bluuebunny/crossref_metadata_2025 huggingface dataset:
Unicast and multicast QoS routing with soft-constraint logic programming
Authors: Bistarelli Stefano , Montanari Ugo , Rossi Francesca , Santini Francesco
Published: November 2010

We present a formal model to represent and solve the unicast/multicast routing problem in networks withquality-of-service(QoS) requirements. To attain this, first we translate the network adapting it to a weighted graph (unicast) orand-orgraph (multicast), where the weight on a connector corresponds to the multidimensional cost of sending a packet on the related network link: each component of the weights vector represents a different QoS metric value (e.g., bandwidth). The second step consists in writing this graph as a program insoft-constraint logic programming(SCLP): the engine of this framework is then able to find the best paths/trees by optimizing their costs and solving the constraints imposed on them (e.g.delay≤ 40 ms), thus finding a solution to QoS routing problems.C-semiringstructures are a convenient tool to model QoS metrics. At last, we provide an implementation of the framework over scale-free networks and we suggest how the performance can be improved. The article highlights the expressivity of SCLP.
Rare Variant Association Analysis Methods for Complex Traits
Authors: Asimit Jennifer , Zeggini Eleftheria
Published: November 2010

There has been increasing interest in rare variants and their association with disease, and several rare variant–disease associations have already been detected. The usual association tests for common variants are underpowered for detecting variants of lower frequency, so alternative approaches are required. In addition to reviewing the association analysis methods for rare variants, we discuss the limitations of genome-wide association studies in identifying rare variants and the problems that arise in the imputation of rare variants.
Metabolic benefits of resistance training and fast glycolytic skeletal muscle
Authors: LeBrasseur Nathan K. , Walsh Kenneth , Arany Zoltan
Published: November 2010

Skeletal muscle exhibits remarkable plasticity with respect to its metabolic properties. Recent work has shown that interventions such as resistance training, genetic alterations and pharmacological strategies that increase muscle mass and glycolytic capacity, and not necessarily oxidative competence, can improve body composition and systemic metabolism. We review here recent advances in our understanding of the signaling and transcriptional regulatory pathways of this strategy and review new evidence obtained from mice and humans that supports the notion that increasing muscle mass and glycolytic capacity may effectively counter insulin resistance and type 2 diabetes mellitus.
Exercise training reverses impaired skeletal muscle metabolism induced by artificial selection for low aerobic capacity
Authors: Lessard Sarah J. , Rivas Donato A. , Stephenson Erin J. , Yaspelkis Ben B. , Koch Lauren G. , Britton Steven L. , Hawley John A.
Published: November 2010

We have used a novel model of genetically imparted endurance exercise capacity and metabolic health to study the genetic and environmental contributions to skeletal muscle glucose and lipid metabolism. We hypothesized that metabolic abnormalities associated with low intrinsic running capacity would be ameliorated by exercise training. Selective breeding for 22 generations resulted in rat models with a fivefold difference in intrinsic aerobic capacity. Low (LCR)- and high (HCR)-capacity runners remained sedentary (SED) or underwent 6 wk of exercise training (EXT). Insulin-stimulated glucose transport, insulin signal transduction, and rates of palmitate oxidation were lower in LCR SED vs. HCR SED ( P < 0.05). Decreases in glucose and lipid metabolism were associated with decreased β2-adrenergic receptor (β2-AR), and reduced expression of Nur77 target proteins that are critical regulators of muscle glucose and lipid metabolism [uncoupling protein-3 (UCP3), fatty acid transporter (FAT)/CD36; P < 0.01 and P < 0.05, respectively]. EXT reversed the impairments to glucose and lipid metabolism observed in the skeletal muscle of LCR, while increasing the expression of β2-AR, Nur77, GLUT4, UCP3, and FAT/CD36 ( P < 0.05) in this tissue. However, no metabolic improvements were observed following exercise training in HCR. Our results demonstrate that metabolic impairments resulting from genetic factors (low intrinsic aerobic capacity) can be overcome by an environmental intervention (exercise training). Furthermore, we identify Nur77 as a potential mechanism for improved skeletal muscle metabolism in response to EXT.
Whole transcriptome analysis of the fasting and fed Burmese python heart: insights into extreme physiological cardiac adaptation
Authors: Wall Christopher E. , Cozza Steven , Riquelme Cecilia A. , McCombie W. Richard , Heimiller Joseph K. , Marr Thomas G. , Leinwand Leslie A.
Published: November 2010

The infrequently feeding Burmese python ( Python molurus ) experiences significant and rapid postprandial cardiac hypertrophy followed by regression as digestion is completed. To begin to explore the molecular mechanisms of this response, we have sequenced and assembled the fasted and postfed Burmese python heart transcriptomes with Illumina technology using the chicken ( Gallus gallus ) genome as a reference. In addition, we have used RNA-seq analysis to identify differences in the expression of biological processes and signaling pathways between fasted, 1 day postfed (DPF), and 3 DPF hearts. Out of a combined transcriptome of ∼2,800 mRNAs, 464 genes were differentially expressed. Genes showing differential expression at 1 DPF compared with fasted were enriched for biological processes involved in metabolism and energetics, while genes showing differential expression at 3 DPF compared with fasted were enriched for processes involved in biogenesis, structural remodeling, and organization. Moreover, we present evidence for the activation of physiological and not pathological signaling pathways in this rapid, novel model of cardiac growth in pythons. Together, our data provide the first comprehensive gene expression profile for a reptile heart.
Chemopreventive Effects of Pioglitazone on Chemically Induced Lung Carcinogenesis in Mice
Authors: Wang Yian , James Michael , Wen Weidong , Lu Yan , Szabo Eva , Lubet Ronald A. , You Ming
Published: November 2010

Pioglitazone [(RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione] is a ligand of nuclear receptor peroxisome proliferator-activated receptor γ that is approved for the treatment of type II diabetes mellitus. Activation of peroxisome proliferator-activated receptor γ has been associated with anticancer activities in a variety of cancer cell lines through inhibition of proliferation and promotion of apoptosis. We examined the effect of pioglitazone on lung cancer development in carcinogen-induced lung adenocarcinoma and squamous cell carcinoma (SCC). When pioglitazone was administered beginning 8 weeks after the first carcinogen treatment when microscopic adenomas already existed, pioglitazone significantly inhibited tumor load (sum of tumor volume per lung in average) by 64% (P < 0.05) in p53wt/wt mice and 50% (P < 0.05) in p53wt/Ala135Val mice in the lung adenocarcinoma model. Delayed administration of pioglitazone caused a limited (35%, P < 0.05) decrease in lung SCC. Induction of apoptosis occurred in both model systems. These data show that pioglitazone significantly inhibited progression of both adenocarcinoma and SCC in the two mouse model systems. Mol Cancer Ther; 9(11); 3074–82. ©2010 AACR.
Description of new and known species of the rare nematode genera Qudsiella Jairajpuri, 1967 and Swangeria Thorne, 1939 (Belondiridae: Dorylaimida)
Authors: Ahmad Wasim , Naz Tabbasam
Published: November 2010

Two new and a known species of the rare genera Qudsiella and Swangeria are
described and illustrated. Qudsiella tropica sp. n. is characterised by
having a 1.3-1.5 mm long body, a rounded lip region continuous with the
body, 3 μm long odontostyle with distinct lumen and aperture, vulva located
at 40-42% from anterior end, long filiform tail, 26-30 μm long spicules and
three or four regularly spaced ventromedian supplements. Qudsiella gracilis
is redescribed based on specimens collected from India, Japan and Nicaragua.
Swangeria longicauda sp. n. is characterised by a 1.2-1.3 mm long body,
truncate lip region continuous with the body, 2.5-3 μm long attenuated
odontostyle, expanded part of pharynx occupying ca 34-35% of total neck
length and long filiform tail. The diagnosis of each genus is emended.
Biopesticides with complex modes of action: direct and indirect effects of DiTera® on Meloidogyne incognita
Authors: Spence Kenneth O. , Lewis Edwin E.
Published: November 2010

Bionematicides may exhibit complex modes of action based on: i) direct lethal
or sub-lethal effects on the nematode; ii) promotion of plant growth and
damage tolerance; and/or iii) influencing the interaction between the plant
and the nematode by inducing plant defences. A suite of assays was conducted
to characterise the mode of action of the commercial bionematicide DiTera®
(Valent Biosciences, Chicago, IL, USA). Agar-based behavioural assays
revealed significant chemotactic responses of second-stage juveniles of
Meloidogyne incognita to DiTera with concentrations of 1.0% and 0.1% being
repellent and 0.01% being attractive to M. incognita. In addition, exposure
to 1.0% DiTera reduced the velocity and increased the meander of nematodes
in no-choice tests. These experiments were complemented with soil-based
assays. Rhizotron and minirhizotron assays that allowed spatially explicit
evaluation of root growth demonstrated root proliferation of Solanum
lycopersicum cv. Rutgers in response to localised applications of DiTera.
Our results confirm that DiTera can positively affect plant growth and may
influence nematode foraging behaviour. However, results of the soil-based
assays provided little support for the hypothesis that DiTera has direct or
indirect (plant-mediated) effects on M. incognita performance. This is in
contrast to some of the published literature, and it may be that the chosen
methods were not appropriate to detect these effects.
Schistonchus (Aphelenchoididae) from Ficus (Moraceae) in Australia, with description of S. aculeata sp. n.
Authors: Davies Kerrie , Bartholomaeus Faerlie , Ye Weimin , Kanzaki Natsumi , Giblin-Davis Robin
Published: November 2010

A checklist of Schistonchus collected from Ficus spp. in Australia and stored
in the Waite Nematode Collection at the University of Adelaide is presented.
Within Australia, Schistonchus contains 12 morphospecies and four nominal
species, based on a combination of the following characters: body shape when
heat-relaxed, position of excretory pore, length of post-uterine sac,
spicule form, and number and position of caudal papillae. Up to four
morphospecies of Schistonchus have been collected from one species of Ficus
and, in several cases, one morphospecies of Schistonchus has been collected
from more than one host fig species. A phylogenetic tree based on D2/D3
sequences showed that Australian collections of Schistonchus fall into two
clades, suggestive of endemic and introduced lineages with host switching.
Schistonchus aculeata sp. n. is described from F. aculeata and F. opposita
and differentiated from other species of Schistonchus by having the
excretory pore opening near the lips, a short post-uterine sac,
rosethorn-shaped spicules, arcuate gubernaculum or thickening of dorsal
wall, amoeboid sperm, and three pairs of caudal papillae (one pair
adcloacal, one just posterior to mid-tail, and one near the tail tip),
association with Kradibia spp. pollinating wasps and apparent
biogeographical range. A key to the known species and morphospecies of
Schistonchus from Australia is presented.
Upper-Level Atmospheric Circulation Patterns and Ground-Level Ozone in the Atlanta Metropolitan Area
Authors: Diem Jeremy E. , Hursey Melissa A. , Morris Imani R. , Murray Amanda C. , Rodriguez Ricardo A.
Published: November 2010

The purpose of this paper is to identify middle-troposphere circulation patterns associated with high ozone concentrations during June–August of 2000–07 in the Atlanta, Georgia, metropolitan statistical area (MSA), which is located in the southeastern United States. The methods involved classifying daily 500-hPa geopotential height fields into synoptic types, determining the mean atmospheric conditions (i.e., daytime temperature, daytime relative humidity, daytime cloud cover, morning mixing height, and afternoon mixing height) for the types, determining the mean daily maximum 8-h average ozone concentrations for the types, and performing back-trajectory analyses for high-ozone types. There were a total of 12 synoptic types, and significantly high ozone concentrations across the MSA coincided with the three following types: Atlanta under a continental anticyclone, Atlanta to the east of a continental anticyclone and west of a trough, and Atlanta under the western side of a trough. The continental-anticyclone type was much more prevalent than the other two types. When the MSA was under or just to the east of a continental anticyclone, atmospheric conditions were conducive to increased in situ ozone production and pollutant carryover from the previous day. Between 45% and 60% of the days with those circulation patterns had ozone concentrations exceeding the federal standard. When the Atlanta MSA was under the western side of a trough, not only did the potential for in situ ozone production and pollutant carryover contribute to high ozone concentrations, but there also was a high potential for pollutant transport from the Ohio River valley into the Atlanta MSA.
Blunted Affect is Associated With Hypothalamic—Pituitary—Adrenal Axis (HPA) Hypoactivity and Elevated CSF-Interleukin-1 Beta (IL-1β) in Response to Lumbar Puncture
Authors: FitzGerald Leah
Published: November 2010

Objective. Proinflammatory activity has been suggested as one of the psychophysiological mechanisms responsible for the health risks associated with stress and mood disorders. There have been limited studies evaluating central immune and hypothalamic— pituitary—adrenal (HPA) axis responses to experimental stress in healthy women. The current study compared, under a controlled condition, the baseline measures and biological and psychological responses to a physical stressor (lumbar puncture [LP]) of healthy women who exhibited an abnormal serum cortisol response (nonresponders [NRs]) to the LP to those of normal controls (responders [Rs]), allowing assessment of stress responsivity and the functional integrity of the feedback system of the HPA axis, sympathetic nervous system (SNS), and neuroimmune axis. Method. Serum adrenocorticotropic hormone (ACTH), cortisol, interleukin (IL)-6, IL-1sR, and central IL-1β, IL-6, norepineprhine (NE), corticotropin-releasing factor (CRF), and affective states (using the Stress Symptom Rating Questionnaire) were measured in five NRs and seven Rs. Results. Compared with NR subjects, Rs had significantly higher levels of ACTH and central IL-1β, higher ratings of attention, and lower perceived stress and anxiety. There were no differences between the groups in serum cortisol, IL-6, or IL-1sR or in central IL-6, NE, and CRF. Conclusions. Women with significantly elevated IL-1β (NRs) responded to an extreme physical stressor with an attenuated HPA system and abnormal subjective ratings compared to healthy women with lower values of central IL-1β. These findings support the suppression of the effects of HPA-axis cortisol on proinflammatory cytokine production. It is possible that these differences in the psychoneuroimmunological profiles of NRs will lead to increased psychobiological vulnerability and predict future health risk.
Physical Activity in Childhood Asthma: Friend or Foe?
Authors: Berntsen Sveinung
Published: November 2010

Physical activity has been considered as a double-edged sword for children with asthma. Children with asthma are recommended to participate in physical activities like their healthy nonasthmatic peers because regular physical activity positively affects psychological functioning, quality of life, morbidity, and aerobic fitness in children with asthma. However, uncontrolled asthma with ongoing exercise-induced bronchoconstriction may limit participation in sports, free play, and daily living. Observations also suggest that high-intensity exercise performed in cold air, seasonal allergens, pollutants, or respiratory virus infections may increase the risk for asthma in the highly active child. In contrast, a sedentary lifestyle has been highlighted as the explanation for the increased prevalence of asthma in the past decades. However, there is no consensus on whether a low level of physical activity increases the severity or risk of asthma. Use of asthma medications and good asthma control can make the conditions favorable for a physically active lifestyle and influence physical activity level and the level of aerobic fitness.
Optimizing Tailored Health Communications
Authors: Terre Lisa
Published: November 2010

This review discusses evidence-based perspectives on tailored health communications for lifestyle modification. Future directions for inquiry and practice also are addressed.
Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?
Authors: Crow Andrew R. , Song Seng , Suppa Sara J. , Ma Shuhua , Reilly Michael P. , Andre Pierrette , McKenzie Steven E. , Lazarus Alan H.
Published: November 2010

To explore the potential for monoclonal antibodies as a treatment for immune thrombocytopenia (ITP) and to further explore their mechanisms of action, we tested 8 monoclonal CD44 antibodies in murine ITP and found 4 antibodies that could successfully ameliorate ITP; 2 of these antibodies function at a full 3-log fold lower dosage compared with IVIg. Further characterization of the 2 most successful antibodies (5035–41.1D and KM114) demonstrated that, similar to IVIg: (1) the presence of the inhibitory IgG receptor FcγRIIB was required for their ameliorative function, (2) complement-deficient mice responded to anti-CD44 treatment, and (3) human transgenic FcγRIIA-expressing mice also responded to the CD44 therapeutic modality. Dissimilar to IVIg, the Fc portion of the CD44 antibody was not required. These data demonstrate that CD44 antibodies can function therapeutically in murine ITP and that they could potentially provide a very-low-dose recombinant therapy for the amelioration of human ITP.
High IGSF4 expression in pediatric M5 acute myeloid leukemia with t(9;11)(p22;q23)
Authors: Kuipers Jenny E. , Coenen Eva A. , Balgobind Brian V. , Stary Jan , Baruchel Andre , de Haas Valerie , de Bont Eveline S. J. M. , Reinhardt Dirk , Kaspers Gertjan J. L. , Cloos Jacqueline , Danen-van Oorschot Astrid A. , den Boer Monique L. , Marschalek Rolf , Meyer Claus , Pieters Rob , Zwaan C. Michel , van den Heuvel-Eibrink Marry M.
Published: November 2010

Pediatric mixed-lineage leukemia (MLL)–rearranged acute monoblastic leukemia with t(9;11)(p22;q23) has a favorable outcome compared with other MLL-rearranged AML. The biologic background for this difference remains unknown. Therefore, we compared gene expression profiles (GEPs; Affymetrix HGU133 + 2.0) of 26 t(9;11)(p22;q23) patients with 42 other MLL-rearranged AML patients to identify differentially expressed genes. IGSF4, a cell-cell adhesion molecule, was found to be highly expressed in t(9;11)(p22;q23) patients, which was confirmed by real-time quantitative polymerase chain reaction and Western blot. IGSF4 expression within t(9;11)(p22;q23) patients was 4.9 times greater in French-American-British morphology classification (FAB)–M5 versus other FAB-types (P = .001). Methylation status investigation showed that high IGSF4-expressing t(9;11)(p22;q23) patients with FAB-M5 have no promoter hypermethylation, whereas all other cases do. Cell-line incubation with demethylating agent decitabine resulted in promoter demethylation and increased expression of IGSF4. Down-regulation of IGSF4 by siRNA did not affect proliferation or drug sensitivity. In a cohort of 79 MLL-rearranged AML cases, we show significant better overall survival for cases with high IGSF4 expression (5-year overall survival 0.70 vs 0.37, P = .03) In conclusion, we identified IGSF4 overexpression to be discriminative for t(9;11)(p22;q23) patients with FAB-M5, regulated partially by promoter methylation and resulting in survival benefit.
Soluble perlecan domain i enhances vascular endothelial growth factor-165 activity and receptor phosphorylation in human bone marrow endothelial cells
Authors: Muthusamy Arivalagan , Cooper Carlton R , Gomes Ronald R
Published: November 2010

Background

Immobilized recombinant perlecan domain I (PlnDI) binds and modulates the activity of heparin-binding growth factors, in vitro. However, activities for PlnDI, in solution, have not been reported. In this study, we assessed the ability of soluble forms to modulate vascular endothelial growth factor-165 (VEGF165) enhanced capillary tube-like formation, and VEGF receptor-2 phosphorylation of human bone marrow endothelial cells, in vitro.

Results

In solution, PlnDI binds VEGF165 in a heparan sulfate and pH dependent manner. Capillary tube-like formation is enhanced by exogenous PlnDI; however, PlnDI/VEGF165 mixtures combine to enhance formation beyond that stimulated by either PlnDI or VEGF165 alone. PlnDI also stimulates VEGF receptor-2 phosphorylation, and mixtures of PlnDI/VEGF165 reduce the time required for peak VEGF receptor-2 phosphorylation (Tyr-951), and increase Akt phosphorylation. PlnDI binds both immobilized neuropilin-1 and VEGF receptor-2, but has a greater affinity for neuropilin-1. PlnDI binding to neuropilin-1, but not to VEGF receptor-2 is dependent upon the heparan sulfate chains adorning PlnDI. Interestingly, the presence of VEGF165 but not VEGF121 significantly enhances PlnDI binding to Neuropilin-1 and VEGF receptor-2.

Conclusions

Our observations suggest soluble forms of PlnDI are biologically active. Moreover, PlnDI heparan sulfate chains alone or together with VEGF165 can enhance VEGFR-2 signaling and angiogenic events, in vitro. We propose PlnDI liberated during basement membrane or extracellular matrix turnover may have similar activities, in vivo.
SHOX2 DNA Methylation is a Biomarker for the diagnosis of lung cancer based on bronchial aspirates
Authors: Schmidt Bernd , Liebenberg Volker , Dietrich Dimo , Schlegel Thomas , Kneip Christoph , Seegebarth Anke , Flemming Nadja , Seemann Stefanie , Distler Jürgen , Lewin Jörn , Tetzner Reimo , Weickmann Sabine , Wille Ulrike , Liloglou Triantafillos , Raji Olaide , Walshaw Martin , Fleischhacker Michael , Witt Christian , Field John K
Published: November 2010

Background

This study aimed to show that SHOX2 DNA methylation is a tumor marker in patients with suspected lung cancer by using bronchial fluid aspirated during bronchoscopy. Such a biomarker would be clinically valuable, especially when, following the first bronchoscopy, a final diagnosis cannot be established by histology or cytology. A test with a low false positive rate can reduce the need for further invasive and costly procedures and ensure early treatment.

Methods

Marker discovery was carried out by differential methylation hybridization (DMH) and real-time PCR. The real-time PCR based HeavyMethyl technology was used for quantitative analysis of DNA methylation of SHOX2 using bronchial aspirates from two clinical centres in a case-control study. Fresh-frozen and Saccomanno-fixed samples were used to show the tumor marker performance in different sample types of clinical relevance.

Results

Valid measurements were obtained from a total of 523 patient samples (242 controls, 281 cases). DNA methylation of SHOX2 allowed to distinguish between malignant and benign lung disease, i.e. abscesses, infections, obstructive lung diseases, sarcoidosis, scleroderma, stenoses, at high specificity (68% sensitivity [95% CI 62-73%], 95% specificity [95% CI 91-97%]).

Conclusions

Hypermethylation of SHOX2 in bronchial aspirates appears to be a clinically useful tumor marker for identifying subjects with lung carcinoma, especially if histological and cytological findings after bronchoscopy are ambiguous.
Association of polymorphisms of interleukin-18 gene promoter region with polycystic ovary syndrome in chinese population
Authors: Yang Yan , Qiao Jie , Li Mei-zhi
Published: November 2010

Background

Recent research shows that polycystic ovary syndrome (PCOS) may have an association with low-grade chronic inflammation, and that PCOS may induce an increase in serum interleukin-18 (IL-18) levels.

Methods

To investigate the polymorphisms of the IL-18 gene promoters with PCOS, two single nucleotide polymorphisms (SNPs) in the promoter of the IL-18 gene (at positions -607C/A and -137G/C) in 118 Chinese women with PCOS and 79 controls were evaluated using polymerase chain reaction (PCR).

Results

No significant differences were found in the genotype distribution, allele frequency and haplotype frequency between the PCOS and control groups. Further analysis demonstrated a relationship between IL-18 gene promoter polymorphisms and PCOS insulin resistance (IR). Regarding the -137 allele frequency, G and C allele frequencies were 93.5% and 6.5%, respectively, in the PCOS with IR patients; G and C allele frequencies were 85.4% and 14.6%, respectively, in PCOS patients without IR (chi2 = 3.601, P = 0.048).

Conclusions

The presence of a polymorphism in the IL-18 gene was found to have no correlation with the occurrence of PCOS. Carriage of the C allele at position -137 in the promoter of the IL-18 gene may play a protective role from the development of PCOS IR.
Categorisation of continuous risk factors in epidemiological publications: a survey of current practice
Authors: Turner Elizabeth L , Dobson Joanna E , Pocock Stuart J
Published: November 2010

Background

Reports of observational epidemiological studies often categorise (group) continuous risk factor (exposure) variables. However, there has been little systematic assessment of how categorisation is practiced or reported in the literature and no extended guidelines for the practice have been identified. Thus, we assessed the nature of such practice in the epidemiological literature. Two months (December 2007 and January 2008) of five epidemiological and five general medical journals were reviewed. All articles that examined the relationship between continuous risk factors and health outcomes were surveyed using a standard proforma, with the focus on the primary risk factor. Using the survey results we provide illustrative examples and, combined with ideas from the broader literature and from experience, we offer guidelines for good practice.

Results

Of the 254 articles reviewed, 58 were included in our survey. Categorisation occurred in 50 (86%) of them. Of those, 42% also analysed the variable continuously and 24% considered alternative groupings. Most (78%) used 3 to 5 groups. No articles relied solely on dichotomisation, although it did feature prominently in 3 articles. The choice of group boundaries varied: 34% used quantiles, 18% equally spaced categories, 12% external criteria, 34% other approaches and 2% did not describe the approach used. Categorical risk estimates were most commonly (66%) presented as pairwise comparisons to a reference group, usually the highest or lowest (79%). Reporting of categorical analysis was mostly in tables; only 20% in figures.

Conclusions

Categorical analyses of continuous risk factors are common. Accordingly, we provide recommendations for good practice. Key issues include pre-defining appropriate choice of groupings and analysis strategies, clear presentation of grouped findings in tables and figures, and drawing valid conclusions from categorical analyses, avoiding injudicious use of multiple alternative analyses.
Mammalian circadian clock and metabolism – the epigenetic link
Authors: Bellet Marina Maria , Sassone-Corsi Paolo
Published: November 2010

Circadian rhythms regulate a wide variety of physiological and metabolic processes. The clock machinery comprises complex transcriptional–translational feedback loops that, through the action of specific transcription factors, modulate the expression of as many as 10% of cellular transcripts. This marked change in gene expression necessarily implicates a global regulation of chromatin remodeling. Indeed, various descriptive studies have indicated that histone modifications occur at promoters of clock-controlled genes (CCGs) in a circadian manner. The finding that CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyl transferase (HAT) activity has paved the way to unraveling the molecular mechanisms that govern circadian chromatin remodeling. A search for the histone deacetylase (HDAC) that counterbalances CLOCK activity revealed that SIRT1, a nicotinamide adenin dinucleotide (NAD+)-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of aging, inflammation and metabolism. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link between energy balance, chromatin remodeling and circadian physiology. Here we review recent studies that support the existence of this link and discuss their implications for understanding mammalian physiology and pathology.
Dampened activity of E2F1–DP and Myb–MuvB transcription factors inDrosophilaendocycling cells
Authors: Maqbool Shahina B. , Mehrotra Sonam , Kolpakas Alexis , Durden Chris , Zhang Bingqing , Zhong Hua , Calvi Brian R.
Published: November 2010

The endocycle is a variant cell cycle comprised of alternating gap (G) and DNA synthesis (S) phases (endoreplication) without mitosis (M), which results in DNA polyploidy and large cell size. Endocycles occur widely in nature, but much remains to be learned about the regulation of this modified cell cycle. Here, we compared gene expression profiles of mitotic cycling larval brain and disc cells with the endocycling cells of fat body and salivary gland of the Drosophila larva. The results indicated that many genes that are positively regulated by the heterodimeric E2F1–DP or Myb–MuvB complex transcription factors are expressed at lower levels in endocycling cells. Many of these target genes have functions in M phase, suggesting that dampened E2F1 and Myb activity promote endocycles. Many other E2F1 target genes that are required for DNA replication were also repressed in endocycling cells, an unexpected result given that these cells must duplicate up to thousands of genome copies during each S phase. For some EF2-regulated genes, the lower level of mRNA in endocycling cells resulted in lower protein concentration, whereas for other genes it did not, suggesting a contribution of post-transcriptional regulation. Both knockdown and overexpression of E2F1–DP and Myb–MuvB impaired endocycles, indicating that transcriptional activation and repression must be balanced. Our data suggest that dampened transcriptional activation by E2F1–DP and Myb–MuvB is important to repress mitosis and coordinate the endocycle transcriptional and protein stability oscillators.
Rhabdomyolysis in a Patient Receiving High-Dose Simvastatin After the Induction of Therapeutic Hypothermia
Authors: Dearing Natalie , Norgard Nicholas B
Published: November 2010

Objective:

To report a case of rhabdomyolysis in a patient receiving high-dose simvastatin after the induction of therapeutic hypothermia.

Case Summary:

A 45-year-old African American male was brought to the emergency department for a witnessed cardiac arrest. He was placed on a therapeutic hypothermia protocol and his simvastatin dose was increased from 40 to 80 mg at bedtime. Target core temperature (34 °C) was reached within 8 hours and was maintained for 24 hours. His admission creatine kinase was 965 units/L, which decreased to 153 units/L by day 4. On day 5, the patient voided a large quantity of orange-brown urine and had a dramatically increased creatine kinase (8523 unit/L) level and myoglobinuria. Statin therapy was subsequently discontinued. Creatine kinase remained elevated for 2 days, then gradually declined toward normal levels over the following week.

Discussion:

Simvastatin undergoes extensive first-pass metabolism mediated by CYP3A4, making it susceptible to significant drug interactions. Therapeutic hypothermia has been shown to significantly reduce the clearance of CYP3A4 substrates. We attribute this patient's rhabdomyolysis to a therapy-drug interaction between the therapeutic hypothermia and the administration of high-dose simvastatin. We believe that the induced hypothermia caused a reduction in simvastatin clearance, leading to toxic plasma concentrations. According to the Naranjo probability scale, it was probable that the rhabdomyolysis was related to simvastatin use. The Horn Drug Interaction Probability Scale likewise classified the probability of a causal relationship between the potential therapy-drug interaction and the event as probable.

Conclusions:

Clinicians must be aware of the pharmacokinetic effects of therapeutic hypothermia to prevent potential drug-therapy interactions. It may be prudent to avoid the use of CYP3A4 substrates that are not essential treatments in patients undergoing therapeutic hypothermia until more information is known about their safety in this patient population.
Role of Glucocorticoids in Tuning Hindbrain Stress Integration
Authors: Zhang Rong , Jankord Ryan , Flak Jonathan N. , Solomon Matia B. , D'Alessio David A. , Herman James P.
Published: November 2010

The nucleus of the solitary tract (NTS) is a critical integrative site for coordination of autonomic and endocrine stress responses. Stress-excitatory signals from the NTS are communicated by both catecholaminergic [norepinephrine (NE), epinephrine (E)] and noncatecholaminergic [e.g., glucagon-like peptide-1 (GLP-1)] neurons. Recent studies suggest that outputs of the NE/E and GLP-1 neurons of the NTS are selectively engaged during acute stress. This study was designed to test mechanisms of chronic stress integration in the paraventricular nucleus, focusing on the role of glucocorticoids. Our data indicate that chronic variable stress (CVS) causes downregulation of preproglucagon (GLP-1 precursor) mRNA in the NTS and reduction of GLP-1 innervation to the paraventricular nucleus of the hypothalamus. Glucocorticoids were necessary for preproglucagon (PPG) reduction in CVS animals and were sufficient to lower PPG mRNA in otherwise unstressed animals. The data are consistent with a glucocorticoid-mediated withdrawal of GLP-1 in key stress circuits. In contrast, expression of tyrosine hydroxylase mRNA, the rate-limiting enzyme in catecholamine synthesis, was increased by stress in a glucocorticoid-independent manner. These suggest differential roles of ascending catecholamine and GLP-1 systems in chronic stress, with withdrawal of GLP-1 involved in stress adaptation and enhanced NE/E capacity responsible for facilitation of responses to novel stress experiences.
Reaching Activity in the Medial Posterior Parietal Cortex of Monkeys Is Modulated by Visual Feedback
Authors: Bosco Annalisa , Breveglieri Rossella , Chinellato Eris , Galletti Claudio , Fattori Patrizia
Published: November 2010

Reaching and grasping an object is an action that can be performed in light, as well as in darkness. Area V6A is a visuomotor area of the medial posterior parietal cortex involved in the control of reaching movements. It contains reaching neurons as well as neurons modulated by passive somatosensory and visual stimulations. In the present work we analyze the effect of visual feedback on reaching activity of V6A neurons. Three macaques were trained to execute reaching movements in two conditions: in darkness, where only the reaching target was visible, and in full light, where the monkey also saw its own moving arm and the environment. Approximately 85% of V6A neurons (127/149) were significantly related to the task in at least one of the two conditions. The majority of task-related cells (69%) showed reach-related activity in both visual conditions, some were modulated only in light (15%), while others only in dark (16%). The sight of the moving arm often changed dramatically the cell's response to arm movements. In some cases the reaching activity was enhanced and in others it was reduced or disappeared altogether. These neuronal properties may represent differences in the degree to which cells are influenced by feedback control versus feedforward movement planning. On average, reach-related modulations were stronger in light than in dark, a phenomenon similar to that observed in brain imaging experiments in the human medial posterior parietal cortex, a region likely homologous to macaque area V6A.
MicroRNA Loss Enhances Learning and Memory in Mice
Authors: Konopka Witold , Kiryk Anna , Novak Martin , Herwerth Marina , Parkitna Jan Rodriguez , Wawrzyniak Marcin , Kowarsch Andreas , Michaluk Piotr , Dzwonek Joanna , Arnsperger Tabea , Wilczynski Grzegorz , Merkenschlager Matthias , Theis Fabian J. , Köhr Georg , Kaczmarek Leszek , Schütz Günther
Published: November 2010

Dicer-dependent noncoding RNAs, including microRNAs (miRNAs), play an important role in a modulation of translation of mRNA transcripts necessary for differentiation in many cell types.In vivoexperiments using cell type-specificDicer1gene inactivation in neurons showed its essential role for neuronal development and survival. However, little is known about the consequences of a loss of miRNAs in adult, fully differentiated neurons. To address this question, we used an inducible variant of the Cre recombinase (tamoxifen-inducible CreERT2) under control ofCamk2agene regulatory elements. After induction ofDicer1gene deletion in adult mouse forebrain, we observed a progressive loss of a whole set of brain-specific miRNAs. Animals were tested in a battery of both aversively and appetitively motivated cognitive tasks, such as Morris water maze, IntelliCage system, or trace fear conditioning. Compatible with rather long half-life of miRNAs in hippocampal neurons, we observed an enhancement of memory strength of mutant mice 12 weeks after theDicer1gene mutation, before the onset of neurodegenerative process. In acute brain slices, immediately after high-frequency stimulation of the Schaffer collaterals, the efficacy at CA3-to-CA1 synapses was higher in mutant than in control mice, whereas long-term potentiation was comparable between genotypes. This phenotype was reflected at the subcellular and molecular level by the elongated filopodia-like shaped dendritic spines and an increased translation of synaptic plasticity-related proteins, such as BDNF and MMP-9 in mutant animals. The presented work shows miRNAs as key players in the learning and memory process of mammals.
Pathological Sprouting of Adult Nociceptors in Chronic Prostate Cancer-Induced Bone Pain
Authors: Jimenez-Andrade Juan M. , Bloom Aaron P. , Stake James I. , Mantyh William G. , Taylor Reid N. , Freeman Katie T. , Ghilardi Joseph R. , Kuskowski Michael A. , Mantyh Patrick W.
Published: November 2010

Pain frequently accompanies cancer. What remains unclear is why this pain frequently becomes more severe and difficult to control with disease progression. Here we test the hypothesis that with disease progression, sensory nerve fibers that innervate the tumor-bearing tissue undergo a pathological sprouting and reorganization, which in other nonmalignant pathologies has been shown to generate and maintain chronic pain. Injection of canine prostate cancer cells into mouse bone induces a remarkable sprouting of calcitonin gene-related peptide (CGRP+) and neurofilament 200 kDa (NF200+) sensory nerve fibers. Nearly all sensory nerve fibers that undergo sprouting also coexpress tropomyosin receptor kinase A (TrkA+). This ectopic sprouting occurs in sensory nerve fibers that are in close proximity to colonies of prostate cancer cells, tumor-associated stromal cells and newly formed woven bone, which together form sclerotic lesions that closely mirror the osteoblastic bone lesions induced by metastatic prostate tumors in humans. Preventive treatment with an antibody that sequesters nerve growth factor (NGF), administered when the pain and bone remodeling were first observed, blocks this ectopic sprouting and attenuates cancer pain. Interestingly, reverse transcription PCR analysis indicated that the prostate cancer cells themselves do not express detectable levels of mRNA coding for NGF. This suggests that the tumor-associated stromal cells express and release NGF, which drives the pathological reorganization of nearby TrkA+sensory nerve fibers. Therapies that prevent this reorganization of sensory nerve fibers may provide insight into the evolving mechanisms that drive cancer pain and lead to more effective control of this chronic pain state.
Kinesin-12, a Mitotic Microtubule-Associated Motor Protein, Impacts Axonal Growth, Navigation, and Branching
Authors: Liu Mei , Nadar Vidya C. , Kozielski Frank , Kozlowska Marta , Yu Wenqian , Baas Peter W.
Published: November 2010

Kinesin-12 (also called Kif15) is a mitotic motor protein that continues to be expressed in developing neurons. Depletion of kinesin-12 causes axons to grow faster, more than doubles the frequency of microtubule transport in both directions in the axon, prevents growth cones from turning properly, and enhances the invasion of microtubules into filopodia. These results are remarkably similar to those obtained in previous studies in which neurons were depleted of kinesin-5 (also called Eg5 or Kif11), another mitotic motor protein that continues to be expressed in developing neurons. However, there are also notable differences in the phenotypes obtained with depleting each of these motors. Depleting kinesin-12 decreases axonal branching and growth cone size, whereas inhibiting kinesin-5 increases these parameters. In addition, depleting kinesin-12 diminishes the appearance of growth-cone-like waves along the length of the axon, an effect not observed with depletion of kinesin-5. Finally, depletion of kinesin-12 abolishes the “waggling” behavior of microtubules that occurs as they assemble along actin bundles within filopodia, whereas inhibition of kinesin-5 does not. Interestingly, and perhaps relevant to these differences in phenotype, in biochemical studies, kinesin-12 coimmunoprecipitates with actin but kinesin-5 does not. Collectively, these findings support a scenario whereby kinesin-12 shares functions with kinesin-5 related to microtubule–microtubule interactions, but kinesin-12 has other functions not shared by kinesin-5 that are related to the ability of kinesin-12 to interact with actin.
The Mouse Homeobox GeneGbx2Is Required for the Development of Cholinergic Interneurons in the Striatum
Authors: Chen Li , Chatterjee Mallika , Li James Y. H.
Published: November 2010

Mammalian forebrain cholinergic neurons are composed of local circuit neurons in the striatum and projection neurons in the basal forebrain. These neurons are known to arise from a common pool of progenitors that primarily resides in the medial ganglionic eminence (MGE). However, little is known about the genetic programs that differentiate these two types of cholinergic neurons. Using inducible genetic fate mapping, here we examined the developmental fate of cells that express the homeodomain transcription factor Gbx2 in the MGE. We show that theGbx2lineage-derived cells that undergo tangential migration exclusively give rise to almost all cholinergic interneurons in the striatum, whereas those undergoing radial migration mainly produce noncholinergic neurons in the basal forebrain. Deletion ofGbx2throughout the mouse embryo or specifically in the MGE results in abnormal distribution and significant reduction of cholinergic neurons in the striatum. We show that early-born (before embryonic day 12.5) cholinergic interneurons preferentially populate the lateral aspect of the striatum and mature earlier than late-born (after embryonic day 12.5) neurons, which normally reside in the medial part of the striatum. In the absence ofGbx2, early-born striatal cholinergic precursors display abnormal neurite outgrowth and increased complexity, and abnormally contribute to the medial part of the caudate–putamen, whereas late-born striatal cholinergic interneurons are mostly missing. Together, our data demonstrate thatGbx2is required for the development of striatal cholinergic interneurons, perhaps by regulating tangential migration of the striatal cholinergic precursors.
Radiation Recall with Anticancer Agents
Authors: Burris Howard A. , Hurtig Jane
Published: November 2010

Radiation recall is an acute inflammatory reaction confined to previously irradiated areas that can be triggered when chemotherapy agents are administered after radiotherapy. It remains a poorly understood phenomenon, but increased awareness may aid early diagnosis and appropriate management. A diverse range of drugs used in the treatment of cancer has been associated with radiation recall. As most data come from case reports, it is not possible to determine the true incidence, but to date the antineoplastic drugs for which radiation recall reactions have been most commonly reported include the anthracycline doxorubicin, the taxanes docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine. Radiation recall is drug-specific for any individual patient; it is not possible to predict which patients will react to which drugs, and rechallenge does not uniformly induce a reaction. There are no identifiable characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of chemotherapy.
Earliest occurrence of the Pteranodontidae (Archosauria: Pterosauria) in North America: new material from the Austin Group of Texas
Authors: Myers Timothy S.
Published: November 2010

Remains of a pteranodontid pterosaur are recorded in the basal Austin Group of North Texas. The specimen described here comprises a partial left wing and strongly resemblesPteranodonalthough diagnostic features of that genus are lacking. With an estimated early Coniacian age, this specimen represents the earliest occurrence of the Pteranodontidae in North America and the second earliest occurrence worldwide, predated only byOrnithostomafrom the Cambridge Greensand of England. Pterosaur material recovered from the Eagle Ford and Austin groups of Texas records an early Late Cretaceous change in the composition of North American pterosaur communities between the late Cenomanian and the early Coniacian. This faunal transition appears to be primarily a decrease in morphological disparity rather than a significant reduction in taxonomic diversity. However, the lack of Early CretaceousLagerstättenin North America may produce underestimates of true pterosaur richness during this interval, thereby obscuring a subsequent drop in diversity.