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Objectives To leverage the high clinical heterogeneity of systemic lupus erythematosus (SLE), we developed and validated a new stratification scheme by integrating genome-scale transcriptomic profiles to identify patient subtypes sharing similar transcriptomic markers and drug targets. Methods A normalized compendium of transcription profiles was created from peripheral blood mononuclear cells (PBMCs) of 1046 SLE patients and 86 healthy controls (HCs), covering an intersection of 13 689 genes from six microarray datasets. Upregulated differentially expressed genes were subjected to functional and network analysis in which samples were grouped using unsupervised clustering to identify patient subtypes. Then, clustering stability was evaluated by the stratification of six integrated RNA-sequencing datasets using the same method. Finally, the Xgboost classifier was applied to the independent datasets to identify factors associated with treatment outcomes. Results Based on 278 upregulated DEGs of the transcript profiles, SLE patients were classified into three subtypes (subtype A–C) each with distinct molecular and cellular signatures. Neutrophil activation-related pathways were markedly activated in subtype A (named NE-driving), whereas lymphocyte and IFN-related pathways were more enriched in subtype B (IFN-driving). As the most severe subtype, subtype C [NE-IFN-dual-driving (Dual-driving)] shared functional mechanisms with both NE-driving and IFN-driving, which was closely associated with clinical features and could be used to predict the responses of treatment. Conclusion We developed the largest cohesive SLE transcriptomic compendium for deep stratification using the most comprehensive microarray and RNA sequencing datasets to date. This result could guide future design of molecular diagnosis and the development of stratified therapy for SLE patients. [ABSTRACT FROM AUTHOR]

Background and Aims Ulcerative colitis [UC] is a complex heterogeneous disease. This study aims to reveal the underlying molecular features of UC using genome-scale transcriptomes of patients with UC, and to develop and validate a novel stratification scheme. Methods A normalised compendium was created using colon tissue samples (455 patients with UC and 147 healthy controls [HCs]), covering genes from 10 microarray datasets. Upregulated differentially expressed genes [DEGs] were subjected to functional network analysis, wherein samples were grouped using unsupervised clustering. Additionally, the robustness of subclustering was further assessed by two RNA sequencing datasets [100 patients with UC and 16 HCs]. Finally, the Xgboost classifier was applied to the independent datasets to evaluate the efficacy of different biologics in patients with UC. Results Based on 267 upregulated DEGs of the transcript profiles, UC patients were classified into three subtypes [subtypes A–C] with distinct molecular and cellular signatures. Epithelial activation-related pathways were significantly enriched in subtype A [named epithelial proliferation], whereas subtype C was characterised as the immune activation subtype with prominent immune cells and proinflammatory signatures. Subtype B [named mixed] was modestly activated in all the signalling pathways. Notably, subtype A showed a stronger association with the superior response of biologics such as golimumab, infliximab, vedolizumab, and ustekinumab compared with subtype C. Conclusions We conducted a deep stratification of mucosal tissue using the most comprehensive microarray and RNA sequencing data, providing critical insights into pathophysiological features of UC, which could serve as a template for stratified treatment approaches. [ABSTRACT FROM AUTHOR]

We exploit a discontinuity in the New York Stock Exchange Designated Market Maker (DMM) contract to identify causal effects of DMM participation on equilibrium market outcomes. We document that contractual features that enhance DMM participation are associated with increased depth, narrower bid-ask spreads, and higher rates of price improvement, with most of the improvements attributable to increases in liquidity provision on markets other than the NYSE. These results cannot be attributed to the mechanical effects of the contractual changes and support the interpretation that market making is characterized by strategic complementarity. Received October 7, 2017; editorial decision December 10, 2018 by Editor Itay Goldstein. [ABSTRACT FROM AUTHOR]

We examine how the relationship between competition and risk-taking changes with the ex ante bank equity capital ratio. We show that competition in the banking market, on average, mitigates risk-taking by banks. This relationship, however, can be altered by a bank's ex ante equity capital ratio. More specifically, when face with increased competition, banks with low ex ante equity capital ratios engage in relatively larger reductions in risk-taking. They do so primarily by decreasing the risk in their lending portfolios. In contrast, banks with high enough ex ante equity capital ratios might not reduce their risk-taking at all. (JEL G21, G32, O16, D40, G18) [ABSTRACT FROM AUTHOR]

Background Complement C5 mediates pro-inflammatory responses in many immune-related renal diseases. Given that the C5a level is elevated in diabetes, we investigated whether activation of C5a/C5aR signalling plays a pathogenic role in diabetic nephropathy (DN) and the therapeutic potential of C5a inhibition for renal fibrosis. Methods Human renal biopsies from patients with DN and control subjects were used for immunohistochemical staining of complement C5 components. Renal function and tubulointerstitial injury were compared between db/m mice, vehicle-treated mice and C5a inhibitor–treated db/db mice. A cell culture model of tubule epithelial cells (HK-2) was used to demonstrate the effect of C5a on the renal fibrotic pathway. Results Increased levels of C5a, but not of its receptor C5aR, were detected in renal tubules from patients with DN. The intensity of C5a staining was positively correlated with the progression of the disease. In db/db mice, administration of a novel C5a inhibitor, NOX-D21, reduced the serum triglyceride level and attenuated the upregulation of diacylglycerolacyltransferase-1 and sterol-regulatory element binding protein-1 expression and lipid accumulation in diabetic kidney. NOX-D21-treated diabetic mice also had reduced serum blood urea nitrogen and creatinine levels with less glomerular and tubulointerstitial damage. Renal transforming growth factor beta 1 (TGF-β1), fibronectin and collagen type I expressions were reduced by NOX-D21. In HK-2 cells, C5a stimulated TGF-β production through the activation of the PI3K/Akt signalling pathway. Conclusions Blockade of C5a signalling by NOX-D21 moderates altered lipid metabolism in diabetes and improved tubulointerstitial fibrosis by reduction of lipid accumulation and TGF-β-driven fibrosis in diabetic kidney. [ABSTRACT FROM AUTHOR]

In this article, we continue our study [16] on the long time dynamics of radial solutions to defocusing energy critical wave equation with a trapping radial potential in 3 + 1 dimensions. For generic radial potentials (in the topological sense), there are only finitely many steady states which might be either stable or unstable. We first observe that there can be stable excited states (i.e., a steady state which is not the ground state) if the potential is large and attractive, although all small excited states are unstable. We prove that the set of initial data for which solutions scatter to any one unstable excited state forms a finite co-dimensional connected C¹ manifold in energy space. This amounts to the construction of the global path-connected, and unique, center-stable manifold associated with, but not necessarily close to, any unstable steady state. In particular, the set of data for which solutions scatter to unstable states has empty interior in the energy space, and generic radial solutions scatter to one of the stable steady states. Our main tools are (1) near any given finite energy radial initial data (u0, u1) for which the solution u(t) scatters to some unstable steady state φ we construct a C¹ manifold containing (u0, u1) with the property that any solution starting on the manifold scatters to φ; moreover, any solution remaining near the manifold for all positive times lies on the manifold and (2) an exterior energy inequality from [9, 10, 16]. The latter is used to obtain a result in the spirit of the one-pass theorem [22], albeit with completely different techniques. [ABSTRACT FROM AUTHOR]

For unattended telescopes in Antarctic, the remote operation, autonomous observation and control are essential. An EPICS-(Experimental Physics and Industrial Control System) and RTS2-(Remote Telescope System, 2nd Version) based autonomous observation and control system with remoted operation is introduced in this paper. EPICS is a set of open source software tools, libraries and applications developed collaboratively and used worldwide to create distributed soft real-time control systems for scientific instruments while RTS2 is an open source environment for control of a fully autonomous observatory. Using the advantage of EPICS and RTS2, respectively, a combined integrated software framework for autonomous observation and control is established that use RTS2 to fulfil the function of astronomical observation and use EPICS to fulfil the device control of telescope. A command and status interface for EPICS and RTS2 is designed to make the EPICS IOC (Input/Output Controller) components integrate to RTS2 directly. For the specification and requirement of control system of telescope in Antarctic, core components named Executor and Auto-focus for autonomous observation is designed and implemented with remote operation user interface based on browser-server mode. The whole system including the telescope is tested in Lijiang Observatory in Yunnan Province for practical observation to complete the autonomous observation and control, including telescope control, camera control, dome control, weather information acquisition with the local and remote operation. [ABSTRACT FROM AUTHOR]

Using noninvasive in vivo functional magnetic resonance imaging (fMRI), we demonstrate that the enhancement of odorant response of olfactory receptor neurons by zinc nanoparticles leads to increase in activity in olfaction-related and higher order areas of the dog brain. To study conscious dogs, we employed behavioral training and optical motion tracking for reducing head motion artifacts. We obtained brain activation maps from dogs in both anesthetized state and fully conscious and unrestrained state. The enhancement effect of zinc nanoparticles was higher in conscious dogs with more activation in higher order areas as compared with anesthetized dogs. In conscious dogs, voxels in the olfactory bulb and hippocampus showed higher activity to odorants mixed with zinc nanoparticles as compared with pure odorants, odorants mixed with gold nanoparticles as well as zinc nanoparticles alone. These regions have been implicated in odor intensity processing in other species including humans. If the enhancement effect of zinc nanoparticles observed in vivo are confirmed by future behavioral studies, zinc nanoparticles may provide a way for enhancing the olfactory sensitivity of canines for detection of target substances such as explosives and contraband substances at very low concentrations, which would otherwise go undetected. [ABSTRACT FROM AUTHOR]

The DNA damage response helps to maintain genome integrity, suppress tumorigenesis, and mediate the effects of radiotherapy and chemotherapy. Our previous studies have shown that Smad1 is upregulated and activated by Atm in DNA damage response, which can further bind to p53 and promote p53 stabilization. Here we report another aspect of the interplay between p53 and Smad1. Comparison of rectal tumor against paired paraneoplastic specimens and analysis of >500 colorectal tumors revealed that Smad1 was upregulated in tumor samples, which was attributable to p53 defects. Using MEFs as a model, we found that knockdown of the elevated Smad1 in p53 -/- MEFs promoted cell proliferation, E1A/Ras-induced cell transformation, and tumorigenesis. Mechanistic studies suggest that elevated Smad1 and momentary activation inhibit cell proliferation by upregulating p57Kip2 and enhancing Atm-Chk2 activation. Surprisingly, elevated Smad1 appears to have a negative effect on chemotherapy, as colorectal tumors, primary cancer cells, and cell lines with Smad1 knockdown all showed an increase in chemosensitivity, which could be attributable to elevated p57Kip2. These findings underscore the significance of Smad1-p53 interaction in tumor suppression and reveal an unexpected role for Smad1 in chemoresistance of colorectal cancers. [ABSTRACT FROM AUTHOR]

The article offers a study to define awareness, control of hypertension in adults in Southwest China and to investigate relevant personal characteristics, antihypertensive drug use among patients with hypertension. Topics include data from a population-based high-risk cardiovascular screening study was collected; and concluded that Hypertension awareness, treatment, and control in community-dwelling residents are poor, and the proportion of drug combination therapy is low in Southwest China.

Abstract: Background: Triple valve surgery (TVS) is still of choice for advanced rheumatic heart disease (RHD), which has been associated with reported poor early and late outcomes. We describe the short- and long-term results after TVS in last two decades in Mainland China. Methods: From January 1985 to January 2005, a total of 871 patients (217 men, 654 women), with mean age of 42±11 years, underwent primary TVS for isolated advanced RHD. All patients received replacement procedures in mitral and aortic position (845 mechanical, 26 bioprosthetic), and 840 patients received repair procedures and the other 31 received replacement procedures in tricuspid position (9 mechanical, 22 bioprosthetic). Preoperative, perioperative, and postoperative data were retrospectively analyzed and risk factors affecting early and late survival were evaluated. Results: The 30-day hospital mortality was 8% (n =71). Presence of ascites, New York Heart Association (NYHA) class IV and lower left ventricular ejection fraction (LVEF) were identified as independent risk factors for hospital mortality. Overall long-term survival rate was 71%±3% at 5 years, and 59%±5% at 10 years. The cardiac survival rate was 75%±3% at 5 years and 63%±4% at 10 years. The event-free survival rate at 5 years and 10 years was 61%±6% and 41%±13%, respectively. Multivariate analysis revealed advanced age, NYHA class IV and lower LVEF were associated with increased late mortality. The freedom from thromboembolism and anticoagulation-related hemorrhage at 10 years was 90%±4% and 81%±5%, respectively. Of the 508 patients still alive, 376 (74%) were in NYHA class I and II. Conclusions: Primary TVS for advanced RHD appears to offer satisfactory short- and long-term results with excellent symptomatic improvement. Cardiac-related late mortality following TVS may be improved by early surgical treatment before NYHA class IV or deterioration of LVEF occurs. [Copyright &y& Elsevier]