Shedding light on the elusive role of endothelial cells in cytomegalovirus dissemination.

Cytomegalovirus (CMV) is frequently transmitted by solid organ transplantation and is associated with graft failure. By forming the boundary between circulation and organ parenchyma, endothelial cells (EC) are suited for bidirectional virus spread from and to the transplant. We applied Cre/loxP-mediated green-fluorescence-tagging of EC-derived murine CMV (MCMV) to quantify the role of infected EC in transplantation-associated CMV dissemination in the mouse model. Both EC- and non-EC-derived virus originating from infected Tie2-cre(+) heart and kidney transplants were readily transmitted to MCMV-naïve recipients by primary viremia. In contrast, when a Tie2-cre(+) transplant was infected by primary viremia in an infected recipient, the recombined EC-derived virus poorly spread to recipient tissues. Similarly, in reverse direction, EC-derived virus from infected Tie2-cre(+) recipient tissues poorly spread to the transplant. These data contradict any privileged role of EC in CMV dissemination and challenge an indiscriminate applicability of the primary and secondary viremia concept of virus dissemination

Properties of the Galactic population of cataclysmic variables in hard X-rays

We measure the spatial distribution and hard X-ray luminosity function of cataclysmic variables (CVs) using the INTEGRAL all-sky survey in the 17-60 keV energy band. The vast majority of the INTEGRAL detected CVs are intermediate polars with luminosities in the range 10^{32}-10^{34} erg/sec. The scale height of the Galactic disk population of CVs is found to be 130{+90}{-50} pc. The CV luminosity function measured with INTEGRAL in hard X-rays is compatible with that previously determined at lower energies (3--20 keV) using a largely independent sample of sources detected by RXTE (located at |b|>10deg as opposed to the INTEGRAL sample, strongly concentrated to the Galactic plane). The cumulative 17-60 keV luminosity density of CVs per unit stellar mass is found to be (1.3+/-0.3)x10^{27} erg/sec/Msun and is thus comparable to that of low-mass X-ray binaries in this energy band. Therefore, faint but numerous CVs are expected to provide an important contribution to the cumulative hard X-ray emission of galaxies.Comment: 8 pages, 8 figures. Submitted to A&

Acute safety, effectiveness, and real-world clinical usage of ultra-high density mapping for ablation of cardiac arrhythmias: results of the TRUE HD study

AIMS: The objective of this study was to verify acute safety, performance, and usage of a novel ultra-high density mapping system in patients undergoing ablation procedure in a real-world clinical setting. METHODS AND RESULTS: The TRUE HD study enrolled patients undergoing catheter ablation with mapping for all arrhythmias (excluding de novo atrial fibrillation) who were followed for 1 month. Safety was determined by collecting all serious adverse events and adverse events associated with the study devices. Performance was determined as the composite of: ability to map the arrhythmia/substrate, complete the ablation applications, arrhythmia termination (where applicable), and ablation validation. Use of mapping system in the ablation validation workflow was also evaluated. Among the 519 patients who underwent a complete (504) or attempted (15) procedure, 21 (4%) serious ablation-related complications were collected, with 3 (0.57%) potentially related to the mapping catheter. Four hundred and twenty treated patients resulted in a successful procedure confirmed by arrhythmia-specific validation techniques (83.3%; 95% confidence interval: 79.8-86.5%). A total of 1419 electroanatomical maps were created with a median acquisition time of 9:23 min per map. Of these, 372 maps in 222 (44%) patients were collected for ablation validation purposes. Following validation mapping, 162/222 (73%) patients required additional ablation. CONCLUSION: In the TRUE HD study mapping was associated with rates of acute success and complications consistent with previously published reports. Importantly, a low percentage of events (0.57%) was attributed to the mapping catheter. When performed, validation mapping was useful for identifying additional targets for ablation in the majority of patients

Association of estradiol and visceral fat with structural brain networks and memory performance in adults

Importance Changes in estradiol during aging are associated with increased dementia risk. It remains unclear how estradiol supports cognitive health and whether risk factors, such as midlife obesity, are exacerbated by estrogen loss. Objectives To assess whether visceral adipose tissue (VAT) moderates the association between age and brain network structure and to investigate whether estradiol moderates the association between VAT and brain network structure. Design, Setting, and Participants Cross-sectional study of data from 974 cognitively healthy adults in Germany who participated in the Health Study of the Leipzig Research Centre for Civilization Diseases, a previously described population-based cohort study. Two moderation analyses were performed, including VAT as the moderator variable between age and brain network structure and estradiol as the moderator variable between VAT and brain network structure. The study was conducted from August 1, 2011, to November 23, 2014. Analyses were conducted from August 2017 to September 201

Testosterone imbalance may link depression and increased body weight in premenopausal women

Accumulating evidence supports a link between depression and being overweight in women. Given previously reported sex differences in fat accumulation and depression prevalence, as well as the likely role of sex hormones in both overweight and mood disorders, we hypothesised that the depression-overweight association may be mediated by sex hormones. To this end, we investigated the association of being overweight with depression, and then considered the role of sex hormones in relation to being overweight and depression in a large population-based cohort. We included a total of 3124 women, 970 premenopausal and 2154 postmenopausal from the LIFE-Adult cohort study in our analyses. We evaluated associations between being overweight (BMI >25 kg/m2), sex hormone levels, and depressive symptomatology according to Centre for Epidemiologic Studies Depression (CES-D) scores, and explored mediation of depression in a mediation model. Being overweight was significantly associated with depressive symptoms in premenopausal but not postmenopausal women. Both premenopausal and postmenopausal overweight women had higher free testosterone levels compared with normal weight women. Premenopausal women with depressive symptomatology had higher free testosterone levels compared to women without. We found a significant mediation effect of depressive symptomatology in overweight premenopausal women through free testosterone level. These findings highlight the association between being overweight and depressed, and suggest that high free testosterone levels may play a significant role in depression of overweight premenopausal women. Based on this, pharmacological approaches targeting androgen levels in overweight depressed females, in particular when standard anti-depressive treatments fail, could be of specific clinical relevance

MIA-Prognosis: A Deep Learning Framework to Predict Therapy Response

Predicting clinical outcome is remarkably important but challenging. Research efforts have been paid on seeking significant biomarkers associated with the therapy response or/and patient survival. However, these biomarkers are generally costly and invasive, and possibly dissatifactory for novel therapy. On the other hand, multi-modal, heterogeneous, unaligned temporal data is continuously generated in clinical practice. This paper aims at a unified deep learning approach to predict patient prognosis and therapy response, with easily accessible data, e.g., radiographics, laboratory and clinical information. Prior arts focus on modeling single data modality, or ignore the temporal changes. Importantly, the clinical time series is asynchronous in practice, i.e., recorded with irregular intervals. In this study, we formalize the prognosis modeling as a multi-modal asynchronous time series classification task, and propose a MIA-Prognosis framework with Measurement, Intervention and Assessment (MIA) information to predict therapy response, where a Simple Temporal Attention (SimTA) module is developed to process the asynchronous time series. Experiments on synthetic dataset validate the superiory of SimTA over standard RNN-based approaches. Furthermore, we experiment the proposed method on an in-house, retrospective dataset of real-world non-small cell lung cancer patients under anti-PD-1 immunotherapy. The proposed method achieves promising performance on predicting the immunotherapy response. Notably, our predictive model could further stratify low-risk and high-risk patients in terms of long-term survival.Comment: MICCAI 2020 (Early Accepted; Student Travel Award

From trial to population: A study of a family-based community intervention for childhood overweight implemented at scale

To assess how outcomes associated with participation in a family-based weight management intervention (MEND 7–13, Mind, Exercise, Nutrition..Do it!) for childhood overweight or obesity implemented at scale in the community vary by child, family, neighbourhood and MEND programme characteristics

The Adaptor Function of TRAPPC2 in Mammalian TRAPPs Explains TRAPPC2-Associated SEDT and TRAPPC9-Associated Congenital Intellectual Disability

Background: The TRAPP (Transport protein particle) complex is a conserved protein complex functioning at various steps in vesicle transport. Although yeast has three functionally and structurally distinct forms, TRAPPI, II and III, emerging evidence suggests that mammalian TRAPP complex may be different. Mutations in the TRAPP complex subunit 2 (TRAPPC2) cause X-linked spondyloepiphyseal dysplasia tarda, while mutations in the TRAPP complex subunit 9 (TRAPPC9) cause postnatal mental retardation with microcephaly. The structural interplay between these subunits found in mammalian equivalent of TRAPPI and those specific to TRAPPII and TRAPPIII remains largely unknown and we undertook the present study to examine the interaction between these subunits. Here, we reveal that the mammalian equivalent of the TRAPPII complex is structurally distinct from the yeast counterpart thus leading to insight into mechanism of disease. Principal Findings: We analyzed how TRAPPII- or TRAPPIII- specific subunits interact with the six-subunit core complex of TRAPP by co-immunoprecipitation in mammalian cells. TRAPPC2 binds to TRAPPII-specific subunit TRAPPC9, which in turn binds to TRAPPC10. Unexpectedly, TRAPPC2 can also bind to the putative TRAPPIII-specific subunit, TRAPPC8. Endogenous TRAPPC9-positive TRAPPII complex does not contain TRAPPC8, suggesting that TRAPPC2 binds to either TRAPPC9 or TRAPPC8 during the formation of the mammalian equivalents of TRAPPII or TRAPPIII, respectively. Therefore, TRAPPC2 serves as an adaptor for the formation of these complexes. A disease-causing mutation of TRAPPC2, D47Y, failed to interact with either TRAPPC9 or TRAPPC8, suggesting that aspartate 47 in TRAPPC2 is at or near the site of interaction with TRAPPC9 or TRAPPC8, mediating the formation of TRAPPII and/or TRAPPIII. Furthermore, disease-causing deletional mutants of TRAPPC9 all failed to interact with TRAPPC2 and TRAPPC10. Conclusions: TRAPPC2 serves as an adaptor for the formation of TRAPPII or TRAPPIII in mammalian cells. The mammalian equivalent of TRAPPII is likely different from the yeast TRAPPII structurally. © 2011 Zong et al.published_or_final_versio

Cytogerontology since 1881: A reappraisal of August Weismann and a review of modern progress

Cytogerontology, the science of cellular ageing, originated in 1881 with the prediction by August Weismann that the somatic cells of higher animals have limited division potential. Weismann's prediction was derived by considering the role of natural selection in regulating the duration of an organism's life. For various reasons, Weismann's ideas on ageing fell into neglect following his death in 1914, and cytogerontology has only reappeared as a major research area following the demonstration by Hayflick and Moorhead in the early 1960s that diploid human fibroblasts are restricted to a finite number of divisions in vitro. In this review we give a detailed account of Weismann's theory, and we reveal that his ideas were both more extensive in their scope and more pertinent to current research than is generally recognised. We also appraise the progress which has been made over the past hundred years in investigating the causes of ageing, with particular emphasis being given to (i) the evolution of ageing, and (ii) ageing at the cellular level. We critically assess the current state of knowledge in these areas and recommend a series of points as primary targets for future research

Knowledge based identification of essential signaling from genome-scale siRNA experiments

<p>Abstract</p> <p>Background</p> <p>A systems biology interpretation of genome-scale RNA interference (RNAi) experiments is complicated by scope, experimental variability and network signaling robustness. Over representation approaches (ORA), such as the Hypergeometric or z-score, are an established statistical framework used to associate RNA interference effectors to biologically annotated gene sets or pathways. These methods, however, do not directly take advantage of our growing understanding of the interactome. Furthermore, these methods can miss partial pathway activation and may be biased by protein complexes. Here we present a novel ORA, protein interaction permutation analysis (PIPA), that takes advantage of canonical pathways and established protein interactions to identify pathways enriched for protein interactions connecting RNAi hits.</p> <p>Results</p> <p>We use PIPA to analyze genome-scale siRNA cell growth screens performed in HeLa and TOV cell lines. First we show that interacting gene pair siRNA hits are more reproducible than single gene hits. Using protein interactions, PIPA identifies enriched pathways not found using the standard Hypergeometric analysis including the FAK <it>cytoskeletal remodeling pathway</it>. Different branches of the <it>FAK </it>pathway are distinctly essential in HeLa versus TOV cell lines while other portions are uneffected by siRNA perturbations. Enriched hits belong to protein interactions associated with cell cycle regulation, anti-apoptosis, and signal transduction.</p> <p>Conclusion</p> <p>PIPA provides an analytical framework to interpret siRNA screen data by merging biologically annotated gene sets with the human interactome. As a result we identify pathways and signaling hypotheses that are statistically enriched to effect cell growth in human cell lines. This method provides a complementary approach to standard gene set enrichment that utilizes the additional knowledge of specific interactions within biological gene sets. </p