Correcting pervasive errors in RNA crystallography through enumerative structure prediction

Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors and steric clashes. To address these problems, we present enumerative real-space refinement assisted by electron density under Rosetta (ERRASER), coupled to Python-based hierarchical environment for integrated 'xtallography' (PHENIX) diffraction-based refinement. On 24 data sets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves the average Rfree factor, resolves functionally important discrepancies in noncanonical structure and refines low-resolution models to better match higher-resolution models

Metastatic pleomorphic sarcoma to left atrium

Although several thousand patients are diagnosed with sarcoma annually in the United States, metastases to the heart are very uncommon. In this case report, an overall low frequency cancer presents masquerading with common cardiac symptomology. This case illustrates the importance for detailed diagnostic cardiac evaluations and heightened suspicion by physicians to consider metastatic disease to the heart in cancer patients with cardiovascular complications. Also discussed is a review of surgical and chemotherapeutic options for this problem

Fatal alcohol intoxication in women: A forensic autopsy study from Slovakia

<p>Abstract</p> <p>Background</p> <p>Plenty of information related to alcoholism can be found in the literature, however, the studies have mostly dealt with the predominance of male alcoholism and data related to addiction in women are desperately scarce and difficult to find. Basic demographic data focusing on the impact of acute alcohol intoxication on the circumstances of death and social behaviour in the alcohol addicted female population are needed especially in the prevention of alcohol related mortality.</p> <p>Methods</p> <p>A retrospective forensic autopsy study of all accidental deaths due to alcohol intoxication over a 12-year period was performed in order to evaluate the locations, circumstances, mechanisms and causes of death.</p> <p>Results</p> <p>A sample of 171 cases of intoxicated women who died due to blood alcohol concentration (BAC) equal to or higher than 2 g/kg was selected. Among them 36.26% (62/171) of women died due to acute alcohol intoxication (AAI). We noted an increase in the number of deaths in women due to AAI from 2 in 1994 up to 5 in 2005 (an elevation of 150% between the years 1994-2005). The age structure of deaths in women due to BAC and AAI followed the Gaussian distribution with a dominant group of women aged 41-50 years (45.16% and 35.09% respectively). The most frequent place of death (98%) among women intoxicated by alcohol was their own home. The study suggests a close connection between AAI and violence against women.</p> <p>Conclusions</p> <p>The increasing number of cases of death of women suffering from AAI has drawn attention to the serious problem of alcoholism in women in the Slovak Republic during the process of integration into "western" lifestyle and culture.</p

YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins

E5 proteins are amongst the least understood of the Human Papillomavirus (HPV) encoded gene products. They are small, membrane-integrated proteins known to modulate a number of critical host pathways associated with pathogenesis including growth factor receptor signaling and immune evasion. Their role in the virus life cycle is less clear, indicating a role in the productive stages of the life cycle. However, a mechanism for this is currently lacking. Here we describe the identification of a novel binding partner of E5, YIPF4 using yeast two-hybrid analysis. YIPF4 is also a poorly characterized membrane spanning protein. Mutagenesis studies implicated the transmembrane regions of each protein as important for their interaction. Binding to YIPF4 was found for all E5 proteins tested suggesting that this interaction may mediate a conserved E5 function. In normal human keratinocytes YIPF4 expression was down-regulated upon differentiation and this reduction was partially rescued in cells harbouring HPV. Despite the conserved nature of the interaction with E5, siRNA mediated depletion of YIPF4 failed to impede two well-characterized functions of E5, namely EGFR trafficking or HLA class I presentation. Continued studies of YIPF4 are warranted to determine its role in the PV life cycle

Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming

Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing endothelial contraction and transient microvascular leakage. Using this model, we show that EB recovery requires a CD31 receptor-induced, robust glycolytic response sustaining junction re-annealing. Mechanistically, this response involves src-homology phosphatase activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant \u3b2-catenin translocation to the nucleus, collectively leading to cMyc transcription. CD31 signals also sustain mitochondrial respiration, however this pathway does not contribute to junction remodeling. We further show that pathologic microvascular leakage in CD31-deficient mice can be corrected by enhancing the glycolytic flux via pharmacological Akt or AMPK activation, thus providing a molecular platform for the therapeutic control of EB response