What do we know and when do we know it?

Two essential aspects of virtual screening are considered: experimental design and performance metrics. In the design of any retrospective virtual screen, choices have to be made as to the purpose of the exercise. Is the goal to compare methods? Is the interest in a particular type of target or all targets? Are we simulating a ‘real-world’ setting, or teasing out distinguishing features of a method? What are the confidence limits for the results? What should be reported in a publication? In particular, what criteria should be used to decide between different performance metrics? Comparing the field of molecular modeling to other endeavors, such as medical statistics, criminology, or computer hardware evaluation indicates some clear directions. Taken together these suggest the modeling field has a long way to go to provide effective assessment of its approaches, either to itself or to a broader audience, but that there are no technical reasons why progress cannot be made

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

The Association between Kidney Function, Coronary Artery Disease, and Clinical Outcome in Patients Undergoing Coronary Angiography

To characterize the association between chronic kidney disease (CKD), mortality, severity of coronary artery disease (CAD), treatment modality of CAD, and type of coronary stents among patients undergoing coronary angiography (CAG), we retrospectively reviewed the electronic medical records of the patients who underwent CAG at Seoul National University Bundang Hospital in Korea between May 2003 and January 2006. CKD was staged using an estimated glomerular filtration rate (eGFR) from the creatinine value prior to CAG. There were 3,637 patients included. The presence of CAD was 48% in CKD stage 1, 61% in stage 2, 73% in stage 3, 87% in stage 4, and 81% in stage 5. Survival rate gradually diminished for patients with decreasing renal function. No significant differences in all-cause and cardiac mortality were observed by medical treatment, PCI or CABG, in CKD patients with an eGFR less than 60 mL/min/1.73 m2. CKD patients with drug-eluting stents showed significantly lower all-cause mortality (5.4% vs. 13.3%) and incidence of myocardial infarction (1.7% vs. 10%) than those with bare metal stents. In conclusion, an eGFR is a strong independent prognostic marker among patients undergoing CAG and the severity of CAD increases progressively with worsening renal function

Maternal risk factors for abnormal placental growth: The national collaborative perinatal project

<p>Abstract</p> <p>Background</p> <p>Previous studies of maternal risk factors for abnormal placental growth have focused on placental weight and placental ratio as measures of placental growth. We sought to identify maternal risk factors for placental weight and two neglected dimensions of placental growth: placental thickness and chorionic plate area.</p> <p>Methods</p> <p>We conducted an analysis of 24,135 mother-placenta pairs enrolled in the National Collaborative Perinatal Project, a prospective cohort study of pregnancy and child health. We defined growth restriction as < 10^thpercentile and hypertrophy as > 90^thpercentile for three placental growth dimensions: placental weight, placental thickness and chorionic plate area. We constructed parallel multinomial logistic regression analyses to identify (a) predictors of restricted growth (vs. normal) and (b) predictors of hypertrophic growth (vs. normal).</p> <p>Results</p> <p>Black race was associated with an increased likelihood of growth restriction for placental weight, thickness and chorionic plate area, but was associated with a reduced likelihood of hypertrophy for these three placental growth dimensions. We observed an increased likelihood of growth restriction for placental weight and chorionic plate area among mothers with hypertensive disease at 24 weeks or beyond. Anemia was associated with a reduced likelihood of growth restriction for placental weight and chorionic plate area. Pre-pregnancy BMI and pregnancy weight gain were associated with a reduced likelihood of growth restriction and an increased likelihood of hypertrophy for all three dimensions of placental growth.</p> <p>Conclusion</p> <p>Maternal risk factors are either associated with placental growth restriction or placental hypertrophy not both. Our findings suggest that the placenta may have compensatory responses to certain maternal risk factors suggesting different underlying biological mechanisms.</p

Modelling study of dimerization in mammalian defensins

BACKGROUND: Defensins are antimicrobial peptides of innate immunity functioning by non-specific binding to anionic phospholipids in bacterial membranes. Their cationicity, amphipathicity and ability to oligomerize are considered key factors for their action. Based on structural information on human β-defensin 2, we examine homologous defensins from various mammalian species for conserved functional physico-chemical characteristics. RESULTS: Based on homology greater than 40%, structural models of 8 homologs of HBD-2 were constructed. A conserved pattern of electrostatics and dynamics was observed across 6 of the examined defensins; models backed by energetics suggest that the defensins in these 6 organisms are characterized by dimerization-linked enhanced functional potentials. In contrast, dimerization is not energetically favoured in the sheep, goat and mouse defensins, suggesting that they function efficiently as monomers. CONCLUSION: β-defensin 2 from some mammals may work as monomers while those in others, including humans, work as oligomers. This could potentially be used to design human defensins that may be effective at lower concentrations and hence have therapeutic benefits

The uncoupling protein 1 gene, UCP1, is expressed in mammalian islet cells and associated with acute insulin response to glucose in African American families from the IRAS Family Study

BACKGROUND: Variants of uncoupling protein genes UCP1 and UCP2 have been associated with a range of traits. We wished to evaluate contributions of known UCP1 and UCP2 variants to metabolic traits in the Insulin Resistance and Atherosclerosis (IRAS) Family Study. METHODS: We genotyped five promoter or coding single nucleotide polymorphisms (SNPs) in 239 African American (AA) participants and 583 Hispanic participants from San Antonio (SA) and San Luis Valley. Generalized estimating equations using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation were computed for the test of genotypic association, and dominant, additive and recessive models. Tests were adjusted for age, gender and BMI (glucose homeostasis and lipid traits), or age and gender (obesity traits), and empirical P-values estimated using a gene dropping approach. RESULTS: UCP1 A-3826G was associated with AIR(g )in AA (P = 0.006) and approached significance in Hispanic families (P = 0.054); and with HDL-C levels in SA families (P = 0.0004). Although UCP1 expression is reported to be restricted to adipose tissue, RT-PCR indicated that UCP1 is expressed in human pancreas and MIN-6 cells, and immunohistochemistry demonstrated co-localization of UCP1 protein with insulin in human islets. UCP2 A55V was associated with waist circumference (P = 0.045) in AA, and BMI in SA (P = 0.018); and UCP2 G-866A with waist-to-hip ratio in AA (P = 0.016). CONCLUSION: This study suggests a functional variant of UCP1 contributes to the variance of AIR(g )in an AA population; the plausibility of this unexpected association is supported by the novel finding that UCP1 is expressed in islets

Season of birth and handedness in Serbian high school students

<p>Abstract</p> <p>Background</p> <p>Although behavioural dominance of the right hand in humans is likely to be under genetic control, departures from this population norm, i.e. left- or non-right-handedness, are believed to be influenced by environmental factors. Among many such environmental factors including, for example, low birth weight, testosterone level, and maternal age at birth, season of birth has occasionally been investigated. The overall empirical evidence for the season of birth effect is mixed.</p> <p>Methods</p> <p>We have investigated the effect of season of birth in an epidemiologically robust sample of randomly selected young people (n = 977), all born in the same year. A Kolmogorov-Smirnov type statistical test was used to determine season of birth.</p> <p>Results</p> <p>Neither the right-handed nor the non-right-handed groups demonstrated birth asymmetry relative to the normal population birth distribution. There was no between-group difference in the seasonal distribution of birth when comparing the right-handed to the non-right-handed groups.</p> <p>Conclusion</p> <p>The present study failed to provide support for a season of birth effect on atypical lateralisation of handedness in humans.</p

Mitochondrial Membrane Potential in Human Neutrophils Is Maintained by Complex III Activity in the Absence of Supercomplex Organisation

textabstractBackground: Neutrophils depend mainly on glycolysis for their enegry provision. Their mitochondria maintain a membrace potential (ΔΨm), which is usually generated by the repiratory chain complexes. We investigated the source of ΔΨm in neutrophils, as compared to peripheral blood mononuclear leukocytes and HL-60 cells, and whether neutrophils can still utilise this ΔΨm for the generation of ATP. Methods and Principal Findings: Individual activity of the oxidative phosphorylation complexes was significantly reduced in neutrophils, except for complex II and V, but ΔΨm was still decreased byinhibition of complex III, confirming the role of the respiratory chain in maintaining ΔΨm. Complex V did not maintain ΔΨm by consumption of ATP, as has previously been suggested for eosinophils shuttle. Furthermore, respiratory supercomplexes, which contribute to efficient coupling of the respiratory chain to ATP synthesis, were ladding in neutrophil mitochondria. When HL-60 cells were differentiated to neutrophil-like cells, they lost mitochondrial supercimplex organisation while gaining increased aerobic glycolysis, just like neutrophils. Conclusions: We show that neutrophils can maintain ΔΨm via the glycerol-3-phosphate shuttle, wereby their mitochondria play an important role in the regulation of aerobic glycolysis, rather than producing energy themselves. This peculiar mitochondrial phenotype is acquired during differentiation from myeloid precursors

PubChem3D: a new resource for scientists

<p>Abstract</p> <p>Background</p> <p>PubChem is an open repository for small molecules and their experimental biological activity. PubChem integrates and provides search, retrieval, visualization, analysis, and programmatic access tools in an effort to maximize the utility of contributed information. There are many diverse chemical structures with similar biological efficacies against targets available in PubChem that are difficult to interrelate using traditional 2-D similarity methods. A new layer called PubChem3D is added to PubChem to assist in this analysis.</p> <p>Description</p> <p>PubChem generates a 3-D conformer model description for 92.3% of all records in the PubChem Compound database (when considering the parent compound of salts). Each of these conformer models is sampled to remove redundancy, guaranteeing a minimum (non-hydrogen atom pair-wise) RMSD between conformers. A diverse conformer ordering gives a maximal description of the conformational diversity of a molecule when only a subset of available conformers is used. A pre-computed search per compound record gives immediate access to a set of 3-D similar compounds (called "Similar Conformers") in PubChem and their respective superpositions. Systematic augmentation of PubChem resources to include a 3-D layer provides users with new capabilities to search, subset, visualize, analyze, and download data.</p> <p>A series of retrospective studies help to demonstrate important connections between chemical structures and their biological function that are not obvious using 2-D similarity but are readily apparent by 3-D similarity.</p> <p>Conclusions</p> <p>The addition of PubChem3D to the existing contents of PubChem is a considerable achievement, given the scope, scale, and the fact that the resource is publicly accessible and free. With the ability to uncover latent structure-activity relationships of chemical structures, while complementing 2-D similarity analysis approaches, PubChem3D represents a new resource for scientists to exploit when exploring the biological annotations in PubChem.</p

Avian Influenza Viruses Infect Primary Human Bronchial Epithelial Cells Unconstrained by Sialic Acid α2,3 Residues

Avian influenza viruses (AIV) are an important emerging threat to public health. It is thought that sialic acid (sia) receptors are barriers in cross-species transmission where the binding preferences of AIV and human influenza viruses are sias α2,3 versus α2,6, respectively. In this study, we show that a normal fully differentiated, primary human bronchial epithelial cell model is readily infected by low pathogenic H5N1, H5N2 and H5N3 AIV, which primarily bind to sia α2,3 moieties, and replicate in these cells independent of specific sias on the cell surface. NHBE cells treated with neuraminidase prior to infection are infected by AIV despite removal of sia α2,3 moieties. Following AIV infection, higher levels of IP-10 and RANTES are secreted compared to human influenza virus infection, indicating differential chemokine expression patterns, a feature that may contribute to differences in disease pathogenesis between avian and human influenza virus infections in humans