bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells
Authors: Gay Lauren A. , Sethuraman Sunantha , Thomas Merin , Turner Peter C. , Renne Rolf 
Published: January 2018

ABSTRACT
Kaposi's sarcoma (KS) tumors are derived from endothelial cells and express Kaposi's sarcoma-associated herpesvirus (KSHV) microRNAs (miRNAs). Although miRNA targets have been identified in B cell lymphoma-derived cells and epithelial cells, little has been done to characterize the KSHV miRNA targetome in endothelial cells. A recent innovation in the identification of miRNA targetomes, cross-linking, ligation, and sequencing of hybrids (CLASH), unambiguously identifies miRNAs and their targets by ligating the two species while both species are still bound within the RNA-induced silencing complex (RISC). We developed a streamlined quick CLASH (qCLASH) protocol that requires a lower cell input than the original method and therefore has the potential to be used on patient biopsy samples. Additionally, we developed a fast-growing, KSHV-negative endothelial cell line derived from telomerase-immortalized vein endothelial long-term culture (TIVE-LTC) cells. qCLASH was performed on uninfected cells and cells infected with either wild-type KSHV or a mutant virus lacking miR-K12-11/11*. More than 1,400 cellular targets of KSHV miRNAs were identified. Many of the targets identified by qCLASH lacked a canonical seed sequence match. Additionally, most target regions in mRNAs originated from the coding DNA sequence (CDS) rather than the 3′ untranslated region (UTR). This set of genes includes some that were previously identified in B cells and some new genes that warrant further study. Pathway analysis of endothelial cell targets showed enrichment in cell cycle control, apoptosis, and glycolysis pathways, among others. Characterization of these new targets and the functional consequences of their repression will be important in furthering our understanding of the role of KSHV miRNAs in oncogenesis.

IMPORTANCE
KS lesions consist of endothelial cells latently infected with KSHV. Cells that make up these lesions express KSHV miRNAs. Identification of the targets of KSHV miRNAs will help us understand their role in viral oncogenesis. The cross-linking and sequencing of hybrids (CLASH) protocol is a method for unambiguously identifying miRNA targetomes. We developed a streamlined version of CLASH, called quick CLASH (qCLASH). qCLASH requires a lower initial input of cells than for its parent protocol. Additionally, a new fast-growing KSHV-negative endothelial cell line, named TIVE-EX-LTC cells, was established. qCLASH was performed on TIVE-EX-LTC cells latently infected with wild-type (WT) KSHV or a mutant virus lacking miR-K12-11/11*. A number of novel targets of KSHV miRNAs were identified, including targets of miR-K12-11, the ortholog of the cellular oncogenic miRNA (oncomiR) miR-155. Many of the miRNA targets were involved in processes related to oncogenesis, such as glycolysis, apoptosis, and cell cycle control.
Efficacy of additional topical betamethasone in persistent cystoid macular oedema after carbonic anhydrase inhibitor treatments in retinitis pigmentosa
Authors: Kitahata Shohei , Hirami Yasuhiko , Takagi Seiji , Kime Cody , Fujihara Masashi , Kurimoto Yasuo , Takahashi Masayo 
Published: January 2018

ObjectiveWe investigated the efficacy of additional topical betamethasone in persistent cystoid macular oedema (CMO) after carbonic anhydrase inhibitors (CAIs) therapy.Methods and analysisThis retrospective cohort study included 16 eyes of 10 patients with retinitis pigmentosa (RP). All patients were previously administered CAI for at least 3 months to treat CMO secondary to RP and lacking an effective reduction (≥11%) of central foveal thickness (CFT). We administered topical 0.1% betamethasone daily in each affected eye following a preceding course of the CAI medication as a first treatment. CMO was diagnosed using spectral-domain optical coherence tomography. CFT was regarded as the average of vertical and horizontal foveal thickness. Best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were obtained from patient medical records. We compared the CFT and BCVA between baseline and the average of 1–3, 5–7, 10–14 and 16–20 months period.ResultsIn treatments with brinzolamide in 14 eyes, dorzolamide in 2 eyes and bromfenac in 2 eyes, CFT effectively decreased in 12 of 16 eyes (81%). CFT decreased significantly in 1–3 months (326±102 µm; n=16; P=0.029) and 5–7 months (297±102 µm; n=12; P=0.022) compared with baseline but not within 10–14 months (271±96 µm; n=9; P=0.485) or 16–20 months (281±134 µm; n=9; P=0.289). There were no significant intergroup differences in BCVA throughout the study. Betamethasone treatment was stopped in three patients because of IOP elevation.ConclusionOur data suggested that additional betamethasone might improve treatments for persistent CMO. Topical steroids could be an alternative option for managing persistent CMO in RP.
What drives UK military personnel to seek mental healthcare, work strain or something else?
Authors: Jones Norman , Coetzee R 
Published: January 2018

BackgroundThe numbers of UK military personnel referred to military departments of community mental health (DCMH) have increased annually over recent years; the reasons for such an increase are unclear.MethodData for this study were derived from 549 DCMH attendees and 3682 serving regular military personnel. DCMH attendees completed a checklist of potential reasons for help-seeking. Cohort members provided data on perceived mental health problems and help-seeking from specialist mental health services. Both samples provided work strain and basic sociodemographic data. Work strain levels were compared among cohort and DCMH help seekers and non-help seekers using adjusted logistic regression analyses.ResultsPerceiving that mental health-related stigmatisation had reduced and being prompted to seek help by attending a health promotion event were among the least frequent reasons for seeking help in DCMH attendees. Realising that help was needed and being urged to seek help by one’s partner, friends or family were the most common. Working very hard and experiencing excessive work were the most common work strain factors. Overall, the greatest levels of work strain were found among DCMH attendees. In all subsamples, work strain was significantly associated with experiencing a perceived mental health problem irrespective of whether help was sought or not.ConclusionWork strain was significantly associated with experiencing a stressful, emotional, mental health or alcohol problem and was the highest among current DCMH help seekers. Recognising that help was required and being prompted by a significant other were the main drivers for help-seeking among DCMH attendees.
Minimum Cell Connection in Line Segment Arrangements
Authors: Alt Helmut , Cabello Sergio , Giannopoulos Panos , Knauer Christian 
Published: January 2018

We study the complexity of the following cell connection problems in segment arrangements. Given a set of straight-line segments in the plane and two points [Formula: see text] and [Formula: see text] in different cells of the induced arrangement: [(i)] compute the minimum number of segments one needs to remove so that there is a path connecting [Formula: see text] to [Formula: see text] that does not intersect any of the remaining segments; [(ii)] compute the minimum number of segments one needs to remove so that the arrangement induced by the remaining segments has a single cell. We show that problems (i) and (ii) are NP-hard and discuss some special, tractable cases. Most notably, we provide a near-linear-time algorithm for a variant of problem (i) where the path connecting [Formula: see text] to [Formula: see text] must stay inside a given polygon [Formula: see text] with a constant number of holes, the segments are contained in [Formula: see text], and the endpoints of the segments are on the boundary of [Formula: see text]. The approach for this latter result uses homotopy of paths to group the segments into clusters with the property that either all segments in a cluster or none participate in an optimal solution.
Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma
Authors: Groß Anja , Schulz Catrine , Kolb Jasmine , Koster Jan , Wehner Sibylle , Czaplinski Sebastian , Khilan Abdulghani , Rohrer Hermann , Harter Patrick N. , Klingebiel Thomas , Langer Julian D. , Geerts Dirk , Schulte Dorothea 
Published: January 2018

Abstract
Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.
Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935–47. ©2018 AACR.
Discovery of Potent and Selective MRCK Inhibitors with Therapeutic Effect on Skin Cancer
Authors: Unbekandt Mathieu , Belshaw Simone , Bower Justin , Clarke Maeve , Cordes Jacqueline , Crighton Diane , Croft Daniel R. , Drysdale Martin J. , Garnett Mathew J. , Gill Kathryn , Gray Christopher , Greenhalgh David A. , Hall James A.M. , Konczal Jennifer , Lilla Sergio , McArthur Duncan , McConnell Patricia , McDonald Laura , McGarry Lynn , McKinnon Heather , McMenemy Carol , Mezna Mokdad , Morrice Nicolas A. , Munro June , Naylor Gregory , Rath Nicola , Schüttelkopf Alexander W. , Sime Mairi , Olson Michael F. 
Published: January 2018

Abstract
The myotonic dystrophy–related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin–myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here, we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphologic changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent antiproliferative effects with greatest activity in hematologic cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.
Significance: The development of selective small-molecule inhibitors of the Cdc42-binding MRCK kinases reveals their essential roles in cancer cell viability, migration, and invasive character. Cancer Res; 78(8); 2096–114. ©2018 AACR.
Dethroning the Fano Factor: A Flexible, Model-Based Approach to Partitioning Neural Variability
Authors: Charles Adam S. , Park Mijung , Weller J. Patrick , Horwitz Gregory D. , Pillow Jonathan W. 
Published: January 2018

Neurons in many brain areas exhibit high trial-to-trial variability, with spike counts that are overdispersed relative to a Poisson distribution. Recent work (Goris, Movshon, & Simoncelli, 2014 ) has proposed to explain this variability in terms of a multiplicative interaction between a stochastic gain variable and a stimulus-dependent Poisson firing rate, which produces quadratic relationships between spike count mean and variance. Here we examine this quadratic assumption and propose a more flexible family of models that can account for a more diverse set of mean-variance relationships. Our model contains additive gaussian noise that is transformed nonlinearly to produce a Poisson spike rate. Different choices of the nonlinear function can give rise to qualitatively different mean-variance relationships, ranging from sublinear to linear to quadratic. Intriguingly, a rectified squaring nonlinearity produces a linear mean-variance function, corresponding to responses with a constant Fano factor. We describe a computationally efficient method for fitting this model to data and demonstrate that a majority of neurons in a V1 population are better described by a model with a nonquadratic relationship between mean and variance. Finally, we demonstrate a practical use of our model via an application to Bayesian adaptive stimulus selection in closed-loop neurophysiology experiments, which shows that accounting for overdispersion can lead to dramatic improvements in adaptive tuning curve estimation.
On the Development of the Critique of Political Economy as a Critical Social Theory of Economic Objectivity
Authors: O’Kane Chris 
Published: January 2018

AbstractThis review-essay assays Werner Bonefeld’s timely attempt to unite contemporary critical theory with the critique of political economy. I begin by contextualising Bonefeld’s contribution in relation to the dearth of material on this issue in contemporary anglophone critical theory. I then discuss the anglophone reception of Adornian critical theory and provide an overview of the development of the subterranean critical-theoretical interpretations of the critique of political economy that Adorno influenced which have been occluded by the former. This sets up my discussion of how Bonefeld has taken up, criticised and developed this subterranean strand in critical theory and the critique of political economy. I close with some criticisms of how Bonefeld addresses the relationship between critical theory and the critique of political economy and point toward several areas of further investigation that are intended to extend this approach to the contemporary critical theory of society.
Shared Water Resources in West Africa
Authors: Odili Nwamaka Chigozie 
Published: January 2018

AbstractSince the adoption of the General Act of Berlin in 1885, which dealt,inter alia, with the Niger River, more agreements have been contracted for the management of some of the shared watercourses in West Africa, particularly in the post-colonial era. Although only six out of its numerous shared watercourses are regulated by legal instruments, West Africa contributed through these agreements to the development of international water prior to the adoption of theunWatercourses and theuneceWater Conventions in the 1990s. Initial instruments dealt primarily with navigation, while later agreements addressed the need for co-operation and incorporated other principles of customary international water law. The two conventions have, no doubt, influenced this trend, raising the question of whether riparian states in West Africa need to be parties to either or both water conventions to enhance management, sharing, and protections of their shared watercourses.
Statistical Prediction of Waterspout Probability for the Florida Keys
Authors: Devanas Andrew , Stefanova Lydia 
Published: January 2018

Abstract
A statistical model of waterspout probability was developed for wet-season (June–September) days over the Florida Keys. An analysis was performed on over 200 separate variables derived from Key West 1200 UTC daily wet-season soundings during the period 2006–14. These variables were separated into two subsets: days on which a waterspout was reported anywhere in the Florida Keys coastal waters and days on which no waterspouts were reported. Days on which waterspouts were reported were determined from the National Weather Service (NWS) Key West local storm reports. The sounding at Key West was used for this analysis since it was assumed to be representative of the atmospheric environment over the area evaluated in this study. The probability of a waterspout report day was modeled using multiple logistic regression with selected predictors obtained from the sounding variables. The final model containing eight separate variables was validated using repeated fivefold cross validation, and its performance was compared to that of an existing waterspout index used as a benchmark. The performance of the model was further validated in forecast mode using an independent verification wet-season dataset from 2015–16 that was not used to define or train the model. The eight-predictor model was found to produce a probability forecast with robust skill relative to climatology and superior to the benchmark waterspout index in both the cross validation and in the independent verification.
Early animal model evaluation of an implantable contrast agent to enhance magnetic resonance imaging of arterial bypass vein grafts
Authors: Mitsouras Dimitrios , Tao Ming , de Vries Margreet R , Trocha Kaspar , Miranda Oscar R , Vemula Praveen Kumar , Ding Kui , Imanzadeh Amir , Schoen Frederick J , Karp Jeffrey M , Ozaki C Keith , Rybicki Frank J 
Published: January 2018

Background Non-invasive monitoring of autologous vein graft (VG) bypass grafts is largely limited to detecting late luminal narrowing. Although magnetic resonance imaging (MRI) delineates vein graft intima, media, and adventitia, which may detect early failure, the scan time required to achieve sufficient resolution is at present impractical. Purpose To study VG visualization enhancement in vivo and delineate whether a covalently attached MRI contrast agent would enable quicker longitudinal imaging of the VG wall. Material and Methods Sixteen 12-week-old male C57BL/6J mice underwent carotid interposition vein grafting. The inferior vena cava of nine donor mice was treated with a gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based contrast agent, with control VGs labeled with a vehicle. T1-weighted (T1W) MRI was performed serially at postoperative weeks 1, 4, 12, and 20. A portion of animals was sacrificed for histopathology following each imaging time point. Results MRI signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher for treated VGs in the first three time points (1.73 × higher SNR, P = 0.0006, and 5.83 × higher CNR at the first time point, P = 0.0006). However, MRI signal enhancement decreased consistently in the study period, to 1.29 × higher SNR and 2.64 × higher CNR, by the final time point. There were no apparent differences in graft morphometric analyses in Masson’s trichrome-stained sections. Conclusion A MRI contrast agent that binds covalently to the VG wall provides significant increase in T1W MRI signal with no observed adverse effects in a mouse model. Further optimization of the contrast agent to enhance its durability is required.
Against the stream: Antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants
Authors: Moncrieff Joanna 
Published: January 2018

SummaryAlthough antidepressants are regarded as effective and specific treatments, they are barely superior to placebo in randomised trials, and differences are unlikely to be clinically relevant. The conventional disease-centred understanding of drug action regards antidepressants as targeting an underlying brain process, but an alternative ‘drug-centred’ view suggests they are psychoactive substances that modify normal mental states and behaviour. These alterations, such as numbing of emotions, may reduce feelings of depression, and also create amplified placebo effects in randomised trials. Patients should be informed that there is no evidence that antidepressants work by correcting a chemical imbalance, that antidepressants have mind-altering effects, and that evidence suggests they produce no noticeable benefit compared with placebo.Declaration of interestThe author is co-chairperson of the Critical Psychiatry Network.
Weekday and seasonal patterns in psychiatric referrals in three major London A&E departments, 2012–2014
Authors: Dove James , Mistry Amit , Werbeloff Nomi , Osborn David , Turjanski Nora 
Published: January 2018

Aims and methodTo identify temporal and demographic trends in referrals made to psychiatric liaison services. Routine clinical data from 16 105 individual referrals from three central London accident and emergency (A&E) departments to psychiatric liaison services from 2012 to 2014 were obtained and analysed using the Clinical Record Interactive Search (CRIS).ResultsReferrals from A&E to psychiatric liaison services increased 16% over the 3-year study period. There were fewer referrals to psychiatric liaison services in winter months compared with other seasons. There were fewer referrals to psychiatric liaison services over the weekend compared with weekdays (average 15.4 daily weekday referrals v. 13.2 weekend, z = 5.1, P < 0.001), and weekend referrals were slightly less likely to result in admission to psychiatric hospital (11.3% v. 12.8%, respectively, χ2 = 6.33, P = 0.01).Clinical implicationsPsychiatric staffing in A&E and inpatient psychiatric wards requires planning to meet temporal and regional variations in the pattern of demand.Declaration of interestNone.
Qualitative systematic review of barriers and facilitators to patient-involved antipsychotic prescribing
Authors: Pedley Rebecca , McWilliams Caitlin , Lovell Karina , Brooks Helen , Rushton Kelly , Drake Richard J. , Rumbold Barnaby , Bell Vicky , Bee Penny 
Published: January 2018

BackgroundDespite policy and practice mandates for patient involvement, people with serious mental illness often feel marginalised in decisions about antipsychotic medication.AimsTo examine stakeholder perspectives of barriers and facilitators to involving people with serious mental illness in antipsychotic prescribing decisions.MethodSystematic thematic synthesis.ResultsSynthesis of 29 studies identified the following key influences on involvement: patient's capability, desire and expectation for involvement, organisational context, and the consultation setting and processes.ConclusionsOptimal patient involvement in antipsychotic decisions demands that individual and contextual barriers are addressed. There was divergence in perceived barriers to involvement identified by patients and prescribers. For example, patients felt that lack of time in consultations was a barrier to involvement, something seldom raised by prescribers, who identified organisational barriers. Patients must understand their rights to involvement and the value of their expertise. Organisational initiatives should mandate prescriber responsibility to overcome barriers to involvement.Declaration of interestNone.