12 16 Unknown live coral 0 \<1 \<1 \<1 1 1 Total live coral cover 63 68 74 51 56 62 ![nMDS genus data.\ nMDS genus data with stress value of 0.16. Station factor (Bray-Curtis dissimilarities test, *R*^2^ = 0.41, *p* \< 0.001); temporal factor (Bray-Curtis dissimilarities test, *R*^2^ = 0.19, *p* \< 0.001). 2012A refers to pre-typhoon data and 2012B refers to post-typhoon data, both from [@ref-56].](peerj-05-3573-g001){#fig-1} ![Community weight mean (CWM) of trait values.\ Community weight mean (CWM) of trait values representing the contribution (%) of corals representing each given morphology. Significant results are shaded with a grey background (Kruskal-Wallis/Conover tests, \* *p* \< 0.05; \*\*\* *p* \< 0.01). 2012A refers to pre-typhoon data and 2012B refers to post-typhoon data, both from [@ref-56]. (A) Arborescent; (B) Plate-like; (C) Laminar & Foliose; (D) Massive & Submassive; (E) Bushy; (F) Columnar; (G) Unattached; (H) Encrusting.](peerj-05-3573-g002){#fig-2} Percent cover of coral rubble/coralline algae decreased from 31% to 27% at station 2 between 2012b and 2014 from 27% to 7% between 2014 and 2015 ([Table 1](#table-1){ref-type="table"}). This followed a 29% increase in coral rubble/coralline algae directly after typhoon Jelawat ([@ref-56]). At station 3, coral rubble/coralline algae decreased from 49% to 32% between 2012b and 2014 and from 32% to 22% between 2014 and 2015. Discussion ========== Data are sparse on the recolonization of mesophotic reefs. The diversification of mesophotic coral reef organisms after a disturbance may occur as a result of horizontal connectivity with other mesophotic reefs or vertical connectivity with shallow water reefs ([@ref-32]). Species with wide depth ranges are more likely to benefit from vertical connectivity, while horizontal connectivity would most likely affect only the acquisition of symbiotic zooxanthellae for species that acquire *Symbiodinium* from the water column ([@ref-8]; [@ref-32]). Over a short time, it is likely that a storm disturbance would open up space in the area previously documented with nearly 100% *Pachyseris* coverage ([@ref-40]), allowing more opportunistic species a chance to prosper. Station 2 showed a diversification of coral species in the three years after Typhoon 17 (Jelawat) created vacant ecological niches ([Table 1](#table-1){ref-type="table"}). *Pachyseris* (foliose morphology) cover decreased immediately following the typhoon ([@ref-56]), allowing the increased growth of arborescent, bushy, columnar, massive, and encrusting morphologies ([Fig. 3](#fig-3){ref-type="fig"}), although significant increases were only seen in bushy genera at this station (Kruskal-Wallis/Conover test, *p* \< 0.01). At least six of the 'massive' genera (*Astreopora*, *Caulastrea*, *Favites*, *Galaxea*, *Goniastrea*, *Plerogyra*) have been noted to be 'stress-tolerant' and four 'weedy' genera (fast growing with high turnover) are known to do well under disturbance (*Goniastrea, Porites*, *Seriatopora*, *Stylophora*) ([@ref-12]). However, the dominant genus (*Pachyseris*) on Ryugu Reef is a 'generalist' ([@ref-12]). It appears that Typhoon Jelawat created the opportunity for genera aside from *Pachyseris* to increase coverage, and these genera could possibly consist of opportunistic species at upper mesophotic depths. Similarly, areas of the Great Barrier Reef recovered at different rates after disturbances, with the fastest recovery rates occurring when more space was available as a result of reduced coral cover ([@ref-20]). At Ryugu Reef, coral rubble cover decreased from the post-typhoon survey of 2012 ([Table 1](#table-1){ref-type="table"}), and *Pachyseris* coral cover continually decreased in the four years post-typhoon. Following damages from the typhoon, diversification of the area previously dominated by *Pachyseris* corals occurred, with an increase in cover of genera such as *Seriatopora* and *Galaxea*. It is possible that colonies of these genera were previously present but in much smaller numbers than *Pachyseris* or that these genera contain opportunistic species. {#fig-3} Immediately after Typhoon 17, little change in coral community assemblage was evident at the shallower station 3, suggesting that the diverse/complex community was more resistant due to lower impact on individual genera than the impact on the *Pachyseris*-dominated community ([@ref-56]). At station 3, corals recovered with progressive recolonization of the available substrate via surviving corals between 2012 (post-typhoon) and 2015 ([Table 1](#table-1){ref-type="table"}). Cover of *Acropora*, *Ctenactis*, *Danafungia, Porites*, *Seriatopora,* and *Stylophora* increased, suggesting that bushy and unattached coral genera did better than the foliose genera (*Montipora*, *Mycedium*, *Oxypora*, *Pachyseris*) that stabilized with no significant increase or decrease in cover at station 3 ([Table 1](#table-1){ref-type="table"}). Major shifts in functional groups were evident at both stations 2 and 3 post-typhoon ([Fig. 1](#fig-1){ref-type="fig"}). Foliose genera decreased at stations 2 and 3 after the typhoon, with a significant decrease as of 2015 at station 2 (Kruskal-Wallis/Conover test, *p* \< 0.05). These results are similar to a previous shallow-water study on the Great Barrier Reef in which foliose coral colonies declined drastically after a storm event ([@ref-43]). Bushy coral genera increased at both Ryugu stations post-typhoon (Kruskal-Wallis/Conover test, *p* \< 0.01). The functional shift shows that beyond the apparent recovery of Ryugu Reef, the trajectory followed could lead ultimately to a fundamentally different coral community, as previously reported from the Great Barrier Reef ([@ref-23]). However, maturation of the coral assemblage with time may lead to the return of a state dominated by generalist *Pachyseris* corals ([@ref-12]). Continued monitoring of Ryugu Reef will determine whether this community will return to the initial state recorded prior to Typhoon 17 or if eventually the ecosystem might reach stability in an alternative configuration. [@ref-56] hypothesized that mesophotic reefs such as Ryugu would be resilient and recover quickly after disturbance to the original conditions of the reef. The current data do not support this hypothesis as a shift in community structure to more bushy and columnar morphologies and less foliose morphologies was observed. The large *Pachyseris* stand at station 2 was heavily damaged after Typhoon 17 (Jelawat) in 2012, but showed signs of recovery in 2015 with only slight diversification of the coral community. This fast recovery, combined with behavioral characteristics, may enable *Pachyseris* spp. to outcompete other coral genera at upper mesophotic depths, allowing Ryugu Reef to return to the initial, pre-typhoon coral assemblage. However, if Ryugu Reef coral genera are limited by their growth rates as many other mesophotic coral genera are ([@ref-17]; [@ref-31]; [@ref-36]; [@ref-55]), it is more likely that there will be a permanent shift with increasing presence of weedy or stress-tolerant species ([@ref-38]; [@ref-47]; [@ref-2]; [@ref-30]). While the dominant genera are changing on Ryugu Reef, there were no new species recorded, suggesting the regrowth of damaged corals or local recruitment. Examinations of shallow *Acropora* corals around Okinawa Main Island ([@ref-49]) and on the Great Barrier Reef after Cyclone Yasi ([@ref-37]) both suggest the importance of local recruitment for replenishment of *Acropora* species, and such research remains to be conducted on corals of deeper reefs such as Ryugu Reef. The high live coral cover of Ryugu Reef suggests that although mesophotic reefs may be affected by large storms, recovery may be facilitated by the relative stability of the mesophotic zone. Supplemental Information ======================== 10.7717/peerj.3573/supp-1 ###### Data for statistical analyses ###### Click here for additional data file. 10.7717/peerj.3573/supp-2 ###### Supplementary Material Table S1: Trait data Morpho-functional groups of observed Scleractinia operational taxonomic units at Ryugu, Okinawa, Japan, 2012--2015. ###### Click here for additional data file. We thank boat captain Tokunobu Toyama for assistance in surveys. We also thank MISE lab members I Kawamura, Y Kushida, V Nestor, T Kubomura, and H Kise, who assisted with surveys. Dr. Z Richards (Western Australian Museum, Curtin University) is thanked for advice on morpho-functional groups. Suggestions from Tom Bridge and Bert Hoeksema improved an earlier version of this manuscript. Additional Information and Declarations ======================================= James D. Reimer is an Academic Editor for PeerJ. Taku Ohara is an employee of Benthos Divers, Onna, Okinawa, Japan. [Kristine N. White](#author-1){ref-type="contrib"} performed the experiments, analyzed the data, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper. [David K. Weinstein](#author-2){ref-type="contrib"} analyzed the data, wrote the paper, reviewed drafts of the paper. [Taku Ohara](#author-3){ref-type="contrib"} conceived and designed the experiments, performed the experiments, contributed reagents/materials/analysis tools, reviewed drafts of the paper. [Vianney Denis](#author-4){ref-type="contrib"} analyzed the data, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper. [Javier Montenegro](#author-5){ref-type="contrib"} performed the experiments, prepared figures and/or tables, reviewed drafts of the paper. [James D. Reimer](#author-6){ref-type="contrib"} conceived and designed the experiments, performed the experiments, contributed reagents/materials/analysis tools, wrote the paper, reviewed drafts of the paper. The following information was supplied regarding data availability: Data used for statistical analyses is uploaded as a [Supplemental File](#supplemental-information){ref-type="supplementary-material"}.

@prefix : <http://example.org/> . @prefix foaf: <http://xmlns.com/foaf/0.1/> . :c foaf:name "Chris" . :c foaf:mbox "chris@example.org" . :d foaf:name "Dan" . :d foaf:mbox "dan@example.org" . :c foaf:knows :d .

Dick Simpson Richard Charles "Dick" Simpson (born July 28, 1943 in Washington, D.C.) is an American former Major League Baseball right fielder and center fielder. He played from 1962-1969 for the Los Angeles/California Angels, Cincinnati Reds, St. Louis Cardinals, Houston Astros, New York Yankees and Seattle Pilots. During an 8-year baseball career, Simpson hit .207, 15 home runs, and 56 runs batted in. He was listed at 6'4" and 176 lbs. Originally signed by the Angels as a free agent in 1961, he made his debut with them on September 21, 1962 at age 19 against the Cleveland Indians. He pinch hit for pitcher Fred Newman and singled off Mudcat Grant, driving in Leo Burke in his only at bat. Simpson appeared in five more games for the Angels that season, then returned to the team in 1964. Before the 1964 season began, Angels general manager Fred Haney touted Simpson as a possible Rookie of the Year candidate. In December of 1965, Simpson would also be involved in a trade to Cincinnati in a deal involving future Hall of Famer Frank Robinson. Major transactions On December 2, 1965, he was traded by the Angels to the Baltimore Orioles for Norm Siebern. One week later on December 9, he was traded by the Orioles along with Jack Baldschun and Milt Pappas to the Reds for Frank Robinson. On January 11, 1968, the Reds traded him to the Cardinals for Alex Johnson. The Cardinals traded him with Hal Gilson to the Astros for Ron Davis on June 15, 1968. On December 4, 1968, he was traded by the Astros to the Yankees for Dooley Womack. Was traded for José Vidal of the Seattle Pilots by the Yankees on May 19, 1969. Was traded by the Pilots, along with Steve Whitaker, to the San Francisco Giants for Bobby Bolin on December 12, 1969. Other information Was the second youngest player in 1962, trailing only Ed Kirkpatrick. Was considered one of the fastest players of his day, but still only stole 10 career bases. Did not play in the major leagues in 1963. Hit a leadoff home run on the first pitch from Mickey Lolich in a June 9, 1969 game. This would end up being the only run Lolich gave up in the game, a game in which he struck out 16 batters. That was the final home run of Simpson's career. His uniform numbers: 10 (1962, 1964–1965), 20 (1966–1967), 12 (1968), 37 (1968), 9 (1969), 16 (1969). He earned $7,000 in 1965 and $16,000 in 1969. Collected his final career hit off Fred Talbot on August 12, 1969. He is the father of Colton Simpson, author of the book Inside the Crips, and serving a 126-year sentence under California's 3-strikes law. References External links , or Retrosheet Venezuelan Professional Baseball League statistics Category:1943 births Category:African-American baseball players Category:Baseball players from Washington, D.C. Category:California Angels players Category:Cincinnati Reds players Category:Estrellas Orientales (VPBL) players Category:Hawaii Islanders players Category:Houston Astros players Category:Living people Category:Los Angeles Angels players Category:Major League Baseball right fielders Category:New York Yankees players Category:Phoenix Giants players Category:St. Louis Cardinals players Category:San Jose Bees players Category:Seattle Pilots players Category:Statesville Owls players

Q: Python numpy, skip columns & read csv file I've got a CSV file with 20 columns & about 60000 rows. I'd like to read fields 2 to 20 only. I've tried the below code but the browser(using ipython) freezes & it just goes n for ages import numpy as np from numpy import genfromtxt myFile = 'sampleData.csv' myData = genfromtxt(myFile, delimiter=',', usecols(2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19) print myData How could I tweak this to work better & actually produce output please? A: import pandas as pd myFile = 'sampleData.csv' df = pd.DataFrame(pd.read_csv(myFile,skiprows=1)) // Skipping header print df This works like a charm

The influence of immigration on the mental health of those seeking psychiatric care in southern Israel: a comparison of new immigrants to veteran residents. The wave of immigration from the countries of the former Soviet Union from 1990 to 2006 brought to Israel over 1,000,000 people. Many of them suffer from different diseases including mental disorders. Although the majority of older persons are free of serious psychopathology, 15-20% of the elderly people may be in need of psychiatric services. The aim of the study is to compare the mental health parameters of two elderly groups living in the southern part of Israel who suffer from severe mental problems: new immigrants from the former USSR (NI) in contrast to veteran Israelis (VR). In this retrospective study we compare two groups of aged inhabitants (NI and VR) from the southern region of Israel who sought psychiatric services (both outpatient and inpatient). The comparison concerns socio-demographic characteristics of people in care in a mental health center, rate of use of these services and diagnoses of the patients. One hundred and fifty-six (1.2%) NI sought psychiatric help versus 584 (2.1%) VR. The major findings include the significantly increased number of adjustment disorders and the significantly lower number of organo-mental diagnoses among psychiatrically hospitalized NI in comparison to VR. No differences were found in the frequency of mood or psychotic disorders between the two groups. Immigration is acknowledged to be a major stressor which may increase the emotional distress of an immigrant and in some cases may even lead to psychopathological reactions. NI are prone not to seek medical aid in outpatient facilities until a real worsening of mental health status compels them to be hospitalized.

PML-N out to counter anti-govt protest LAHORE - The PML-N government has expedited efforts to consolidate its frontiers against the August 14 onslaught of Pakistan Tehrike Insaaf (PTI) and Pakistan Awami Tehreek which are attacking the government, but for varied purposes. Contacts with the political parties hold the key to the government efforts to muster their support against the forces which the government believes are out to get everything topsy-turvy. The government is asking PTI and PAT to shun the protest move on the Independence Day in view of the national sentiments attached to this big event, but they stuck to their guns.The PML-N governments at the Centre and the Punjab complain that both PTI and PAT are not willing to give up the protest plans. However, a turning point can come if both the parties decide to stage a combined sit-in at Islamabad D-Chowk on the Independence Day that can create a real trouble for the government. The PAT which speaks of bringing about a revolution by way of scrapping the whole system of election, governance and bureaucracy in the country is taking time to announce a final date for the protest. Reports suggest PAT Chairman Qadri who has come to the frontline overriding PML-Q is playing his cards close to his chest. He is watching the situation closely and can agree on a joint protest with PTI against the government on any other agreed date if not on August 14. On the other hand, PTI wants fresh polls within the current system to get rid of the PML-N government. Both the parties claim they will topple the government on that day. The government has so far not planned to counter the protest, but to dilute the effect of the opposition protest through peaceful means. It has worked out 15-day-long celebrations of the Independence Day, starting from August 1, in all the four provincial metropolises of the country with the main function in Islamabad on August 14. The government is using this independence programme also to meet its political ends as the political leaders and the foreign diplomats are also being invited to the big day celebrations. Reports suggest that from August 1 onwards till the Independence Day strict vigilance will be maintained in the federal and the provincial capitals which will help the government to keep a close eye on the PAT and PTI protest preparations and adopt measures to fail them. The Islamabad Independence Day programme would naturally demand a high security for which the charge has been given to Interior Minister Ch Nisar Ali Khan who can prevent the protesters from entering the federal capital. Sources in the party say the PML-N is broadening its political support. They also say PTI Chairman Imran Khan could also be invited to the freedom day celebrations. At the same a concern strikes the mind what the situation would be if Khan accepts the invitation to reach the venue along with his thousands of workers and supporters. Sources confide that a three-member committee, headed by Irfan Siddiqui, is busy meeting the political leaders while the main leaders of the party are in touch with those close to them. In a meeting with Siddiqi, the JI leadership agreed to support the government to protect democracy although this party is an ally of PTI in PK. Prime Minister Nawaz Sharif himself had a meeting with Opposition Leader in the National Assembly Khursheed Shah who has time and again pledged commitment of his party to democracy. Khursheed Shah has also been guided on the same lines by PPP Co-chairman Asif Ali Zardari. The PM also held a meeting with the MQM delegation last days on the Karachi law and order situation, but the sources said the body language of the MQM leaders at the meeting showed this party would remain neutral and side with safety of the democratic system. KP Governor Sardar Mehtab Khan also met former interior minister Aftab Ahmad Sherpao who pledged his support to democracy. The PM also met JUI-F Amir Maulana Fazlur Rehman who, later, told media persons he did not support any anti-democracy and anti-government move. PML-N has also activated its ulem, women, youth and other wings to project the development projects and programmes to the public to counter the adverse propaganda. The sources say the main fear of the government is not from PTI and PAT, but it is afraid of an action from the third force.

Your Funbook Here Addictive Love (BeBe & CeCe Winans) All I wannna do is just explainWhy that we feel the way we doWhat a joy to share with youFor me to live is Christ, to die is gainIf anymore I need to sayTh list goes on and on all dayI’ll cherish that moment for lifeAnd I know it might sound crazyIt’s alright, take a seat, hold tight Time to admit it, time we should admit itI’m so addictedYou see He’s taken my heartAnd showed me the right wayNo doubt about it,(doubt about it, no doubt)See I’m lost without itYou see this love takes me higherI didn’t know why thenI found it was addicted love Now that we’ve evened up the scoreWhat do you mean there’s so much moreI need to tell why we adoreThe reason why I smile when I, when I wake upAnd also the reason why I dreamMy love, my joy, my everythingAnd I’ll cherish that moment for lifeAnd I know it might sound crazyIt’s alright, take a seat, hold tight So much loveHe’s given to me everything I longed forAnd everything I needThat means I’m never alone, so gladAnd everything I’ve dreamed and muchMore, so much moreAnd I’ll cherish that moment for life,For the rest of my life, yeahAnd I know it might sund crazy, but it’s not crazy,I’m not crazyI’ve never known anyone to love meQuite the way you doAnd I’ll tell you it’s hopeless, I’veFinally noticed thatI’m just forever addicted, forever, forever in love This is so great to listen. I am really thankful to http://onlymedotme4.wordpress.com/ for always making me recall these sweet songs. She is very awesome person possessing great qualities of heart and soul together. Thank you much for your nice comment. Really Inspiring Music ! Keep Enjoying !

Michali Mazor is a 15 year old, high school junior who is wonderful with kids, and plans to pursue a career in education. This multi-talented young woman combines her love of children and love of writing by introducing kids to a book that will encourage them to dream while promoting their pride in themselves today. Vitamins are natural elements that are vital for the health and growth of all animals. Though required in minute amounts, these substances must be gotten through food, as the body is unable to manufacture sufficient amounts. Every vitamin has its own unique functions, and therefore cannot be replaced by another. Scientific research studies have shown that vitamins attained from food are by far more nutritiously beneficial that those gotten from synthetic supplements. Many nutritionists and other health care professionals concur that a healthy diet that consists of lean proteins, fruits, vegetables and fortified grains provides all the essential vitamins needed. Teach your children good habits early on. As a person grows older it becomes increasingly more challenging to change one’s habit, as habits that are continually practiced become part of an individual’s personality. Good habits formed at youth make all the difference.” ~Aristotle Ms. Charlotte Mason, a renowned British teacher and educator (1842-1923) asserted that fundamental to good education is the development of good habits. The best way to break a bad habit is to drop it. ~Leo Aikman A fun way to teach your young child the good habit of tidiness and organization is to read MazorBooks children’s book: “Clothes Have Feelings Too! Charlie Learns to Care for His Things written by 16 year old Ari Mazor -CHARLIE’S CLOTHES STAGE A REVOLT!– Like many kids, when Charlie undresses he throws his dirty clothes on the floor. But Charlie’s clothes have had it up to here! They’ve decided to teach Charlie a lesson. What did Charlie’s clothes do? And did Charlie learn his lesson? Keep reading. You will love the characters & you will laugh! And then you will want to read it again and again. Educators long believed that reading affects the brain function and thus the learning ability of children and adults. With the advent of innovative brain imaging scans, research scientists have been able to ascertain changes in the brain physiology, and its circuitry. Neurophysiologists long believed that the development and structure of the brain was due solely to genetic predisposition and influence. An infant is born with a significant number of nerve cells or neurons that are required for learning throughout their lives. However, further studies have indicated that infant stimulation by reading and other interactions with caregivers creates the connections that form the pathways needed for learning. As the child matures into adolescence many of the infrequently used connections are lost allowing for those oft used to remain and grow strong. It is during period that the brain reorganizes its circuitry and prepares itself for learning more complex concepts and ideas. Thus exposure of the child to reading activities in the formidable first years of life lays the foundation for an organized and highly functioning brain.

We present a brief but nearly self-contained proof of a formula for the Weil-Petersson Hessian of the geodesic length of a closed curve (either simple or not simple) on a hyperbolic surface. The formula is the sum of ...

INTRODUCTION ============ Most systemic embolizations are caused by thrombi in the left side of the heart. Several hypercoagulable states have been associated with aortic thrombosis; indeed, Laperche et al. \[[@b1-vsi-32-186]\] reported that 17% of patients with thrombosis of the aortic arch had evidence of hematostatic disorders. Antiphospholipid syndrome (APS) is a disorder of coagulation that usually manifests as arterial and venous thromboses or pregnancy-related complications such as miscarriage, stillbirth, and severe preeclampsia. The most common site of arterial thrombosis in APS is the central nervous system, with half of the cases resulting in strokes and transient ischemic attacks \[[@b2-vsi-32-186]\]. The major source of arterial systemic emboli is the heart, whereas systemic thrombi originating from the aorta are much less common \[[@b3-vsi-32-186]\]. We hereby report the case of successful anticoagulation management in an APS patient with mobile thrombi within the aorta. CASE ==== A 58-year-old male patient presented to the emergency department with vomiting, dysarthria, and right-sided upper and lower limb weakness. Of note, he had a history of cerebral infarction associated with left-sided weakness 4 years previously, that recovered fully on aspirin medication, but no history of diabetes, hypertension, or arrhythmias. He was a smoker with a 30 pack-year history. There was no family history of thrombosis or malignancy. On examination, his chest X-ray and electrocardiogram was normal. However, magnetic resonance imaging of the brain revealed multiple acute embolic infarctions of the left frontal and parietotemporal lobes ([Fig. 1](#f1-vsi-32-186){ref-type="fig"}). Diagnostic work-up to determine the cause of the infarctions included transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), magnetic resonance angiography (MRA) of the brain and neck, and computed tomography angiography (CTA). Normal cardiac function was observed on TTE, with no atrial fibrillation or thrombus seen in the heart and ascending aorta. MRA revealed no thrombus, atheroma, or stenotic lesion in the carotid and intracranial arteries. However, TEE and CTA revealed multiple mobile thrombi within the ascending aorta and aortic arch ([Fig. 2](#f2-vsi-32-186){ref-type="fig"}). Serological investigations for anti-cardiolipin, anti-double stranded DNA, anti-ssA/Ro, anti-ssB/La, lupus anticoagulant, and anti-phospholipid antibodies showed normal values. However, the protein S antigen level was decreased (37%), while anti-beta-2 glycoprotein 1 (anti-beta-2 GP 1) antibody level was increased (36.8 U/mL). In view of high risk of postoperative cerebral infarction, and given that the size of the thrombi were small, the patient was initiated on medical therapy instead of surgery. He initially received low-molecular-weight-heparin for 4 days before being switched to continuous heparin infusion, which maintained the activated partial thromboplastin time levels within a target range of 60--80 sec. On day 10 of admission, he was started on warfarin (on top of the heparin infusion), with daily monitoring of the prothrombin time (PT)/international normalized ratio (INR). A repeat TEE and CTA on day 12 of admission did not demonstrate any remaining thrombus ([Fig. 3](#f3-vsi-32-186){ref-type="fig"}); the heparin infusion was therefore stopped and the warfarin dosage adjusted accordingly. The patient was discharged on day 13 of admission with maintenance warfarin, with a targeted PT/INR range of 3--4. A confirmatory diagnosis of APS was made when a second positive anti-beta-2 GP 1 antibody level was obtained during his outpatient clinic followup; he was then started on hydroxychloroquine as the management of APS. The patient recovered completely and remained well during his subsequent follow-up, with no symptoms of distal embolic event and no recurrence of aorta thrombi seen on CTA 3 months post-discharge. DISCUSSION ========== APS occurs as a result of autoimmune production of antibodies against the cell membrane's phospholipid. The Sapporo criteria require one clinical event (vascular thrombosis or pregnancy mortality before 10 weeks of gestation), and two antibody blood tests spaced at least 12 weeks apart that confirm the presence of either lupus anticoagulant, anti-cardiolipin, or anti-beta-2 GP 1 antibodies for the diagnosis of APS \[[@b4-vsi-32-186]\]. In the present case, APS was confirmed based on the presence of multiple thrombi within the aorta, as well as positivity of anti-beta-2 GP 1 antibodies on two occasions. In general, TTE, TEE, and CT scan can be used for the radiological diagnosis of an aortic thrombus. TTE visualizes the aortic root and proximal ascending aorta; in some patients, it can demonstrate the aortic arch from suprasternal notch views. However, most echocardiographers advocate the use of TEE for the diagnosis of mobile thrombi within the heart or aorta \[[@b5-vsi-32-186]\]; TEE is more accurate than TTE as the probe is located closer to the aorta and can be used at a higher frequency \[[@b1-vsi-32-186], [@b3-vsi-32-186]\]. CT scanning is an alternative modality used to evaluate aortic thrombus; it can sometimes detect thrombi in areas that are not visualized by TEE \[[@b6-vsi-32-186]\]. To the best of our knowledge, no randomized studies have evaluated the advantage of surgical approach compared to medical therapy with regards to management of aortic thrombosis. In medical treatment, anticoagulation and thrombolytic therapy are considered first-line attempts in preventing embolization of the aortic thrombus. Anticoagulation is not harmful in patients with aortic thrombi; in fact, there were fewer strokes in patients who received anticoagulation therapy \[[@b7-vsi-32-186]\]. On the other hand, there is a risk of thrombolytic agents selectively lysing a thrombus, and releasing the bulk of the lesion into the blood stream, leading to systemic embolization \[[@b8-vsi-32-186]\]. Reports of successful surgical therapy in cases of first or recurrent thrombi have been described. These reports suggested that surgical therapy is a better option for selected patients with acceptable surgery for cardiopulmonary bypass and medical treatment failure \[[@b7-vsi-32-186],[@b8-vsi-32-186]\]. We report this rare case in which thrombi within the ascending aorta and aortic arch of a patient with APS was successfully-treated medically. The current recommendation for treatment of thrombosis in APS is long-term warfarin, of which the duration and intensity of treatment are still under debate \[[@b9-vsi-32-186]\]. Cohen et al. \[[@b10-vsi-32-186]\] suggested that the treatment of a first unprovoked venous thrombosis in patients with APS is long-term anticoagulation with a target PT/INR range of 2--3. However, the treatment of arterial thrombosis in patients with APS is controversial due to the lack of prospective studies. Most of the recommendations for treatment with higher intensity warfarin (PT/INR 3--4) in these patients comes from retrospective reviews of patient cohorts. These studies concluded that higher intensity warfarin is superior to standard treatment (whereby the target PT/INR range is 2--3) \[[@b11-vsi-32-186]--[@b13-vsi-32-186]\]. A recent systemic review of secondary thromboprophylaxis for arterial thrombosis in patients with APS showed that patients treated with higher intensity warfarin rarely experience recurrent events. Bleeding complications appear to be similar in patients on higher intensity warfarin in comparison to standard treatment \[[@b14-vsi-32-186]\]. Based on these reports, we initiated our patient on warfarin, with a target PT/INR range of 3--4. However, we agree that the treatment of arterial thrombosis in patients with APS continues to be a controversial subject; hence, more prospective studies are required. {#f1-vsi-32-186} {#f2-vsi-32-186} {#f3-vsi-32-186} [^1]: Conflict of interest: None.

Detection of haematologic effects of mosquito biting using an animal model. The studies on haematologic changes in humans or animals as a result of mosquito bites are few. This study was undertaken to examines changes in the blood picture of mice (Mus musculus) exposed to Culex pipiens biting. Mice exposed to mosquito bites either once or twice (with 7 days between the two bites) showed insignificantly higher (P >0.05) counts of the total blood cells, platelets and hemoglobin content than normal mice with the highest level (11 %) was in WBCs following the second bite. Mosquito biting exerts its effects largely upon the differential WBCs. Exposure of mice once or twice to mosquito bites resulted in increased numbers of the 5 WBC types. Compared to control mice cells, the highest (P<0.01) levels of basophils (7.19-fold, 72.02 cells/ul), eosinophils (3.59-fold, 216.06 cells/ ul), monocytes (1.34-fold, 288.08 cells/ul) & lymphocytes (1.29 -fold, 1833.74 cells/ul) were after the second bite. Segmented neutrophils significantly (P<0.01) decreased by 2% & 5% of the normal mice count following first and second bite, respectively.

Improved Savitzky-Golay-method-based fluorescence subtraction algorithm for rapid recovery of Raman spectra. In this paper, we propose an improved subtraction algorithm for rapid recovery of Raman spectra that can substantially reduce the computation time. This algorithm is based on an improved Savitzky-Golay (SG) iterative smoothing method, which involves two key novel approaches: (a) the use of the Gauss-Seidel method and (b) the introduction of a relaxation factor into the iterative procedure. By applying a novel successive relaxation (SG-SR) iterative method to the relaxation factor, additional improvement in the convergence speed over the standard Savitzky-Golay procedure is realized. The proposed improved algorithm (the RIA-SG-SR algorithm), which uses SG-SR-based iteration instead of Savitzky-Golay iteration, has been optimized and validated with a mathematically simulated Raman spectrum, as well as experimentally measured Raman spectra from non-biological and biological samples. The method results in a significant reduction in computing cost while yielding consistent rejection of fluorescence and noise for spectra with low signal-to-fluorescence ratios and varied baselines. In the simulation, RIA-SG-SR achieved 1 order of magnitude improvement in iteration number and 2 orders of magnitude improvement in computation time compared with the range-independent background-subtraction algorithm (RIA). Furthermore the computation time of the experimentally measured raw Raman spectrum processing from skin tissue decreased from 6.72 to 0.094 s. In general, the processing of the SG-SR method can be conducted within dozens of milliseconds, which can provide a real-time procedure in practical situations.

[Neuromorphological effects of low doses of ionizing radiation]. Morphological methods were used to study several segments of the rat's brain after gamma-irradiation by 10, 20, 50 and 100 cSv. Tissue samples were investigated shortly after dose delivery, in 24 hours, and after 6, 12, 18 and 24 months since irradiation. Neurons were shown to be sensitive to radiation. Conventionally, the nervous system reaction can be segmented into three stages, i.e. an early response (initial 30 days), revealed changes (by mo. 6) and repair. Life span of irradiated animals was not altered; however, individual morphological variations and even incomplete repair may affect quality of life of radiation disaster fighters and population of contaminated regions.

Hugo Rheinhold Wolfgang Hugo Rheinhold (26 March 1853 – 2 October 1900) was a German sculptor best known for his Affe mit Schädel ("Ape with Skull"). His surname is often misspelled "Reinhold". Life Hugo Rheinhold was born in Oberlahnstein, Prussia, on March 26, 1853. He went to school in Koblenz before entering the merchant trade. When 21, Rheinhold sought success in the United States and became an import and export merchant, living in San Francisco (1874–78), where he had the head office for his business, as well as in Hamburg, where he settled in 1879. The next year he married his childhood sweetheart Emma Levy from Cologne; she was to die in 1882, after only one-and-a-half years of marriage. Emma's death had a huge impact Rheinhold. He sold his successful business and moved to Berlin to study science and philosophy at the Friedrich-Wilhelms University. In 1886, he studied under the sculptors Ernst Herter and Max Kruse, before officially enrolling as a student at the Berlin Academy of Arts (1888–92). He died, aged 47, in Berlin. Works Rheinhold produced a series of notable works within a very short career span. These include: a group of reading monks (Lesende Monche), a tribute to Alfred Nobel (Dynamite in the Service of Mankind), a bust of socialist leader August Bebel and his most famous piece Am Wege (1896) a marble of "an unfortunate young woman with a child at her breast". His biggest bronze work was for Dynamit Nobel AG, a statue titled Dynamite in the Service of Man, which included a tall goddess, possibly representing Athena, with a foot over a prostrate man. The statue was melted down for use in the Second World War for armaments. Rheinhold was protective of his Jewish heritage, and was a strong influence in the Deutsch-Israelitischer Gemeindebund (an association of Jewish corporations). He sculpted Die Kämpfer ("The Warriors") in protest against burgeoning anti-Semitism. His last work, of serpentine deities in a fountain ("Brunnengrotte mit zwei Wassergottheiten"), was exhibited close to his death in 1900. Today, Rheinhold is probably known for his Affe mit Schädel. Notes References Morgan, R., & Moore, A. Hugo Rheinhold's monkey. Boston Medical Library. (Website). 1. Dec. 1998. Retrieved on 1. Dec. 2008. Richter, J., & Schmetzke, A. (2007). Hugo Rheinhold's philosophizing monkey—a modern Owl of the Minerva. NTM—International Journal of History and Ethics of Natural Sciences, Technology and Medicine, 15(2), 81–97. Schmetzke, A. Other Sculptures by Hugo Rheinhold. Hugo Rheinhold ... and his Philosophizing Monkey. (Website). Library, University of Wisconsin–Stevens Point. 8. Dec 1999, last revised 6. Nov. 2008. Retrieved on 1. Dec. 2008. Singer, I., & Mannheimer, S.(1901–1906). Rheinhold, Hugo. In The Jewish Encyclopedia (pp. 399–400). New York: Funk & Wagnalls. External links Hugo Rheinhold ... and his Philosophizing Monkey Varieties of Rheinhold's Philosophizing Darwin Monkey Der Philosophische Affe und die Eule der Minerva Hugo's Philosophical Ape Category:1853 births Category:1900 deaths Category:German sculptors Category:German male sculptors Category:19th-century sculptors

Recommended Games DIY Pest Control (INFOGRAPHIC) Fighting pests at home? The best offense is a clean, dry and air-tight defense. The importance of sanitation cannot be overstated, but cleaning up after yourself is only half the battle. Ultimately, success depends on whether you can stop rodents and insects from getting into your house to begin with. While there is no single solution, implementing these strategies in tandem will help you safeguard your home against uninvited guests. Bob Vila is the home improvement expert widely known as host of TV’s This Old House, Bob Vila’s Home Again, and Bob Vila. Today, Bob continues his mission to help people upgrade their homes and improve their lives with advice online at BobVila.com. His video-rich site offers a full range of fresh, authoritative content – practical tips, inspirational ideas, and more than 1,000 videos from Bob Vila television. Note: The views and opinions expressed in this article are those of the author and do not necessarily reflect the opinion or position of Zillow.

GIS equipment, namely sulfur hexafluoride closed-type combination of electrical appliances, internationally known as the “gas-insulated switchgear” (Gas Insulated Switchgear) was born in the mid 1960s. It put substation primary equipments except transformer including circuit breakers, disconnectors, fast (ground) switch, current transformers, voltage transformers, arrester, bus (three phase or single phase), connecting pipe, transition elements and cable terminals in a fully enclosed metal shell. The medium for insulation and are quenching is 0.4˜0.6 MPa SF6 gas. With the continuous maturing of GIS technology, the area and volume of GIS equipment are getting smaller and the operation is more and more reliable. The failure rate and maintenance workload of GIS put into operation early are obviously lower than other types of switchgear. Therefore, in the transformation of urban network, GIS has been widely used. With the rapid increase of GIS usage in China in recent years and the increase of GIS operation period in early time, the failure rate of GIS has a tendency to increase and is far higher than the GIS accident rate requirements of no more than 0.1 intervals/100*years proposed by IET. GIS is made up of a number of electrical devices, but the fault situation is not the same as the failure of individual electrical equipment. And the failure rate is far lower than the failure rate of independent electrical equipment. Long time in high pressure environment has become a main failure cause of a lot of GIS. GIS equipment need to go through strict process control to ensure the quality of the operation of GIS. But many parts of the process may be a potential risk of GIS failure. According to the failure occurred in the manufacturing and installation aspects. Although GIS has a high operational reliability, the long-running GIS will inevitably have material deterioration, as well as loose or deformation in the connecting components under electromotive force. The types of GIS faults are various, but the common faults are relatively concentrated. According to the national GIS fault statistics, GIS fault can be divided into mechanical failure, insulation failure, secondary circuit failure, body leakage failure and other failures, in which insulation fault is the most common in partial discharge, and gas leakage is most common in mechanical failure. With the GIS running for a long time, under the influence of long-term vibration, the flange connection will loosen to cause the gas chamber to have the air leakage; At the same time, deterioration of the pot-type insulator will also lead to gas leakage. Once the live gas leakage part is no longer completely enclosed in the inert SF6 gas, the external contact will be affected by the external environment, and the reliability will be reduced. Therefore, real-time monitoring of gas leaks in GIS gas chambers is of great significance for timely detection of GIS anomalies and ensuring the normal operation of GIS. At present, the status monitoring for GIS mainly focuses on monitoring the partial discharge fault of GIS, and forms many methods such as UHF method, ultrasonic method, gas analysis method and so on. And the monitoring technology is more and more mature. The researches on GIS mechanical faults are mainly focused on the monitoring of GIS actuators such as circuit breakers, isolating switches, earthing switches and so on. So far, GIS gas leak monitoring rely mainly on gas pressure of gauge gas chamber. However, gas pressure gauges are insensitive to small gas changes, and gas leakage has become more severe when gas pressure gauges change parameters. In addition, the current gas pressure gauge is still dependent on manual reading to found abnormal. Real-time is poor and efficiency is very low. Therefore, it is necessary to find a more reliable and simple gas leak detection method.

Q: Semicolon after closing curly bracket in PHP I am writing a script to make chunks of a text and send it via SMS. Earlier today i was reviewing some code to split the string in chunks and i saw something I've never seen before. I'm talking about the ";" right after the "}" at the en of the snippet. Why this colon? i know it works but i don't know if it adds some semantics or some instruction to the interpreter, anybody know what is this for? while(1) { $length = (strlen($output)+strlen($words[$i])); if($length>$new_max) { if(count($words) > 0) { $out_array[] = $output; $output = ''; } else { break; } } else { $output = $output." ".$words[$i]; ++$i; }; }; EDIT: Looks clear that the semicolons as well as multiple semicolons together has no effect over the result, but, do you know if it has some effect to the interpreter? is it doing some task (internally) when it parses it? A: I think that those 2 semicolons do nothing here. It is probably being interpreted as an empty expression immediately following the if/while. A: These are unnecessary. They don't hurt the script, just unnecessary. The programmer probably had a habit of adding semicolons to end of every statement. Maybe he got this habit from another programming language, maybe his IDE was showing errors without semicolons or maybe he is just a beginner. In any event, there neither hurt nor help. Also the fact that programmer uses while(1) tells me that he is either extremely lazy, because usually a programmer would write while(true), the only reason to type while 1 is because it's less typing to do. A programmer with any type of formal training will not not write while(1) instead of while(true). This is just my opinion, but it's based on over 10 years of programming in 3 languages.

This website is protected by international Copyright. Copying, duplication or reproduction of content by any means whatsoever is strictly prohibited without the prior written permission of MetalTalk.net. Commercial Exploitation: The information contained herein, including text, images and photographs, must not be copied,adapted, distributed or otherwise used for commercial gain. Any such action would establish liability for a civil action and may give rise to criminal proceedings. None-Commercial Use: Where permission is sought for the purposes of communication and knowledge sharing only, that is with no possibility of commercial gain, then permission will normally be given - providing that MetalTalk.net is acknowledged as the source of such information. MetalTalk.net wish to recognise and acknowledge that some of the material contained herein has been contributed by visitors to the site. Material so submitted is automatically Copyright protected in the name of the contributor - and must not be used, commercially or none-commercially, without the Copyright owner's permission. This site in no way wishes to infringe on anyone's copyright. It is our policy to make every effort to respect the copyrights of outside parties. If you believe that your copyright has been misused, please email us and we will remove the picture(s) or acknowledge the source, as soon as we receive your email. In view of this, please do not submit any material to us that you do not hold copyright over or have permission to distribute freely. The views expressed on this site are the personal opinions of the site authors, columnists and message board posters and do not necessarily represent the views of any of the teams or individuals concerned. MetalTalk.net accepts no responsibility for the content of or the use made of information provided directly or indirectly by this site or by sites which this site links to, and shall not be held liable in respect of any loss suffered therefrom. It is our policy to discourage illegal use of this facility. Whilst every effort is made to avoid listing links to sites that in any way encourage hooliganism or contain other violent, pornographic or illegal material (as defined by legislation in Belgium the United Kingdom and the European Union), the vast amount of links makes it impossible to monitor changes on each and every one of the sites to which this site links. Should you come across a site that contains material that is in violation of this policy, we would be happy to hear from you so that we may remove the respective link. PRIVACY POLICY The operator of this website, Steve Goldby, is committed to protecting your privacy. Please take a moment to read this Privacy Policy. References to "we", "us" and "our" in this Policy are references to MetalTalk.net. This Policy describes what happens to the information which you supply to us, where that information identifies you individually :- e.g. your name and address details. We reserve the right to change the terms of this Privacy Policy from time to time. What information do we hold about you and how is it collected? When you register on this site, some personal information (including your name and email addresses) is collected by us. You may also be asked for your personal information at other times on this site - in connection with activities such as competitions, polls, voting etc. Unlike many other online services, we do not use "cookies" to store and sometimes track information about you. A cookie is a small amount of data sent from the server and stored on your PC's hard drive. Most web browsers are automatically set up to accept cookies, but you can set your browser to refuse cookies or ask your browser to show you where a cookie has been set up. Certain services are only activated by the presence of a cookie and, if you choose to refuse cookies, all features of this site will still be available to you. What do we do with your personal information? We will store your email address in order to help us to provide you with a more personalised service which is tailored to suit your needs. You will receive emails from us for the following purposes: (i) to update and develop records and for assessment and analysis including market and service/product analysis; (ii) to assist in the provision of services/products to you; (iii) to facilitate reviews, developments and improvements to the services/products offered to you. (iv) to notify you of new articles published on MetalTalk.net. Please rest assured that MetalTalk.net will never pass your email address to any third party. By law, you are entitled to: (i) object to your personal information being used for marketing purposes. Should you not wish to receive emails from MetalTalk.net, simply inform us and your email address will be removed from the list. (ii) receive, upon request, a copy of any personal information about you which is held by us. (iii) require the rectification, erasure or blocking of any of your personal information which is inaccurate or not up to date held by us. If you wish to exercise any of these rights, or if you wish to opt-out of any future processing of your personal information held by us, then please write to us at the contact address set out below stating your full name and address and providing any other relevant information. When does this Privacy Policy not apply? This Privacy Policy only applies to the collection of data by us and the use of that data by us. It does not cover third party sites to which we provide links, nor does it cover advertisers and content partners within our service who may also collect your personal information. They may have their own privacy policies and/or terms and conditions of use. Disclaimer: MetalTalk.net accept no legal responsibilty and cannot be held accountable for the content and accuracy of postings on MetalTalk.net Message Board. How do we protect your information? MetalTalk.net is firmly committed to data security. When you place orders, we offer use of a secure server. The secure server software encrypts all information you input before it is sent to us. We take steps to guard against unauthorised access to customer data. Although we make every effort to create a secure environment for your personal information, we cannot guarantee the safety of any personal information which you transmit to us online. Cookies settings If you don't want to receive certain categories of cookies on the MetalTalk website, you can contact us directly to opt-out of them. We will need to set a cookie so that we can remember your choices when you next visit the website from the same browser. At the present time it is not technically possible for us to allow you to carry your settings with you between your browsers and devices so you will need to change these settings from each browser you use. Please also be aware that we make every effort to respect your choices, however, there is the possibility that not all cookies will be captured. If this is a concern then we would recommend that you change your cookie settings via your browser; your browser help function will tell you how. MetalTalk.net does work without cookies, but you will lose some features and functionality if you choose to disable cookies. For example, you won't be able to set the weather to your chosen location. When you move away from this page, your settings will be saved. Contacting Us If you have any questions or concerns about our use of your personal information please write to:

Antaeola antaea Antaeola antaea is a moth of the family Tortricidae first described by Edward Meyrick in 1912. It is found in Sri Lanka. References Category:Moths of Asia Category:Moths described in 1912

[The status of blood pressure over a 10-year period]. The aim of this study is to relate the evolution of blood pressure (BP) measured every 5 years during 10 years in 12,824 healthy adults and children from both sexes. At the first evaluation, 2,856 were 4-15 years of age, 1,471 were 15-25, 6,590 were 25-45 and 1,907 were 45-65. The result of BP were adjusted according to possible effects of age, height or year of examination. Correlation coefficients at 5 and 10 years for the male patients are 0.38 and 0.34 (systolic BP and 0.23 and 0.18 (diastolic BP); for the female patients they are 0.36 and 0.31 (systolic BP) and 0.23 and 0.17 (diastolic BP). The reliability of the correlations increases according to age at first examination: for an initial age between 4 and 10 years, the correlation coefficient between first and last evaluation is 0.14 while for an initial age of 45-65 years it is 0.38 (systolic BP). The predictive value of a relatively high BP defined as percentage of patients whose systolic BP is staying in the upper fifth of the BP distribution ten years later is for increasing age group: 28.7%, 31.1%, 39.7%, 42.5%; that means a relative risk moving from 1.34 to 3.17. Sensitivity of detection of male patients whose systolic BP will be in the upper fifth of the distribution varies from 22 to 42% according to age, with a specificity of 86.3 to 82.2%. The results are sensibly similar in the female patients and for diastolic BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Sunday Morning Book Thread 01-28-2018 William Andrews Clark Memorial Library, UCLA Good morning to all you 'rons, 'ettes, lurkers, and lurkettes. Welcome once again to the stately, prestigious, internationally acclaimed and high-class Sunday Morning Book Thread, a weekly compendium of reviews, observations, and a continuing conversation on books, reading, and publishing by people who follow words with their fingers and whose lips move as they read. Unlike other AoSHQ comment threads, the Sunday Morning Book Thread is so hoity-toity, pants are required. Even if it's these pants, silly as they are, aren't quite as ridiculous as the guy's shoes. He looks like a working class elf. Now Where Was I? For the past few weeks, I've been wondering whether it was time to start doing the book thread again. I thought I'd wait for "the right time", which means when I felt confident enough that I would be up for the sustained effort. But then I realized I'd never feel confident enough, so the best thing to do, as I told CBD, is to just get back on the horse and not worry if I had my mojo back or not. So here I am. This book thread may be short and/or sucky but that's what you'll get. I figure it will be much like recovering my shoulder's range-of-motion, that is, the progress will be slow, incremental, but positive. And while I'm on the subject, let's all give CBD a laurel -- and hearty handshake -- for picking up the book thread with no prior notice whatsoever and doing a good job with it. He's a real lifesaver and I hope I can return the favor to him some day. Moron™ Libraries It's been awhile since I've broadcast one of these appeals, but this week seems appropriate. So, for the benefit of all of you n00bs, from time to time, I have posted pics of Moron™ libraries and so I would like all of you 'rons and 'ettes, if you feel so inclined, to take a photo of your library. Any photo is better than no photo, but I prefer photos that are clear, sharp, and high resolution. Even if it creates a 3-4Mb file, that's OK, I can work with it. It's fun to be able to read the titles off of the spines of your books sitting on the shelves because they get talked about in the comments. Think of it as inviting the entire Moron™ Horde over to your house for tea and we're all standing around in your library looking at your stuff. You can e-mail the photos to me at: aoshqbookthread, followed by the 'at' sign, and then 'G' mail, and then dot cee oh emm It Pays To Increase Your Word Power® A STRULDBRUG is an aged person, or someone who has become incapacitated by age or infirmity. Usage: Hillary Clinton's maiden name is actually Struldbrug. In fact, she comes from a long line of Struldbrugs. Sculpture By Skip From Skip: [T]his is a wood sculpture I made years ago made from a solid maple log. I painted it with stone paint spray and painted the book by hand. Had trouble figuring where to photo it for lighting and background. I don't see any problem with the lighting or background. It looks great. And that "rock" paint really makes it look like Skip was working in stone. The Great Divide It will be worth a half an hour of your time to watch this BBC interview of Jordan Peterson that has been making the rounds on social media this week. Peterson is a psychologist, cultural critic, and professor of psychology at the University of Toronto. He has been recently been drawing flak from the SJW howling mob for questioning SJW orthodoxies in regards to gender issues. Cathy Newman, the hyper-feminist BBC infobabe doing the interview, comes at him with all of the SJWisms in her arsenal, but he just swats them aside like annoying bugs. She's clearly out of her depth. She had no idea who she was dealing with. He knew all about her (As a university professor, I'm sure Peterson is all too familiar with the SJW mindset), but she knew nothing about him. Her stock-in-trade is to take a couple of isolated elements from one of Peterson's complex arguments and use them to put the worst possible spin on it, i.e. "So you're saying women can't run things" and he has to keep saying "No, I didn't say that...No, that's not what I said" over and over again like a broken record. It's so bad that even the liberal Atlantic magazine asks, Why Can't People Hear What Jordan Peterson Is Saying?. Newman clearly didn't, which the interview makes abundantly clear. The social justice warriors have gone so far out there where the buses don't run that they have lost their ability to even comprehend other viewpoints, much less intelligently debate them. Humorous, surprising and informative, Dr. Peterson tells us why skateboarding boys and girls must be left alone, what terrible fate awaits those who criticize too easily, and why you should always pet a cat when you meet one on the street. What does the nervous system of the lowly lobster have to tell us about standing up straight (with our shoulders back) and about success in life? Why did ancient Egyptians worship the capacity to pay careful attention as the highest of gods? What dreadful paths do people tread when they become resentful, arrogant and vengeful? Dr. Peterson journeys broadly, discussing discipline, freedom, adventure and responsibility, distilling the world's wisdom into 12 practical and profound rules for life. 12 Rules for Life shatters the modern commonplaces of science, faith and human nature, while transforming and ennobling the mind and spirit of its readers. $13.99 on Kindle. Here is another good article, this one about Peterson's speaking tour of England, which also serves as a good introduction to Peterson's work and why he is controversial. Not controversial to us, of course. To us, Professor Peterson is just speaking common sense. But he does cause SJW types (like Cathy Newman) to retire to their fainting couches, and that's always fun to watch. Moron Recommendations After reading CBD's thoughts on historical novels in last week's book thread, Dave H. wrote: I would like to direct your attention to a lengthy series of novels written by W E B Griffin and William Butterworth IV... I just finished the latest in the series "Clandestine Operations", entitled "Death at Nuremburg". It revolves around preparations for the trials and the attempts to capture several Nazi SS Officers who had escaped capture in the confusion following the German surrender. Of historical interest is a long discussion of Wewelsburg Castle, in which Himmler was attempting to create a cult to continue the Third Reich after the war. Each of the several series that Griffin has written includes heroes who are far too larger than life...But of interest is the historical background cited in each book he/they have written. Overall, the Clandestine Operations series is about "the birth of the Central Intelligence Agency and the Cold War." Here is the blurb for the first in the series, Top Secret: In the first weeks after World War II, a squeaky-clean new second lieutenant named James D. Cronley Jr. is spotted and recruited for a new enterprise that will eventually be transformed into something called the CIA. One war may have ended, but another one has already begun, against an enemy that is bigger, smarter, and more vicious: the Soviet Union. The Soviets have hit the ground running, and Cronley’s job is to help frustrate them, harass them, and spy on them any way he can. His recruiter thinks he has the potential to become an asset—though, of course, he could also screw up spectacularly. And in his first assignment, it looks like that’s exactly what might happen. He’s got seven days to extract a vital piece of information from a Soviet agent, but Cronley’s managed to rile up his superior officers (he seems to have a talent for it), and if he fails, it could be one of the shortest intelligence careers in history. There are enemies everywhere—and, as Cronley is about to find out, some of them even wear the same uniform he does. My daughter, Sarah Rothman, has published Suicidal Samurai, a historical adventure novel set in Meiji era Japan, which (in my naturally unbiased opinion) is a great story. Here's the back cover blurb: A samurai-cowboy seeking revenge. A secret society with a propensity for murder. An exciting adventure in Victorian Japan. When Mori Makoto returned to Yokohama after fifteen years of exile, he did not expect to be accused of murder. But when he comes across a dead body, Makoto is unwittingly thrust into a murderous plot involving killers from his painful past. Together, with a boisterous policeman, a thrill-seeking American actress, and a beautiful and mysterious shrine maiden, Makoto will find himself up against a dark conspiracy that could threaten the very survival of the new Japanese government. Suicidal Samurai, the first of a new mystery series, is available on Kindle for $0.99. That's a pretty good deal. So that's all for this week. As always, book thread tips, suggestions, bribes, rumors, threats, and insults may be sent to OregonMuse, Proprietor, AoSHQ Book Thread, at the book thread e-mail address: aoshqbookthread, followed by the 'at' sign, and then 'G' mail, and then dot cee oh emm. What have you all been reading this week? Hopefully something good, because, as you all know, life is too short to be reading lousy books.

INTRODUCTION ============ Cutaneous leishmaniasis (CL), despite being a neglected disease, is one of the most important parasitic diseases in Iran due to several factors, including areas of high endemicity \[[@b1-epih-40-e2018032]-[@b3-epih-40-e2018032]\], the annual incidence of more than 24,000 cases \[[@b4-epih-40-e2018032]\], high outbreak rates \[[@b5-epih-40-e2018032]-[@b7-epih-40-e2018032]\], and emergence in new foci \[[@b8-epih-40-e2018032]\]. Zoonotic CL, caused by *Leishmania major*, is distributed mainly in the central \[[@b9-epih-40-e2018032]\] and southwest regions \[[@b10-epih-40-e2018032]\], while anthroponotic CL, caused by *Leishmania tropica*, affects almost all urban areas \[[@b11-epih-40-e2018032]\]. The spatial inequality of CL in Iran makes it a threat to public health and poses major challenges to control strategies \[[@b12-epih-40-e2018032]\]. Studying the spatial and geographic patterns of CL is important because the components of the chain of infection, including the parasite, host vector, and required environmental conditions, are spatially distributed \[[@b13-epih-40-e2018032]-[@b15-epih-40-e2018032]\]. Although several studies have been published on the epidemiological and spatial patterns of leishmaniasis in the general population in Iran, the spatial distribution of CL among special populations, such as the army and military personnel, has not been adequately studied \[[@b16-epih-40-e2018032],[@b17-epih-40-e2018032]\]. The army is the most vulnerable group, with the highest incidence of this disease, due to its distinct spatial status \[[@b18-epih-40-e2018032]\], and immunologically naive troops are sometimes deployed to endemic areas for training or operational activities \[[@b19-epih-40-e2018032],[@b20-epih-40-e2018032]\]. Knowledge of the spatial patterns of CL in at-risk populations can help direct control strategies for truly needy areas and reduce the burden of the disease. When studying the spatial distribution of a disease on a defined map, however, there are some methodological challenges that must be addressed. Overlooking the effect of spatial aggregation when attempting to detect spatial clusters can increase the risk of false detection \[[@b21-epih-40-e2018032]\]. Kulldorff et al. \[[@b22-epih-40-e2018032]\]'s spatial scan statistic was introduced as an efficient method to detect spatial clusters and disease outbreaks. There is degree of population heterogeneity in the various areas of a defined map, and estimating the rate of a disease in low-population areas is accompanied by a degree of uncertainty, a phenomenon known as small area estimation or the sparse data bias; however, the rates in various areas have a degree of spatial autocorrelation, and overlooking this in spatial modeling can also induce serious bias \[[@b23-epih-40-e2018032]-[@b25-epih-40-e2018032]\]. Spatial methods, such as the Besag, York, and Mollié (BYM) spatial model \[[@b25-epih-40-e2018032],[@b26-epih-40-e2018032]\], have been developed to address these challenges. Therefore, using up-to-date data on CL incidence from 2015 to 2017 in Iranian army units (IAUs), the objectives of the present study were to investigate the spatial distribution of CL using a BYM model and to detect significant spatial clusters of CL by applying Kulldorff et al. \[[@b22-epih-40-e2018032]\]'s spatial scan statistic. MATERIALS AND METHODS ===================== Study area and setting ---------------------- Iran is situated in southwestern Asia and is the second largest country in the Middle East, with an area of 1,648,195 km². The country is located between the Caspian Sea in the north and the Persian Gulf and Gulf of Oman in the south. Iran is bordered by Afghanistan, Armenia, Azerbaijan, Iraq, Pakistan, Turkey, and Turkmenistan. The latitude and longitude of Iran are 32.4279°N and 53.6880°E, respectively. Iran has great diversity in topographical features, with elevation extremes ranging from -28 m at the Caspian Sea to 5,610 m at Mount Damavand. The great variations in altitude result in a correspondingly great diversity of environmental conditions, geographical factors, and climate indicators. In Iran, on some days temperatures can easily reach to lower than -30°C and some days reach to more than 40°C; January is the coldest month with a mean temperature of 5 to 10°C and August is the hottest month with mean temperatures of 20 to 30°C. Rainfall has a seasonal pattern, with great variation in the amount of rainfall (e.g., the mean annual rainfall ranges from 100 to 2,000 mm) \[[@b27-epih-40-e2018032]\]. Study design and data source ---------------------------- An ecological study was conducted. The study included confirmed cases of CL registered by the deputy of health of AJA University of Medical Sciences between March 2014 and March 2017. The surveillance system for diseases in army units involves the systematic collection, analysis, and interpretation of health-related outcomes for use in planning, implementing, and evaluating public health and prevention interventions. This surveillance system provides a capacity for the timely referral of confirmed cases to the next higher level and finally to the deputy of health of AJA University of Medical Sciences. Reporting systems vary depending on the type of health-related outcome data and information being reported; for example, confirmed CL cases are reported monthly. The data is registered for each Anno Hegirae Solaris (A.H.S.) or solar Hijri year. A.H.S. is the unit of years used in the official calendar of Iran, with 12 months that roughly range from April of one year to March of the following year. Therefore, each year in this study was defined from April of one year to March of the following year (e.g., April 2014 to March 2015). The data were extracted from regular surveillance reports on CL cases and transferred to Microsoft Excel (Microsoft, Redmond, WA, USA). Then, the data were entered into the Iran ArcGIS shapefile map layer for spatial analysis and to generate spatial visualizations. A queen spatial weight matrix (first order) was defined using GeoDa \[[@b28-epih-40-e2018032]\] for calculating spatial autocorrelation and for hierarchical Bayesian analysis. Weighting based on the queen order indicates whether spatial units share a boundary, so that all spatial units in contact with spatial unit *i* are considered as its neighbors. Statistical analysis -------------------- ### Spatial autocorrelation The global spatial autocorrelation of CL incidence in IAUs at the province level during the study period was checked using the Moran's index (MI). This index varies between -1.0 and 1.0; values near -1.0 indicate negative spatial autocorrelation (clustering of dissimilar values), while those close to 1.0 indicate positive spatial autocorrelation (clustering of similar values) and 0.0 indicates randomness. GeoDa \[[@b28-epih-40-e2018032]\] was used to calculate the MI and to test its statistical significance. ### Spatial mapping The crude incidence rate for area *i* can be calculated through dividing the number of new cases by the number of people residing in area *i*. An important goal of spatial epidemiology is to compare the incidence rates of a disease in different areas. However, the crude incidence rate does not allow valid and robust comparative inferences across areas because it is not corrected for the number of people at risk or the sex and age structure of each area, and it faces several other methodological issues in a spatial setting. In order to derive valid inferences, the incidence rates must be standardized, and indicators such as the standardized incidence ratio (SIR) must be estimated \[[@b29-epih-40-e2018032]\]. In the present study, the incidence rate was corrected only for the population at risk. Since the number of cases in each area follows a Poisson distribution, the SIR is calculated as the ratio of the observed number of incident cases of a disease (*O~i~*) in the study area *i* to the number of cases that would be expected (*E~i~*) if the study area *i* had the standard or total incidence rate. *E~i~* is calculated as follows: E i = n i ∑ i 0 i ∑ i n i , i = 1 , 2 , . . . . I Where *n~i~* is the number of at-risk individuals in area i. Thus, the SIR is calculated as follows: S I R i = O i E i Crude SIRs are not corrected for spatial autocorrelation or small area estimation. Ignoring these methodological issues can result in SIRs that are biased due to overdispersion or extra-Poisson variation \[[@b24-epih-40-e2018032]\]. To obtain maps that remove the sources of overdispersion, hierarchical Bayesian approaches, such as the BYM model, have been introduced \[[@b26-epih-40-e2018032]\]. The BYM model and how the prior and hyperprior are defined for the parameters of interest have been explained in detail elsewhere \[[@b30-epih-40-e2018032]\]. Briefly, the smoothed SIRs (posterior distribution of the parameters) in a BYM model are calculated by combining the predefined information about sources of overdispersion (prior distribution) and the observed data. Sources of overdispersion are explained in the BYM model through 2 random effects: (1) the exchangeable (non-spatial) random effect *u~i~* , which refers to how the SIR in area *i* is shrunk toward the global mean of the study area (the prior distribution of *u~i~* follows a normal distribution, $\left. u_{i} \right.\sim N\left( {0,~\tau_{u}^{2}} \right)$; and (2) the spatial random effect vi , which refers to how the SIR in area i is shrunk towards the local mean of neighboring areas and is defined by a conditional autoregressive model $N\left( {\overline{\nu_{i}},~\tau_{i}^{2}} \right)$. *τ*~u~ and *τ*~v~ are the parameters of precision, and the hyperprior will be defined for them in the next step. We used a gamma (0.01, 0.01) hyperprior for $\tau_{u}^{2}$, a non-informative prior. It has been suggested that this choice involves an empirical trade-off between (a) not using a more than sufficiently informative prior when there is no robust knowledge about the spatial pattern of the outcome (e.g., CL among IAUs) and (b) enough assurance for convergence of the Markov-chain Monte Carlo (MCMC) algorithm when a flat prior is used \[[@b31-epih-40-e2018032]\]. For the spatial random effect, a gamma (0.5, 0.005) hyperprior, which is a diffuse prior, was used for $\tau_{v}^{2}$. It has been proven that with these values, an artificial spatial structure will not be imposed on the estimates of relative risks (RRs)\[[@b31-epih-40-e2018032]\]. For this study, the posterior estimates of the SIRs were obtained by simulating from the joint posterior by means of 50,000 MCMC iterations on 2 parallel chains, with the initial 4,999 discarded in the burn-in phase. The MCMC convergence was checked in several ways. First, the Brooks-Gelman-Rubin (BGR) diagnostic was used, as values of BGR near 1 indicate the convergence of the model \[[@b32-epih-40-e2018032]\]. Second, the integrated autocorrelation time was used to quantify the effects of sampling error on the results to determine whether the samples in the chain were independent. The integrated autocorrelation time directly quantifies the Monte Carlo (MC) error. As rule of thumb, an MC error lower than 5% of the posterior standard deviation (SD) guarantee convergence. Thinning was used to reduce autocorrelation in the samples in the chains, as some samples were discarded from the simulation \[[@b33-epih-40-e2018032]\]. We specified thin= 1 so that the first parameter value would be retained. We used the open-access software OpenBUGS 3.2.3 (<http://openbugs.net/w/FrontPage>) to conduct hierarchical Bayesian analysis. The posterior effect size estimate, median SIR, and Bayesian 95% credible intervals (2.5th and 97.5th sample percentiles) were reported. The code for the BYM model is presented in [Supplementary Material 1](#SD1-epih-40-e2018032){ref-type="supplementary-material"}. ### Spatial cluster analysis Kulldorff et al. \[[@b22-epih-40-e2018032]\]'s purely spatial scan statistic was used to identify spatial clusters with significantly high and low rates. A high-rate cluster was defined as an area where the observed number of CL cases exceeded the expected number, and a low-rate cluster was defined as an area where the observed number was lower than the expected number of cases. The spatial scan statistic imposes thousands or millions of overlapping circular windows to scan the study area. The windows (potential clusters) are centered in each study region. The radius of the window varies continuously in size from zero to a specified upper limit. By default, the maximum spatial window size (MSWS) involved 50% or less of the total population at risk. Often, the set of potential clusters is identified hierarchically, with no geographical overlap. However, the results obtained when using the hierarchical approach to define a set of non-overlapping clusters can be misleading. When the MSWS is set to 50% of the population, the hierarchical no-geographical-overlap approach provides overly large clusters with relatively small RR values, whereas when the upper limits of the MSWS are set with small sizes (e.g., 2%), small clusters with unexpectedly large RRs result \[[@b34-epih-40-e2018032]\]. It has been shown that the Gini coefficient can be used to determine the optimal MSWS \[[@b34-epih-40-e2018032]\]. To create a set of potential clusters based on the Gini index, first, the MSWS is defined with different upper limits for the size of the cluster, and then the hierarchical no-geographical-overlap approach is used to create a collection of clusters for each different upper limit. After that, the Gini index is calculated for a set of non-overlapping clusters of each upper limit, and the collection that maximizes the Gini index is the optimal upper limit \[[@b34-epih-40-e2018032]\]. Since the number of CL cases in each potential cluster has a Poisson distribution, the exponential model-based spatial scan statistic was used as a probability model to perform cluster analysis and testing. For each circular window (identified potential cluster), the likelihood ratio statistic under the Poisson distribution was calculated, as follows: c E c c C \- c C \- E c C \- c Where *C* is the total number of CL cases, *c* is the observed number of CL cases within the window, *E\[c\]* is the crude expected number of CL cases within the window under the null hypothesis, and *C-E\[c\]* is the expected number of CL cases outside the window. The cluster with the maximum log likelihood ratio was taken as the most likely cluster. The maximum likelihood method test was used for deviations from the null hypothesis that the number of CL cases inside and outside of the window would be equal (*H~o~: θ~in~=θ~out~* vs. the alternative hypothesis *H~a~: θ~in~≠θ~out~*). The statistical significance of the detected clusters was tested using MC hypothesis testing with 999 permutations. SaTScan version 9.4.2 (<https://www.satscan.org/>) developed by Kulldorff \[[@b35-epih-40-e2018032]\] was used for spatial cluster analysis. All cartographic manipulations and displays were performed in ArcGIS version 10.3 (Esri, Redlands, CA, USA). RESULTS ======= In total, 1,144 cases of CL were identified, with an incidence rate of 260 per 100,000 (86.66 per 100,000 in each year) during the study period. The MI for CL incidence showed a degree of negative spatial autocorrelation, although it was non-significant (MI, -0.12; p= 0.20 for 999 permutations). The results of the crude SIRs (a frequentist analysis), as well as estimates from the BYM model (a Bayesian analysis), are presented in detail in [Supplementary Materials 2](#SD2-epih-40-e2018032){ref-type="supplementary-material"}[](#SD3-epih-40-e2018032){ref-type="supplementary-material"}[](#SD4-epih-40-e2018032){ref-type="supplementary-material"}-[5](#SD5-epih-40-e2018032){ref-type="supplementary-material"}. As expected, the absence of any CL cases in some provinces resulted in a crude SIR of 0; however, by borrowing information from neighbors, the BYM model provided smoothed results and the SIRs of 0 disappeared. There was little difference between the SIRs estimated in the BYM model and the crude SIRs. The value of MC error (less than 5% of posterior SD) for the estimated smoothed SIRs indicated convergence in the MCMC algorithm. [Figure 1](#f1-epih-40-e2018032){ref-type="fig"} illustrates the smoothed SIRs from the BYM model for the time period of 2014 to 2017. [Figure 1](#f1-epih-40-e2018032){ref-type="fig"} suggests that the incidence of CL was highest in the provinces of Kermanshah (SIR, 67.60), Isfahan (SIR, 6.00), and Khuzestan (SIR, 2.34). [Figure 2](#f2-epih-40-e2018032){ref-type="fig"} illustrates the results of the SaTScan spatial analysis for the most likely cluster and secondary clusters 1 and 2 for the time period of 2014 to 2017. The results of the SaTScan spatial analysis are presented in detail in [Table 1](#t1-epih-40-e2018032){ref-type="table"}. The Gini index of 0.84 indicates great statistical dispersion among the detected clusters. The maximum size cluster was 10%. A total of 10 non-overlapping SaTScan highrate and low-rate clusters were identified, only 1 of which was not a statistically significant circular window. The SaTScan spatial analysis revealed that the most likely primary spatial high-rate cluster (observed to expected \[O/E\], 67.88; LRR, 1,200.62; p\< 0.001) was in Kermanshah Province, implying that the incidence of CL was 67.88 times greater within this cluster than in the rest of the study area during the study period. The most likely low-rate cluster (O/E, 0.03; LRR, 95.11; p\< 0.001) included Razavi Khorasan, North Khorasan, Semnan, and Golestan Provinces, implying that the incidence of CL was 33.33 times lower within this cluster than in the rest of the study area. The spatial patterns of the smoothed SIRs from the BYM model in the 3 distinct time periods of 2014-2015, 2015-2016 and 2016-2017 are shown in [Figure 3](#f3-epih-40-e2018032){ref-type="fig"}. The spatial pattern of the most likely high-rate and low-rate clusters from the SaTScan spatial analysis for the 3 time periods of 2014-2015, 2015-2016, and 2016-2017 are shown in [Supplementary Material 6](#SD6-epih-40-e2018032){ref-type="supplementary-material"}. The estimation performance of the BYM model and the SaTScan spatial analysis was similar. In 2014-2015, the highest rates occurred in Kermanshah Province (SIR, 95.93), followed by Isfahan and Khuzestan Province (SIR, 2.00-4.00) ([Figure 3A](#f3-epih-40-e2018032){ref-type="fig"}). In 2015-2016, the number of CL cases exceeded the expected values in the 4 provinces of Isfahan (SIR, 10.11), Khuzestan (SIR, 1.98), Kerman (SIR, 1.75), and Fars (SIR, 1.12) ([Figure 3B](#f3-epih-40-e2018032){ref-type="fig"}). However, in 2016- 2017, only 2 provinces (Isfahan and Khuzestan) were at an elevated risk for CL (e.g., the number of CL cases in Isfahan Province was 12.27 times higher than was expected) ([Figure 3C](#f3-epih-40-e2018032){ref-type="fig"}). DISCUSSION ========== Spatial analysis at different geographical levels can provide valuable information for developing policies to support the equitable distribution of healthcare and prevention resources. This study aimed to explore and map the spatial distribution of CL in IAUs, with cluster detection of CL incidence at the province level. The incidence of CL was 260 per 100,000 among IAUs during 2014- 2017 (86.66 per 100,000 in each year). A hierarchical Bayesian analysis showed a degree of inequality in the spatial distribution of CL, as the provinces of Isfahan, Khuzestan, Kermanshah, Kerman, and Fars had a higher than expected risk. The spatial scan statistic identified significant clusters that indicated that the most likely clusters of CL were primarily located in Kermanshah, Isfahan, and Khuzestan Provinces. In contrast, the most significant low-rate clusters of CL were identified in the northeastern provinces of Razavi Khorasan, North Khorasan, Golestan, and Semnan. In the present study, the annual incidence rate of CL in IAUs was found to be 86.66 per 100,000, which is in accordance with previous studies that have shown the incidence of CL in the military population to be higher than its incidence in the general population in Iran \[[@b16-epih-40-e2018032],[@b36-epih-40-e2018032]\]. For example, the study of Holakouie-Naieni et al. \[[@b36-epih-40-e2018032]\], which aimed to conduct spatial modeling of CL in Iran from 1983 to 2013, showed that the annual incidence of CL was 30.90 per 100,000 in the Iranian population. The study of Pakzad et al. \[[@b16-epih-40-e2018032]\], which compared the incidence of CL between IAUs and the general population during 2005-2014, showed that the incidence of CL in IAUs (143.68 per 100,000) was higher than the incidence in the general population (25.86 per 100,000). Based on a comparison with the study of Pakzad et al. \[[@b16-epih-40-e2018032]\] it can be deduced that a considerable decline in CL incidence had occurred among IAUs by 2014-2017. Military forces are one of the most vulnerable groups to CL, and special attention to this group is very important for the prevention and control of this disease. The employment conditions of the armed forces are unique, in that soldiers are forced to settle in rural, border, and marginal urban areas and to live in areas where leishmaniasis is endemic; moreover, due to occasional large-scale transportation (e.g., military operations), they transfer the disease to other parts of the country \[[@b17-epih-40-e2018032],[@b19-epih-40-e2018032],[@b37-epih-40-e2018032]\]. Our results showed that the estimation performance of the BYM model and the Poisson model was similar. This implies that there was no underlying extra-Poisson variability in the data and that the introduction of spatial and non-spatial structured random effects in the BYM model fitted to the dataset was of little value for mapping modeling. In other words, modeling a spatial structure when it does not actually exist in the data may lead to a phenomenon known as over-fitting. The main reason for applying the BYM model in the present study was to explain all residual spatial variation, so we focused on providing robust and valid RRs. Our results showed that there was a degree of negative spatial autocorrelation in the distribution of CL among IAUs, although it was non-significant. Moreover, we considered a diffuse prior (e.g., a gamma \[0.5, 0.005\] hyperprior) for the precision parameter of the spatial random effect, as this choice precludes imposing an artificial spatial structure on the data. Although the differences between the SIRs from the Poisson model and those from the BYM model were negligible, explaining structured and unstructured spatial residuals with the BYM model may lead to much less bias in the SIRs. Moreover, a simulation study suggested that the results of ecological associations from the BYM model may be the least biased, even when true extra-Poisson variability does not exist in the dataset \[[@b38-epih-40-e2018032]\]. Our study showed that the provinces located in the western (Kermanshah), central (Isfahan), and south and southwestern areas (Khuzestan) were at a higher risk for CL during the study period. The studies in this field have shown that provinces located in cold regions, such as northern and northwestern Iran, mostly along the Zagros and Alborz mountains, had a lower incidence of CL. Due to the high altitude of those regions, the common vector of CL cannot transmit the pathogen. It has been concluded that the incidence of CL has an inverse correlation with altitude, because cold has a negative effect on the survival of the vector and the parasite of CL \[[@b39-epih-40-e2018032]-[@b41-epih-40-e2018032]\]. Similarly, other studies have shown that dry and desert areas had higher incidence rates due to having appropriate temperatures for carriers and parasites \[[@b42-epih-40-e2018032]\]. Due to variability in climactic conditions and the distinct activities of military forces, the risk of outbreaks should always be considered. The SaTScan spatial analysis showed that the most likely cluster of higher than expected incidence of CL was located in Kermanshah Province. Kermanshah Province is located in a mountainous region along the Zagros mountains in Iran, but within this province, there exists great variability in climactic and ecological conditions, as some counties (e.g., Sarpol-e Zahab and Qasr-e-Shirin) are located in arid and tropical regions. Studies have shown that the majority of CL cases in Kermanshah Province could be attributed to the 2 counties of Sarpol-e Zahab and Qasr-e-Shirin, which have warm and dry weather that provides a suitable setting for the survival of the vector and parasite of CL \[[@b43-epih-40-e2018032],[@b44-epih-40-e2018032]\]. Thus, from the O/E ratio of 67.88 for the Kermanshah cluster, it can be concluded that when environmental conditions permit the chain of infection of CL to be established, outbreaks of CL can occur among army personnel to a remarkable extent. This study also showed that secondary and tertiary high-risk clusters were located in Isfahan and Khuzestan Provinces, respectively. These findings are consistent with studies conducted in this field \[[@b16-epih-40-e2018032],[@b17-epih-40-e2018032]\]. The existence of ideal environmental conditions for the vector, reservoir, and parasite of CL in these provinces has made them active foci for CL \[[@b45-epih-40-e2018032]-[@b47-epih-40-e2018032]\]. Additionally, inappropriate and inadequate sanitary facilities increase the chance of growth and proliferation of reservoirs (rodents) and vectors of CL in these 2 provinces. Our study has several limitations that should be considered. First, an obvious weakness of ecological studies, such as our study, is the ecological fallacy, whereby inferences on the aggregate level may not be true on the individual level. Second, the observed results may have been influenced by the modifiable areal unit problem, which is a well-known problem in geography in which results may be the function of the defined area units. Third, the estimated SIRs for CL may have been influenced by climactic variables, because the components of the chain of CL infection are all environmentally sensitive. However, data on climactic variables were not available in our study. Finally, we used a type of administrative and surveillance data, but results derived from such data should be interpreted with caution, because these data may not have been gathered for research purposes. In conclusion, our study showed that the incidence of CL in IAUs was distributed differently at the province level. Due to the distinct conditions of army personnel, outbreaks of CL in non-endemic areas such as Kermanshah are expected. Additionally, army personnel in regions with clusters of CL, such as Isfahan and Khuzestan Provinces, must be targeted for further prevention and control interventions. We would like to thank the staff of the deputy of health of AJA University of Medical Sciences for providing the data. The authors have no conflicts of interest to declare for this study. SUPPLEMENTARY MATERIALS ======================= Supplementary Material 1: OpenBUGS code for BYM model is available at <http://www.e-epih.org/>. Supplementary Material 2: Table S1 is available at <http://www.e-epih.org/>. Supplementary Material 3: Table S2 is available at <http://www.e-epih.org/>. Supplementary Material 4: Table S3 is available at <http://www.e-epih.org/>. Supplementary Material 5: Table S4 is available at <http://www.e-epih.org/>. Supplementary Material 6: Figure S1 is available at <http://www.e-epih.org/>. {#f1-epih-40-e2018032} {#f2-epih-40-e2018032} {#f3-epih-40-e2018032} ###### Characteristics of detected clusters with a higher or lower than expected incidence of CL in Iranian army units (2014-2017) Optimal Gini coefficient MSC Clusters detected Involved province(s) Observed cases Expected cases O/E RR^[1](#tfn1-epih-40-e2018032){ref-type="table-fn"}^ LLR p-value ----------- -------------------------- ----- ------------------- --------------------------------------------------- ---------------- ---------------- ------- ------------------------------------------------------ ---------- --------- Area rate  High 0.84 0.1 1 Kermanshah 353 5.20 67.88 97.73 1,200.62 \<0.001 2 Isfahan 454 75.40 6.02 9.33 513.24 \<0.001 3 Khuzestan 232 98.8 2.35 2.69 73.71 \<0.001  Low 1 Razavi Khorasan, North Khorasan, Semnan, Golestan 3 104.00 0.03 0.03 95.11 \<0.001 2 Zanjan, Qazvin, Hamadan, Kurdistan, Gilan 1 96.20 0.01 0.01 94.83 \<0.001 3 Kerman, South Khorasan, Hormozgan 15 114.40 0.13 0.12 73.57 \<0.001 4 East Azerbaijan 13 91 0.14 0.13 55.52 \<0.001 5 Bushehr, Fars 28 104 0.27 0.25 41.97 \<0.001 6 West Azerbaijan 2 31.20 0.06 0.06 24.08 \<0.001 7 Qom, Markazi 1 7.80 0.13 0.13 4.76 0.09 CL, cutaneous leishmaniasis; MSC, maximum size cluster; O/E, observed-to-expected; RR, relative risk; LLR, log likelihood ratio. RR was calculated as the observed number of cases divided by the expected number of cases within the cluster divided by the corresponding ratio outside the cluster.

Background {#Sec1} ========== Tiredness is universally understood as an uncomfortable and sometimes disabling symptom that can reduce or prevent physical and mental activity. However, there is little knowledge of its precise nature and cause at a physiological and biochemical level. Chronic or persistent fatigue is under recognised and was found in 30.5 % of 9035 randomly selected adults in the Netherlands interviewed by questionnaire \[[@CR1]\]. Importantly fatigue is a significant cause of impaired quality of life in a diverse range of illnesses including those with cardiorespiratory dysfunction, endocrinopathy, neurological impairment and neoplasia. While many illnesses are accompanied by fatigue, in only a few is it the main and most disabling symptom. In Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) fatigue is the predominant and most disabling symptom. It is frequently accompanied by several other symptoms that suggest a mixture of inflammatory, immune, viral and endocrine dysfunction \[[@CR2]--[@CR4]\]. Much has been written about CFS/ME in terms of physiology and psychology. There are conflicting views on its aetiology, diagnosis and management. Notwithstanding it is a relatively common condition with disabling fatigue as its primary problem \[[@CR5]\] and presently waiting a precise and universally accepted patho-physiologic explanation. It is generally known that specialised services for CFS/ME are insufficient in coping with the demand and sometimes inadequate in the range of therapies offered. Confidently diagnosing CFS/ME as the cause of persistent fatigue can help allay patient and doctor anxiety, reduce the need for expensive investigations, allow early intervention and encourage higher rates of improvement. Historical {#Sec2} ---------- George Beard introduced the term ***neurasthenia*** in 1869 to describe an illness with chronic fatigue as its main symptom. This became a 'respectable' diagnosis from 1910 until 1980. There are a large number of conditions previously meeting many of the criteria for CFS and preceded in some cases by specific etiologic agents. These include myalgic encephalomyelitis (ME), post viral fatigue syndrome (PVFS), chronic fatigue and immune dysfunction (CFIDS), post-infectious fatigue syndrome (PIFS), fibrositis and myalgia. Prevalence of fatigue {#Sec3} --------------------- Studies of the general population suggest a prevalence rate for CFS of between 0.2 and 2.6 % depending on the criteria used \[[@CR5], [@CR6]\]. More recent work suggests a figure of 1 % in the Netherlands \[[@CR1]\]. The institute of medicine (IOM) in the USA has recently estimated that between 836,000 and 2.5 million Americans have CFS/ME \[[@CR7]\]. This gives a prevalence rate of between 0.26 to 0.78 %. Most of the research on prognosis and treatment outcome has focussed on people attending specialist centres, who may be assumed to have more severe and complex difficulties. Nevertheless, studies suggest that a significant proportion of people with CFS/ME will continue to experience symptoms for some time \[[@CR5]\]. Indeed, fewer than 5--6 % of people with CFS/ME return to pre-morbid levels of functioning in the medium to long term \[[@CR6], [@CR8]\]. The prognosis in children is significantly better with 80 % returning to normal health or much improved with mild persisting disability \[[@CR9]\]. Improvement has been reported to be improved with intervention utilising a multidisciplinary treatment programme \[[@CR10]\]. The cost of unexplained fatigue and CFS/ME {#Sec4} ------------------------------------------ Medically unexplained persistent fatigue causes considerable stress and is expensive for both the patient personally and for the UK National Health Service (NHS). A significant number of patients in this category undergo a vast array of expensive laboratory, radiological and other investigations that help to 'exclude' unusual and rare causes of persistent fatigue. In my personal experience I have seen several patients who have undergone whole body Magnetic Resonance Imaging (MRI) scans, echocardiography, tests of mitochondrial function, nutrient analysis, complex tests of immune dysfunction and rare infections totalling well over £10,000. As indicated by Mechanic \[[@CR11]\] over two decades ago it can be difficult for doctors to know how far to pursue an underlying illness in a patient with ongoing and sometimes progressive symptoms. Quite often the cost equation is based on a mixture of the patient's and doctor's acceptance of uncertainty, the intellectual curiosity of the physician and the financial constraints of the individual and the healthcare system. From the perspective of the CFS/ME sufferer the illness has a major impact on their quality of life \[[@CR12]\], employment and in consequence household finance. Indeed approximately 50 % have had to cease employment as a result of their fatigue and other symptoms \[[@CR13]\]. In the case of parents with children with CFS/ME, there was not only a net monthly loss of £247 per household but also increased expenditure of a similar amount \[[@CR14]\]. Additionally, nearly three quarters of mothers of children with CFS/ME had a significantly impaired psychological health as assessed by the general health questionnaire-12 \[[@CR14]\]. In the USA, Jason et al. \[[@CR15]\] determined that CFS/ME cost the economy £9.1 billion based on '37 % decline in household productivity and a 54 % reduction in labor force productivity'. A more recent economic calculation by the Institute of Medicine (IOM) based on an analysis of the relevant literature suggested figures of between \$17 billion to \$24 billion. Diagnosing CFS/ME based on recognised criteria {#Sec5} ---------------------------------------------- Disabling fatigue that is sufficient to impair work, school and leisure activities and present for 6 months in adults and 3 months in children (in the UK the figures are over 4 months for adults and 3 months in children) is the hallmark of CFS/ME. However, it is hoped that diagnosis and therapy is offered as early as possible and especially in children. Nevertheless, all CFS/ME criteria were originally devised to standardise the diagnosis for research purposes. As happens frequently with many research criteria they have over time formed the basis for routine clinical diagnosis and with varying degrees of success. One of the earliest of the CFS/ME criteria included that formulated by Holmes et al. in 1988 \[[@CR16]\] from the US Centre for Disease Control (CDC). These were drafted to help standardise the patient population for research purposes and to avoid the connection with viral infection after investigations failed to confirm past or current infections. The 1994 revision of the CDC case definition by Fukuda et al. \[[@CR17]\] remained the main diagnostic CFS/ME criteria for several years and was used for patient selection in numerous research reports. However, the centrality of the delayed post exertion malaise that characterises CFS was lacking and in 2003 Carruthers proposed the Canadian criteria \[[@CR18]\]. More recently the international ME criteria \[[@CR19]\] have been drafted and both this and the Canadian criteria placed greater emphasis on the exacerbation of physical and mental symptoms by over activity. Unfortunately both sets of criteria are cumbersome and not easily adapted for routine use and particularly in primary care. The most recent criteria for CFS/ME have been proposed by the IOM \[[@CR7]\]. These are simpler to use than previous suggestions but unfortunately do not stringently exclude psychiatric illness. Furthermore, it also appears to select patients with lesser degrees of functional disability and with fewer symptoms \[[@CR20]\]. In the absence of diagnostic symptoms, signs and laboratory abnormalities, the confirmation of CFS/ME as the cause of persistent fatigue is presently based on the exclusion of an underlying medical and psychiatric illness known to be associated with fatigue. However, many primary care physicians have had no undergraduate or postgraduate training in the diagnosis of CFS/ME \[[@CR21], [@CR22]\] nor indeed in its management. In a recent report from a tertiary CFS/ME centre, confirmation of CFS/ME as a cause of persistent disabling fatigue was only evident in 23.3 % of the 279 patients studied. In 21.1 %, the CFS was accompanied by a sleep disorder and/or psychiatric disorder '...not invalidating the diagnosis of CFS'. In the remaining patients, 9.7 % had a predominant sleep disorder, 19.0 % had a psychiatric disorder and 20.8 % a combination of both. In only 2.2 % was 'a classical internal disease' evident \[[@CR23]\]. With the above facts in mind and with certain knowledge about limited financial and manpower resources, I examined in 2008 the most frequent symptoms suffered by those with CFS/ME. These were weighted according to their importance in diagnosing the condition and to the exclusion of other causes of prolonged unexplained fatigue. The hospital and anxiety depression scale \[[@CR24]\] was used to check for significant associated psychological dysfunction and a panel of basic blood investigations used to check for inflammation, autoimmunity, endocrinopathy and organ dysfunction. Patients with CFS/ME diagnosed in this way have been followed in the clinic for up to 7 years and an alternative explanation for the fatigue has been not been forthcoming in any patient. Symptoms and signs noted most frequently in CFS/ME {#Sec6} -------------------------------------------------- In addition to fatigue, individuals with CFS report a variety of other symptoms. These include musculoskeletal pain, sleep disturbance, impairment in short term memory and concentration, sore throat, and headaches of new type, pattern and severity \[[@CR5]--[@CR7]\]. In nearly all cases there is a delayed exacerbation of these symptoms, but particularly the fatigue, by any form of mental or physical exertion. This often leads to withdrawal from a wide range of activities. Symptom severity frequently, and often unpredictably, fluctuates on a daily or weekly basis. This often makes it difficult for patients to plan activities. The unpredictability of set backs contributes significantly to low mood and anxiety which in turn often perpetuates and aggravates CFS symptoms. The frequency of symptoms reported by CFS/ME patients seen in the Sutton CFS service are detailed in Table [1](#Tab1){ref-type="table"}. The results are based on the more than two thousand two hundred patients seen here between 2008 and 2015. When significant, intrusive and present for over 50 % of the time these symptoms are used in helping in the diagnosis of CFS and are included in many of the recent CFS/ME criteria. In contrast there are few signs that are easily discerned on the casual examination. Noteworthy, however, are the presence of an increased respiratory rate with intermittent bouts of sighing, and coldness of the extremities in those with moderate or worse CFS/ME. The reaction of the pupils to direct and prolonged illumination is unusual and the precise mechanism is unclear. These are discussed below.Table 1Symptoms and signs most frequently noted in those with CFS/MESymptomsSignsAching muscles, 90 %+,Pharyngitis, 25 %Non-Restorative sleep, 95 %+Cervical tenderness with or without lymphadenopathy 25 %Daytime nap 3+ times per week, 30 %Muscle weakness, 90 %+Axillary lymph nodes 10 %Impaired concentration, 90 %Cold peripheries in moderate, severe and very severe ME −70 + %Forgetfulness, 85 %Muddled thinking, 80 %+Aching joints, 85 %+Temperature \>37.5C but \<39.0C, 10 %Stress aggravated Fatigue, 90 %Increased respiratory rate, 80 + %Headaches 75 %Altered pupil reflexes, 60 %Weight gain, 50 %Orthostatic intolerance 60 % \[according to the IOM -- \[[@CR7]\] Adapting presently recognised CFS/ME criteria for use in primary care {#Sec7} --------------------------------------------------------------------- After long careful scrutiny of the various CFS/ME criteria and collation of the most important symptoms suffered by those with CFS/ME, I developed a scoring system to help colleagues to diagnose this condition in people presenting with fatigue. This is detailed in Table [2](#Tab2){ref-type="table"} and guidance on the frequency and severity of each symptom is detailed subsequently. As suggested by Jason et al. \[[@CR25]\] a minimum frequency of 50 % and least moderate severity of each symptom is critical in helping to confirm CFS/ME as the mere presence of each may be evident even in a third of healthy controls.Table 2Details of the important symptoms that characterise CFS/ME and their respective scores. See text for further detailsFactorScoreDelayed prolonged post-exertion malaise after increases in physical, mental & emotional activity3Non-restorative sleep with frequent difficulty initiating and/or maintaining sleep2Impaired concentration that is reduced further by external stimuli1Reduced short term memory with word finding difficulty1New onset headaches (\>2/mth and different in character from previous headaches)1Sore throat with cervical tenderness/recurrent flu-like episodes1Arthralgia affecting several joints with stiffness \>1 hr but no swelling1Myalgia affecting multiple groups and exacerbated by mild exertion1Postural instability feeling unstable on standing, prolonged standing or sitting1Hypersensitivity to sounds and lights (smells and to a lesser degree taste also)1 Unfortunately there is no gold standard for diagnosing CFS/ME and certainly there are no specific laboratory or radiological tests available. Nevertheless, the scoring system has now been used in the Sutton CFS/ME service for the last 7 years and assessed in well over two thousand consecutively seen patients. When used in conjunction with the baseline investigations listed in Table [3](#Tab3){ref-type="table"}, it has proven to be remarkably robust when used by a range of healthcare personnel including physicians, nurses and physiotherapists. Indeed the scoring system has positively diagnosed CFS/ME to the exclusion of other causes in even quite complicated cases.Table 3Basic investigations in patients with prolonged fatigue of unknown causeInvestigationCommentsFBCAnaemia, polycythaemia, haematological malignancy can all be associated with fatigue. Red cell MCV may indicate need to check ferritin if reduced and vitamin B12 and folate deficiency if raised.ESRThis is a good test of overall immune activation and a raised level should encourage an assessment of infection, autoimmunity, certain solid organ neoplasms and possible lymphoproliferation.CRPA raised level suggests inflammation somewhere. Where the source of the inflammation is not obvious from the history consider the sinuses, urinary tractUrea, creatinine, electrolytes and Liver Function testsDysfunction in both areas can be accompanied by fatigue. There is an interesting association between Gilberts disease and fatigue \[[@CR81]\] The mechanism is unknown.Thyroid function testsBoth hypo and hyper-thyroidism can be accompanied by fatigue. In a small proportion of patients with anti-thyroid peroxidase antibodies but essentially normal T4 and TSH, low dose thyroxine can be helpful.Autoimmune profile on tissue blockCan help check for Sjogren's syndrome, early primary biliary cirrhosis and autoimmune hepatitis and atropic gastitris. The latter can be associated with vitamin B12 deficiency. A positive ANA here may encourage further tests of autoimmunity.Anti-Tissue Transglutaminase (TTg) or endomysial antibodiesCoeliac disease can present with fatigue and without bowel symptoms.Immunoglobulins and serum protein electrophoresisSerum immunoglobulins are low in antibody deficiency but raised in chronic inflammation/infection. Both conditions can be accompanied by marked fatigueUrine dipstick analysisSimple check for renal inflammation/infection and renal tumours. Using the CFS/ME scoring criteria {#Sec8} --------------------------------- The diagnosis of CFS/ME in adults is based on the presence of variably disabling fatigue of at least 4 months duration (6 months outside of the UK) and 8 or more from 13 points awarded for each of the symptoms and factors detailed in Table [2](#Tab2){ref-type="table"}. However, there is an absolute requirement for some form of post-exertion malaise (PEM) after physical, mental and emotional over activity. To attract the maximum 3 points the PEM must be delayed by at least 12 h after the completion of the specific activity and the extra fatigue and additional ill health must be prolonged with a duration exceeding 24 h. Note that in children the PEM can be immediate and particularly in the very young children. If the PEM is more immediate and certainly less than 3 h after extra activity but the duration is still over 24 h then 2 points are awarded. A rapid PEM (\<1 h) lasting less than 24 h gives 1 point. Alternative causes of the fatigue must be considered if it occurs simultaneously and commensurately with the physical over activity and particularly if there are any cardiorespiratory symptoms. Unrefreshing sleep is a frequently reported by both young and old patients with CFS \[[@CR26]--[@CR28]\] and a disturbance of sleep has been demonstrated on polysomnography by several investigators \[[@CR29]--[@CR32]\]. Many CFS subjects also suffer difficulty with sleep initiation and maintaining sleep \[[@CR29], [@CR32]\]. A demonstrable reduction in the percentage of stage 4 sleep was evident in these patients on polysomnography \[[@CR29]\]. Non-restorative sleep (NRS) affects over 90 % of patients with CFS/ME and often occurs in most, if not every, night. It is important that obstructive sleep apnoea, frequent waking from pain and urinary symptoms are excluded as a cause of NRS. Sleep studies are recommended if there are concerns as to the importance of sleep disturbance in those with chronic fatigue. This is important as recent work suggests that a primary sleep disturbance may explain fatigue in almost a fifth of patients with Fukuda criteria confirmed CFS/ME and is a comorbid problem in a similar proportion \[[@CR23]\]. Two points are given if the NRS is accompanied by difficulty initiating and maintaining the sleep at night time and these difficulties are evident for 5 or more nights per week. However, if the NRS is not accompanied by difficulty initiating or staying asleep this gives 1 point. In both cases the non-restorative nature of the sleep disturbance must persist with hypnotics which many patients use to initiate sleep. Regarding, the neurocognitive problems faced by those with CFS, the two that appear to be most disabling are the impaired concentration and short term memory. These are aggravated by extraneous noise, bright lights and movement. Word finding difficulty is especially frequent and 'following' a conversation is often mentioned as being difficult especially one involving an unfamiliar topic. Both the reduced concentration and the impaired memory are given one point each although it may be argued that the two are related. Thus concentration is required to acquire memory and the latter may be reduced because of problems with the former. Notwithstanding, we have recently shown that deficits in recall are more significant for retrospective than prospective memory and that fatigue, depression and general efficacy were most linked with cognitive failures \[[@CR33]\]. The aching of the muscles of the axial and appendicular skeleton has a quality similar to that experienced when an individual has a viral infection. The muscle creatine kinase is normal and while there is no clear evidence of muscle damage, some have reported mitochondrial abnormalities \[[@CR34]\] and virus like particles. In the absence of fibromyalgia there is no significant and painful tenderness of the muscles. The latter can be seen in polymyositis which like many of the systemic connective tissue disorders can be accompanied by fatigue in a significant proportion of patients \[[@CR35], [@CR36]\]. The arthralgia in CFS/ME is rarely accompanied by joint swelling and there is no synovitis. The majority of patients mention stiffness of the joints which can last over one hour in the morning. Both the myalgia and the arthralgia give one point each only if these symptoms are evident for more than half of the patient's waking hours and the myalgia is aggravated by low level activity. The mechanism of the hypersensitivity to lights and sounds and sometimes smells is unusual and this symptom is rarely seen in any other condition. In this respect some patients with significant CFS/ME may chose to wear sunglasses even in normal daylight. For some the hypersensitivity to smells contributes to their continual nausea. It is unclear whether the myalgia and arthralgia reflect a general hypersensitivity to all sensory stimuli but both need to be present for more than half of the waking time to attract one point each. Many CFS/ME patients report that their joint pain is accompanied by stiffness which lasts for hours and may be present all the time. The joint stiffness in rheumatoid arthritis and the recognised connective tissue disorders is nearly always worse after rest and inactivity and in the morning tends to last only a couple of hours or so. In these conditions synovitis with swelling and warmth of the joints is often seen and particularly with acute flares of disease activity. In contrast joint swelling and warmth was rarely, if ever, seen in any of our CFS/ME patients. Where there is doubt, blood tests looking for inflammation, immune activation and autoimmunity can be very helpful. Sore throat and flu like sensations have been suggested to support the notion that CFS/ME is due to an unrecognised viral infection that activates recurrently. However, throat swabs rarely prove positive for either bacteria or the commonly recognised viruses. Regardless, the sore throat is frequently associated with tenderness of the anterior and sometimes posterior neck although actual lymphadenopathy is frequently absent. To score a point this symptom must be evident one or more day per week and for at least the previous four months. In reference to the flu like sensations these often cause aching of the body and with a low grade fever or sensation of being hot and sweaty. In my experience these can last several hours at a time and occur at least once per week in over two thirds of patients. The presence of eight or more points out of thirteen gives a high probability that the patient has CFS/ME. For research studies I would suggest that subjects should have ten or more. This is the case for the research undertaken at this institution. In borderline cases where the subject has prolonged unexplained fatigue but scores only 7 points, the presence of certain other unusual features may be used to confirm the diagnosis of CFS/ME. These include alcohol intolerance, hypersensitivity to medications, perpetually cold hands and feet and an unusual recurrent sighing pattern of respiration. Assessing chronically fatigued patients with borderline scores {#Sec9} -------------------------------------------------------------- Additional features that may suggest CFS/ME in those with borderline scores include alcohol intolerance which we see in four fifths of our patients. This often commences soon after the onset of the CFS/ME symptoms. In the only other report on this issue, Wooley et al. \[[@CR37]\] reported 67 % of their 114 patients with CFS reducing their intake of alcohol as it made their fatigue worse. In our experience nearly all patients with CFS have reduced their intake of alcohol and I have not seen a single patient who had increased his/her alcohol intake. Moreover, tolerance of 4 units or more of alcohol in a single sitting is unusual and encourages us to revaluate the diagnosis. In this regard fewer than 20 % our patients continue regular alcohol ingestion although even here the amount consumed has been decreased. In regard to a hypersensitivity to drugs this is especially evident to serotonin specific reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) and we see this in at least half of our patients. The hypersensitivity leads many with CFS/ME offered this type of treatment to cease the medication within the first week of commencement. Often this is due to marked imbalance, state of dysreality and general increase in the fatigue and other CFS/ME symptoms. I would suggest that patients with CFS/ME who have developed depression should be commenced at one quarter of the lowest starting dose for a week. This is doubled over the next 2 weeks and subsequent increases are undertaken according to the patient's response. Many people with CFS/ME mention that their hands and feet are perpetually cold. This is often evident on shaking the patient's hand and is seen in over three quarters of patients with moderate or severe CFS/ME. In those with mild CFS/ME, cold peripheries are evident less frequently and in my experience probably a quarter or less of the patients will be aware of this problem. In a small proportion of CFS/ME patients features highly suggestive of acrocyanosis are evident. In my estimation this is less than 5 % although it is interesting that acrocyanosis may be present in 50 % in those with the postural orthostatic tachycardia syndrome (POTS) \[[@CR38]\]. Regardless, the mechanism of the cold peripheries is unclear but may relate to persistently high adrenaline/noradrenaline levels causing peripheral vasoconstriction with a view to maintaining central blood pressure and perfusion of the vital organs. A similar mechanism as well as possible primary hypovolumaemia and adrenaline receptor autoimmunity is proposed in patients with POTS \[[@CR38]\] and the latter is especially frequent in CFS/ME \[[@CR39], [@CR40]\]. More frequent still is orthostatic intolerance suggested to affect over 60 % of CFS/ME patients in the IOM report \[[@CR7]\]. The overlap between CFS/ME and POTS is intriguing as both have fatigue, disturbed sleep and impaired mental processing as frequent symptoms. Further work is clearly required to determine precise differences and overlap between these conditions which may influence and direct specific treatment strategies. Equally important would be investigations into the value of measuring orthostatic intolerance in the clinic as a test aiding the diagnosis of CFS/ME. The respiratory rate in patients with CFS/ME has been infrequently studied. However, hypocapnia has been described in CFS both at rest and on tilt table testing \[[@CR41]\]. However, Saisch et al. \[[@CR42]\] found only a weak association between hyperventilation and fatigue symptoms in 30 patients diagnosed with CFS on the basis of the Oxford and CDC criteria. Regardless, clinical symptoms suggestive of hyperventilation are seen in about of quarter of our patients but many more have an increased respiratory rate. Indeed in the experience of this unit we see an increased respiratory rate in approximately 80 %. This is only slightly less than the 93 % observed in the 100 patients with ME or post-viral fatigue investigated by Rosen et al. \[[@CR43]\]. Interestingly, efforts to reduce the tendency to hyperventilation using breathing control exercises have been found helpful in about a third of our patients in terms of reducing fatigue, impaired concentration and memory and brain fog. These breathing control exercises include the Butekyo method, mindfulness meditation and abdominal breathing exercises. In a smaller proportion of cases the regulation of fast breathing has improved episodes of dysreality that were suggestive of hypocapnia. Abnormalities of the pupils to light are seen in patients with cerebral ischaemic events, certain brain neoplasms, local disturbance in neural transmission and demyelination. Checking the pupil reflexes is often undertaken to detect alterations in the brainstem pathways mediating the perception of light, accommodation to distance and near vision and changes based on ambient illumination. In patients with CFS/ME I have observed two unusual responses that are evident on prolonged illumination of the pupils. The more frequent finding seen in three quarters of patients is a rhythmic contraction and dilatation of the pupils. The second pattern is a paradoxical dilation of the pupils after an initial contraction. The latter is seen in patients with autoimmune autonomic neuropathy that is caused by IgG antibodies to the ganglionic acetylcholine receptor \[[@CR44]\]. However, these auto-antibodies are absent in the patients with CFS with this type of pupil abnormality. Interestingly these CFS/ME patients are more frequently faint on standing, have poor tolerance of prolonged standing and other features of POTS. In my experience other symptoms of a more generalised autonomic neuropathy are absent. The cause of these changes in the pupil reflexes is unclear but a persistent state of adrenergic over activity may be involved. This may oppose the constricting action of direct pupil illumination and produce the fluctuating response in many and a more significant but delayed dilatation in others. Interestingly, a delay in pupil constriction to direct light was reported in depressed patients by Fountoulakis et al. \[[@CR45]\] and attributed to reduced noradrenergic tone. From a clinical perspective, the above five features of CFS/ME may help in confirming the diagnosis when patients have borderline main criteria or where there is doubt for other reasons. In this case the presence of three or more of these additional points of cold peripheries, alcohol intolerance, drug hypersensitivity, altered pupil reflexes and altered respiration gives one extra point. Investigating unexplained fatigue {#Sec10} --------------------------------- It cannot be emphasized enough that the most important part of the diagnostic process in investigating unexplained prolonged fatigue and suspected CFS/ME is a full and careful history and examination. The aforementioned scoring system appears in our hands to be especially useful in diagnosing CFS/ME and distinguishing it from other causes of prolonged fatigue. Unfortunately there is presently no one diagnostic test for CFS/ME. However, a few basic and readily available tests are important to check for the presence of inflammation, immune activation, essential organ dysfunction, endocrine abnormalities, gluten sensitivity and autoimmunity. These tests are detailed in Table [3](#Tab3){ref-type="table"} and negative/normal results make other causes of the fatigue very unlikely. Performed within NHS laboratories the total cost of these tests in 2015 is less than £80. Additional tests may be needed in a small proportion of people and these are guided by the presence of specific symptoms. Other tests are guided by a history of specific exposures to infectious agents such as to ticks which can be associated with Lyme disease. The list here is not exhaustive and further detailed tests may needed and again these are guided by specific patterns of muscle disease, sensory abnormalities, joint problems or endocrine abnormalities. Given the absence of universally acknowledged effective treatment that restores the person back to premorbid health, I would not presently recommend expensive tests of immune and muscle function, nutrient analysis and in depth brain imaging. These tests are best performed in specific research projects and include the enumeration of NK cell numbers, assessment of NK cell cytotoxicity, T and B cell subset analysis and checks of serum/plasma Th1/Th2/Tregs/Th17 associated cytokines. For the same reasons I think it is presently unwise to assess RNAse L levels and perforin activity as there are no easily administered low cost low toxicity treatments presently available. Tests of mitochondrial function are also available but it is presently unclear how these are altered in such a marked and diverse way by inactivity alone. Additionally, the treatments recommended to correct mitochondrial deficiencies are nutritional supplements that that are readily available at modest cost and with virtually no side effects when taken according at recommended daily allowance (RDA). As such a simple trial of these therapies for two or three months may be safely undertaken and without the need for the expensive tests. In my experience the use of these supplements may partially help some of the symptoms of CFS in a small group of patients for a variable period of time but no one has been cured. After full clinical history and examination the tests detailed in Table [4](#Tab4){ref-type="table"} may be considered. Several points in the patient's clinical history may be relevant in tailoring subsequent therapy but are not used in making or supporting the diagnosis of CFS/ME. These include significant negative life events at the time of onset of CFS/ME symptoms. Indeed stress at the time of a triggering infection or event is reported by over half of the patients seen in this service. It is possible that this may impair cellular immune functioning that allows greater viral dissemination and reduced clearance that perpetuates the fatigue and other symptoms \[[@CR46]\]. In these individuals the onset of the CFS is relatively acute and symptoms noted over a period of several days or a few weeks. In others the onset is gradual over many weeks and sometimes months but on-going stress does appear to be evident in the most of the patients. Physical Injury precipitating CFS appears to be rare although there is some evidence that it can lead to fibromyalgia. In contrast CFS/ME occurring after an operation is seen occasionally and perhaps one in fifty patients. Whether the anticipation and the associated stress are important is unclear. Environmental toxins have long been cited as contributing to CFS/ME and organophosphate pesticides as well as multiple vaccinations in the gulf war syndrome are two notable examples \[[@CR47]\].Table 4Further investigations in patients with chronic fatigue of unknown causeClinical Symptoms/SignsAdditional investigationsEvidence of Connective Tissue Disease suggested by Raynaud's phenomenon, mouth ulcers, photosensitive rash, serositis, synovitis,Anti-nuclear antibody assessment on Hep2 cells, antibodies to ENA and dsDNA. Rheumatoid factor analysis and anti-CCP antibodiesMuscle tenderness or history of significant exercise related crampsCreatine Kinase, Lactic dehydrogenase, Liver function tests. Consider EMG and possibly muscle biopsy. Referral for late presenting inherited muscle or glycogen storage diseases.Widespread aches and pains especially in older womenSerum calcium and magnesium estimation and DEXA scan for osteoporosis and hyperparathyroidism. Serum immunoglobulin assessment in basic panel will check for myeloma.Addison's/Cushings diseaseSynacthen/Dexamethasone suppression test. Random cortisol levels can be reduced in CFS/ME and synacthen is advised. Cortisol awakening response is blunted in CFS/ME and might relate to the exacerbation of fatigue in the morning with difficulty getting up in some patients.Tick bites with erythematous rashes and arthralgia and fatigueSerology for Lyme disease -- care with interpretation of results and particularly with results from non-approved laboratories. Lyme disease is rare in the UK especially in areas without deer populations.Neurological abnormalities, reduced mental acuity and progressive confusion, leg weakness and bladder/bowel problemsMRI/CTscan of brain for cerebral atrophy, ischaemic areas, plaques of demyelination, tumours in frontal lobes/para-saggital area and possible Arnold Chiara malformation. Consider also neuropsychological testing.Intolerance of prolonged standing, recurrent syncope/presyncope, tachycardia within 10 min of standing or marked hypotension on standing with tachycardia.Tilt table testing for autonomic dysfunction and further evaluation for postural orthostatic tachycardia'Clicky' joints with previous dislocation(s), early stretch marks and easy bruisingConsider referral for formal evaluation of an underlying or complicating joint hypermobility syndrome.Significant sleep disturbanceSleep studies. Frequent sleep arousals can cause marked daytime fatigue. A family history of CFS/ME and certain personality traits are also noted to be increased in those with CFS/ME including conscientiousness and high personal and parental expectations \[[@CR48]\]. Ciccone et al. \[[@CR49]\] while noting a higher prevalence of psychiatric illness and personality disorder in CFS/ME did not find any major correlation between these and levels of physical functioning and disability. More recently we have noted an increased frequency of CFS/ME symptoms in those with borderline personality disorder which has not hitherto been reported. Previous work has also suggested an increased prevalence of childhood physical, emotional and sexual abuse in those with idiopathic chronic fatigue and chronic fatigue associated with medical and psychiatric illness \[[@CR50]\]. Borsnini et al. \[[@CR51]\] have also confirmed childhood stressors to increase the possibility of subsequent CFS/ME. We do not routinely explore this area in detail as it seldom helps to reduce the symptoms of CFS/ME but does have the possibility of aggravating matters by raising stress and anxiety levels. In some instances where the past impacts significantly on the present, referral to an appropriate psychologist may be helpful. However, patients are warned that there may be an initial deterioration in symptoms before any improvement. Important considerations in the differential diagnosis of CFS/ME {#Sec11} ---------------------------------------------------------------- While virtually all illness is accompanied by at least some fatigue, this is the major problem in those with CFS/ME. The illnesses that have significant levels of fatigue as the main symptom and which may pose greatest difficulty in diagnosis are detailed in Table [5](#Tab5){ref-type="table"}. For many there are laboratory and/or radiological tests available that may establish the diagnosis once the condition has been considered. How joint hypermobility causes significant fatigue is unclear but chronic fatigue was observed in 82 % of 466 adults with self reported JHS assessed by Murray et al. \[[@CR52]\] in an extended on-line questionnaire. Interestingly persistent anxiety and depression were also very frequent in this group of individuals \[[@CR52]\]. In children, JHS has been reported to be much more frequent in those with CFS/ME and with an odds ratio of 3.5 \[[@CR53]\]. In my experience JHS is present in approximately 20 % of patients with CFS/ME and the majority will have Ehlers Danlos Syndrome joint hypermobility type. Interestingly, patients with JHS had a significantly higher frequency of orthostatic intolerance than healthy controls \[[@CR54]\]. In patients with Ehlers Danlos syndrome joint hypermobility type, fatigue is especially frequent and appears related to the degree of orthostatic intolerance \[[@CR55]\]. The present CFS/ME definitions do not consider Ehlers Danlos Syndrome joint hypermobility or JHS as exclusionary conditions. However, the overlap between these conditions and CFS/ME is significant and appears to be underestimated. Future research in CFS/ME needs to separate these groups to see if distinct patho-physiological mechanisms are operative.Table 5Differential diagnosis in patients with prolonged fatigue of unknown causeEasily missed conditions that may cause unexplained fatigueCommentsEhlers Danlos Syndrome type 3 - Joint hypermobility typeUnclear how this predisposes to chronic fatigue and CFS/ME but muscle strengthening around joints and the back can be helpful but not curative.Hypothyroidism, Addison's disease and Pituitary dysfunctionCare with post traumatic head injury leading to pituitary dysfunction -- check for significant head injury even years beforehand. Consider synacthen and glucagon stimulation tests.Sjogren's syndrome, early PBC, other CTDNote that dry eyes and mouth without overt Sjogren's syndrome can be seen in CFS/ME. The autoimmune profile, serum immunoglobulin assessment and ESR should help check for these possibilities.Coeliac diseasePeople with anti-TTg antibodies but without overt celiac disease evident on duodenal biopsy can sometimes see an improvement in their fatigue on gluten avoidanceGeneralised anxiety disorder (GAD) and depressionImportant to note that anxiety and depression can complicate CFS/ME and treatment for these can help fatigue overall.Primary disorders of sleepWhile obstructive sleep apnea can be associated with fatigue and day time sleeping, frequent sleep arousals without significant episodes of apnea can also lead to persistent daytime fatigue.Early dementia, multiple sclerosis and Parkinson's diseaseMS can be associated with marked fatigue, however, the twitching, sensory symptoms and blurring in CFS/ME are brief lasting less than a couple of hours while those in MS last days and weeks. Diagnosing CFS/ME in the elderly is more difficult and several neurological conditions can cause marked fatigue. Fatigue is frequent in early Parkinson's disease.Postural orthostatic tachycardia (POTS)This may be a primary condition with associated fatigue but without the other symptoms of CFS/ME. However POTS is also not uncommon in those with moderate and severe CFS/ME as is vaso-vagal syncope.*Other conditionsThere are several conditions in this category that include cardiac dysfunction, temporomandibular disorder but which are very rare.* Early dementia can rarely present with chronic fatigue and the diagnosis can be very difficult. Two out of the two thousand patients seen in this service had early dementia presenting with fatigue as the main problem. Neuropsychological testing can be helpful and cerebral imaging increasingly useful with disease progression. The Epworth sleep scale is an easily completed self rated questionnaire that can help in the investigation of sleep disturbance in chronic fatigue. A score of 16 or more should encourage a search for sleep factors that may be impacting on the chronic fatigue. This is especially helpful in those patients with significant snoring and high body mass index (BMI). CFS/ME and depression {#Sec12} --------------------- It is commonly acknowledged that fatigue is commonly seen in patients with depression and indeed many other mental illnesses. However, there are several features that show clear difference between those with depression and those with CFS whose illness has not been complicated by depression and anxiety. These are summarised in Table [6](#Tab6){ref-type="table"}. CFS/ME has been, and continues to be, considered by many as a somatisation disorder (see Lakhan and Schofield \[[@CR56]\]). Two points have been used to support this assertion. Firstly the relatively high rate of past psychiatric illness in those with CFS/ME. Thus previous work using the older CFS/ME criteria suggested that two thirds of patients had features of a major depressive illness and one half of all patients with CFS had experienced at least one episode of major depression \[[@CR57], [@CR58]\]. More recently, Nater et al. \[[@CR59]\] using a patient completed Structured Clinical Interview for DSM-IV reported almost nine tenths of CFS patients had one or more lifetime psychiatric diagnosis and over half had one current psychiatric diagnosis. Using the more recent Canadian and International ME criteria to confirm CFS/ME, the frequency of depression is much less \[[@CR60]\] and these criteria do appear to select out those individuals in whom depression may be a significant factor in chronic fatigue.Table 6Clinical features that help to distinguish depression and CFS/MEVariableDepressionCFS/MEPhysical ExertionExercise can improve mood and energy levels overallNearly always causes delayed worsening of the fatigue and other symptomsMoodLowUsually normalMotivationReducedNormal in the majority and in the absence of complicating depressionSleepEarly morning wakening common but difficult initiating sleep also seenDifficulty initiating sleep and getting up in the morningMemoryOften rumination about the past and feelings of guiltWord finding difficulty and precise recollection of recent events.ConcentrationIf engaged can be normalImpaired especially with extraneous noise and movementEnergyPersistently low but with only minor day to day variability and no delayed post-exertion worseningVariable from day to day and accompanied by delayed worsening with physical, mental and emotional exertionAppetiteLow. Weight can go down.Normal. Weight either maintained or sometimes increased.AffectOne of sadness. Reduced spontaneity of action and of facial expressionNormal. Frustration and sometimes anger seen.Interest in outside lifeReduced. No desire to complete previous hobbies or see family and friendsMaintained. Impaired energy reduces ability to continue with hobbies, social life and leisure activities.Response to anti-depressantsFatigue may be improvedLittle or no response if no complicating depression and many are hypersensitive to normal starting doses. The second issue concerns the high frequency of depression associated symptoms in those with CFS. As such the fatigue, non-refreshing sleep, bodily aches, impaired concentration and memory observed in depression has been used to support the notion that those with CFS must have depression if they do not have laboratory evidence of an organic illness. Interestingly the nature of fatigue in depression has not been well investigated and only recently has it been investigated in illnesses presently recognised to be the result of organic processes. These include particularly Sjogren's syndrome, celiac disease, primary biliary cirrhosis and multiple sclerosis. Regardless, the present focus of treatment in CFS/ME in the UK remains centred on the correction of disordered thought processes in relation to fatigue. These include challenging unhelpful patterns of thought as part of CBT, encouraging the patient to do more as means of correcting muscle deconditioning, encouraging them to relax and reduce the ability of adrenaline to deplete mental energy reserves. Further therapies utilising tricyclic anti-depressants (TCA), serotonin specific reuptake inhibitors (SSRI) and serotonin and noradrenline reuptake inhibitors (SNRI) have the aim of increasing the patient's sense of well being and reducing depression. Thus many consider the symptoms of CFS/ME to be primarily psychological in nature. However, significantly low mood is denied by the majority of patients with CFS and particularly by those who have recovered from depression and recognise its clinical features. The majority of patients with CFS/ME are keen to deny that they have depression. Certainly their affect does not often suggest this as a major problem. However, as with all chronic illnesses, depression can set in if the disabling symptoms remain unexplained, there is unpredictability of relapses and there is no improvement despite the best efforts of the patient and his/her physicians. In this regard comorbid depression was noted in a fifth of the Fukada criteria diagnosed patients reported by Mariman et al. \[[@CR23]\]. Three points are relevant in distinguishing depression and CFS/ME. Firstly diagnosing depression according to the DSM IV inherently includes fatigue, which is seen frequently in depression, but is the main symptom of concern in those with CFS/ME. Additionally, many of the physical symptoms seen in depression overlap with those observed frequently in CFS/ME. These include low energy, sleep disturbance, poor memory, impaired concentration and aching. The differences in the specific nature of these and other symptoms seen in these two conditions are detailed in Table [6](#Tab6){ref-type="table"}. Secondly, reports assessing the frequency of depression and anxiety in those with CFS/ME have investigated patients when the diagnosis has been established. By definition this can only be at least four months after the onset of symptoms. By this stage many patients are saddened and perplexed by their illness and it is not surprising that their mood is low and some will be depressed. Nevertheless, many remain positive although frustrated and sometimes angry about the lack of understanding and sympathy shown by many in the caring professions. Thirdly, CFS/ME is more frequent in those with previous depression and there is a tendency to attribute new or on-going fatigue to a reactivation of depression rather than reassessing the specific nature of the fatigue. There are few reports that have aimed to assess the presence of depression at the onset of CFS/ME symptoms. In those suffering an acute onset after a viral type illness, depressive symptoms have been absent although increased levels of work and life associated stress may have been evident. This is also the case in those whose illness started after physical trauma. In any case the presence of coincident depression later in the illness is often reactive to the patient's continuing symptoms and disability. Regardless, its presence can exacerbate the individual's symptoms, further impair quality of life and reduce the efficacy of both the talking and physical therapies. As such its early detection and appropriate treatment can undoubtedly be helpful. As mentioned previously care is required in the use of anti-depressant medication in those with CFS/ME. Thus many agents introduced in conventional dosage induce a state of tension and irritability with a worsening of the fatigue and headaches, increased difficulty sleeping and sometimes muscle twitching. Indeed if these symptoms develop in patients with depression when commenced on SSRI, SNRI or TCAs then an underlying CFS/ME should be suspected and investigated. Although these symptoms can also be seen in people without CFS/ME it is certainly more frequent and prolonged in those with CFS/ME. The mechanism is unclear but a pre-existing state of central nervous system hyperactivity may be aggravated by these agents that often work by inhibiting the reuptake of serotonin and noradrenalin. In some ways the adverse response suffered by CFS/ME patients is similar to a mild serotonin syndrome or in some cases an anti-cholinergic syndrome. Regardless, anti-depressants should be introduced very slowly in those with CFS/ME and probably commencing at a quarter of the lowest strength medication. They should then be increased every two weeks until a therapeutic level is reached although quite often this remains at the lower end of that needed for those without CFS/ME. It should of course be noted that depression and anxiety can manifest many of the symptoms seen in CFS/ME. Additionally, depression and anxiety can complicate CFS/ME and prolonged depression and anxiety can be aggravated by CFS/ME. Separating the two can be difficult and the some of the more important distinguishing features are detailed in Table [6](#Tab6){ref-type="table"}. However, for depression the pattern of sleep disturbance often confirms early morning wakening while in those with CFSME, patients may have difficulty getting up in the morning. Additionally, patients with CFS/ME say that they can start a task but have difficulty finishing it while those with depression find it difficult to initiate the task but once started can often finish it. Interestingly, some people with depression and anxiety resort to increased alcohol ingestion while those with CFS/ME almost never do. CFS/ME and anxiety {#Sec13} ------------------ Anxiety is a frequent problem in patients with CFS/ME and may progress or be complicated by a generalized anxiety disorder, social phobia, panic disorder and agoraphobia \[[@CR61]\]. This is understandable when the unpredictable onset and nature of relapses are considered. A generalised anxiety disorder was also noted to be more frequent in patients with CFS/ME than healthy controls and intriguingly had an early onset in a significant proportion \[[@CR62]\]. Interestingly, the perception of stress has been shown to be increased in women with CFS/fibromyalgia compared to healthy women and in women with a medically accepted illness such as lupus, rheumatoid arthritis and multiple sclerosis \[[@CR63]\]. This was associated with increased depression scores and more frequent unsupportive relationships. In my experience, persistent anxiety is a more significant problem in CFS/ME than depression and quite often more difficult to manage than the latter. CBT can be helpful to a degree but quite often the hypervigilance persists and sometimes the catastrophising also. Indeed Crawley et al. \[[@CR64]\] in the UK, noted a reduction of only 0.6 (95 % CI -0.9 to −0.3) in anxiety assessed using the HADS at 8 to 20 months follow-up after treatment in 6 specialist CFS/ME services. CFS and Treatment {#Sec14} ----------------- There is a large, and increasing, literature on a wide range of treatments used in CFS/ME. These include immunological and pharmacological treatments, nutritional supplements, adaptive pacing, graded exercise, deep relaxation using different approaches and psychological therapy \[[@CR5], [@CR6]\]. Included in the latter is cognitive behaviour therapy (CBT) and various types of life coaching. It would be impossible to cover the merits or otherwise of these treatments in this brief review. However, partly as a result of the unclear aetiology and heterogeneity of the condition, there are no CFS/ME treatments universally accepted by all physicians and patients to provide a permanent cure for the condition. Given that the precise cause of CFS is presently unknown, current treatment strategies should utilise an individualised holistic approach. This should include various combinations of pacing of daily physical and mental activity to prevent relapsing remitting fatigue, optimal diet, appropriate sleep hygiene, pharmacotherapy for any secondary depression/anxiety, graded exercise therapy (GET) and CBT. The UK NICE guidelines on CFS/ME \[[@CR65]\] have focused on GET and CBT in particular. Prinzs et al. \[[@CR66]\] advocated the benefits of CBT which was also supported by the uncontrolled study of 125 CFS patients in the Netherlands by Scheeres et al. in 2008 \[[@CR67]\] who found benefit in just over a third of the patients. Importantly, while cost outcome ratios were estimated to be highly favourable in each recovering patient, it is unclear whether they were favourable as a total cost of the intervention. The Cochrane review in 2008 also supported the use of CBT in CFS/ME although the benefits were modest and the duration of benefit was far from clear \[[@CR68]\]. However, multidisciplinary input with CBT, GET and pharmacological treatment fared no better than exercise, counselling and pharmacological treatment in the Fukada criteria CFS/ME patients reported by Núñez et al. \[[@CR69]\]. A year later the PACE trial \[[@CR70]\] with much larger numbers of patients confirmed that both CBT and GET were statistically beneficial when compared to adaptive pacing and normal medical care. However, the overall improvement after one year of therapy and input was extremely modest and the number of people who managed to return to work was not reported. In contrast to individualised CBT, group CBT investigated in the UK provided little improvement in fatigue \[[@CR71]\]. Regarding other listening therapies, recent work has found little benefit from supportive listening and pragmatic rehabilitation delivered by nurses compared to treatment as usual offered by general practitioners \[[@CR72]\]. Interestingly, multidisciplinary input has allowed a significant number of those with post-infectious CFS to return to work but was totally unsuccessful in those without an infectious onset \[[@CR73]\]. Support groups and a positive physician-patient relationship have proven to be beneficial in the long-term management of CFS \[[@CR74]\]. Overall, GET has been shown to be helpful in reducing fatigue and with a perception of improved sleep and general well being in those with CFS/ME diagnosed using a variety of criteria \[[@CR75]\]. GET also showed little risk of harm to patients but does in my opinion need to be properly supervised by therapists knowledgeable about CFS/ME. The baseline from which the GET is commenced is particularly important as is the rate of increase in the chosen activity. In my opinion the input of a non-judgemental, caring and understanding primary care physician is extremely important in the long term management of those with CFS/ME. The early identification of CFS/ME and its management with firm reassurance, appropriate rest and activity may encourage improvement in a higher proportion than would otherwise be the case. The present CFS/ME literature indicates that concomitant illnesses such as irritable bowel syndrome, fibromyalgia, headaches, and depression need to be treated and tailored to each patient to help significantly improve their quality of life. Psychopharmacologically, the use of SSRIs, SNRIs and TCA are suggested if depression complicates prolonged CFS/ME. In my experience there is no single agent that is superior to others and the precise agent used should be based on the physician's experience and the patient's tolerance to individual agents. Although clinical trials of tricyclic antidepressants have not produced definitive results, it is believed that along with their anti-depressive effect they also promote stage 4, non-rapid eye movement sleep and stimulate the descending inhibitory pathways of pain control. However, as with all medication these need to be introduced at the very lowest dosage and increased only gradually. Efforts at improving sleep and reducing insomnia have also been shown to not only reduce fatigue but also improve recovery from a stressful situation \[[@CR76]\]. Many patients with CFS/ME experience chronic widespread pain. In many this responds poorly to conventional anti-inflammatory agents. The synthetic opiate agonists can be helpful in a small number of patients but have the propensity to induce dependence in some and can also contribute to disturbed attention and bowel disturbance. The gamma amino butyric acid agonists such as gabapentin or pregabalin can be more helpful. Low dose pregabalin can also provide benefit for mild associated anxiety. The headaches suffered by many with CFS/ME can be highly disabling. Not infrequently they have a multifactorial aetiology including an underlying migrainous tendency, cervical spine tension and stress related frontal tension. The migrainous component can be helped by propranolol in those without asthma and peripheral vascular issues and other helpful agents include pizotifen as well as topiramate. For insomnia, melatonin should be tried and in some patients the older anti-histamines such as promethazine and hydroxyzine can be helpful although daytime drowsiness may require careful titration of the dose. The newer non-benzodiazepine hypnotics such as zopiclone also have a place in managing insomnia in CFS/ME although I suggest that their use is restricted to perhaps 3 times week. For the orthostatic intolerance increased salt intake (5gm to 10gm per day) or the isotonic sports drinks can be tried. Fludrocortisone would present an alternative. For other agents such as ivabradine and midodrine referral to a cardiologist with an interest in POTS is suggested. A lot has been written about dietary supplements and exclusion diets in CFS/ME \[[@CR77], [@CR78]\]. In my opinion a healthy well balanced diet with food that the patient enjoys eating is the best treatment for patients with CFS/ME. A small proportion of patients find wheat reduction helpful for reducing abdominal bloating and cramping and occasionally also increases energy levels. If dietary assessment suggests inadequate variety and paucity of specific types of food then dietary supplementation with a multivitamin and multimineral preparation may be appropriate. However, in the absence of any demonstrable nutritional deficiency the use of vitamin and mineral supplements is rarely required. Nevertheless, many patients still use a variety of dietary supplements and these are sometimes also suggested or prescribed by clinicians. Some patients have found benefit from the use of products that contain intermediates in oxidative cellular metabolism. These include factors such as co-enzyme Q, L-carnitine, D-ribose and nicotamide adenine dinucleotide (NAD). Regarding the latter Forsyth et al. \[[@CR79]\], reported promising results with reduced NADH therapy that improved adenosine triphosphate levels. In my experience many of these compounds appear to provide only temporary benefit and few patients report consistent and definite benefit beyond a few weeks and occasionally months. Conclusions {#Sec15} =========== In many ways it is unfortunate for sufferers with CFS/ME that it is a symptom based diagnosis without any easily discerned distinguishing physical or laboratory findings \[[@CR5], [@CR7]\]. There is, at present, no consistent pattern of immune dysregulation, endocrine dysfunction, nutritional deficiency, persistent infection or food allergy/hypersensitivity evident in this condition. It is likely that CFS/ME is a heterogeneous disorder \[[@CR80]\] with multiple causes and exacerbating factors. Early diagnosis based on positive criteria reduces the need for expensive investigations and can reduce the prolonged stress that accompanies ill health symptoms without a diagnosis. Overall this may also allow an improved understanding of the condition and early intervention that may encourage improvement. I would like to thank Invest in ME (IiME) for their encouragement in committing to paper my efforts to develop the scoring system. I would also to acknowledge the help of all my colleagues at the Sutton CFS Service in assessing the scoring system. Funding {#FPar1} ======= Not applicable and none received. Availability of data and materials {#FPar2} ================================== All data and material is available from BMC FP. Author's contributions {#FPar3} ====================== Dr Bansal conceived and wrote the whole article. Author's information {#FPar4} ==================== Dr Bansal is a consultant in Immunology and Allergy and head of the Sutton CFS Service. Competing interests {#FPar5} =================== I confirm that I have read BioMed Central's guidance on competing interests and can confirm I do not have any conflicting or competing interests related to this manuscript. Consent for publication {#FPar6} ======================= Not applicable. Ethics approval and consent to participate {#FPar7} ========================================== Not applicable.

Q: JList: displaying other thing than stored I have a JList Component and I would like to store paths of the images but to display name of image, not the path. I have a code of pressing Opening File Button like that: public void openButtonActionPerformed() { int returnVal = fc.showDialog(null, "Open"); if (returnVal == JFileChooser.APPROVE_OPTION) { file = fc.getSelectedFile(); } jList1.setCellRenderer(new JavaRenderer()); } And: class JavaRenderer extends DefaultListCellRenderer { public JavaRenderer(){ //setOpaque(true); } public File file; public Component getListCellRendererComponent(JList list, Object value, int index, boolean isSelected, boolean hasFocus) { if (value instanceof File) { File file = (file) value; return super.getListCellRendererComponent(list, file.getName(), index, isSelected, hasFocus); }else { return super.getListCellRendererComponent(list, value, index, isSelected, hasFocus); } } } But it still doesn't work. Can you help me with that? A: You can use jList.setCellRenderer() where you pass new DefaultListCellRenderer() with overrided method getListCellRendererComponent(JList list, Object value, int index, boolean isSelected, boolean cellHasFocus) value - is an object that you insert to JList, so you can store it but show another label: if (value instanceof File) { File file = (File) value; return super.getListCellRendererComponent(list, file.getName(), index, isSelected, cellHasFocus); } else { return super.getListCellRendererComponent(list, value, index, isSelected, cellHasFocus); }

Robot Sophia has been doing the rounds for the last few months now, playing rock, paper, scissors with Jimmy Fallon on The Tonight Show, cracking jokes on Good Morning Britain or naming Indian actor Shah Rukh Khan as her favourite actor while (completely coincidentally) in India for the World Congress on Information Technology.

QUESTION 1A small public sector organization needs helps planning the architectural design of its AEM system. The reorganization’s few staff members resist learning new technologies. What is the most important factor for the architect to consider while planning the system design? QUESTION 2A software company plans to display the real-time price of its stock on its employee intranet. The stock quote is provided by a third-party vendor. Which two factors are most relevant to the solution design for this capability? (Choose two.) A. The name of the vendor providing the stock quoteB. The ticket symbol of the companyC. The payload format in which the stock price is returned from the vendorD. The authentication requirements imposed by the vendorE. The rate limits imposed by the vendor QUESTION 4A digital publisher is migrating to AEM. The primary goal is to provide a more user-friendly page authoring interface. The current content management system has been built in house by staff developers, runs on a top of a MySql database, and uses forms for content editing. Discovery meetings are being held with the business owners and content authors. What is the most significant and relevant conceptual change from the current CMS? A. AEM uses a hierarchy-based repository.B. AEM does NOT use a relational database.C. AEM allows authors to drag-and-drop components to build pages.D. AEM is written in Java. Answer: C QUESTION 5A packaged goods company is migrating its current site to AEM. The company has a presence in the US, but is expanding into two other countries within 12 months of launch on AEM. During which two tasks should the architect consider this expansion goal? (Choose two.) QUESTION 6An architect is helping a multi-national news company design its project and determine requirements. The functionality requires several external feeds to display breaking news and live scores for major sporting events. What is the most important factor for the architect to consider when meeting the performance requirements? A. The authentication requirements from each feedB. The number of JCR nodes each feed item requiresC. The import frequency of the feedD. The payload type in which the feeds are returned Answer: C QUESTION 7A financial institution is identified as a business user. AEM/Campaigns/Segmentation rules must be based on the traits/data provided from the back end of the system. Which two types of information must be captured in the discovery session? (Choose two.) A. Whether any traits are combined to establish a segmentB. Format in which segmentation traits are retrievedC. Keys/values for segmentation traitsD. How back end service is integrated to retrieve customer data

1. Field of the Invention The present invention relates to a switch device suitable for use in, for example, a driving switch of a vehicle-mounted power window apparatus, which is capable of selectively operating two sets of switch elements by rockably operating an operating knob. 2. Description of the Related Art Conventionally, as a driving switch of a vehicle-mounted power switch, a driving switch is proposed in which two sets of slide-type switch elements are juxtaposed to each other and an operating rod of an operating knob is rockably operated to turn on the respective switch elements (for example, see Japanese Examined Patent Application Publication No. 5-80770). FIG. 11 is an explanatory view illustrating a conventional example of such a driving switch. In this drawing, the switch unit 1 generally has a structure in which two sets of slider-type switch elements are disposed within the case (not shown) whose upper opening is covered with a cover member 2. Driving shafts 3 and 4 of the respective switch elements protrude outward from elongated holes 2a and 2b of the cover member 2. The two sets of switch elements are disposed in the case in a straight line that coincides with the sliding direction (right-and-left direction in the drawing) of the driving shafts 3 and 4. Terminals 5 of a plurality of fixed contact pieces are exposed into the case and protrude downward from the case. Although not shown, each of the switch elements is provided with a slider having the driving shaft 3 (or 4) protruding therefrom, movable contact pieces that are fixed to the slider and brought into contact with or separated from the fixed contact pieces during operation, a coil spring that normally biases the slider toward an initial position illustrated in FIG. 11, and a plate spring that is brought into resilient contact with the slider and normally biasing the movable contact pieces toward the fixed contact pieces. The above-mentioned conventional switch unit 1 is assembled into a housing 6. An operating knob 7 is disposed in a mounting recess 6a of the housing 6. The operating knob 7 can swing about a spindle 8, and operating rod 9 moves (tilts) in the direction of the arrow “A” or “B” along with the swinging of the operating rod 7. Also, the tip of the operating rod 9 is inserted between the driving shafts 3 and 4 of the two sets of switch elements. Thus, when an operator pushes in the operating knob 7 to move the operating rod 9 in the direction of the arrow “A”, the operating rod 9 causes the driving shaft 3 to be pushed in and slid in the left direction in the drawing against the biasing force of the coil spring. As a result, the movable contact pieces, which integrally slide with the driving shaft 3, are brought into contact with or separated from the corresponding fixed contact pieces, such that one switch element is switched from its OFF state to its ON state. In this state, when a pushing force applied to the operating knob 7 is removed, the coil spring, which has been compressed by the sliding of the driving shaft 3, biases the slider to cause the driving shaft 3 to be slid in the opposite direction. Therefore, the switch element is automatically returned to its OFF state in FIG. 11. The operation of the switch element when an operator pulls up the operating knob 7 to move the operating rod 9 in the direction of the arrow “B” is basically the same as the above-mentioned operation. Here, when the operating rod 9 pushes in the driving shaft 4 in the right direction in the drawing to allow the sliding of the driving shaft 4, the other switch element is switched from its OFF state to its ON state. When operating force applied to the operating knob 7 is removed, the switch element is automatically returned to its OFF state. In the above-mentioned conventional example, the driving shafts 3 and 4 slides in a straight line. However, the operating rod 9 that pushes in the driving shafts 3 and 4 are members swinging about the spindle 8. Thus, the driving shafts 3 and 4 are pushed in a direction upwardly inclined with respect to the sliding direction. In addition, during operation, the driving shafts 3 and 4 are pressed against the peripheral walls of the elongated holes 2a and 2b, or the slider is pressed against the inner wall of the case 2 while being inclined. This may increase sliding resistance partially and undesirably and result in the sense of irregularity or saccade. Therefore, a problem occurs in that a good sense of operational touch is rarely obtained. Meanwhile, if the operating rod 9 is made long to arrange the spindle 8 away from the driving shafts 3 and 4, the driving shafts 3 and 4 can be pushed substantially in the sliding direction. However, in that case, the operating knob 7 may significantly protrude upward from the mounting groove 6a of the housing, which is not preferable.

Q: How do I find the proper wires for service drop? I have 125 amp service, and bought two #1 AWG black-colored wires for the electrician to use in his replacement. I couldn't find a white wire that size, or bare copper. Neither at Lowes nor Home Depot. In my search, I found somewhere that said you don't necessarily have to buy the same size conductor for the neutral wire. That the neutral wire has to be at least 70% the size of the hot wire. Is this true? And if it is, what size in AWG would this be? And does the wire have to be insulated? My state follows NEC. A: The maximum current for 1 AWG used in power transmission is 211 amps.(source) 70% of that is 147.7 amps. 2 AWG is rated at 94 amps, and 3 AWG is rated at 75 amps. So there is no smaller wire rated at 70% or larger. You'll have to use 1 AWG (or larger) for all wires. You could try an electrical supply house for other colors of 1 AWG, but I've found they only sell big spools (250+ feet) of such wire. Try contacting a commercial electrician. They often carry those big spools around and might be willing to sell you a few feet of it. Of course they'll also want to charge you a $75 delivery fee and a $95 installation fee, but you should be able to avoid the first by going to them to pick it up, and the latter by firmly insisting that you don't want them to do it. Standard counter is they'll tell you it is illegal/dangerous/immoral for you to do it yourself. Stand your ground.

Update: you can now view a full gallery of campaign images after the break. And yes – the Art Deco elements are definitely in full force. Mert & Marcus are still the photographers of choice for Gucci, this time shooting the fashion house’s campaign for spring 2012. While the solid gold backdrop could be something from the opulent side of the ’40s, there’s little about the outfits – worn by Abbey Lee Kershaw and Karmen Pedaru – that’s suggestive of the overt “Hard Deco” theme that graced the runway. Click the thumbnails for full pictures: Perhaps further imagery from the campaign will head further down the ‘Deco path.

Q: NumPy ValueError: The truth value of an array with more than one element is ambiguous. Use a.any() or a.all() I was calculating eigenvectors and eigenvalues of a matrix in NumPy and just wanted to check the results via assert(). This would throw a ValueError that I don't quite understand, since printing those comparisons works just fine. Any tips how I could get this assert() working? import numpy as np A = np.array([[3,5,0], [5,7,12], [0,12,5]]) eig_val, eig_vec = np.linalg.eig(A) print('eigenvalue:', eig_val) print('eigenvector:', eig_vec) for col in range(A.shape[0]): assert( (A.dot(eig_vec[:,col])) == (eig_val[col] * eig_vec[:,col]) ) A: The error message explains it pretty well: ValueError: The truth value of an array with more than one element is ambiguous. Use a.any() or a.all() What should bool(np.array([False, False, True])) return? You can make several plausible arguments: (1) True, because bool(np.array(x)) should return the same as bool(list(x)), and non-empty lists are truelike; (2) True, because at least one element is True; (3) False, because not all elements are True; and that's not even considering the complexity of the N-d case. So, since "the truth value of an array with more than one element is ambiguous", you should use .any() or .all(), for example: >>> v = np.array([1,2,3]) == np.array([1,2,4]) >>> v array([ True, True, False], dtype=bool) >>> v.any() True >>> v.all() False and you might want to consider np.allclose if you're comparing arrays of floats: >>> np.allclose(np.array([1,2,3+1e-8]), np.array([1,2,3])) True A: As it says, it is ambiguous. Your array comparison returns a boolean array. Methods any() and all() reduce values over the array (either logical_or or logical_and). Moreover, you probably don't want to check for equality. You should replace your condition with: np.allclose(A.dot(eig_vec[:,col]), eig_val[col] * eig_vec[:,col])

Introduction ============ Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis, with prognosis unaffected by the grade of the tumor. Standard of care (SOC) therapy includes radiation without concomitant surgery; no chemotherapy has been demonstrated to be effective against a DIPG \[[@r1]\]. Nanotechnology could offer some therapeutic options for treatment of DIPGs, along with other brain tumors. Nanotechnology constructs (nanoparticles that are less than 100 nm, hydrodynamic radius \[[@r2]\]) have been used and are being developed for phase III trials for treatment of various cancers. Cancers, such as liver and lung cancers, led the field as potential recipients of nano-derived therapeutic particles \[[@r3]-[@r5]\]. These types of cancers were more common and more easily accessed as compared to brain tumors. To date, multiple nanoparticles have been tested to increase delivery of chemotherapies to tumors while minimizing systemic effects of the drugs. One specific advantage of treatment with nanoparticles is that these do not diffuse freely like small molecules and have increased permeability and retention in tumor tissue \[[@r6]\]. In the treatment of brain tumors, nanoparticles have been developed that are able to cross the blood brain barrier 
(BBB) when administered through conventional delivery routes, such as intravenous injection. Once delivered, these agents can be used for both enhanced imaging \[[@r7]\] and for targeted delivery of therapies \[[@r2]\] in brain tumors. However, there are no published articles specifically focused upon the delivery of chemotherapy into DIPGs. The current literature concentrates on nanoparticles developed for the treatment of glioblastoma multiforme (GBMs), which are grade IV gliomas that can occur anywhere in the central nervous system and share some similarities with DIPGs. Nevertheless, these data are promising for the next steps in diagnosis and treatment of DIPGs. This review will discuss and highlight the data that exist for treatment of GBMs and examine potential extrapolations into treatment of DIPGs where data for DIPGs are not available. Novel drug options for packaging into nanoparticles include CDK inhibitors, which have been demonstrated, in murine DIPG models, to prolong survival \[[@r8]\]. Similarly, Wee1 inhibitors in combination with radiation have been demonstrated to decrease survival of DIPG cells in culture \[[@r9]\]. More classic chemotherapeutic agents, such as carboplatin and temozolomide have been packaged into nanoparticles and could potentially be used against DIPGs \[[@r10], [@r11]\]. Barriers to Treatment of DIPGS ------------------------------ Surgery, whether it be debulking or resection, is not therapeutic for treatment of DIPGs due to the exquisite location of the tumors. Biopsy is safe, though not done in all institutions at diagnosis or after progression because of concerns for morbidity of surgery while clinical presentation and imaging are fairly reliable in determining the diagnosis of a DIPG \[[@r12]-[@r14]\]. Unfortunately, chemotherapy does not prolong survival of DIPG patients. The theories for these limitations are various. In general, it is thought that the anatomy of the pons and the locally intact BBB limit infusion of chemotherapy to the pons in DIPGs \[[@r14]\]. In addition, there is also evidence that drug efflux transporters limit the efficacy of chemo-
therapeutic agents \[[@r15]\]. Finally, it is possible that the infiltrative tumor in an already restricted area increases the anisotropy of the area, diminishing the amount of systemic chemotherapy that can diffuse through the area of the tumor \[[@r16]\]. These limitations in such a devastating disease have lead to multiple approaches in modern medicine in an attempt to change the survival chances for affected children. One area of cancer therapy that is gaining momentum in this challenging arena, *i.e.* the pons affected by DIPG, is nanotechnology. Nanoparticles for Treatment of DIPGS ------------------------------------ There are multiple forms of nanoparticles currently being investigated for treatment of brain tumors (Fig. **1**). Nanoparticles based upon stable elements, such as gold \[[@r17]-[@r19]\], silver \[[@r20]\], iron, and carbon \[[@r10]\] are made. Organic nanoparticles include liposome and micelle particles, both of which are phospholipid formulations, though of different sizes and lamellar composition. Polymer nanoparticles, such as poly-(D,L-lactic-co-glycolic acid) (PLGA) are also used \[[@r21]\]. In spite of the variety of nanoparticles available, delivery into the brain has remained a challenge due in large part to the non-specific and non-targeted delivery of these nanoparticles. Targeting of nanoparticles is now possible, 
as there are delivery techniques that address the BBB limitations mentioned above. Solid-state Nanoparticles ------------------------- Gold nanoparticles (Au NPs) are inert solid nanoparticles used for delivery of chemotherapy or detection of tumors \[[@r22], [@r23]\]. These formulations can be specifically targeted to increase uptake by glioma cells and have been demonstrated to increase overall survival in murine GBM models \[[@r24]\]. In one study, Au NPs were conjugated with Gd-labeled DNA and were shown to cross the BBB in glioblastoma cells and *in vivo* mouse models. They demonstrated that these agents can penetrate tumor parenchyma and silence genetic signals and subsequently decrease tumor load \[[@r25]\]. In another study, drug delivery vectors based on Au NPs were designed *via* conjugation of aspartate stabilized Au NPs to temozolomide drug. These carriers delivered temozolomide, a cytotoxic drug, to treat recurring malignant glioma. These studies also revealed the low cytotoxicity of the drug delivery agent and the potential to internalize temozolomide inside glioma cells \[[@r26]\]. Another study reported a formulation of a Au NP-based drug carrier *via* electrostatic interaction of anionic gellan gum coating on Au NPs to cationic doxorubicin HCL (DOX, an anthracycline anti-cancer drug). Effective loading of DOX onto Au NPs increased cytotoxicity in human glioma cell lines \[[@r27]\]. Further, PEGylation has been utilized to prepare different formulations of RGD peptide (integrin) conjugated Au NPs to maximize the targeting efficiency to U87 glioma cell lines. The ligand density was controlled by using amine or carboxyl conjugated thiolated PEG to improve targeted nanoparticle efficacy \[[@r28]\]. Another study highlighted the design of DOX conjugated Au NPs using hydrazone linkage which were further made targeted *via* fabrication with Angiopep-2 decorated PEG. These multifunctional nano-
particles termed as An-PEG-DOX-AuNPs were shown to target glioma cells and displayed accumulation. Release of DOX was facilitated by low pH milieu \[[@r29]\]. Gold nanoparticles (Au NPs) have also been utilized for selective targeting of brain tumors and subsequent Au NP-induced radiosensitization \[[@r30]\]. PEGylated Au NPs as an adjuvant to the radiation therapy were delivered in *in vitro* and *in vivo* systems. Au NPs significantly increased DNA damage induced by the ionizing radiation and induced stunting of newly formed blood brain vessels. Furthermore, this combinatorial treatment increased the survival of mice with orthotopic brain tumors. In a similar study, Bobyk *et al*. \[[@r31]\] used commercial Au NPs to illustrate the radio-
sensitization efficacy of gold in killing glioma cells, which was more efficient than irradiation alone. Further advances in this approach have used chemo-radiotherapy of cisplatin-conjugated Au NPs \[[@r32]\]. This strategy worked *via* the synergy of irradiation with high atomic number gold and platinum molecules and cisplatin thereby producing ionizing photoelectrons and auger electrons which caused complete killing of cells *in vitro*. Another study used Au NPs in combination with cold plasma for plasma therapy of tumor cells \[[@r33]\]. Au NPs along with cold plasma induced cell death up to 30% more than the cells treated with plasma alone. All these strategies based upon synergistic approaches have a huge potential in killing glioma cells and reducing harm to healthy cells. Shutao *et al*. \[[@r34]\] used supramolecular Au NPs prepared from 2 nm gold colloids to demonstrate enhanced photo-
thermal effects of gold towards glioma cells. These supra-
molecular Au NPs were further conjugated with cRGD peptide to target the overexpressed integrins in glioma cells leading to a more targeted therapy. Besides radiosensitization and photothermal therapy, Au NPs have also been used as a vehicle to deliver biomolecules to demonstrate therapeutic effects. Jensen *et al*. \[[@r35]\] covalently functionalized Au NPs with small interfering RNA (siRNA) duplexes. These Au NPs-siRNA complexes were taken up by the glial cells and transformed the cells. In the *in vivo* model, these agents crossed the BBB and increased intramural apoptosis and reduced tumor burden and progression in xenograft models without harmful side effects. In one other study, temozolomide loaded gold nanostructures \[[@r26]\] were found efficient in lowering chemoresistance and killed 82.7% of cancer stem cells as compared to 42% using temozolomide alone. Au NPs have also been used in photodynamic therapy (PDT) of glioblastoma by selectively delivering photosensitizers such as silicon phthalocyanine (Pc 4) \[[@r18]\]. The widespread use of PDT in brain tumor therapy has been partially hampered by non-targeted phototoxicity towards healthy tissue and lack of target specificity. Therefore, overexpressed glioma cell surface receptors, *i.e.*, epidermal growth factor receptor (EGF) and transferrin receptor (TfR) have been utilized as targeting moieties. EGF-targeted AuNPs loaded with Pc4 \[[@r18]\] were able to reduce cytotoxicity and increase the drug delivery efficiency. Other targets including TfR demonstrated that Tf-targeted Au NPs loaded with Pc 4 were able to cross the BBB using transcytosis and target glial cells both *in vitro* and *in vivo* to deliver Pc 4 drug for PDT therapy \[[@r36]\]. For targeted glioma therapy, one study designed integrin (cRGD) targeting, NIR-responsive and robust AuNR/PEG-PCL hybrid nanoparticles (cRGD-HNs) for targeted chemo-
therapy of human glioma xenografts in mice \[[@r24]\]. Ligand-directed AuNR/PEG-PCL hybrid nanoparticles demonstrated tumor-targeting as well as greater spatiotemporal and rate control over drug release *in vivo*. In another targeted therapy approach \[[@r37]\], Au NPs functionalized with RGD-(GC)(2) peptide were designed and demonstrated efficient cellular uptake in U87 cells. Silver nanoparticles are primarily used due to their anti-infective properties. However, they can also be used to increase apoptosis in GBM cells, *in vitro*. These nanoparticles combine silver with chitosan and alginate complexes \[[@r20]\]. In addition, silver nanoparticles may be useful radiation sensitizers for glioma radiotherapy \[[@r38]\]. Carbon nanotubes are another form of targetable nanoparticles. These nanotubes are coated with polymers to control release of embedded chemotherapies and therefore have the potential to deliver significantly more chemotherapy than can be achieved systemically \[[@r39]\]. There are, however, concerns regarding toxicity to healthy tissues from the carbon nanoparticles, themselves \[[@r40]\]. *In vitro* glioma cytotoxicity is seen while cellular toxicity from the carbon nanotubules on initial assessment has not been noted \[[@r41]\]. Iron oxide nanoparticles have unique therapeutic benefits. These nanoparticles are targetable by both magnetic guidance and ligand targeting. Furthermore, they can be designed to have a staged delivery of multiple chemotherapeutic agents, such as doxorubicin and curcumin, for complex activity against glioma cells. To date, the efficacy data for these formulations are still *in vitro* \[[@r42]\]. Lipid-based Nanoparticles ------------------------- Liposomes and micelles can be targeted with multiple types of products, including: proteins, antibodies \[[@r43]\], and viral particles \[[@r44]\]. Liposomes are bilayer or multilayer nanoparticles, which are capable of transporting both hydrophilic and hydrophobic therapeutics. Micelles, being unilamellar, are significantly smaller than liposomes (potentially increasing their bioavailability due to increased permeability), but can carry only hydrophobic therapeutics, unless hydrophilic molecules are attached as ligands to the outer surface of the micelles. Both of these nanoparticle vehicles improve the solubility and stability of drugs being delivered to tumor cells. PEGylation (coating micelles or liposomes with polyethylene glycol) increases the stability and allows targeting of the nanoparticles \[[@r45]\]. Targets of DIPGs and GBMs share similarities (*e.g*. epidermal growth factor receptor, transferrin receptor, fibroblast growth factor, *etc*.), though there is heterogeneity between these tumor types and specific cellular targets for DIPGs have not been convincingly identified \[[@r9], [@r46], [@r47]\]. Liposomes represent one of the most promising systemic delivery strategies to improve the chemotherapy for GBM \[[@r48]-[@r50]\]. Liposomes can carry either hydrophobic or hydrophilic drugs, protecting them from unfavorable conditions \[[@r51], [@r52]\]. Particularly, liposomes conjugated with polyethylene glycol (PEG) can evade recognition by opsonins and the subsequent clearance by the reticuloendothelial system (RES), and hence they stay long in circulation with sustained drug release \[[@r53]-[@r57]\]. Size-wise, nanoscale liposomes tend to accumulate at tumor interstitium and promote drug delivery efficiency, owing to the vascular feature of tumors, referred to as enhanced penetration and retention (EPR) effect \[[@r58]-[@r60]\]. Further, liposomes can be constructed with special moieties for targeted delivery, achieving higher delivery efficiency and minimizing side effects \[[@r61]-[@r65]\]. So far, doxorubicin has been the most investigated drug for liposomal delivery to treat GBM. This drug is known to be useful against multiple tumor types \[[@r66], [@r67]\], and its free form has been demonstrated to be one of the most effective substances against glioblastoma cells *in vitro* \[[@r68]\]. However, free doxorubicin has no significant effect against GBM *in vivo* due to poor BBB penetration \[[@r69]-[@r72]\] -- BBB cells express ATP-dependent efflux pump, P-glycoprotein (P-gp), restricting free doxorubicin from passing BBB \[[@r71]\], which works similarly in glial tumor cells against many therapeutic agents \[[@r73]-[@r75]\]. Besides, the therapeutic potential of doxorubicin has been limited by its chronic cardiac toxicity. Hence, the motivation for research on liposome encapsulated doxorubicin. The PEGylated liposome-encapsulated form of doxorubicin (Doxil) has been developed to treat various cancers and is commercially available. Pre-clinical and clinical studies of Doxil for GBM therapy showed that in comparison to free doxorubicin, Doxil featured intense accumulation at the tumor tissue, improved suppression of tumor growth, and reduced cardiac toxicity \[[@r63], [@r64], [@r76], [@r77]\]. Further, targeting moieties conjugated to liposomal doxorubicin are being studied to enhance the drug's therapeutic index \[[@r61]-[@r65]\] as well as to improve the drug's cellular uptake and internalization. For example, an immuno-liposomal doxorubicin was fabricated with the monoclonal antibody 225, targeting the epidermal growth factor receptor (EGFR) that is overexpressed in many tumors, and it showed improved therapeutic efficacy in mouse models carrying human glioblastoma tumors with respect to non-targeted liposomal doxorubicin \[[@r78], [@r79]\]. Other examples of targeting moieties which showed positive results with liposomal doxorubicin against GBM include human interlecukin-13 (IL-13) for targeting IL-13Rα2 receptor, the PGERPPR peptide for targeting Neuropilin-1 (NPR-1) \[[@r80]\], folate for targeting folate receptors \[[@r81]\], the atherosclerotic plaque specific peptide-1 (AP-1) of 9 amino acids sequence for targeting interleukin-4 receptors (IL-4R) \[[@r82]\], *etc*. The enhanced drug accumulation of Doxil compared to free doxorubicin at the glioma tissues is usually ascribed to the PEGylated liposomes' capability to penetrate the BBB \[[@r63], [@r64], [@r76]-[@r82]\]. Counter intuitively, liposomes are not supposed to cross the normal BBB \[[@r83], [@r84]\]. BBB acts as a barrier through P-gp as well as because of its tight junction \[[@r85]\]. P-gp does not block liposomes, but the physiologic upper limit of pore size in the BBB of malignant glioma microvasculature is \~12 nm \[[@r86]\], smaller than the usual size of a liposome particle. Therefore, the penetration of the liposomes through BBB in above cases is probably due to the disrupted BBB in brain tumors \[[@r87]-[@r91]\]. Specifically in the GBM case, when the tumor begins to grow beyond 1-2 mm in diameter within the brain parenchyma, the BBB becomes compromised both structurally and functionally \[[@r92]\]. Nevertheless, liposomes can be constructed to actively penetrate BBB through receptor-mediated endocytosis. The receptors for insulin, transferrin, endothelial growth factors, amino acids, and various metabolic nutrients are expressed on the BBB \[[@r93]\]. Dual-targeting liposomal doxorubicin with both transferrin and folate has been proven effective in penetrating the BBB \[[@r81]\]. Moreover, the BBB can be disrupted by ultrasound, assisting liposomal delivery to brain tumors \[[@r82], [@r94], [@r95]\]. Beyond doxorubicin, many chemotherapeutic agents have been involved in preclinical studies for liposomal delivery to treat GBM, including epirubicin \[[@r79]\], vinorelbine \[[@r79]\], daunorubicin \[[@r96]\], docetaxel \[[@r97]\], irinotecan \[[@r98]-[@r100]\], vincristine \[[@r98]\], topotecan \[[@r101]-[@r104]\], among others. Within these various cases of liposomal delivery, observations of increased drug accumulation at tumor sites, sustained drug activity, improved drug anti-tumor efficacy, and reduced adverse side-effects with respect to free drug delivery are consistent. Cytarabine-packaged liposomes have been demonstrated to prolong the time to neurological progression in adults with neoplastic meningitis, though the response rate was no different from standard of care methotrexate \[[@r105]\]. Liposome encapsulated drugs are tolerable and feasible for administration to patients with brain tumors, though they have not yet been proven to improve overall survival. Likely, this is related to the formulation of the targeting moieties and the release dynamics, which remains to be optimized for maximum clinical efficacy. Additionally, the direct intra-cerebral infusion approach, convection-enhanced delivery (CED), as an alternative to the usual intravenous administration has been attempted with liposomal irinotecan \[[@r100]\] and liposomal topotecan \[[@r101], [@r103], [@r104]\]. The advantage of CED is to bypass the BBB and minimize systemic drug exposure for fewer side effects \[[@r106], [@r107]\]. The work with liposomal irinotecan and topotecan demonstrated superior therapeutic efficacy by CED. For the benefit of clinical trials to monitor the real-time drug distribution after CED execution, the co-convection with liposomal gadodiamide, enabling MRI imaging, has been proposed \[[@r101]\]. Liposomes can also assist gene therapy against GBM. Traditionally, a gene therapy employs a viral vector to deliver the therapeutic DNA. In comparison, liposomes are easier to prepare, and liposomal delivery is advantageous for safety, low toxicity and absence of high neutralizing antibody levels. In general, the studies on gene therapy for GBM follow one of two approaches: (1) Suicide gene therapy using the herpes simplex thymidine kinase (HSV-tk) to sensitize tumor cells to ganciclovir (GCV) \[[@r108]-[@r110]\] or (2) Immune gene therapy using cytokine genes. Preclinical studies of interferon β (INF-β) and human interlukin 12 (IL-12) gene transfer using liposomes displayed positive results \[[@r111]-[@r114]\], and clinical studies have been warranted or already performed \[[@r115]-[@r118]\]. Moreover, for liposomal gene therapy, a hybrid vector of HVJ-liposome (HVJ: hemagglutinating virus of Japan or Sendai virus) has been developed \[[@r119]\], which can fuse with cellular plasma membrane, releasing the contents into the cytoplasm, in contrast to usual liposome vectors that are taken up into cells by endocytosis. HVJ-liposome is fabricated by fusing liposomes with UV-inactivated HVJ. The hybrid vectors deliver genes efficiently \[[@r120]-[@r124]\] and clinical trials are under way to treat GBM with suicide gene therapy \[[@r119]\] (clinicaltrials.gov \# NCT02414165). Further, the gene therapy using HVJ-liposomes can be improved by targeting-modification of the hybrid vectors or rendering long-term expression of transgene *in vivo* \[[@r119]\]. Liposomes are also being developed to carry other genetic materials that may act as therapeutic agents for GBM therapy. For example, vascular endothelial growth factor (VEGF) siRNA can be protected from RNase degradation by liposomal packaging and delivered into gliomas *via* EPR effects and active targeting. VEGF, which is highly expressed in gliomas \[[@r125], [@r126]\], is reduced and, consequently, new blood vessel growth to gliomas is inhibited \[[@r97]\]. Ultrasound-sensitive nanobubbles are also being developed as nanoparticles. These are often assembled into micelles and/or liposomes for delivery of therapeutic agents, such as small interfering RNAs (siRNAs), into glioma cells \[[@r127]\]. These siRNAs can interact with and inhibit oncogenes to promote apoptosis and inhibit proliferation \[[@r128], [@r129]\]. Polymer-based Nanoparticles --------------------------- PLGA nanoparticles have been developed that are designed to selectively penetrate the glioma parenchyma \[[@r130]\]. These particles are believed to be beneficial because of their biodegradable nature. They deliver chemotherapy, with current technology and development, into murine glioma models, with targeted delivery into gliosarcoma cells \[[@r131]\]. Similar formulations of these polymer nanoparticles demonstrate *in vitro* glioma cell death \[[@r132]\]. Improved survival in the animal models has not yet been demonstrated, as these nanoparticles continue to be optimized for therapy. Therapeutic Combinations in Nanoparticles ----------------------------------------- Combination therapies of nanoparticles are also being developed. Carbon and iron nanoparticles are being made to increase biomedical applications of magnetic nanoparticles. These combinations, in addition to targeted delivery of chemotherapy, affect the C and G2/M phases of cell cycle progression leading to increased pro-apoptotic activity in murine glioma cells *in vitro* \[[@r133]\]. PLGA compounds are being combined with liposomes in order to increase the circulation time and enable targeting of drug and gene delivery to brain tumor tissues \[[@r134]\]. A combination of stem cells and nanoparticles has been demonstrated to increase distribution and retention of chemotherapy into brain tumor tissues \[[@r135], [@r136]\]. In fact, a phase I/II clinical trial of nanoparticle chemo-
therapy for adults with recurrent GBM has been completed and has demonstrated prolonged overall survival compared to historical therapy on the Stupp protocol \[[@r137]\]. Currently, a nano-liposomal phase I trial is in its recruitment phase. This study is investigating nano-packaged irinotecan in treatment of GBM and other high-grade gliomas in adults (clinicaltrials.gov \# NCT02022644). Impact of Administration Route ------------------------------ Targeting and transport of nanoparticles to solid tumors have been extensively studied. Despite several advances, nanoparticle transport at high concentrations to tumors is still a challenge, especially to inaccessible locales within the brain and brainstem. Different routes of administration may result in varying patterns of biodistribution of the nano-
particles and appears to be an important parameter in the delivery of therapeutic agents to DIPG. Conventional routes of administration for GBM and DIPG include intranasal, oral, intra-carotid or intravenous (i.v.) administration \[[@r138]-[@r161]\]. Intravenous administration *via* the carotid artery, femoral or tail vein in small animals has been the most successful in achieving significant accumulation of nanoparticles across the BBB. Oral and interperioteneal (i.p.) administration allow the nanoparticles to cross the BBB and reach the CNS after longer periods of circulation owing to the time necessary to cross other barriers such as the intestinal and peritoneal walls. During intranasal administration, nanoparticles must cross the mucosal barrier and be taken up by neurons and supporting cells before reaching the brain *via* an intra-axonal route. In humans, intravenous administration is certainly the most common form of delivery of nanoparticles, though alternatives are being investigated. Convection enhanced delivery (CED) is a delivery system that is able to circumvent the blood brain barrier \[[@r162]\]. Once perfected, this could be a potential delivery route for nanoparticles, though it is an invasive approach. Another delivery route that is interesting for delivery of nanoparticles into DIPGs is intranasal, as this approach circumvents the hepatic vascular system, minimizing first pass metabolism, while enhancing noninvasive delivery into the brainstem, specifically \[[@r163]\]. Approaches to enteral delivery of nanoparticles are also being investigated \[[@r164]\], though these will perforce have to deal with the first pass metabolism of medications in the liver. Nanoparticles for Imaging of DIPGS ---------------------------------- The diagnosis of DIPG is based on conventional interpretations of radiographic findings. Using magnetic resonance imaging (MRI), the tumor appears as a large expansile brainstem mass with an epicenter within the pons. DIPG are hypo- or iso-intense on T1-weighted images, hyper-intense on T2-weighted images, and relatively homogenous on fluid attenuated inversion recovery (FLAIR) sequences \[[@r165]\]. Contrast enhancement is variable, but these tumors rarely enhance at diagnosis. Typical clinical presentation and MRI has thus become standard practice for diagnosing DIPG. Surveillance imaging can be used to monitor response and progression of disease, but clinical assessment is more reliable because imaging still suffers from lack of molecular targets and contrast agents to infiltrate the DIPG. Given DIPG's invasive nature and indistinct borders, measurement of tumor size and volume is problematic and suffers significantly from inter-observer variability when using MRI \[[@r166]\]. In addition, MRI cannot reliably differentiate between tumor and treatment responses during the course of radiation therapy. MR perfusion and magnetic resonance spectroscopy (MRS) have shown some promise as new non-invasive imaging techniques to identify DIPG response to anti-tumor agents but thus far have not been proven clinically useful. For example, MR perfusion studies have been used to evaluate DIPG vessel density and permeability. Increased blood flow may be associated with tumor grade or malignant transformation \[[@r167]\]. Price *et al.* demonstrated that the relative cerebral blood volume (rCBV) determined by perfusion imaging correlated with cell proliferation in adults with high-grade gliomas \[[@r167]\]. In a study of children with DIPG, increased perfusion at any single time point was associated with shorter survival \[[@r168]\]. MRS has been used to evaluate predictive markers of response, such as the ratio of choline to N-acetyl aspartate (NAA). A higher choline:NAA ratio in children with DIPG was associated with a greater mortality when compared to a cohorts with lower ratios. Changes over time were also associated with outcome, suggesting that a dynamic increase was inversely associated with survival and vice versa \[[@r169]\]. Several types of nanoparticles could be developed to identify molecular targets within the DIPG or deliver chemotherapeutics that do not easily accumulate in the tumor. Nanoparticles used for imaging include magnetic nanoparticles and fluorescent nanoparticles. Theranostic nanoparticles are specific, individualized therapies that improve imaging of targeted tissue while delivering therapy to the same tissue, and are often made with iron \[[@r170], [@r171]\]. Magnetic nanoparticles are a form of theranostic nano-
particles that have unique paramagnetic properties, which support their detection by MRI \[[@r172]\]. Alternately, fluorescent nanoparticles can increase the detection of a microscopic tumor in real time, clinically (during surgery) and with imaging \[[@r173]\]. Magnetic nanoparticles of particularly useful due to their helpfulness in attaining targeted imaging of brain tumors. Similar to gadolinium-based contrast agents, they rely upon diffusion across a damaged BBB to demonstrate enhancement. However, they can be targeted specifically to tumor tissue, dramatically reducing the subtleties and challenges of interpretation of MRIs when using traditional gadolinium contrast agents. Magnetic nanoparticles may also be preferable to gadolinium based nanoparticles because they have no known renal effects and they circulate for longer than gadolinium based contrast agents (24-72 hours after systemic administration) \[[@r2]\]. However, they are not biodegradable and may have long-term risks related to deposition of the iron or other metals \[[@r174]\]. Gold nanoparticles can chelate to gadolinium for improved imaging. These nanoparticles provide prolonged retention of the gadolinium, as well as targeted delivery. An exciting combination therapy includes combined drug delivery with gadolinium delivery for therapeutic drug delivery and imaging in one compound \[[@r175]\]. Fluorescent nanoparticles can be used to increase surgical resection of tumors, though this is not truly relevant to DIPGs, because DIPGs that are biopsied receive stereotactic biopsies, in the current therapeutic era. However, in research for DIPGs fluorescent nanoparticles are often used to determine the location of tumors with non-invasive, targeted imaging. One such interesting fluorescence imaging nanoparticle is a silver nanoplate, coated with polymers, noted to be useful in rat imaging \[[@r176]\]. Conclusion ========== Nanotechnology has been developed to deliver therapies in non-targeted and targeted fashion into brain tumors, especially GBM. Such development has not yet occurred in DIPGs, which are considered to be an "orphan disease." Perfection of the delivery system for nanoparticles is needed in brain tumors, in general. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG. This work were supported by the South Carolina 
Clinical & Translational Research (SCTR) Institute, with an academic home at the Medical University of South Carolina CTSA, NIH/CATS grant number UL1TR000062 (AMB). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. CONFLICT OF INTEREST ==================== The authors confirm that this article content has no conflict of interest. {#F1}

Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol. Indole-3-carbinol (I3C), present in cruciferous vegetables, and its major in vivo product 3,3'-diindolylmethane (DIM), have been reported to suppress estrogen-responsive cancers. This effect may be mediated through the modification of cytochrome P450 (CYP) complement and activities leading to estrogen detoxification. We examined the effects of a 4-day treatment of female Sprague-Dawley rats with DIM at 8.4 and 42 mg/kg body weight (bwt), on the hepatic CYP protein level, CYP1A1, 1A2, 2B1/2 and 3A1/2 probe activities and CYP-dependent metabolism of 17beta-estradiol (E2) and estrone (E1). At 42 mg/kg bwt, DIM effected a small increase (2.8-fold) in CYP1A1 activity, and at both dose levels it reduced CYP3A1/2 activity by approximately 40%. At the higher dose level, DIM decreased the rates of oxidation of E2 to 4-OH-E2, 4-OH-E1, 6alpha-OH-E2 and 6(alpha+beta)-OH-E1 by 39, 44, 71 and 60%, respectively, and E1 to 6(alpha+beta)-OH-E1 by 39%. These effects were considerably different from those of I3C reported by us previously. We also examined the effects of DIM and I3C on the hepatic microsomal metabolism of tamoxifen (TAM). Whereas metabolism of TAM was unaffected by DIM, formation of N-desmethyl-TAM (and its presumed derivative) was increased approximately 3-fold by I3C at 250 mg/kg bwt. Since N-desmethyl-TAM is transformed to a genotoxic metabolite, dietary exposure to I3C may enhance hepatic carcinogenicity of TAM in the rat. The differences between I3C and DIM in CYP-mediated activities and metabolism indicate that DIM is not a proximate intermediate in the mechanism of action of I3C.

Q: C# to F# Interop: How to specify a C# method's optional parameter in F# function type signature? I have the following method in some C# code: Qux MyFunc(Foo foo, Bar bar, int baz = 1); I want to add it as a field on my new F# Record type. I will assign the C# function later, to my record field, in F# code. If I ignore the default nature of the final parameter baz, then my type would look like this: type MyType = { MyFunc: Foo * Bar * int -> Qux } However, because we have the optional C# parameter, I wish to reflect that. I have tried using the Optional Attribute mentioned here, but it doesn't work: type MyType = { MyFunc: Foo * Bar * [<Optional;DefaultParameterValue(null)>] int -> Qux } I have also tried other combinations such as the question mark prefix e.g. ?baz. What is the correct way to do this (if it is at all possible)? Update & summary Whilst it is possible to do this on a type member, it is not possible to do this on a value (Record). I'm using F# 3.1, so this might be possible in future. To be fair in rewarding points, I will upvote @Daniel-Fabian who confirmed this is the case, and mark @Mark-Seemann's workaround as the answer, because although it wasn't quite the answer that I was looking for, it solved my problem. A: You write your signature with a ? for optional parameters. member this.MyFunc (foo, bar, ?baz) = Qux or for just the signature abstract member MyFunc : Foo * Bar * [<OptionalArgument>] baz : int option -> Qux as is also written in http://msdn.microsoft.com/en-us/library/dd233213.aspx. However, it won't work in your case, because optional parameters are only allowed to type members and not values. A: I'm not going to claim that I have a very elegant solution, but the following works. Assume that the MyFunc method is declared on Class1. You can declare the MyType record like this: type MyType = { MyFunc: Foo * Bar * option<int> -> Qux } This doesn't enable you to directly assign the original MyFunc method to the record, but a little helper function does: let myFunc (h : Class1) (foo, bar, baz : int option) = match baz with | Some(i) -> h.MyFunc(foo, bar, i) | _ -> h.MyFunc(foo, bar) Now you can create a value of MyType like this: let mt = { MyFunc = myFunc c1 } assuming that c1 is an instance of Class1. You can now use it to get various values of Qux: let q2 = mt.MyFunc(Foo(), Bar(), None) let q3 = mt.MyFunc(Foo(), Bar(), Some(42))

Untitled Document Churches my Ancestors were married andbaptized in St. Boniface Church- Located in Neuenkirchen,Oldenburg, GermanySt. Killian's Church- Located in Lugde, Westfalen,GermanySt. Johann's Church- Located in Osnabruck, Hanover,GermanySt. Victor's Church- Located in Damme, Oldenburg,GermanySt. Gertrude's Church- Located in Lohne, Oldenburg,GermanyOld St. Mary's Church- Located in Cincinnati, OhioSt.Peter and St. Paul's Church- Located in St. Petersburg, OhioHolyTrinity Church- Located in Cincinnati, OhioSt. Augustine Church-Located in Minster, OhioSt. Nicholas Church- Located in Osgood,OhioSt. John's Church- Located in Maria Stein, OhioSt. RoseChurch- Located in St. Rose, Ohio St. Victors is were the Luebke, Kohrs, and Putofffamilies would have went.St. Boniface church is were John HenryMeyer and Anna Marie Gertrude Lienesch were married.St. Killian'schurch is were many of the Schneidewind family members are buried. Theyare buried in the floor of the church. This was a great honor researvedfor aristocratic people.St. Johann church is were John HenryPohlmann and Catherine Hagemann would have been baptized. St.Gertrude was the church the Hoyng's would have attended.St. Peterand St. Paul church is were Blazius Fisher married Anna MarieWieman.St. Rose church is were Arnold Kleinhenz married BerhardinaPohlmanHoly Trinity church is were Henry Overman married Marie AgnesBoeckmanSt. John's church is were John Henry Brackman and also theKohr's family are buriedSt. Nicholas church is were Ken Meyermarried Carol Tuente.St. Augustine church is were Jerry Meyer andLinda Fisher had there burial masses.Elmer Tuente's burial mass wasat St. Nicholas.Ben Tuente Sr. and Anna Buddendict are buried in thecemetery at St. Rose.Henry J. Brackman and Anna Luebke are buried inOsgood, OhioThe Fisher, Veit, Schnippel, Reineke, and Herbstfamilies are buried in Freyburg, Ohio.The brothers and sisters ofMarie Agnes Boeckman are buried in Cassella, Ohio.Micheal Veit isburied near Schonau, BavariaFred Winner and Elisabeth Bruns areburied in The Precious Blood cemetery of Chickasaw, OhioBen TuenteJr. and Caroline Winner are buried in Osgood, Ohio.The parents ofFred Winner and Elisabeth Bruns are buried in Egypt, Ohio.JohannFranz Christian Winner is buried in Egypt, Ohio.Anna Marie Fisher(Wieman) is buried in Fryburg.Peter Kleinhenz and Barbara Link areburied in St. Rose, Ohio.Many of the Tuente and Kleinhenz relationis buried in St. Rose cemetery. Churches that my Ancestors were married andBaptized in Jerry Meyer and Linda Fisher are buried in Minsteralong with Joe Meyer and Regina Kleinhenz and John Bernard Meyer andMarie Agnes Putoff. A sister of Marie Agnes Putoff is also buried inMinster. Minnie, a sister of Regina, is also buried inMinster.William Brackman, a brother to Leona Brackman, is buried inOsgood.Carl Bernard Hoyng is buried in Egypt, Ohio.ElisabethTiesem is buried in St. John's cemetery in Maria Stein, Ohio.JohannHeinrich Kohrs is also buried in St. John's cemetery.VincentBrackman, a brother to Henry Brackman, is buried in St. John'scemeteryEmma Brackman is also buried in St. John'sCemetary.Marie Clara Franz is buried in Hartford, Kansas.AnnaHerbst, a sister to Catherine Herbst, is buried in Germany.Henry andHerman Tuente are buried in Freckenhorst, Germany.Henry Kohrs, abrother to Elisabeth Kohrs, is buried in Covington, Ky.CarolineOverman is buried in St. Rose cemetery.John Kleinhenz, a brother toArnold Kleinhenz, is buried in Decator, IN.John W. Kleinhenz, abrother to Regina Kleinhenz is buried in St. Mary's, OhioJosephKleinhenz is buried in St. Rose.

A group of people from Mississippi Market Co-op in St. Paul, MN decided to take the Eat Local America Challenge and this is what happened. Monday, July 28, 2008 Drinking Local Just about everytime an Eat Local Challenge comes up in public conversation, someone mentions upping their percentage of local beer or vodka to meet the challenge guidelines. It's true- we have a decent number of small breweries and even some hard liquor made nearby, I'm told. But I'd be hard pressed to name a single local alcoholic beverage. The only alcohol in our house is a 2 oz. mini-bottle of tequila I use for making margarita cupcakes and some vanilla extract- neither of which are local. My partner is straight edge, so no alcohol for him. And me- I come from a long line of alcoholics (recovering, thank God) and keep my drinks to about one per year. So I won't be kicking back with a cold local brew anytime soon. I will, however, be kicking back with a cold Mulberry Root Beer, though! We started making our own root beer a few years ago. It's not hard to do and the supplies are pretty cheap. Northern Brewing on Grand Ave. has everything you'll need as far as equipment goes and the roots/herbs can be procured at your local co-op. There's a gazillion combinations you can use, but we thought it'd be fun to use up some mulberries in this one. Stir together all fruits/herbs and 1 gallon of the filtered water in a large stockpot. Bring to a simmer and boil for 30 minutes. Then remove from heat and allow to cool to room temperature. Prepare a strainer over another larger pot, carboy, or empty bulk peanut butter bucket. Strain the mulberry-spice liquid, gently pressing the mulberries to get the juice out. Discard strained solids. Add the remaining gallon of water to the jug and stir. Make sure the temperature is lukewarm- no hotter. Then stir the yeast with 1/4 cup of water in a little cup. Add to the jug and stir vigorously. Your brew is now ready to bottle. It takes some strong bottles to package this up as the carbonation can get pretty fierce. I really recommend only using bail-top bottles designed for this purpose. These should be sterilized with hot water and soap before bottling. We use a spigot rigged up on an old 5 gallon bucket and put a plastic hose over the nozzle that attaches to a bottling wand. But you can get creative about how to get the soda into the bottle- just keep it sterile. The soda needs to stay in a warmish place (no problem in summer) for a few days. Usually they take about 48 hours for the carbonation to build, but we check after 24 just in case. You might want to open them outside as they can be lots of fun to open- like champagne that's been shaken up. Once you know they're at the right fizzy consistency, bring them into the basement or a refrigerator to stop the yeast and get those brews ready for drinking! PS- I can't really guarantee how this brew will taste when finished because it's still sitting on the kitchen floor growing bubbles. But my temperature-test taste was rockin good- kindof like a spiced cherry vanilla soda.