Identification of genes specifically expressed in the accumulated visceral adipose tissue of OLETF rats.
The Otsuka Long-Evans Tokushima fatty (OLETF) rat is an animal model of type 2 diabetes, characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. To elucidate the underlying molecular mechanism of obesity and its related complications, we used representational difference analysis and identified the genes more abundantly and specifically expressed in the visceral adipose tissue (VAT) of obese OLETF rats compared with the diabetes-resistant counterpart, that is, Long-Evans Tokushima Otsuka (LETO) rats. By Northern blot analysis, we confirmed the differential expression of 13 genes, including 3 novel genes. The upregulated expression of well-characterized lipid metabolic enzymes, such as lipoprotein lipase, phosphoenolpyruvate carboxykinase, and cholesterol esterase, were observed in VAT of OLETF rats. We demonstrated the differential expression of secreted proteins in VAT of OLETF rats, such as thrombospondin 1 and contrapsin-like protease inhibitor. In contrast to lipid enzymes, the secreted proteins revealed exclusive mRNA expression and they were not detected in VAT of LETO rats. Furthermore, the novel genes OL-16 and OL-64 were also expressed specifically in VAT of OLETF rats and were absent in that of LETO rats and other tissues, including subdermal and brown adipose tissues. The C-terminal partial amino acid sequence of OL-64 revealed that it showed approximately 40% homology with alpha(1)-antitrypsin and it seemed to be a new member of the serine proteinase inhibitor (SERPIN) gene family. VAT of OLEFT rats had a unique gene expression profile, and the accumulated VAT-specific known and novel secreted proteins may play a role(s) in the pathogenesis of obesity and its related complications.


The inhibitory effect of trifluoromethylphenylpiperazine on [3H]acetylcholine release in guinea pig hippocampal synaptosomes is mediated by a 5-hydroxytryptamine1 receptor distinct from 1A, 1B, and 1C subtypes.
The effect of the serotonergic receptor agonist 1-(m-trifluoromethylphenyl)piperazine (TFMPP) was studied on the K(+)-evoked [3H]acetylcholine [( 3H]ACh) release from guinea pig hippocampal synaptosomes loaded with [3H]choline. TFMPP (5-1,000 microM) inhibited the evoked ACh release in a dose-dependent manner (IC50 = 81.8 microM). The inhibitory effect of TFMPP was mimicked by CGS-12066B (10, 30, and 100 microM), a 5-hydroxytryptamine1B (5-HT1B)/5-HT1D receptor agonist; 1-(m-chlorophenyl)piperazine (100 microM), a 5-HT1C/5-HT1B receptor agonist; and 5-carboxamidotryptamine (10 microM), a nonselective 5-HT1 receptor agonist. 8-Hydroxy-2-(di-n-propylamino)tetralin (10 and 100 microM), a 5-HT1A receptor agonist, and quipazine (10 and 100 microM), a 5-HT2 receptor agonist, did not have any significant effect. Serotonergic antagonists, such as dihydroergotamine (0.1 and 1 microM), metergoline (0.1 microM), methysergide (0.5 and 1 microM), or yohimbine (1 and 10 microM), blocked the TFMPP effect dose-dependently. In contrast, methiotepine (0.3 and 1 microM), propranolol (1 microM), ketanserin (0.1 microM), mesulergine (0.1 microM), ICS 205930 (0.1 and 1 microM), and spiroperidol (1 and 7 microM) did not affect the TFMPP-induced inhibition of the evoked ACh release. These data suggest that, in guinea pig hippocampus, the K(+)-evoked ACh release is modulated by a 5-HT1 receptor distinct from the 5-HT1A, 5-HT1B, and 5-HT1C subtypes.


PhenoDis: a comprehensive database for phenotypic characterization of rare cardiac diseases.
Thoroughly annotated data resources are a key requirement in phenotype dependent analysis and diagnosis of diseases in the area of precision medicine. Recent work has shown that curation and systematic annotation of human phenome data can significantly improve the quality and selectivity for the interpretation of inherited diseases. We have therefore developed PhenoDis, a comprehensive, manually annotated database providing symptomatic, genetic and imprinting information about rare cardiac diseases. PhenoDis includes 214 rare cardiac diseases from Orphanet and 94 more from OMIM. For phenotypic characterization of the diseases, we performed manual annotation of diseases with articles from the biomedical literature. Detailed description of disease symptoms required the use of 2247 different terms from the Human Phenotype Ontology (HPO). Diseases listed in PhenoDis frequently cover a broad spectrum of symptoms with 28% from the branch of 'cardiovascular abnormality' and others from areas such as neurological (11.5%) and metabolism (6%). We collected extensive information on the frequency of symptoms in respective diseases as well as on disease-associated genes and imprinting data. The analysis of the abundance of symptoms in patient studies revealed that most of the annotated symptoms (71%) are found in less than half of the patients of a particular disease. Comprehensive and systematic characterization of symptoms including their frequency is a pivotal prerequisite for computer based prediction of diseases and disease causing genetic variants. To this end, PhenoDis provides in-depth annotation for a complete group of rare diseases, including information on pathogenic and likely pathogenic genetic variants for 206 diseases as listed in ClinVar. We integrated all results in an online database ( http://mips.helmholtz-muenchen.de/phenodis/ ) with multiple search options and provide the complete dataset for download. PhenoDis provides a comprehensive set of manually annotated rare cardiac diseases that enables computational approaches for disease prediction via decision support systems and phenotype-driven strategies for the identification of disease causing genes.


Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders.
Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored. To assess what impact mitochondrial lineages encompassing ancient mtDNA functional polymorphisms, termed haplogroups, have on ASD risk. In this cohort study, individuals with autism and their families were studied using the Autism Genetic Resource Exchange cohort genome-wide association studies data previously generated at the Children's Hospital of Philadelphia. From October 2010 to January 2017, we analyzed the data and used the mtDNA single-nucleotide polymorphisms interrogated by the Illumina HumanHap 550 chip to determine the mtDNA haplogroups of the individuals. Taking into account the familial structure of the Autism Genetic Resource Exchange data, we then determined whether the mtDNA haplogroups correlate with ASD risk. Odds ratios of mitochondrial haplogroup as predictors of ASD risk. Of 1624 patients with autism included in this study, 1299 were boys (80%) and 325 were girls (20%). Families in the Autism Genetic Resource Exchange collection (933 families, encompassing 4041 individuals: 1624 patients with ASD and 2417 healthy parents and siblings) had been previously recruited in the United States with no restrictions on age, sex, race/ethnicity, or socioeconomic status. Relative to the most common European haplogroup HHV, European haplogroups I, J, K, O-X, T, and U were associated with increased risk of ASD, as were Asian and Native American haplogroups A and M, with odds ratios ranging from 1.55 (95% CI, 1.16-2.06) to 2.18 (95% CI, 1.59-3) (adjusted P < .04). Hence, mtDNA haplogroup variation is an important risk factor for ASD. Because haplogroups I, J, K, O-X, T, and U encompass 55% of the European population, mtDNA lineages must make a significant contribution to overall ASD risk.


Reference noise method of removing powerline noise from recorded signals.
Powerline contamination of recorded signals represents a major source of noise in electrophysiology and impairs the use of recordings for research. In this article we present simple and effective method for cancelling 50 Hz (or 60 Hz) noise using a reference noise signal and average noise cycle subtraction. This method is capable of reliably removing not only the fundamental powerline frequency but also its harmonic frequencies. The efficiency of this method appears to be superior to other commonly used methods such as notch filtering or adaptive filtering. Our experience and results show that this method can be efficiently used with very low signal-to-noise ratios, while preserving original signal waveform.


Multi-Omics Driven Metabolic Network Reconstruction and Analysis of Lignocellulosic Carbon Utilization in Rhodosporidium toruloides.
An oleaginous yeast Rhodosporidium toruloides is a promising host for converting lignocellulosic biomass to bioproducts and biofuels. In this work, we performed multi-omics analysis of lignocellulosic carbon utilization in R. toruloides and reconstructed the genome-scale metabolic network of R. toruloides. High-quality metabolic network models for model organisms and orthologous protein mapping were used to build a draft metabolic network reconstruction. The reconstruction was manually curated to build a metabolic model using functional annotation and multi-omics data including transcriptomics, proteomics, metabolomics, and RB-TDNA sequencing. The multi-omics data and metabolic model were used to investigate R. toruloides metabolism including lipid accumulation and lignocellulosic carbon utilization. The developed metabolic model was validated against high-throughput growth phenotyping and gene fitness data, and further refined to resolve the inconsistencies between prediction and data. We believe that this is the most complete and accurate metabolic network model available for R. toruloides to date.


Safety of Schizochytrium sp. oil as a novel food pursuant to Regulation (EU) 2015/2283.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the safety of Schizochytrium sp. oil as a novel food (NF) pursuant to Regulation (EU) 2015/2283. Schizochytrium sp. is a single-cell microalga. The strain WZU477, used by the applicant (Progress Biotech bv), was found to belong to the species Schizochytrium limacinum and was obtained in a marine environment from rotted mangrove forest leaves. The NF, an oil rich in docosahexaenoic acid (DHA), is isolated from the microalgae by mechanical extraction. The applicant proposed to use the NF in infant formulae (IF) and follow-on formulae (FOF). The use level defined by the applicant was derived from Regulation (EU) 2016/127, which states the mandatory addition of DHA to IF and FOF at the level of 20-50 mg/100 kcal. The intake of DHA resulting from the use of the NF in IF and FOF is not expected to pose safety concerns. The composition of the NF indicates the absence of marine biotoxins in the NF. Furthermore, Schizochytrium limacinum was attributed the qualified presumption of safety (QPS) status with the qualification 'for production purposes only'. Based on the information provided, the microalga is not expected to survive the manufacturing process. Toxicological tests conducted with the NF were not performed. However, based on the available toxicological data on various forms of oils derived from Schizochytrium sp., the QPS status of the source of the NF, the production process and the composition of the NF, the Panel considers there are no concerns with regard to toxicity of the NF. The Panel concludes that the NF is safe under the proposed conditions of use.


The Demographic Development of the First Farmers in Anatolia.
The archaeological documentation of the development of sedentary farming societies in Anatolia is not yet mirrored by a genetic understanding of the human populations involved, in contrast to the spread of farming in Europe [1-3]. Sedentary farming communities emerged in parts of the Fertile Crescent during the tenth millennium and early ninth millennium calibrated (cal) BC and had appeared in central Anatolia by 8300 cal BC [4]. Farming spread into west Anatolia by the early seventh millennium cal BC and quasi-synchronously into Europe, although the timing and process of this movement remain unclear. Using genome sequence data that we generated from nine central Anatolian Neolithic individuals, we studied the transition period from early Aceramic (Pre-Pottery) to the later Pottery Neolithic, when farming expanded west of the Fertile Crescent. We find that genetic diversity in the earliest farmers was conspicuously low, on a par with European foraging groups. With the advent of the Pottery Neolithic, genetic variation within societies reached levels later found in early European farmers. Our results confirm that the earliest Neolithic central Anatolians belonged to the same gene pool as the first Neolithic migrants spreading into Europe. Further, genetic affinities between later Anatolian farmers and fourth to third millennium BC Chalcolithic south Europeans suggest an additional wave of Anatolian migrants, after the initial Neolithic spread but before the Yamnaya-related migrations. We propose that the earliest farming societies demographically resembled foragers and that only after regional gene flow and rising heterogeneity did the farming population expansions into Europe occur.


Emergence of Content-Agnostic Information Processing by a Robot Using Active Inference, Visual Attention, Working Memory, and Planning.
Generalization by learning is an essential cognitive competency for humans. For example, we can manipulate even unfamiliar objects and can generate mental images before enacting a preplan. How is this possible? Our study investigated this problem by revisiting our previous study (Jung, Matsumoto, & Tani, 2019), which examined the problem of vision-based, goal-directed planning by robots performing a task of block stacking. By extending the previous study, our work introduces a large network comprising dynamically interacting submodules, including visual working memory (VWMs), a visual attention module, and an executive network. The executive network predicts motor signals, visual images, and various controls for attention, as well as masking of visual information. The most significant difference from the previous study is that our current model contains an additional VWM. The entire network is trained by using predictive coding and an optimal visuomotor plan to achieve a given goal state is inferred using active inference. Results indicate that our current model performs significantly better than that used in Jung et al. (2019), especially when manipulating blocks with unlearned colors and textures. Simulation results revealed that the observed generalization was achieved because content-agnostic information processing developed through synergistic interaction between the second VWM and other modules during the course of learning, in which memorizing image contents and transforming them are dissociated. This letter verifies this claim by conducting both qualitative and quantitative analysis of simulation results.


Topographical and chemical effects of electrochemically assisted deposited hydroxyapatite coatings on osteoblast-like cells.
A recently commercialised hydroxyapatite electrochemically assisted chemical deposition technique (BoneMaster) has been shown to induce increased bone apposition; whether this response is caused by the surface topography or chemistry is unknown. An in-vitro examination using human osteoblast-like cells was performed on a series of BoneMaster-coated surfaces. The chemistry was separated from the topography using a thin gold coating; Thermanox coverslips were used as a control. BoneMaster surfaces showed significantly greater alkaline phosphatase activity and osteocalcin production compared with controls; however, no difference was found between the gold-coated and uncoated BoneMaster samples, indicating topography is the main contributing factor.


Vision Improvement with Refractive Correction Does Not Completely Exclude Major Eye Diseases: Analyses of Visually Impaired South Korean Population in the Korea National Health and Nutrition Examination Survey 2009-2011.
To investigate the association between vision improvement with refractive correction in the visually impaired eyes and the prevalence of ocular comorbidities in the South Korean population. The data of 24,620 individuals in the Korea National Health and Nutrition Examination Survey (KNHANES 2009-2011) were reviewed. Visual impairment was defined as a presenting visual acuity < 20/60. The participants with visual impairment in at least one eye were divided into 3 groups according to the best-corrected visual acuity (group 1: <20/30, group 2: ≥20/30 but <20/25, and group 3: ≥20/25). The prevalence of ocular comorbidities was estimated and compared between the three groups. Visual impairment in at least one eye was found in 3031 individuals. Groups 1, 2, and 3 comprised 23.5%, 22.2%, and 54.3% of these visually impaired eyes, respectively. The prevalence of cataract, diabetic retinopathy, age-related macular degeneration, corneal opacity, blepharoptosis, and pterygium was similar to or even higher in group 2 compared to group 1. The prevalence of glaucoma and age-related macular degeneration was 5.40% and 11.39%, respectively, in group 2 and 3.31% and 3.76%, respectively, in group 3. Appropriate ophthalmologic examination is necessary even if people exhibit vision improvement after optical correction.


A psycho-legal perspective on sexual offending in individuals with autism Spectrum disorder.
It is important to consider whether there are innate vulnerabilities that increase the risk of an individual with an autistic spectrum disorder (ASD), predominantly those defendants with a diagnosis of Asperger's Syndrome, being charged and convicted of a sexual offence. The significance of such can be readily seen in recent English case law, with judgments on appeal finding convictions unsafe where there have been a number of failings in the Judge's summing up. In this article, we will consider the gravity of Judges omitting to highlight a defendant's diagnosis of autism spectrum disorder and the necessity of detailed explanations to jury members regarding the condition and its effect upon thoughts and behaviour. Consideration will be specifically given to the necessity to prove sexual motivation in such offences and the judicial direction required in relation to whether the appellant's actions had been sexually motivated. Recognition of the social impairments inherent in ASDs are vital to this work and we shall consider whether the difficulty with the capacity to develop appropriate, consenting sexual relationships as a result of impaired social cognition may be one of the factors which increases the risk of sexual offending in individuals with ASD (Higgs & Carter, 2015).


Meiotic long non-coding meiRNA accumulates as a dot at its genetic locus facilitated by Mmi1 and plays as a decoy to lure Mmi1.
Long non-coding RNAs (lncRNAs) play key roles in the formation of nuclear bodies. In the fission yeast Schizosaccharomyces pombe, a lncRNA species termed meiRNA forms a nuclear dot structure at its own genetic locus, the sme2 locus, with its protein-binding partner Mei2. This dot structure, called Mei2 dot, promotes the progression of meiosis by suppressing Mmi1, a crucial factor involved in the selective elimination of meiosis-specific transcripts. The meiRNA itself is a target of Mmi1-mediated elimination and is supposed to function as a decoy to lure Mmi1. However, detailed mechanisms underlying the formation of Mei2 dot and inactivation of Mmi1 remain ambiguous. Here, we show that the localization of meiRNA, at its genetic locus sme2, depends on its association with Mmi1. We also demonstrate that one of the multiple Mmi1 foci in mitotic cells localizes to the sme2 locus. Furthermore, the overexpression of meiRNA promotes the accumulation of Mmi1 to the sme2 locus even in the absence of Mei2 and reduces the activity of Mmi1. These findings indicate that the retention of meiRNA at its genetic locus is facilitated by Mmi1, which then attracts scattered Mmi1 to inhibit its function.


Benchmarking pluripotent stem cell-derived organoid models.
Cerebral organoids are stem cell-derived, self-organizing three-dimensional cultures. Owing to the remarkable degree to which they recreate the cellular diversity observed in the human brain, they have attracted significant interest as a novel model system for research and drug development, as well as capturing the public imagination. However, many questions remain about the extent to which these cultures recapitulate neurodevelopment and the defining features of the human brain. To clarify the fidelity of human organoid models, Bhaduri and colleagues compared the molecular profile of brain organoid cells with that of primary cells from fetal brain. They observed that, whilst brain organoids broadly recapitulate the cellular profile of human brain, they lack the subtypes of cell classes seen in human brain. In addition, they showed marked expression of cellular stress markers, which could be reversed by transplanting organoid cells into neonatal mouse brain. The authors hypothesise that in vitro culture induces a cellular stress response and that it is this that impairs maturation. Thus, whilst their findings strike a note of caution in the use of organoids as a model for early human brain development, they lay a foundation for improving the accuracy of organoid models in the future.


Cytogenetic characterization of a BCR-ABL transduced mouse cell line.
Most patients with Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) show evidence of secondary chromosome aberrations that may influence the course of disease and response to treatment. To better understand how these secondary chromosomal aberrations occur and to investigate whether the p185/p190 BCR-ABL fusion protein may directly induce an increased chromosomal instability and subsequently the appearance of clonal chromosome aberrations, three BRC-ABL (p185/ p190)-transduced mouse pre-B cell lines were analyzed by spectral karyotyping and fluorescence in situ hybridization. The human wild-type BCR-ABL gene was expressed at a level comparable with that in human Ph-positive leukemias at diagnosis. All BCR-ABL-transduced cell lines acquired similar clonal chromosomal aberrations. Trisomy 5 was always present, followed by loss of the Y chromosome, trisomy of chromosomes 12 and 18, and an unbalanced translocation between chromosomes X and 12. Thus, ectopic p185/p190 BCR-ABL expression, such as p210 BCR-ABL, PML-RARA, or C-MYC transduction, may induce an increased chromosomal instability leading to clonal karyotypic evolution, which may mimic secondary chromosome aberrations in human Ph-positive ALL.


Patterns, control and complications of diabetes from a hospital based registry established in a low income country.
Diabetes registry enables practitioners to measure the characteristics and patterns of diabetes across their patient population. They also provide insight into practice patterns which can be very effective in improving care and preventing complications. The aim of this study was to assess the patterns, control levels and complications at the baseline of the patients attending clinic at the large tertiary care hospital in Karachi, Pakistan with the help of the registry. This can be used as a reference to monitor the control and also for a comparison between peer groups. This was a cross sectional study with the data obtained from diabetes registry collected with the help of pre-designed questionnaire. HbA1c was used as a central diabetes measure and other related factors and complications were assessed with it. Only 16.6% of the participants had optimal HbA1c ≤ 7.0%. 52.9% of the patients were classified as having poor control defined by HbA1c of >8%. Three fourth of the study population were obese according to Asian specific BMI cutoffs and majority had type 2 diabetes with duration of diabetes ranging from less than one to about 35 years, mean(SD) duration being 7.6 years (7.1). Overall only 4% of the patients were on combine target of HbA1c, LDL and BP. Results of multivariable logistic regression showed that the odds of having optimal glycemic control increased by 3% with every one year increase in age. In addition, having longer duration of diabetes was associated with 56% lower odds of having good glycemic control. Moreover, having higher triglyceride levels was associated with 1% lower odds of having good glycemic control. This highlights the large burden of sub optimally controlled people with diabetes in Pakistani population, a low income country with huge diabetes prevalence and ineffective primary health care system creating enormous health and economic burden.


Changes in attentional processing following neurofeedback in patients with persistent post-concussive symptoms: a pilot study.
Persistent post-concussive symptoms (PPCS) often include attention deficits, particularly orienting and executive attention. Research in other clinical populations has demonstrated that neurofeedback therapy (NFT) is effective at improving orienting and executive attention, although its effects on attentional networks in patients with PPCS are unknown. In this single-group pilot study, we examined attention-related event-related potentials (ERPs) - N1 and P3 - and cognitive outcomes following Live Z-score training (LZT), a variant of NFT. No changes in early selective attention, as indexed by N1 amplitude, were observed; however, P3 amplitude, which indexes neural resource allocation, increased following LZT and returned to baseline by 3 months. Cognitive performance improved following treatment, which was sustained at 3 months. The magnitude of change in P3 and ANT performance did not differ between orienting or executive attention, suggesting LZT improved general attentional processing efficiency. Our results suggest that LZT may positively affect attention globally, but does not target specific attention networks. These pilot data warrant the initiation of a clinical trial evaluating the effectiveness of LZT for treating attention deficits in patients with PPCS.


Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome.
Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.


A novel terrestrial fish habitat inside emergent logs.
Reports of new habitats for a major group of organisms are rare. Fishes display diverse adaptations for temporary (amphibious) existence on land, but to our knowledge, none have ever been reported regularly living inside emergent logs. Here, we show that the mangrove killifish, Kryptolebias marmoratus, a species previously known to emerse (leave the water) regularly, is now known to emerse and aggregate in large numbers inside decaying mangrove logs that have been "galleried" by terrestrial insects. This behavior has now been documented in both Belize, Central America, and Florida, U.S.A., populations and represents the first known case of fishes entering terrestrial woody material. The dense packing of fish in the narrow log galleries may imply a novel social context in which intraspecific aggressive behaviors are reduced, possibly mediated by the physiological limitations imposed within this restrictive habitat.


Perceptions and practices of adapted physical educators on the teaching of social skills.
The purpose of this study was to determine adapted physical educators' perceptions and practices about teaching social skills to students with disabilities. A questionnaire based on Bandura's social learning theory concept of modeling was developed and mailed to an entire frame of 426 adapted physical education teachers in the state of Ohio. Face and content validity as well as test/retest reliability (0.89) were established. Of those that were surveyed, 53% (225 teachers; 148 females and 77 males) responded. Results indicate that 93% (209) believe it is important to explicitly teach social skills in PE; however, 60% (135) expressed not feeling properly prepared to teach them. Teachers with more than 20 years of teaching experience were more likely to actually teach social skills. When compared with other teachers with less years teaching, however, they identified a greater need for training in the teaching of social skills. Results are discussed relative to teacher preparation and practices as well as social skills taught for general education and community integration.


Erythrocyte 22Na efflux and urinary sodium excretion in essential hypertension.
1. The rate constant for total 22Na efflux from erythrocytes was examined in patients with mild to moderate hypertension and in normotensive controls. No difference in 22Na efflux rate constant was found when the cells from both groups were incubated in artificial medium. When the cells from both groups were incubated in their own plasma, the rate constant for Na efflux was significantly elevated for hypertensive patients compared with controls (0.40 +/- 0.02, 0.36 +/- 0.01 respectively; P < 0.05). 2. In hypertensive patients sodium efflux rate constant varied inversely with 24 h urinary sodium excretion when erythrocytes were incubated in artificial medium (r = -0.34, P < 0.05) or in plasma (r = -0.42, P < 0.05). No association between sodium efflux rate constant and urinary sodium excretion occurred in normotensive subjects. 3. These findings provide further evidence that sodium is an important aetiological factor in hypertension. In 'salt-sensitive' individuals dietary sodium may interact with the regulation of cellular sodium transport via both humoral and cellular mechanisms to elevate blood pressure.


Inhibition of angiotensin converting enzyme activity by flavanol-rich foods.
Angiotensin converting enzyme (ACE) activity was evaluated in the presence of flavanol-rich foods, i.e., wines, chocolates, and teas, and of purified flavonoids. All foods assayed inhibited ACE activity, red wines being more effective than white wine, and green tea more effective than black tea. The inhibition of ACE activity was associated with both phenolic and flavanol content in the foods. When isolated polyphenols were assayed, procyanidins (dimer and hexamer) and epigallocatechin significantly inhibited enzyme activity; similar concentrations of (+)-catechin, (-)-epicatechin, gallic acid, chlorogenic acid, caffeic acid, quercetin, kaempferol, and resveratrol were ineffective. When ACE activity was assayed in rat kidney membranes in the presence of chocolate extracts or purified procyanidins, it was observed that the inhibition depended on the chocolate content of flavanols and the number of flavanol units constituting the procyanidin. These experiments demonstrate that flavanols either isolated or present in foods could inhibit ACE activity. The occurrence of such inhibition in vivo needs to be determined, although is supported by the association between the consumption of flavanol-rich foods and reductions in blood pressure observed in several experimental models.


Asynchronous spiking photonic neuron for lightwave neuromorphic signal processing.
We developed an asynchronous spiking photonic neuron that forms the basic building block for hybrid analog/digital lightwave neuromorphic processing. Our approach enables completely asynchronous spiking in response to input signals while maximizing the throughput relative to synchronous approaches. Asynchronous operation is achieved by generating the spike source for the photonic neuron through four-wave mixing. This hybrid analog/digital photonic neuron has an electro-absorption modulator as the temporal integration unit for analog processing, while the digital processing portion employs optical thresholding in a highly Ge-doped nonlinear loop mirror.


Genes related to long polar fimbriae of pathogenic Escherichia coli strains as reliable markers to identify virulent isolates.
Lpf (stands for long polar fimbriae) is one of the few adhesive factors of enterohemorrhagic Escherichia coli O157:H7 associated with colonization of the intestine. E. coli O157:H7 strains possess two lpf loci encoding highly regulated fimbrial structures. Database analysis of the genes encoding the major fimbrial subunits demonstrated that they are present in commensal as well as pathogenic (both intestinal and extraintestinal) E. coli strains and in Salmonella strains and that the lpfA1 and lpfA2 genes are highly prevalent among LEE (locus of enterocyte effacement)-positive E. coli strains associated with severe and/or epidemic disease. Further DNA sequence analysis of the lpfA1 and lpfA2 genes from different attaching-and-effacing E. coli strains has led us to the identification of several polymorphisms and the classification of the major fimbrial subunits into distinct variants. Using collections of pathogenic E. coli isolates from Europe and Latin America, we demonstrated that the different lpfA types are associated with the presence of specific intimin (eae) adhesin variants and, most importantly, that they are found in specific E. coli pathotypes. Our results showed that the use of these fimbrial genes as markers, in combination with the different intimin types, resulted in a specific test for the identification of E. coli O157:H7, distinguishing it from other pathogenic E. coli strains.


Role of CBCT in Prediction of Oro-antral Communication Post Third Molar Extraction: A Retrospective Study.
Oro-antral communication (OAC) is one of the most frequently encountered complications during third molar extraction. Various radiographic factors, like excessive maxillary sinus pneumatization, long periods of edentulism, periapical lesions, etc., have been considered high-risk factors for OAC. However, a panoramic radiograph has not proven to be accurate in predicting the chances of OAC. Through this retrospective study, we evaluated the efficacy of a CBCT in predicting the incidence of OAC after maxillary third molar extraction. We conducted a retrospective study in our department, which included the patients who had undergone extraction of a maxillary third molar over five years with the presence of panoramic X-rays and/or CBCT scans prior to extraction. Primary outcomes assessed from the case files were intra-operative complications like OAC, root fracture, tuberosity fracture, pterygoid plate fracture, etc. The incidence of these complications was correlated with the presence or absence of CBCT before extraction. Out of 920 extracted maxillary third molar, only 148 teeth (16.1%) had a CBCT record before extraction. The most commonly encountered complication was broken inaccessible root piece/s (4.9%), followed by OAC (3.5%). An inter-group comparison showed that a significantly higher percentage of patients (p < 0.001) with CBCT records had an incidence of OAC (11.5%) as against the group of patients with no CBCT record (1.9%). A CBCT scan prior to cases with high-risk factors for OAC can be a valuable tool in accurately predicting the chances of OAC after maxillary third molar extraction.


A Welch-type test for homogeneity of contrasts under heteroscedasticity with application to meta-analysis.
A common problem that arises in the meta-analysis of several studies, each with independent treatment and control groups, is to test for the homogeneity of effect sizes without the assumptions of equal variances of the treatment and the control groups and of equal variances among the separate studies. A commonly used test statistic, frequently denoted as Q, is the weighted sum of squares of the differences of the individual effect sizes from the mean effect size, with weights inversely proportional to the variances of the effect sizes. The primary contributions of this article are the presentation of improved and very accurate approximations to the distributions of the Q statistic when the effect size is a linear contrast such as the difference between the treatment and control means. Our improved approximation to the distribution of Q under the null hypothesis is based on a multiple of an F-distribution; its use yields a substantial reduction in the type I error rate of the homogeneity test. Our improved approximation to the distribution of Q under an alternative hypothesis is based on a shift of a chi-square distribution; its use allows for much greater accuracy in the computation of the power of the homogeneity test. These two improved approximate distributions are developed using the Welch methodology of approximating the moments of Q by the use of multivariate Taylor expansions. The quality of these approximations is studied by simulation. A secondary contribution of this article is a study of how best to combine the variances of the treatment and control groups (needed for the calculation of weights in the Q statistic). Our conclusion, based on simulations, is that use of pooled variances can result in substantially erroneous conclusions.


In vivo gastrocnemius muscle fascicle length in children with and without diplegic cerebral palsy.
The effect of spastic cerebral palsy on in vivo gastrocnemius muscle fascicle length is not clear. Similarity of fascicle lengths in children with diplegia and typically developing children, but shortening of fascicle lengths in the paretic legs of children with hemiplegia compared with the non-paretic legs, are both reported. In the former case, comparisons were made between fascicle lengths normalized to leg length, whereas in the latter case, absolute fascicle lengths were compared. The inherent assumptions when normalizing fascicle length (measured via ultrasonography) were not validated, raising the possibility that inappropriate normalization contributed to the controversy. We used statistical methods to control the potential confounding effect of leg length on fascicle length, and tested the feasibility of the normalization method for a group of 18 children with diplegia (nine males, nine females; mean age 8y 7mo [SD 3y 11mo], range 2-15y; Gross Motor Function Classification System levels II and III) and 50 typically developing children (20 males, 30 females; mean age 9y 1mo [SD 2y 4mo], range 4-14y). Children with diplegia, as a group, had shorter absolute and normalized fascicle lengths (p<0.05) but we could not refute the appropriateness of the normalization method. Other methodological issues (such as sample characteristics) might have contributed to the apparent controversy between the studies.


Cardiorespiratory fitness and fat oxidation during exercise as protective factors for insulin resistance in sedentary women with overweight or obesity.
obesity is a global pandemic and it is the biggest risk factor for death worldwide nowadays. Studies suggest that both cardiorespiratory fitness and fat oxidation in exercise are related to insulin resistance and type 2 diabetes mellitus, and they could be used as metabolic fitness markers. the aim of this study is to determine if cardiorespiratory fitness (VO2) and fat oxidation during exercise are protective factors of insulin resistance (IR) in sedentary women with obesity or overweight. sixty women were selected for fat oxidation analysis and 55 for cardiorespiratory fitness analysis that fitted the inclusion and exclusion criteria. VO2, maximal fat oxidation (MFO) and the intensity where MFO is reached (FATmax) were determined through an incremental test on a cycle ergometer with gas analysis. The subjects with a Homeostatic model assessment of IR index greater or equal to 2.5 were considered as insulin-resistant. Participants were divided into 2 groups, IR group (n = 38) and Non-IR group (n = 22). VO2(%) and MFO were lower in the IR group (76.1% vs.83.2%; p = 0.015 and 1.08 mg × kg-1 × min-1 vs. 1.62 mg × kg-1 × min-1; p= 0.044, respectively) compared to the Non-IR group. There was an association between VO2(%) and IR (OR = 0.92, p = 0.017) and between MFO and IR (OR = 0.52, p = 0.035), both models adjusted for age and body mass index. VO2(%) and MFO are independent protective factors for IR. No association was found between FATmax and IR.


Global characterization of the oocyte-to-embryo transition in Caenorhabditis elegans uncovers a novel mRNA clearance mechanism.
The oocyte-to-embryo transition (OET) is thought to be mainly driven by post-transcriptional gene regulation. However, expression of both RNAs and proteins during the OET has not been comprehensively assayed. Furthermore, specific molecular mechanisms that regulate gene expression during OET are largely unknown. Here, we quantify and analyze transcriptome-wide, expression of mRNAs and thousands of proteins in Caenorhabditis elegans oocytes, 1-cell, and 2-cell embryos. This represents a first comprehensive gene expression atlas during the OET in animals. We discovered a first wave of degradation in which thousands of mRNAs are cleared shortly after fertilization. Sequence analysis revealed a statistically highly significant presence of a polyC motif in the 3' untranslated regions of most of these degraded mRNAs. Transgenic reporter assays demonstrated that this polyC motif is required and sufficient for mRNA degradation after fertilization. We show that orthologs of human polyC-binding protein specifically bind this motif. Our data suggest a mechanism in which the polyC motif and binding partners direct degradation of maternal mRNAs. Our data also indicate that endogenous siRNAs but not miRNAs promote mRNA clearance during the OET.


Applying next-generation sequencing to unravel the mutational landscape in viral quasispecies.
Next-generation sequencing (NGS) has revolutionized the scale and depth of biomedical sciences. Because of its unique ability for the detection of sub-clonal variants within genetically diverse populations, NGS has been successfully applied to analyze and quantify the exceptionally-high diversity within viral quasispecies, and many low-frequency drug- or vaccine-resistant mutations of therapeutic importance have been discovered. Although many works have intensively discussed the latest NGS approaches and applications in general, none of them has focused on applying NGS in viral quasispecies studies, mostly due to the limited ability of current NGS technologies to accurately detect and quantify rare viral variants. Here, we summarize several error-correction strategies that have been developed to enhance the detection accuracy of minority variants. We also discuss critical considerations for preparing a sequencing library from viral RNAs and for analyzing NGS data to unravel the mutational landscape.


Sex and vision II: color appearance of monochromatic lights.
Because cerebral cortex has a very large number of testosterone receptors, we examined the possible sex differences in color appearance of monochromatic lights across the visible spectrum. There is a history of men and women perceiving color differently. However, all of these studies deal with higher cognitive functions which may be culture-biased. We study basic visual functions, such as color appearance, without reference to any objects. We present here a detailed analysis of sex differences in primary chromatic sensations. We tested large groups of young adults with normal vision, including spatial and temporal resolution, and stereopsis. Based on standard color-screening and anomaloscope data, we excluded all color-deficient observers. Stimuli were equi-luminant monochromatic lights across the spectrum. They were foveally-viewed flashes presented against a dark background. The elicited sensations were measured using magnitude estimation of hue and saturation. When the only permitted hue terms are red (R) yellow (Y), green (G), blue (B), alone or in combination, such hue descriptions are language-independent and the hue and saturation values can be used to derive a wide range of color-discrimination functions. There were relatively small but clear and significant, differences between males and females in the hue sensations elicited by almost the entire spectrum. Generally, males required a slightly longer wavelength to experience the same hue as did females. The spectral loci of the unique hues are not correlated with anomaloscope matches; these matches are directly determined by the spectral sensitivities of L- and M-cones (genes for these cones are on the X-chromosomes). Nor are there correlations between loci of pairs of unique hues (R, Y, G, B). Wavelength-discrimination functions derived from the scaling data show that males have a broader range of poorer discrimination in the middle of the spectrum. The precise values for all the data depend on whether Newtonian or Maxwellian optics were used, but the sex differences were the same for both optical systems. As with our associated paper on spatio-temporal vision, there are marked sex differences in color vision. The color-appearances we measured are determined by inputs from thalamic neurons (LGN) to individual neurons in primary visual cortex. This convergence from LGN to cortex is guided by the cortex during embryogenesis. We hypothesize that testosterone plays a major role, somehow leading to different connectivities for males and females: color appearance requires a re-combination and re-weighting of neuronal inputs from the LGN to the cortex, which, as we show, depends on the sex of the participant.


Oxidized proteins: mechanisms of removal and consequences of accumulation.
Elevated levels of oxidized proteins are reported in diseased tissue from age-related pathologies such as atherosclerosis, neurodegenerative disorders, and cataract. Unlike the precise mechanisms that exist for the repair of nucleic acids, lipids, and carbohydrates, the primary pathway for the repair of oxidized proteins is complete catabolism to their constitutive amino acids. This process can be inefficient as is evidenced by their accumulation. It is generally considered that damaged proteins are degraded by the proteasome; however, this is only true for mildly oxidized proteins, because substrates must be unfolded to enter the narrow catalytic core. Rather, evidence suggests that moderately or heavily oxidized proteins are endocytosed and enter the endosomal/lysosomal system, indicating co-operation between the proteasomes and the lysosomes. Heavily modified substrates are incompletely degraded and accumulate within the lysosomal compartments resulting in the formation of lipofuscin-like, autofluorescent aggregates. Accumulation eventually results in impaired turnover of large organelles such as proteasomes and mitochondria, lysosomal destablization, leakage of proteases into the cytosol and apoptosis. In this review, we summarize reports published since our last assessments of the field of oxidized protein degradation including a role for modified proteins in the induction of apoptosis.


GA2LEN (Global Allergy and Asthma European Network) addresses the allergy and asthma 'epidemic'.
Allergic diseases represent a major health problem in Europe. They are increasing in prevalence, severity and costs. The Global Allergy and Asthma European Network (GA(2)LEN), a Sixth EU Framework Program for Research and Technological Development (FP6) Network of Excellence, was created in 2005 as a vehicle to ensure excellence in research bringing together research and clinical institutions to combat fragmentation in the European research area and to tackle allergy in its globality. The Global Allergy and Asthma European Network has benefited greatly from the voluntary efforts of researchers who are strongly committed to this model of pan-European collaboration. The network was organized in order to increase networking for scientific projects in allergy and asthma around Europe and to make GA(2)LEN the world leader in the field. Besides these activities, research has also been carried out and the first papers are being published. Achievements of the Global Allergy and Asthma European Network can be grouped as follows: (i) those for a durable infrastructure built up during the project phase, (ii) those which are project-related and based on these novel infrastructures, and (iii) the development and implementation of guidelines. The major achievements of GA(2)LEN are reported in this paper.


Development of a simple incubation system for metabolism studies with precision-cut liver slices.
The use of precision-cut liver slices for toxicity and drug metabolism studies becomes more and more popular. So far, most of these studies are conducted using the dynamic organ culture system as incubation system. However, this system has some disadvantages, especially for the study of drug metabolism. Therefore, the aim of this study was to develop a simple incubation system for precision-cut liver slices. Rat liver slices were incubated individually in 12-well culture plates filled with 1.5 ml Krebs-Henseleit buffer, pH 7.4. Instead of glucose, fructose was used as carbohydrate source. The plates were put on a gyratory shaker (90 rpm) in a temperature controlled incubator (37 degrees C) under an atmosphere of 95% air/5% CO2. Under these conditions slices could be kept viable for at least 11 hr, which seems to be long enough for metabolism studies. Slice thickness was a critical factor in both studies on optimal incubation conditions and metabolism studies. A correlation was found between slice thickness (i.e. slice weight) and metabolite production (amount formed/mg slice) as demonstrated with tolbutamide and diazepam as test substances. It is demonstrated that a variation in slice thickness does not alter the number of cells involved in drug metabolism (i.e. the absolute amount of metabolite formed per slice does not alter). In conclusion, the way liver slices are incubated as well as the thickness of slices highly determines the results of studies on incubation conditions and metabolism studies with precision-cut liver slices.


Molecular Imaging of Deoxycytidine Kinase Activity Using Deoxycytidine-Enhanced CEST MRI.
Deoxycytidine kinase (DCK) is a key enzyme for the activation of a broad spectrum of nucleoside-based chemotherapy drugs (e.g., gemcitabine); low DCK activity is one of the most important causes of cancer drug-resistance. Noninvasive imaging methods that can quantify DCK activity are invaluable for assessing tumor resistance and predicting treatment efficacy. Here we developed a "natural" MRI approach to detect DCK activity using its natural substrate deoxycytidine (dC) as the imaging probe, which can be detected directly by chemical exchange saturation transfer (CEST) MRI without any synthetic labeling. CEST MRI contrast of dC and its phosphorylated form, dCTP, successfully discriminated DCK activity in two mouse leukemia cell lines with different DCK expression. This dC-enhanced CEST MRI in xenograft leukemic cancer mouse models demonstrated that DCK(+) tumors have a distinctive dynamic CEST contrast enhancement and a significantly higher CEST contrast than DCK(-) tumors (AUC0-60 min = 0.47 ± 0.25 and 0.20 ± 0.13, respectively; P = 0.026, paired Student t test, n = 4) at 1 hour after the injection of dC. dC-enhanced CEST contrast also correlated well with tumor responses to gemcitabine treatment. This study demonstrates a novel MR molecular imaging approach for predicting cancer resistance using natural, nonradioactive, nonmetallic, and clinically available agents. This method has great potential for pursuing personalized chemotherapy by stratifying patients with different DCK activity. SIGNIFICANCE: A new molecular MRI method that detects deoxycytidine kinase activity using its natural substrate deoxycytidine has great translational potential for clinical assessment of tumor resistance and prediction of treatment efficacy.


High-resolution functional profiling of a gammaherpesvirus RTA locus in the context of the viral genome.
Gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus are associated with multiple human cancers. Our goal was to develop a quantitative, high-throughput functional profiling system to identify viral cis-elements and protein subdomains critical for virus replication in the context of the herpesvirus genome. In gamma-2 herpesviruses, the transactivating factor RTA is essential for initiation of lytic gene expression and viral reactivation. We used the RTA locus as a model to develop the functional profiling approach. The mutant murine gammaherpesvirus 68 viral library, containing 15-bp random insertions in the RTA locus, was passaged in murine fibroblast cells for multiple rounds of selection. The effect of each 15-bp insertion was characterized using fluorescent-PCR profiling. We identified 1,229 insertions in the 3,845-bp RTA locus, of which 393, 282, and 554 were critically impaired, attenuated, and tolerated, respectively, for viral growth. The functional profiling phenotypes were verified by examining several individual RTA mutant clones for transactivating function of the RTA promoter and transcomplementing function of the RTA-null virus. Thus, the profiling approach enabled us to identify several novel functional domains in the RTA locus in the context of the herpesvirus genome. Importantly, our study has demonstrated a novel system to conduct high-density functional genetic mapping. The genome-scale expansion of the genetic profiling approach will expedite the functional genomics research on herpesvirus.


Intra-individual variability of the metabolic effect of inhaled insulin together with an absorption enhancer.
To study the metabolic effect and the variability of the effect elicited by inhalation of 87.2 U insulin powder combined with an absorption enhancer. The metabolic effect was compared with that of 10.2 U regular insulin injected subcutaneously and of 5.5 U regular insulin given intravenously In this single-center open euglycemic glucose clamp study 13 healthy male volunteers received 5 insulin administrations on separate study days: once as an intravenous dose, once as a subcutaneous injection, and 3 times by inhalation, in randomized order. Glucose infusion rates (GIRs) necessary to keep blood glucose concentrations constant at 5.0 mmol/l were determined over an 8-h period after administration. After inhalation of the insulin powder aerosol, the onset of action was substantially more rapid than after subcutaneous insulin injection, and maximal action was reached earlier (86+/-47 vs. 182+/-53 min, P<0.0001). The maximal glucose infusion rate after inhalation of insulin was comparable to that after subcutaneous insulin injection (9.2+/-2.6 vs. 8.8+/-2.8 mg x kg(-1) x min(-1), NS). The metabolic effect in the first 2 h after inhalation was significantly greater than that after subcutaneous insulin injection (amount of glucose infused: 0.88+/-0.25 vs. 0.59+/-0.20 g x kg(-1) x 120 min(-1), P<0.0001). However, the total metabolic effect after inhalation and subcutaneous injection was comparable (2.50+/-0.76 vs. 2.56+/-0.69 g x kg(-1) x 480 min(-1), NS). The relative bioefficacy of inhaled insulin calculated in relation to the data from the subcutaneous insulin application was 12.0+/-3.5% (absolute bioefficacy 10.1+/-3.1%) but was highest in the first 2 h after application (18.5+/-3.7%; absolute bioefficacy 8.2+/-4.1%). The intraindividual variability of the metabolic response induced by insulin inhalation was 14+/-9% for the maximal glucose infusion rate, 15+/-10% for the time-to-maximal effect, and 16+/-12% for the total amount of glucose infused. This feasibility study shows that inhaled insulin with an absorption enhancer has a pronounced metabolic effect compared with the results of a previous study of inhaled insulin without an enhancer. The intraindividual variability of the metabolic effect was comparable with that of inhaled and subcutaneously injected insulin.


Maternal age at birth and childhood type 1 diabetes: a pooled analysis of 30 observational studies.
The aim if the study was to investigate whether children born to older mothers have an increased risk of type 1 diabetes by performing a pooled analysis of previous studies using individual patient data to adjust for recognized confounders. Relevant studies published before June 2009 were identified from MEDLINE, Web of Science, and EMBASE. Authors of studies were contacted and asked to provide individual patient data or conduct prespecified analyses. Risk estimates of type 1 diabetes by maternal age were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were used to derive combined odds ratios and to investigate heterogeneity among studies. Data were available for 5 cohort and 25 case-control studies, including 14,724 cases of type 1 diabetes. Overall, there was, on average, a 5% (95% CI 2-9) increase in childhood type 1 diabetes odds per 5-year increase in maternal age (P = 0.006), but there was heterogeneity among studies (heterogeneity I(2) = 70%). In studies with a low risk of bias, there was a more marked increase in diabetes odds of 10% per 5-year increase in maternal age. Adjustments for potential confounders little altered these estimates. There was evidence of a weak but significant linear increase in the risk of childhood type 1 diabetes across the range of maternal ages, but the magnitude of association varied between studies. A very small percentage of the increase in the incidence of childhood type 1 diabetes in recent years could be explained by increases in maternal age.


Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction.
Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatin-like glycoprotein secreted by Snail(+) tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis-in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45(-)ALCAM(+) cells derived from bone marrow. CD45(-)ALCAM(+) cells induced bone metastasis de novo, but they also generated CD8(low) T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interference-mediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM(+) cells and CD8(low) T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM(+) cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer.


Intact human ceruloplasmin oxidatively modifies low density lipoprotein.
Ceruloplasmin is a plasma protein that carries most of the copper found in the blood. Although its elevation after inflammation and trauma has led to its classification as an acute phase protein, its physiological role is uncertain. A frequently reported activity of ceruloplasmin is its ability to suppress oxidation of lipids. In light of the intense recent interest in the oxidation of plasma LDL, we investigated the effects of ceruloplasmin on the oxidation of this lipoprotein. In contrast to our expectations, highly purified, undegraded human ceruloplasmin enhanced rather than suppressed copper ion-mediated oxidation of LDL. Ceruloplasmin increased the oxidative modification of LDL as measured by thiobarbituric acid-reacting substances by at least 25-fold in 20 h, and increased electrophoretic mobility, conjugated dienes, and total lipid peroxides. In contrast, ceruloplasmin that was degraded to a complex containing 115- and 19-kD fragments inhibited cupric ion oxidation of LDL, as did commercial preparations, which were also degraded. However, the antioxidant capability of degraded ceruloplasmin in this system was similar to that of other proteins, including albumin. The copper in ceruloplasmin responsible for oxidant activity was not removed by ultrafiltration, indicating a tight association. Treatment of ceruloplasmin with Chelex-100 removed one of seven copper atoms per molecule and completely blocked oxidant activity. Restoration of the copper to ceruloplasmin also restored oxidant activity. These data indicate that ceruloplasmin, depending on the integrity of its structure and its bound copper, can exert a potent oxidant rather than antioxidant action on LDL. Our results invite speculation that ceruloplasmin may be in part responsible for oxidation of LDL in blood or in the arterial wall and may thus have a physiological role that is quite distinct from what is commonly believed.


Exiguobacterium aestuarii sp. nov. and Exiguobacterium marinum sp. nov., isolated from a tidal flat of the Yellow Sea in Korea.
Three Gram-variable, rod-shaped bacterial strains, TF-16(T), TF-19 and TF-80(T), were isolated from a tidal flat of Daepo Beach (Yellow Sea) near Mokpo City, Korea, and their taxonomic positions were investigated by a polyphasic approach. These isolates grew optimally in the presence of 2 % NaCl and at 30 degrees C. Their peptidoglycan types were based on l-Lys-Gly. The predominant menaquinone detected in the three strains was MK-7. The three strains contained large amounts of the branched fatty acids iso-C(17 : 0), anteiso-C(13 : 0), iso-C(13 : 0) and iso-C(15 : 0). The DNA G+C contents of strains TF-16(T), TF-19 and TF-80(T) were 48.6, 48.4 and 48.0 mol%, respectively. The three strains formed a coherent cluster with Exiguobacterium species in a phylogenetic tree based on 16S rRNA gene sequences. They showed closest phylogenetic affiliation to Exiguobacterium aurantiacum, with 16S rRNA gene sequence similarity values of 98.1-98.3 %. The three strains exhibited 16S rRNA gene sequence similarity values of 94.0-94.6 % to the type strains of other Exiguobacterium species. Levels of DNA-DNA relatedness indicated that strains TF-16(T) and TF-19 and strain TF-80(T) are members of two species that are separate from E. aurantiacum. On the basis of phenotypic, phylogenetic and genetic data, strains TF-16(T) and TF-19 and strain TF-80(T) represent two novel species in the genus Exiguobacterium; the names Exiguobacterium aestuarii sp. nov. (type strain TF-16(T)=KCTC 19035(T)=DSM 16306(T); reference strain TF-19) and Exiguobacterium marinum sp. nov. (type strain TF-80(T)=KCTC 19036(T)=DSM 16307(T)) are proposed.


The role of dynamic ligand exchange in the oxidation chemistry of cerium(iii).
The CeIII/IV couple is useful for many applications in organic, inorganic, and materials chemistry. However, attaining a general method to access both oxidations states through reversible solution redox chemistry remains challenging. Herein we report the synthesis, characterization, and oxidation chemistry of the novel Ce/Li REMB heterochiral diastereomer, 1-Ce(het). The solution exchange processes of 1-RE(het) (RE = Ce and Yb) were investigated to estimate rates of ligand and cation exchange relevant in homochiral and heterochiral frameworks. A detailed mechanistic investigation following the solution dynamics of 1-Ce(het) revealed reactivity controlled both by ligand reorganization and redistribution processes. Ligand reorganization was responsible for the kinetics associated with the chemical oxidation reaction, whereas ligand redistribution and exchange dictated the isolated products.


Harnessing tunable scanning probe techniques to measure shear enhanced adhesion of gecko-inspired fibrillar arrays.
The hierarchical arrays of mesoscale to nanoscale fibrillar structures on a gecko's foot enable the animal to climb surfaces of varying roughness. Adhesion force between the fibrillar structures and various surfaces is maximized after the gecko drags its foot in one direction, which has also been demonstrated to improve the adhesion forces of artificial fibrillar arrays. Essential conditions that influence the magnitude of these interactions include the lateral distance traveled and velocity between the contacting surfaces, as well as the velocity at which the two surfaces are subsequently separated. These parameters have, however, not been systematically investigated to assess the adhesion properties of artificial adhesives. We introduce a systematic study that investigates these conditions using a scanning probe microscope to measure the adhesion forces of artificial adhesives through a process that mimics the mechanism by which a gecko climbs. The measured adhesion response was different for arrays of shorter and longer fibrils. These results from 9000 independent measurements also provide further insight into the dynamics of the interactions between fibrillar arrays and contacting surfaces. These studies establish scanning probe microscopy techniques as a versatile approach for measuring a variety of adhesion properties of artificial fibrillar adhesives.


Traction for low-back pain with or without sciatica.
Various types of traction are used in the treatment of low-back pain (LBP), often in conjunction with other treatments. To determine the effectiveness of traction in the management of LBP. We searched The Cochrane Library 2004, Issue 4, MEDLINE, EMBASE, and CINAHL to November 2004, references in relevant reviews, and our personal files. Randomized controlled trials (RCTs) examining any type of traction for the treatment of acute (less than four weeks duration), sub-acute (four to 12 weeks) or chronic (more than 12 weeks) non-specific LBP with or without sciatica. Study selection, methodological quality assessment and data extraction were done independently by sets of two reviewers. As available studies did not provide sufficient data for statistical pooling, a qualitative analysis was performed. Twenty-four RCTs, involving 2177 patients (1016 receiving traction) were included in the review. Five trials were considered high quality. There is strong evidence that there is no significant difference in short or long-term outcomes between either continuous or intermittent traction and placebo, sham, or other treatments for patients with a mixed duration of LBP, with or without sciatica. There is moderate evidence that: autotraction is more effective other forms of traction are no more effective than placebo, sham or no treatment for patients with a mixed duration of LBP with sciatica. There is limited evidence that: there is no significant difference in outcomes between a standard physical therapy program with continuous traction and the same program without traction, for patients with a mixed duration of LBP, with or without sciatica autotraction on its own is more effective than a physical therapy program that includes Tru-Trac traction for patients with a mixed duration of LBP with sciatica. There is conflicting evidence regarding the short-term effectiveness of either continuous or intermittent traction compared to placebo, sham or other treatments, in the management of patients who have either chronic LBP or a mixed duration of LBP with sciatica. The evidence suggests that traction is probably not effective. Neither continuous nor intermittent traction by itself was more effective in improving pain, disability or work absence than placebo, sham or other treatments for patients with a mixed duration of LBP, with or without sciatica. Although trials studying patients with sciatica had methodological limitations and inconsistent results, there was moderate evidence that autotraction was more effective than mechanical traction for global improvement in this population.


The cirrhotic liver is depleted of docosahexaenoic acid (DHA), a key modulator of NF-κB and TGFβ pathways in hepatic stellate cells.
Liver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks TGFβ and NF-κB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression, leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs targeting NF-κB and TGFβ pathways and inducing ADPR expression and quiescence in these cells.


Using trial-level data and multilevel modeling to investigate within-task change in event-related potentials.
EEG data, and specifically the ERP, provide psychologists with the power to examine quickly occurring cognitive processes at the native temporal resolution at which they occur. Despite the advantages conferred by ERPs to examine processes at different points in time, ERP researchers commonly ignore the trial-to-trial temporal dimension by collapsing across trials of similar types (i.e., the signal averaging approach) because of constraints imposed by repeated measures ANOVA. Here, we present the advantages of using multilevel modeling (MLM) to examine trial-level data to investigate change in neurocognitive processes across the course of an experiment. Two examples are presented to illustrate the usefulness of this technique. The first demonstrates decreasing differentiation in N170 amplitude to faces of different races across the course of a race categorization task. The second demonstrates attenuation of the ERN as participants commit more errors within a task designed to measure implicit racial bias. Although the examples presented here are within the realm of social psychology, the use of MLM to analyze trial-level EEG data has the potential to contribute to a number of different theoretical domains within psychology.


Severe hemorrhage complicating the Klippel-Trénaunay-Weber syndrome.
The Klippel-Trénaunay-Weber (KTW) syndrome is a congenital disorder of angiogenesis characterized by macular nevus, skeletal and soft tissue hypertrophy, venous varicosities, and arteriovenous fistulas. Disseminated intravascular coagulation (DIC) and the Kasabach-Merritt syndrome, a consumptive coagulopathy with thrombocytopenia, are both associated with the KTW syndrome. We describe a 30-year-old woman with KTW syndrome and Kasabach-Merritt syndrome who had DIC with severe hemorrhage after a routine gynecologic procedure. The bleeding was controlled with the use of intravenous low-dose heparin and antithrombin III.


Reproductive health of bass in the Potomac, U.S.A., drainage: part 1. Exploring the effects of proximity to wastewater treatment plant discharge.
Intersex (specifically, testicular oocytes) has been observed in male smallmouth bass (SMB; Micropterus dolomieu) and other centrarchids in the South Branch of the Potomac River, U.S.A., and forks of the Shenandoah River, U.S.A., during the past five years. This condition often is associated with exposure to estrogenic endocrine-disrupting chemicals in some fish species, but such chemicals and their sources have yet to be identified in the Potomac. In an attempt to better understand the plausible causes of this condition, we investigated the reproductive health of bass sampled up- and downstream of wastewater treatment plant (WWTP) effluent point sources on the Potomac River in Maryland, U.S.A. Smallmouth bass were sampled from the Conococheague Creek and the Monocacy River, and largemouth bass (LMB; Micropterus salmoides) were collected near the Blue Plains WWTP on the mainstem of the Potomac River. Chemical analyses of compounds captured in passive samplers at these locations also were conducted. A high prevalence of intersex (82-100%) was identified in male SMB at all sites regardless of collection area. A lower prevalence of intersex (23%) was identified in male LMB collected at the Blue Plains site. When up- and downstream fish were compared, significant differences were noted only in fish from the Conococheague. Differences included condition factor, gonadosomatic index, plasma vitellogenin concentration, and estrogen to testosterone ratio. In general, chemicals associated with wastewater effluent, storm-water runoff, and agriculture were more prevalent at the downstream sampling sites. An exception was atrazine and its associated metabolites, which were present in greater concentrations at the upstream sites. It appears that proximity to effluent from WWTPs may influence the reproductive health of bass in the Potomac watershed, but inputs from other sources likely contribute to the widespread, high incidence of testicular oocytes.


Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma.
Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear.In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO-211H (scarcely expressing APN/CD13) MPM cells.High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO-211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone.Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression.


Pulsatile flow visualization in the abdominal aorta under differing physiologic conditions: implications for increased susceptibility to atherosclerosis.
The infrarenal abdominal aorta is a common site for clinically significant atherosclerosis. As has been shown in other susceptible locations, vessel geometry, flow division rates, and pulsatility may result in hemodynamic conditions which influence the preferential localization of disease in the abdominal aorta segment. Pulsatile flow visualization was performed in a glass model of the aorta constructed from measurements of angiograms and cadaver aortas. Flow rates and pulsatile waveforms were varied to reflect typical physiological conditions. Under normal resting conditions, the flow patterns in the infrarenal aorta were more complex than those in the suprarenal location. Time varying vortex patterns appeared at the level of the renal arteries and propagated through the infrarenal aorta into the common iliac arteries. A region of oscillating velocity direction extended from the renal arteries to the aortic bifurcation along the posterior wall. Dye became trapped along the posterior wall, requiring several cardiac cycles for clearance. In contrast, there was rapid clearance of the dye in the anterior aorta. Under postprandial conditions, the flow patterns in the aorta were basically unchanged. Simulated exercise conditions created laminar hemodynamic features very different from the resting conditions, including a decrease in dye residence time. This study reveals significant time-dependent variations in the hemodynamics of the abdominal aorta under differing physiologic conditions. Hemodynamic factors such as low wall shear stress, oscillating shear direction, and high particle residence time may be related to the clinically seen preferential plaque localization in the infrarenal aorta.


Atomic partition of the optical rotatory power of methylhydroperoxide.
We applied a methodology capable of resolving the optical rotatory power into atomic contributions. The individual atomic contributions to the optical rotatory power and molecular chirality of the methylhydroperoxide are obtained via a canonical transformation of the Hamiltonian by which the electric dipolar moment operator is transformed to the acceleration gauge formalism and the magnetic dipolar moment operator to the torque formalism. The gross atomic isotropic contributions have been evaluated for the carbon, the nonequivalent oxygen, and the nonequivalent hydrogen atoms of methylhydroperoxide, employing a very large Gaussian basis set which is close to the Hartree-Fock limit.


Functional outcomes of cleft lip surgery. Part III: Measurement of lip forces.
To investigate lip force dynamics among participants with a repaired cleft of the lip and noncleft control participants. A parallel, three-group, nonrandomized clinical trial. Forty-eight participants with cleft lip and 36 noncleft participants. Participants attended two separate visits. At each visit, they were instructed to produce fine motor control and maximum compression forces with each upper and lower lip in response to visual force targets. Measures of force were extracted, and the data were fit using regression techniques. The upper and lower lips of the participants with a cleft lip demonstrated less time on target, while the lower lips had shorter rise time but higher peak forces, a higher rate of force recruitment, and increased maxima of the first derivative of force compared with the noncleft participants. For all participants, there was a learning effect for certain force variables between the two visits and with increasing age. For participants with a cleft lip, force regulation of the circumoral region within the operating range presumed important for facial and speech animation is compromised because of impairments in force recruitment, gradation, fractionation, and stability. In the presence of a change in upper lip tissue mechanics due to scarring or neuromotor impairment, such as a cleft, the lower lip typically exhibits compensatory motor actions.


A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury.
Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TSPO) mainly localized to the mitochondrial outer membrane is predominantly expressed in glia within the central nervous system during inflammatory conditions. This study investigated the effect of a TSPO agonist, etifoxine, on neuroinflammation and brain injury after ischemia/reperfusion. We used a mouse model of middle cerebral artery occlusion (MCAO) to examine the therapeutic potential and mechanisms of neuroprotection by etifoxine. TSPO was upregulated in Iba1+ or CD11b+CD45int cells from mice subjected to MCAO and reperfusion. Etifoxine significantly attenuated neurodeficits and infarct volume after MCAO and reperfusion. The attenuation was pronounced in mice subjected to 30, 60, or 90 min MCAO. Etifoxine reduced production of pro-inflammatory factors in the ischemic brain. In addition, etifoxine treatment led to decreased expression of interleukin-1β, interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthase by microglia. Notably, the benefit of etifoxine against brain infarction was ablated in mice depleted of microglia using a colony-stimulating factor 1 receptor inhibitor. These findings indicate that the TSPO agonist, etifoxine, reduces neuroinflammation and brain injury after ischemia/reperfusion. The therapeutic potential of targeting TSPO requires further investigations in ischemic stroke.


Surgical outcome of stage IIIA- cN2/pN2 non-small-cell lung cancer patients in Japanese lung cancer registry study in 2004.
The role of surgery in the treatment of non-small-cell lung cancer (NSCLC) with clinically manifested mediastinal node metastasis is controversial even in resectable cases because it is often accompanied by systemic micrometastasis. However, surgery is occasionally indicated for cases with single-station N2 disease or within multimodal treatment regimens, and in clinical trials. The aim of this study is to evaluate surgical outcomes in a modern cohort of patients with clinical (c-) stage IIIA-N2 NSCLC whose nodal metastasis was confirmed by pathology (cN2/pN2). From the central database of lung cancer patients undergoing surgery in 2004, which was founded by the Japanese Joint Committee for Lung Cancer Registration, data of patients having all conditions of NSCLC, c-stage IIIA, cN2, and pN2 were extracted, and the clinicopathologic profile of patients and surgical outcomes were evaluated. Among 11,663 registered NSCLC cases, 436 patients (3.8%) (332 men and 104 women) had been extracted. Their mean age was 65 years, and histologic types included adenocarcinoma (n = 246), squamous cell carcinoma (n = 132), and others (n = 58). The proportion of R0 resection was 82.5% and the proportion of the hospital deaths among the cause of death was 2.3%. The 5-year survival rate was 30.1% for the selected group of patients. The postoperative prognosis was significantly better than those of corresponding populations extracted from the 1994 (p = 0.0001) and 1999 databases (p = 0.0411). Men and women experienced a significantly different survival outcome (p = 0.025) with 5-year survivals of 27.5% and 37.8%, respectively. Single-station N2 cases occupied 60.9 % of the cohort and showed a significantly better prognosis than multistation N2 (p = 0.0053, 35.8 % versus 22.0 % survival rate at 5 years). The surgical outcomes of c-stage IIIA-cN2/pN2 NSCLC patients in 2004 were favorable in comparison with those ever reported.


Unsubscribe, pleeezz!!!: management and training of media competence in computer-mediated communication.
Computer-mediated communication (CMC) has created a new communication divide. Mostly, this division is due to technical and access problems. Overlooked is yet another divide in terms of user communication competence. This contribution focuses on media competence based on theories about communication competence and theories about CMC. Two field studies are presented: an analysis of a virtual seminar chat communication (22 participants, 3 weeks' duration) and an analysis of unsubscribe-failures within 2 years of a German mailing list (average of 1,000 subscriptions). Data from both studies reveal that help-seeking CMC users with low media-specific competence experience setbacks in terms of interpersonal relations and information gathering. There is a spiral of neutral to negative reactions and an increase in stress and aggression-related language in the reaction of the addressed peers. From the perspective of external raters, we found a contraintuitive result: The style, content, and wording of the message of the respondent is considered as an indicator for a less competent and socially attractive person behind the follow-up message than those of the initial message. On the one hand, media experts are needed and appreciated as technical problem-solvers; on the other hand, they might be perceived as socially narrow-minded freaks who are less interested in the task itself than in CMC-based task completion. This leads to the question of how sensibility for the social context, task orientation, and media competence can be combined (and trained for) in one person. Two competence trainings for text-based synchronous and asynchronous communication are introduced as interventions.


Mechanisms of action of Ru(ii) polypyridyl complexes in living cells upon light irradiation.
The unique photophysical properties of Ru(ii) polypyridyl complexes make them very attractive candidates as photosensitisers in Photodynamic Therapy (PDT). However, to date, there are not many studies exploring in detail the mechanism(s) of action of such compounds in living systems upon light irradiation. This feature article provides an overview of the most in-depth biological studies on such compounds.


Inhibition of parasite invasion by monoclonal antibody against epidermal growth factor-like domain of Plasmodium vivax merozoite surface protein 1 paralog.
The Plasmodium vivax merozoite surface protein 1 paralog (PvMSP1P), which has epidermal growth factor (EGF)-like domains, was identified as a novel erythrocyte adhesive molecule. This EGF-like domain (PvMSP1P-19) elicited high level of acquired immune response in patients. Antibodies against PvMSP1P significantly reduced erythrocyte adhesion activity to its unknown receptor. To determine PvMSP1P-19-specific antibody function and B-cell epitopes in vivax patients, five monoclonal antibodies (mAbs) and 18-mer peptides were generated. The mAb functions were determined by erythrocyte-binding inhibition assay and invasion inhibition assay with P. knowlesi. B-cell epitopes of PvMSP1P-19 domains were evaluated by peptide microarray. The pvmsp1p-19 sequences showed limited polymorphism in P. vivax worldwide isolates. The 1BH9-A10 showed erythrocyte binding inhibitory by interaction with the N-terminus of PvMSP1P-19, while this mAb failed to recognize PkMSP1P-19 suggesting the species-specific for P. vivax. Other mAbs showed cross-reactivity with PkMSP1P-19. Among them, the 2AF4-A2 and 2AF4-A6 mAb significantly reduced parasite invasion through C-terminal recognition. The linear B-cell epitope in naturally exposed P. vivax patient was identified at three linear epitopes. In this study, PvMSP1P-19 N-terminal-specific 1BH9-A10 and C-terminal-specific 2AF4 mAbs showed functional activity for epitope recognition suggesting that PvMSP1P may be useful for vaccine development strategy for specific single epitope to prevent P. vivax invasion.


CO₂ emission factors for waste incineration: Influence from source separation of recyclable materials.
CO(2)-loads from combustible waste are important inputs for national CO(2) inventories and life-cycle assessments (LCA). CO(2) emissions from waste incinerators are often expressed by emission factors in kg fossil CO(2) emitted per GJ energy content of the waste. Various studies have shown considerable variations between emission factors for different incinerators, but the background for these variations has not been thoroughly examined. One important reason may be variations in collection of recyclable materials as source separation alters the composition of the residual waste incinerated. The objective of this study was to quantify the importance of source separation for determination of emission factors for incineration of residual household waste. This was done by mimicking various source separation scenarios and based on waste composition data calculating resulting emission factors for residual waste routed to incineration. Emission factors ranged from 27 to 40 kg CO(2)/GJ. The results appeared most sensitive towards variations in waste composition and water content. Recycling rates and lower heating values could not be used as simple indicators of the resulting emission factors for residual household waste; however the fossil carbon ratio of the waste after source separation was found to be appropriately correlated with the emission factor. Based on the results, it is recommended to carefully evaluate the source separation and collection systems behind reported literature values when comparing different studies and when using the values for environmental assessment purposes.


Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs.
Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Glycine receptors (GlyRs) are key players in mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structures have provided insights into the molecular architecture of GlyR, several mechanistic questions pertaining to channel function are still unanswered. Here, we present Cryo-EM structures of the full-length GlyR protein complex reconstituted into lipid nanodiscs that are captured in the unliganded (closed), glycine-bound (open and desensitized), and allosteric modulator-bound conformations. A comparison of these states reveals global conformational changes underlying GlyR channel gating and modulation. The functional state assignments were validated by molecular dynamics simulations, and the observed permeation events are in agreement with the anion selectivity and conductance of GlyR. These studies provide the structural basis for gating, ion selectivity, and single-channel conductance properties of GlyR in a lipid environment.


Prepregnancy weight and antepartum insulin secretion predict glucose tolerance five years after gestational diabetes mellitus.
To identify phenotypic, genotypic, and metabolic parameters measured at the time of antepartum diagnosis of gestational diabetes mellitus that can indicate the risk of diabetes mellitus at early postpartum (< or = 6 mo after delivery) and at a 5-yr follow-up. The recommendations from the National Diabetes Data Group and International Workshop Conferences on Gestational Diabetes Mellitus were used for screening, diagnosing, and subclassifying gestational diabetes mellitus. National Diabetes Data Group criteria were also used for classification of glucose tolerance postpartum. Plasma glucose, insulin, and free fatty acids were measured after an overnight fast. Plasma glucose and insulin were measured 15, 30, 60, 120, and 180 min after the 100-g oral glucose load. Postpartum glucose tolerance was evaluated at 3-6 mo (early), 1 yr, and annually thereafter. The 5-yr cumulative incidence of diabetes during follow-up after gestational diabetes mellitus was nearly 50%. Among those who had diabetes within 5 yr, a history of diabetes in only the mother was nearly threefold more common than a history of diabetes in only the father (30 vs. 11%, P < 0.01). Those who displayed diabetes at early postpartum (< or = 6 mo) testing had significantly higher antepartum glucose levels at 60, 120, and 180 min compared with those whose early postpartum results were normal. They were also relatively insulinopenic at antepartum testing. Their fasting, acutely stimulated (15 and 30 min), and integrated 3-h response to oral glucose were all significantly lower relative to women who remained normal or had impaired glucose tolerance at early postpartum testing. Women who developed diabetes between 6 mo and 5 yr postpartum were more obese before the index pregnancy, and they had lower fasting, acutely stimulated (15 and 30 min), and integrated (1-3 h) insulin levels compared with women who remained normal or displayed impaired glucose tolerance at 5 yr postpartum. A multiple logistic regression model showed that diabetes present at early postpartum testing was independently associated with higher 2-h glucose and lower basal and total integrated insulin level. Later (> or = 6 mo-5 yr postpartum) development of diabetes was independently associated with prepregnancy weight and impaired insulin secretion at diagnosis of gestational diabetes mellitus. Impaired beta-cell function and obesity at diagnosis of GDM were associated with the development of diabetes during a 5-yr, follow-up period. Studies designed to prevent diabetes in this high-risk group should examine strategies to maintain both optimal beta-cell function and maximum insulin sensitivity.


Virtual superheroes: using superpowers in virtual reality to encourage prosocial behavior.
Recent studies have shown that playing prosocial video games leads to greater subsequent prosocial behavior in the real world. However, immersive virtual reality allows people to occupy avatars that are different from them in a perceptually realistic manner. We examine how occupying an avatar with the superhero ability to fly increases helping behavior. Using a two-by-two design, participants were either given the power of flight (their arm movements were tracked to control their flight akin to Superman's flying ability) or rode as a passenger in a helicopter, and were assigned one of two tasks, either to help find a missing diabetic child in need of insulin or to tour a virtual city. Participants in the "super-flight" conditions helped the experimenter pick up spilled pens after their virtual experience significantly more than those who were virtual passengers in a helicopter. The results indicate that having the "superpower" of flight leads to greater helping behavior in the real world, regardless of how participants used that power. A possible mechanism for this result is that having the power of flight primed concepts and prototypes associated with superheroes (e.g., Superman). This research illustrates the potential of using experiences in virtual reality technology to increase prosocial behavior in the physical world.


Phenobarbital Versus Lorazepam for Management of Alcohol Withdrawal Syndrome: A Retrospective Cohort Study.
Introduction Annually, 500,000 episodes of alcohol withdrawal syndrome (AWS) are severe enough to require clinical attention. A symptom-triggered lorazepam regimen remains the standard of care for the management of hospitalized AWS patients. However, phenobarbital has also been shown to be an effective adjunctive therapy for severe AWS, reducing benzodiazepine use in the emergency department (ED) and the intensive care unit (ICU). The purpose of this study is to compare hospital length of stay (LOS) for AWS patients using phenobarbital-based versus lorazepam-based treatment protocols as monotherapy for management of AWS on general medical units. Methods This is a retrospective cohort study over a two-year period (March, 2016 to March, 2018), conducted at three hospitals within the St. Joseph Mercy Health System. We included 606 patients with a primary diagnosis of AWS or alcohol intoxication who met our inclusion criteria (543 in the lorazepam cohort and 63 in the phenobarbital cohort). Adjusted comparisons were done using propensity scoring methods. Hospital LOS was set as the primary outcome. Secondary outcomes included all-cause 30-day readmission, alcohol-related 30-day readmission, 30-day ED visits after discharge, and need for ICU transfer during hospital stay. Results Patients who received phenobarbital had a statistically significant shorter hospital LOS as compared to patients who received lorazepam (2.8 versus 3.6 days, P < 0.001). Furthermore, the phenobarbital treatment group had statistically significant lower rates of all-cause 30-day readmission (11.11% versus 14.18%, P = 0.020) and 30-day ED visits after discharge (11.11% versus 18.6%, P = 0.015). No statistical significance was detected for alcohol-related 30-day readmission and the need for ICU transfer between the treatment groups. Conclusion This study suggests that phenobarbital may be a reasonable alternative to lorazepam in the management of AWS patients admitted to general medical units. Larger scale, well-executed, and adequately powered prospective studies and randomized controlled trials are needed to corroborate these findings.