KFC Server: interactive forecasting of protein interaction hot spots

The KFC Server is a web-based implementation of the KFC (Knowledge-based FADE and Contacts) model—a machine learning approach for the prediction of binding hot spots, or the subset of residues that account for most of a protein interface's; binding free energy. The server facilitates the automated analysis of a user submitted protein–protein or protein–DNA interface and the visualization of its hot spot predictions. For each residue in the interface, the KFC Server characterizes its local structural environment, compares that environment to the environments of experimentally determined hot spots and predicts if the interface residue is a hot spot. After the computational analysis, the user can visualize the results using an interactive job viewer able to quickly highlight predicted hot spots and surrounding structural features within the protein structure. The KFC Server is accessible at http://kfc.mitchell-lab.org

On Shape Transformations and Shape Fluctuations of Cellular Compartments and Vesicles

We discuss the shape formation and shape transitions of simple bilayer vesicles in context with their role in biology. In the first part several classes of shape changes of vesicles of one lipid component are described and it is shown that these can be explained in terms of the bending energy concept in particular augmented by the bilayer coupling hypothesis. In the second part shape changes and vesicle fission of vesicles composed of membranes of lipid mixtures are reported. These are explained in terms of coupling between local curvature and phase separation

Vitamin D intake is associated with insulin sensitivity in African American, but not European American, women

<p>Abstract</p> <p>Background</p> <p>The prevalence of type 2 diabetes is higher among African Americans (AA) vs European Americans (EA), independent of obesity and other known confounders. Although the reason for this disparity is not known, it is possible that relatively low levels of vitamin D among AA may contribute, as vitamin D has been positively associated with insulin sensitivity in some studies. The objective of this study was to test the hypothesis that dietary vitamin D would be associated with a robust measure of insulin sensitivity in AA and EA women.</p> <p>Methods</p> <p>Subjects were 115 African American (AA) and 137 European American (EA) healthy, premenopausal women. Dietary intake was determined with 4-day food records; the insulin sensitivity index (S_I) with a frequently-sampled intravenous glucose tolerance test and minimal modeling; the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) with fasting insulin and glucose; and body composition with dual-energy X-ray absorptiometry.</p> <p>Results</p> <p>Vitamin D intake was positively associated with S_I(standardized β = 0.18, <it>P </it>= 0.05) and inversely associated with HOMA-IR (standardized β = -0.26, <it>P </it>= 0.007) in AA, and the relationships were independent of age, total body fat, energy intake, and % kcal from fat. Vitamin D intake was not significantly associated with indices of insulin sensitivity/resistance in EA (standardized β = 0.03, <it>P </it>= 0.74 and standardized β = 0.02, <it>P </it>= 0.85 for S_Iand HOMA-IR, respectively). Similar to vitamin D, dietary calcium was associated with S_Iand HOMA-IR among AA but not EA.</p> <p>Conclusions</p> <p>This study provides novel findings that dietary vitamin D and calcium were independently associated with insulin sensitivity in AA, but not EA. Promotion of these nutrients in the diet may reduce health disparities in type 2 diabetes risk among AA, although longitudinal and intervention studies are required.</p

Quality Incentives for Federally Qualified Health Centers, Rural Health Clinics and Free Clinics: A Report to Congress

This report to Congress is submitted pursuant to Section 13113(b) of the American Recovery and Reinvestment Act of 2009 (hereafter, the Recovery Act), under Title XIII, also known as the Health Information Technology for Economic and Clinical Health Act or the HITECH Act. The Section requires the Secretary of Health and Human Services to provide a study that examines methods to create efficient reimbursement incentives for improving health care quality in federally qualified health centers, rural health clinics, and free clinics. The report discusses current initiatives and incentives that apply to these categories of primary care clinics and the current knowledge regarding quality of care and the use of health information technology in this sector. Insofar as the report was authorized under the HITECH Act, it particularly addresses issues related to the use of health information technology by these clinics

Codon-based analysis of selection pressure and genetic structure in the Psammobates tentorius (Bell, 1828) species complex, and phylogeny inferred from both codons and amino acid sequences

This study used codon analysis (dN/dS and Tv/Ti) to investigate selection pressure and genetic structure in the highly polymorphic Psammobates tentorius species complex, and amino acid sequences to construct a phylogeny tree for it. Our results revealed a strong selection signal at node ‘C2 + C3’, possibly driven by aridity intensification resulting from the development of the Benguela Current. A similar signal was noticed at C3, possibly due to the same driving force. These findings suggest that environmental selection pressure favoured those groups and that further cladogenic events were possible. Selection pressure was also found to be high at C1, C4 and C7, which may indicate that they are also favoured by the current selection pressure. The codon-based phylogeny did not retrieve any potentially undescribed species, but nonetheless provided support for the validity of the seven distinct clades retrieved with the DNA sequence data. The amino acid sequence-based phylogeny generally supported the seven lineages as valid putative species. Investigation at the genomic scale could, however, help to solve the issue. In general, we found the codon, dN, dS, Tv, Ti and amino acid sequence-based phylogenetic inferences useful in species delimitation and recommend their use in species delimitation studies

A Constitutive Model for Long Time Duration Mechanical Behavior in Insensitive High Explosives

An anisotropic constitutive model for the long term dimensional stability of insensitive high explosives is proposed. Elastic, creep, thermal, and ratchet growth strains are developed. Pressure and temperature effects are considered. The constitutive model is implemented in an implicit finite element code and compared to a variety of experimental data

Requirement of histone deacetylase1 (HDAC1) in signal transducer and activator of transcription 3 (STAT3) nucleocytoplasmic distribution

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that plays a crucial role in interleukin-6 (IL-6) signaling, mediating the acute-phase induction of the human Angiotensinogen (hAGT) gene in hepatocytes. We showed earlier that IL-6 induces acetylation of the STAT3 NH2-terminus by the recruitment of the p300 coactivator. We had also observed a physical interaction of STAT3 and Histone Deacetylase1 (HDAC1) in an IL-6-dependent manner that leads to transcriptional repression. In this study, we sought to elucidate the mechanism by which HDAC1 controls STAT3 transcriptional activity. Here, we mapped the interacting domains of both STAT3 and HDAC1 and found that the COOH-terminal domain of HDAC1 is necessary for IL-6-induced STAT3 transcriptional repression, whereas the NH2-terminal acetylation domain of STAT3 is required for HDAC1 binding. Interestingly, over expression of HDAC1 in HepG2 cells leads to significantly reduced amounts of nuclear STAT3 after IL-6 induction, whereas silencing of HDAC1 resulted in accumulation of total and acetylated STAT3 in the nucleus. We have found that HDAC1 knockdown also interferes with the responsiveness of the STAT3-dependent MCP1 target gene expression to IL-6, as confirmed by real-time RT–PCR analysis. Together, our study reveals the novel functional consequences of IL-6-induced STAT3-HDAC1 interaction on nucleocytoplasmic distribution of STAT3

Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage.

One fundamental but understudied mechanism of gene regulation in disease is allele-specific expression (ASE), the preferential expression of one allele. We leveraged RNA-sequencing data from human brain to assess ASE in autism spectrum disorder (ASD). When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite to the canonical pattern. Importantly, genes showing ASE in ASD are enriched in those downregulated in ASD postmortem brains and in genes harboring de novo mutations in ASD. Two regions, 14q32 and 15q11, containing all known orphan C/D box small nucleolar RNAs (snoRNAs), are particularly enriched in shifts to higher minor allele expression. We demonstrate that this allele shifting enhances snoRNA-targeted splicing changes in ASD-related target genes in idiopathic ASD and 15q11-q13 duplication syndrome. Together, these results implicate allelic imbalance and dysregulation of orphan C/D box snoRNAs in ASD pathogenesis

MicroRNA-218 instructs proper assembly of hippocampal networks

The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of Mir218-2 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks