Space Station and Space Cabin Testing

For Earth Orbiting Space Stations neither expandable, extensible, nor converted propellant tanks appear as suitable for manned operations as a specially designed cabin regardless of the mission to be performed. While an interesting possibility, use of converted propellant tanks offer little advantage when viewed in the light of the overall space station system problem. During the past two years studies have been conducted in some depth of the cabins associated with space station systems suitable for launch by Titan III C, Saturn IB, and Saturn 5 boosters. These studies have considered various crew complements, supporting ferries f and the effects of rotation for the generation of artificial G . Considering the requirements for integrating power supplies, thermal control* life support, attitude control, orbit propulsion, specific mission equipment, rendezvous, docking, communications, navigation, and crew creature comforts, the development of an efficient usable cabin becomes a task of significant proportions. Applying the constraints of removable and storable equipment to the fixed sizes and shapes of booster tankage makes the problem more difficult, the results less than optimum, and the increased cost substantial

Selective inhibitors of trypanosomal uridylyl transferase RET1 establish druggability of RNA post-transcriptional modifications.

Non-coding RNAs are crucial regulators for a vast array of cellular processes and have been implicated in human disease. These biological processes represent a hitherto untapped resource in our fight against disease. In this work we identify small molecule inhibitors of a non-coding RNA uridylylation pathway. The TUTase family of enzymes is important for modulating non-coding RNA pathways in both human cancer and pathogen systems. We demonstrate that this new class of drug target can be accessed with traditional drug discovery techniques. Using the Trypanosoma brucei TUTase, RET1, we identify TUTase inhibitors and lay the groundwork for the use of this new target class as a therapeutic opportunity for the under-served disease area of African Trypanosomiasis. In a broader sense this work demonstrates the therapeutic potential for targeting RNA post-transcriptional modifications with small molecules in human disease.This work was supported by two grants from the European Research Council (RG58558, RG67639) and a grant from Cancer Research UK (RG51661) to E.A.MThis is the author accepted manuscript. The final version is available from [publisher] via http://dx.doi.org/10.1080/15476286.2015.113742

Computational approaches for understanding the diagnosis and treatment of Parkinson's disease

This study describes how the application of evolutionary algorithms (EAs) can be used to study motor function in humans with Parkinson's disease (PD) and in animal models of PD. Human data is obtained using commercially available sensors via a range of non-invasive procedures that follow conventional clinical practice. EAs can then be used to classify human data for a range of uses, including diagnosis and disease monitoring. New results are presented that demonstrate how EAs can also be used to classify fruit flies with and without genetic mutations that cause Parkinson's by using measurements of the proboscis extension reflex. The case is made for a computational approach that can be applied across human and animal studies of PD and lays the way for evaluation of existing and new drug therapies in a truly objective way

Evaluating Depressive Symptoms in Schizophrenia: A Psychometric Comparison of the Calgary Depression Scale for Schizophrenia and the Hamilton Depression Rating Scale

Background: The aim of this study was to compare two measures of depression in patients with schizophrenia and schizophrenia spectrum disorder, including patients with delusional and schizoaffective disorder, to conclude implications for their application. Sampling and Methods: A total of 278 patients were assessed using the Calgary Depression Scale for Schizophrenia (CDSS) and the Hamilton Depression Rating Scale (HAMD-17). The Positive and Negative Syndrome Scale (PANSS) was also applied. At admission and discharge, a principal component analysis was performed with each depression scale. The two depression rating scales were furthermore compared using correlation and regression analyses. Results: Three factors were revealed for the CDSS and HAMD-17 factor component analysis. A very similar item loading was found for the CDSS at admission and discharge, whereas results of the loadings of the HAMD-17 items were less stable. The first two factors of the CDSS revealed correlations with positive, negative and general psychopathology. In contrast, multiple significant correlations were found for the HAMD-17 factors and the PANSS sub-scores. Multiple regression analyses demonstrated that the HAMD-17 accounted more for the positive and negative symptom domains than the CDSS. Conclusions:The present results suggest that compared to the HAMD-17, the CDSS is a more specific instrument to measure depressive symptoms in schizophrenia and schizophrenia spectrum disorder, especially in acutely ill patients. Copyright (c) 2012 S. Karger AG, Base

Determinants of per diem Hospital Costs in Mental Health

INTRODUCTION:An understanding of differences in hospital costs between patient groups is relevant for the efficient organisation of inpatient care. The main aim of this study was to confirm the hypothesis that eight a priori identified cost drivers influence per diem hospital costs. A second aim was to explore further variables that might influence hospital costs. METHODS:The study included 667 inpatient episodes consecutively discharged in 2014 at the psychiatric hospital of the Medical Centre-University of Freiburg. Fifty-one patient characteristics were analysed. Per diem costs were calculated from the hospital perspective based on a detailed documentation of resource use. Mixed-effects maximum likelihood regression and an ensemble of conditional inference trees were used to analyse data. RESULTS:The study confirmed the a priori hypothesis that not being of middle age (33-64 years), danger to self, involuntary admission, problems in the activities of daily living, the presence of delusional symptoms, the presence of affective symptoms, short length of stay and the discharging ward affect per diem hospital costs. A patient classification system for prospective per diem payment was suggested with the highest per diem hospital costs in episodes having both delusional symptoms and involuntary admissions and the lowest hospital costs in episodes having neither delusional symptoms nor somatic comorbidities. CONCLUSION:Although reliable cost drivers were identified, idiosyncrasies of mental health care complicated the identification of clear and consistent differences in hospital costs between patient groups. Further research could greatly inform current discussions about inpatient mental health reimbursement, in particular with multicentre studies that might find algorithms to split patients in more resource-homogeneous groups

Assessing the activity of faults in continental interiors: Palaeoseismic insights from SE Kazakhstan

The presence of fault scarps is a first-order criterion for identifying active faults. Yet the preservation of these features depends on the recurrence interval between surface rupturing events, combined with the rates of erosional and depositional processes that act on the landscape. Within arid continental interiors single earthquake scarps can be preserved for thousands of years, and yet the interval between surface ruptures on faults in these regions may be much longer, such that the lack of evidence for surface faulting in the morphology may not preclude activity on those faults. In this study we investigate the 50 km-long ‘Toraigyr’ thrust fault in the northern Tien Shan. From palaeoseismological trenching we show that two surface rupturing earthquakes occurred in the last $\textbf{39.9±2.7 ka}$ BP, but only the most recent event (3.15–3.6 ka BP) has a clear morphological expression. We conclude that a landscape reset took place in between the two events, likely as a consequence of the climatic change at the end of the last glacial maximum. These findings illustrate that in the Tien Shan evidence for the most recent active faulting can be easily obliterated by climatic processes due to the long earthquake recurrence intervals. Our results illustrate the problems related to the assessment of active tectonic deformation and seismic hazard assessments in continental interior settings.This study was financed by NERC and ESRC (Earthquakes without Frontiers project, Grant code: EwF_NE/J02001X/1_1), and the Centre for Observation and Modelling of Earthquakes and Tectonics (COMET). KOMPSAT-2 imagery was obtained through a category-1 award to RTW. EJC thanks St. Edmund Hall for travel support. RTW was supported during this research by a University Research Fellowship from the Royal Society of London

piRNAs Can Trigger a Multigenerational Epigenetic Memory in the Germline of C. elegans

SummaryTransgenerational effects have wide-ranging implications for human health, biological adaptation, and evolution; however, their mechanisms and biology remain poorly understood. Here, we demonstrate that a germline nuclear small RNA/chromatin pathway can maintain stable inheritance for many generations when triggered by a piRNA-dependent foreign RNA response in C.elegans. Using forward genetic screens and candidate approaches, we find that a core set of nuclear RNAi and chromatin factors is required for multigenerational inheritance of environmental RNAi and piRNA silencing. These include a germline-specific nuclear Argonaute HRDE1/WAGO-9, a HP1 ortholog HPL-2, and two putative histone methyltransferases, SET-25 and SET-32. piRNAs can trigger highly stable long-term silencing lasting at least 20 generations. Once established, this long-term memory becomes independent of the piRNA trigger but remains dependent on the nuclear RNAi/chromatin pathway. Our data present a multigenerational epigenetic inheritance mechanism induced by piRNAs.Graphical AbstractHighlights► Multigenerational inheritance and piRNAs converge on same nuclear silencing pathway ► HRDE1/WAGO-9 and chromatin factors required for inheritance of piRNA silencing ► piRNAs can induce multigenerational silencing for more than 20 generations. ► Long-term memory independent of piRNA triggers but remains dependent on nuclear pathwayMultigenerational inheritance and piRNAs converge on same silencing pathway, in which both nuclear WAGOs and chromatin factors are required. The piRNA trigger can be lost, but the nuclear silencing pathway maintains the silencing for more than 20 generations

ILC3 function as a double-edged sword in inflammatory bowel diseases

Inflammatory bowel diseases (IBD), composed mainly of Crohn’s disease (CD) and ulcerative colitis (UC), are strongly implicated in the development of intestinal inflammation lesions. Its exact etiology and pathogenesis are still undetermined. Recently accumulating evidence supports that group 3 innate lymphoid cells (ILC3) are responsible for gastrointestinal mucosal homeostasis through moderate generation of IL-22, IL-17, and GM-CSF in the physiological state. ILC3 contribute to the progression and aggravation of IBD while both IL-22 and IL-17, along with IFN-γ, are overexpressed by the dysregulation of NCR− ILC3 or NCR+ ILC3 function and the bias of NCR+ ILC3 towards ILC1 as well as regulatory ILC dysfunction in the pathological state. Herein, we feature the group 3 innate lymphoid cells’ development, biological function, maintenance of gut homeostasis, mediation of IBD occurrence, and potential application to IBD therapy

Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells

The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage