Predicting Important Residues and Interaction Pathways in Proteins Using Gaussian Network Model: Binding and Stability of HLA Proteins

A statistical thermodynamics approach is proposed to determine structurally and functionally important residues in native proteins that are involved in energy exchange with a ligand and other residues along an interaction pathway. The structure-function relationships, ligand binding and allosteric activities of ten structures of HLA Class I proteins of the immune system are studied by the Gaussian Network Model. Five of these models are associated with inflammatory rheumatic disease and the remaining five are properly functioning. In the Gaussian Network Model, the protein structures are modeled as an elastic network where the inter-residue interactions are harmonic. Important residues and the interaction pathways in the proteins are identified by focusing on the largest eigenvalue of the residue interaction matrix. Predicted important residues match those known from previous experimental and clinical work. Graph perturbation is used to determine the response of the important residues along the interaction pathway. Differences in response patterns of the two sets of proteins are identified and their relations to disease are discussed

Multiple Phosphatidylinositol 3-Kinases Regulate Vaccinia Virus Morphogenesis

Poxvirus morphogenesis is a complex process that involves the successive wrapping of the virus in host cell membranes. We screened by plaque assay a focused library of kinase inhibitors for those that caused a reduction in viral growth and identified several compounds that selectively inhibit phosphatidylinositol 3-kinase (PI3K). Previous studies demonstrated that PI3Ks mediate poxviral entry. Using growth curves and electron microscopy in conjunction with inhibitors, we show that that PI3Ks additionally regulate morphogenesis at two distinct steps: immature to mature virion (IMV) transition, and IMV envelopment to form intracellular enveloped virions (IEV). Cells derived from animals lacking the p85 regulatory subunit of Type I PI3Ks (p85α−/−β−/−) presented phenotypes similar to those observed with PI3K inhibitors. In addition, VV appear to redundantly use PI3Ks, as PI3K inhibitors further reduce plaque size and number in p85α−/−β−/− cells. Together, these data provide evidence for a novel regulatory mechanism for virion morphogenesis involving phosphatidylinositol dynamics and may represent a new therapeutic target to contain poxviruses

Gender-Related Differences in the Dysfunctional Resting Networks of Migraine Suffers

BACKGROUND: Migraine shows gender-specific incidence and has a higher prevalence in females. However, little is known about gender-related differences in dysfunctional brain organization, which may account for gender-specific vulnerability and characteristics of migraine. In this study, we considered gender-related differences in the topological property of resting functional networks. METHODOLOGY/PRINCIPAL FINDINGS: Data was obtained from 38 migraine patients (18 males and 20 females) and 38 healthy subjects (18 males and 20 females). We used the graph theory analysis, which becomes a powerful tool in investigating complex brain networks on a whole brain scale and could describe functional interactions between brain regions. Using this approach, we compared the brain functional networks between these two groups, and several network properties were investigated, such as small-worldness, network resilience, nodal centrality, and interregional connections. In our findings, these network characters were all disrupted in patients suffering from chronic migraine. More importantly, these functional damages in the migraine-affected brain had a skewed balance between males and females. In female patients, brain functional networks showed worse resilience, more regions exhibited decreased nodal centrality, and more functional connections revealed abnormalities than in male patients. CONCLUSIONS: These results indicated that migraine may have an additional influence on females and lead to more dysfunctional organization in their resting functional networks

EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY

Objectives: Postpartum depression (PPD) is a common disorder that affects 10-15% of postpartum women, and it can have negative effects on both the mother and newborn. Recent studies have suggested that low levels of vitamin D are associated with poor mood and depression. The aim of this prospective study was to evaluate a possible association between PPD and serum levels of 25-hydroxy vitamin D3 (25 (OH)D3), a reliable measurement of vitamin D, during mid-pregnancy. Study design: The source population consisted of all pregnant women between 24 and 28 gestational weeks from June 2012 to October 2012 at Bornova Health Research and Application Hospital, Sifa University. In order to better evaluate a possible effect between vitamin D levels and PPD, individuals with characteristics that put them at risk for developing PPD were excluded from the study. Serum 25 (OH)D3 levels were evaluated mid-pregnancy in the study group. Serum 25(OH)D3 concentrations <= 20 ng/mL (50 nmol/L) were classified as a mild deficiency and those <= 10 ng/mL (25 nmol/L) were classified as a severe deficiency. Pregnant subjects having complications during birth or with the newborn after delivery were excluded from the study. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess maternal PPD 1 week, 6 weeks, and 6 months after delivery. A Pearson correlation was used to measure the strength of the associations between the EPDS scores and vitamin D levels analyzed during the three time periods. A logistic regression analysis was used to determine the independent effects of vitamin D on PPD. Results: Six hundred and eighty-seven pregnant women were included in this study. After excluding women due to PPD risk factors (in two stages), 179 pregnant women were screened for vitamin D levels during mid-pregnancy and in the 6th month postpartum. Eleven percent of our study group had severe vitamin D deficiency and 40.3% had mild vitamin D deficiency. The frequency of PPD was 21.6% at the 1st week, 23.2% at 6th week, and 23.7% at the 6th month. There was a significant relationship between low 25 (OH)D3 levels in mid-pregnancy and high EPDS scores, which is indicative of PPD for all three follow-up periods (p = 0.003, p= 0.004 and p < 0.001, respectively). In addition, there was a significant negative correlation between vitamin D levels and EDPS at all three time points (r= -0.2, -0.2, -0.3, respectively). Conclusions: Vitamin D deficiency in mid-pregnancy may be a factor affecting the development of PPD. More extensive studies are required to be carried out on this subject. (C) 2014 Elsevier Ireland Ltd. All rights reserved

ARCHIVES OF ENDOCRINOLOGY METABOLISM

Objective: To investigate whether vitamin D deficiency is associated with high mean platelet volume (MPV) in pregnancies diagnosed with gestational diabetes mellitus (GDM) compared to healthy pregnancies. Subjects and methods: This study included 200 pregnant women. 25-hydroxyvitamin D-3 (25(OH)D-3) and MPV values were monitored between pregnant women with GDM and normal glucose metabolism. Correlation between 25(OH)D-3 and MPV was calculated both in GDM and healthy pregnancies. Both 25(OH)D-3 level in different MPV percentile (= 90 percentile) and MPV value in different 25(OH)D-3 level (= 20 ng/mL) were calculated. Results: Low 25(OH)D-3 level and high MPV were observed both in GDM group (p = 0.007, p = 0.06, respectively) and in glucose metabolism disorders (GMD) group (p = 0.03, p = 0.04, respectively). There was no significant relationship between 25(OH)D-3 and MPV in healthy pregnancies. Whereas, it is observed that there is a negative, but statistically insignificant correlation between MPV and 25(OH)D-3 pregnant women with GMD (r = 0.1, r = -0.7, respectively). MPV values had significantly higher in vitamin D deficient group than pregnant women with normal 25(OH)D-3 level in GMD group (p = 0.04). The optimal 25(OH)D-3 cut off point for predicting future cardiovascular risk was 10.4 ng/mL (area under curve (AUC) = 0.58). Conclusions: Vitamin D deficiency may contribute to an increased risk for future cardiovascular diseases and a risk of thrombotic complications in pregnant women with GDM