Is Droxidopa Safe and Effective in Reducing Symptoms of Neurogenic Orthostatic Hypotension?

Objective: The objective of this selective EBM review is to determine whether or not droxidopa is safe and effective in reducing the symptoms of neurogenic orthostatic hypotension. Study Design: Systemic review of three English-language primary studies, conducted in 2014 or later. Data Sources: Three double-blind, randomized trials comparing the safety and efficacy of droxidopa to placebo in patients with diagnosed neurogenic orthostatic hypotension, found via PubMed in peer-reviewed journals. Outcomes Measured: Improvement of symptoms was measured utilizing patient responses to the Orthostatic Hypotension Questionnaire (OHQ), which consists of a six item Orthostatic Hypotension Symptom Assessment (OSHA) and the four item Orthostatic Hypotension Daily Activity Scale (OHDAS), each measured on a 1-10 scale. Also utilized was the patient-rated Clinical Global Impression (CGI) severity and improvement 7-point scales. Safety was measured through incidence of adverse effects during the randomized trial. Results: Biaggioni, et al, exhibited 46% of droxidopa recipients describing themselves as much or very much improved according to CGI ratings, compared to 27.5% of those receiving placebo, although with a p-score of 0.384. Hauser, et al, exhibited mean improvement in OSHA item 1 at week 1 as 2.3 for droxidopa, compared to 1.3 in the control group, with a p-value of 0.018. Kaufmann, et al, exhibited improvement of greater than 3 units in composite OHQ score in 27.2% of droxidopa recipients compared to 11.4% of placebo recipients, with a p score of 0.016. Numbers needed to harm were presented for each studied, obtained through measurement of adverse effects of experiment vs control during randomized trial, and consisted of -13 in Biaggioni, et al, 38 in Hauser, et al, and 28 in Kaufmann, et al. Conclusions: These results indicate that droxidopa showed statistical improvement in symptoms in two studies and numerical improvement in another, in addition to being relatively well tolerated. However, the difference in end points measured in each studies and inconsistencies in study design prevent any strong conclusion, and further study is required

Genome Mining of Plant NPFs Reveals Varying Conservation of Signature Motifs Associated With the Mechanism of Transport

Nitrogen is essential for all living species and may be taken up from the environment in different forms like nitrate or peptides. In plants, members of a transporter family named NPFs transport nitrate and peptides across biological membranes. NPFs are phylogenetically related to a family of peptide transporters (PTRs) or proton-coupled oligopeptide transporters (POTs) that are evolutionarily conserved in all organisms except in Archaea. POTs are present in low numbers in bacteria, algae and animals. NPFs have expanded in plants and evolved to transport a wide range of substrates including phytohormones and glucosinolates. Functional studies have shown that most NPFs, like POTs, operate as symporters with simultaneous inwardly directed movement of protons. Here we focus on four structural features of NPFs/POTs/PTRs that have been shown by structural and functional studies to be essential to proton-coupled symport transport. The first two features are implicated in proton binding and transport: a conserved motif named ExxER/K, located in the first transmembrane helix (TMH1) and a D/E residue in TMH7 that has been observed in some bacterial and algal transporters. The third and fourth features are two inter-helical salt bridges between residues on TMH1 and TMH7 or TMH4 and TMH10. To understand if the mechanism of transport is conserved in NPFs with the expansion to novel substrates, we collected NPFs sequences from 42 plant genomes. Sequence alignment revealed that the ExxER/K motif is not strictly conserved and its conservation level is different in the NPF subfamilies. The proton binding site on TMH7 is missing in all NPFs with the exception of two NPFs from moss. The two moss NPFs also have a positively charged amino acid on TMH1 that can form the salt bridge with the TMH7 negative residue. None of the other NPFs we examined harbor residues that can form the TMH1–TMH7 salt bridge. In contrast, the amino acids required to form the TMH4–TMH10 salt bridge are highly conserved in NPFs, with some exceptions. These results support the need for further biochemical and structural studies of individual NPFs for a better understanding of the transport mechanism in this family of transporters

Does discussion lead to opinion change within Political Science students? A pedagogical exercise of deliberative democracy

While the model of deliberative democracy gives a crucial role to dialog, empirical evidence has not yet established if discussion helps to reach a better understanding of political issues and, above all, if individuals are prepared to change their views. It is still unclear when the deliberative model, and more specifically discussion, could be usefully employed as a teaching tool, to improve students’ knowledge. This article presents an exercise performed within the Department of Political and Social Sciences at the LUISS University of Rome. Students were asked to discuss in the classroom the issues related to the course, and to cast a vote on selected issues before and after deliberation. Although our sample is not representative, we have gathered evidence from the same population on a rather large number of issues. Students changed their view in 24.6% of cases, and they agreed that discussion increased their understanding, while those with strong ex-ante views resulted more reluctant to change their opinions because of discussion. The analysis also showed the presence of individuals that are more likely to be permeable to discussion while others that are more likely to be impermeable

O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice

Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. Methodology/Principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-κB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKCβII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCβII, significantly reducing atherosclerosis. Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good