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https://www.readbyqxmd.com/read/29054054/conformational-analysis-of-the-human-chemokine-receptor-cxcr3
#1
Raffaele Raucci, Andrea Polo, Alfredo Budillon, Giovanni Colonna, Susan Costantini
In the last years, some studies showed the patho-genetic role of CXCR3 bound to its ligands in many human inflammatory diseases and cancers. Thus, the blockage of the CXCR3 interaction site to its ligands is seen as a possible therapeutic target for the treatment of cancer. The presence of flexible regions in the chemokine receptors determines their capability to develop specific mechanisms of action. We have recently focused on the features of the N-terminal region of human CXCR3 free in solution, where we demonstrate the presence of numerous conformational ensembles, dynamically stabilized by H-bonds...
October 17, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/29053971/a-gut-microbial-mimic-that-hijacks-diabetogenic-autoreactivity-to-suppress-colitis
#2
Roopa Hebbandi Nanjundappa, Francesca Ronchi, Jinguo Wang, Xavier Clemente-Casares, Jun Yamanouchi, Channakeshava Sokke Umeshappa, Yang Yang, Jesús Blanco, Helena Bassolas-Molina, Azucena Salas, Hamza Khan, Robyn M Slattery, Madeleine Wyss, Catherine Mooser, Andrew J Macpherson, Laura K Sycuro, Pau Serra, Derek M McKay, Kathy D McCoy, Pere Santamaria
The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut...
October 19, 2017: Cell
https://www.readbyqxmd.com/read/29053903/galectin-3-an-emerging-biomarker-in-stroke-and-cerebrovascular-diseases
#3
Anand Venkatraman, Shalaka Hardas, Nirav Patel, Navkaranbir Singh Bajaj, Garima Arora, Pankaj Arora
BACKGROUND: The carbohydrate-binding molecule Galectin-3 has garnered significant attention recently as a biomarker for various conditions ranging from cardiac disease to obesity. Though there have been several recent studies investigating its role in stroke and other cerebrovascular diseases, awareness of this emerging biomarker in the wider neurology community is limited. METHODS: We performed a systematic search in PubMed, EMBASE, Scopus, CINAHL, Clinicaltrials...
October 20, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/29053874/tau-pathology-and-neurodegeneration-contribute-to-cognitive-impairment-in-alzheimer-s-disease
#4
Alexandre Bejanin, Daniel R Schonhaut, Renaud La Joie, Joel H Kramer, Suzanne L Baker, Natasha Sosa, Nagehan Ayakta, Averill Cantwell, Mustafa Janabi, Mariella Lauriola, James P O'Neil, Maria L Gorno-Tempini, Zachary A Miller, Howard J Rosen, Bruce L Miller, William J Jagust, Gil D Rabinovici
Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35)...
October 7, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29053845/substitution-of-yor1p-nbd1-residues-improves-the-thermal-stability-of-human-cystic-fibrosis-transmembrane-conductance-regulator
#5
B M Xavier, E Hildebrandt, F Jiang, H Ding, J C Kappes, I L Urbatsch
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a plasma membrane chloride channel protein that regulates vertebrate fluid homeostasis. The inefficiency of wild type human CFTR protein folding/trafficking is exacerbated by genetic mutations that can cause protein misfolding in the endoplasmic reticulum (ER) and subsequent degradation. This project investigates small changes in protein sequence that can alter the thermal stability of the large multi-domain CFTR protein. We target a conserved 70-residue α-subdomain located in the first nucleotide-binding domain that hosts the common misfolding mutation ∆F508...
October 19, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/29053830/friedreich-s-ataxia-clinical-features-pathogenesis-and-management
#6
A Cook, P Giunti
Introduction: Friedreich's ataxia is the most common inherited ataxia. Sources of data: Literature search using PubMed with keywords Friedreich's ataxia together with published papers known to the authors. Areas of agreement: The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets...
October 19, 2017: British Medical Bulletin
https://www.readbyqxmd.com/read/29053790/the-hippo-signaling-pathway-in-pancreatic-%C3%AE-cells-functions-and-regulations
#7
Amin Ardestani, Kathrin Maedler
Hippo signaling is an evolutionarily conserved pathway that critically regulates development and homeostasis of various tissues in response to a wide range of extracellular and intracellular signals. As an emerging significant player in many diseases, the Hippo pathway is also involved in the pathophysiology of diabetes on the level of the pancreatic islets. Multiple lines of evidence uncover the importance of Hippo signaling in pancreas development as well as in the regulation of β-cell survival, proliferation and regeneration...
October 18, 2017: Endocrine Reviews
https://www.readbyqxmd.com/read/29053770/tourette-syndrome-a-disorder-of-the-social-decision-making-network
#8
Roger L Albin
Tourette syndrome is a common neurodevelopmental disorder defined by characteristic involuntary movements, tics, with both motor and phonic components. Tourette syndrome is usually conceptualized as a basal ganglia disorder, with an emphasis on striatal dysfunction. While considerable evidence is consistent with these concepts, imaging data suggest diffuse functional and structural abnormalities in Tourette syndrome brain. Tourette syndrome exhibits features that are difficult to explain solely based on basal ganglia circuit dysfunctions...
August 22, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29053743/in-vitro-modeling-of-experimental-succinic-semialdehyde-dehydrogenase-deficiency-ssadhd-using-brain-derived-neural-stem-cells
#9
Kara R Vogel, Garrett R Ainslie, Erwin E Jansen, Gajja S Salomons, Jean-Baptiste Roullet, K Michael Gibson
We explored the utility of neural stem cells (NSCs) as an in vitro model for evaluating preclinical therapeutics in succinic semialdehyde dehydrogenase-deficient (SSADHD) mice. NSCs were obtained from aldh5a1+/+ and aldh5a1-/- mice (aldh5a1 = aldehyde dehydrogenase 5a1 = SSADH). Multiple parameters were evaluated including: (1) production of GHB (γ-hydroxybutyrate), the biochemical hallmark of SSADHD; (2) rescue from cell death with the dual mTOR (mechanistic target of rapamycin) inhibitor, XL-765, an agent previously shown to rescue aldh5a1-/- mice from premature lethality; (3) mitochondrial number, total reactive oxygen species, and mitochondrial superoxide production, all previously documented as abnormal in aldh5a1-/- mice; (4) total ATP levels and ATP consumption; and (5) selected gene expression profiles associated with epilepsy, a prominent feature in both experimental and human SSADHD...
2017: PloS One
https://www.readbyqxmd.com/read/29053707/high-glucose-augments-angiotensinogen-in-human-renal-proximal-tubular-cells-through-hepatocyte-nuclear-factor-5
#10
Juan Wang, Yuki Shibayama, Hiroyuki Kobori, Ya Liu, Hideki Kobara, Tsutomu Masaki, Zhiyu Wang, Akira Nishiyama
High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5...
2017: PloS One
https://www.readbyqxmd.com/read/29053684/remotely-supervised-transcranial-direct-current-stimulation-an-update-on-safety-and-tolerability
#11
Michael T Shaw, Margaret Kasschau, Bryan Dobbs, Natalie Pawlak, William Pau, Kathleen Sherman, Marom Bikson, Abhishek Datta, Leigh E Charvet
The remotely supervised tDCS (RS-tDCS) protocol enables participation from home through guided and monitored self-administration of tDCS treatment while maintaining clinical standards. The current consensus regarding the efficacy of tDCS is that multiple treatment sessions are needed to observe targeted behavioral reductions in symptom burden. However, the requirement for patients to travel to clinic daily for stimulation sessions presents a major obstacle for potential participants, due to work or family obligations or limited ability to travel...
October 7, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29053676/laminotomy-for-lumbar-dorsal-root-ganglion-access-and-injection-in-swine
#12
Mark D Unger, Timothy P Maus, Ross C Puffer, Laura K Newman, Bradford L Currier, Andreas S Beutler
Dorsal root ganglia (DRG) are anatomically well defined structures that contain all primary sensory neurons below the head. This fact makes DRG attractive targets for injection of novel therapeutics aimed at treating chronic pain. In small animal models, laminectomy has been used to facilitate DRG injection because it involves surgical removal of the vertebral bone surrounding each DRG. We demonstrate a technique for intraganglionic injection of lumbar DRG in a large animal species, namely, swine. Laminotomy is performed to allow direct access to DRG using standard neurosurgical techniques, instruments, and materials...
October 10, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29053603/clinical-and-genetic-evaluation-of-a-cohort-of-pediatric-patients-with-severe-inherited-retinal-dystrophies
#13
Valentina Di Iorio, Marianthi Karali, Raffaella Brunetti-Pierri, Mariaelena Filippelli, Giuseppina Di Fruscio, Mariateresa Pizzo, Margherita Mutarelli, Vincenzo Nigro, Francesco Testa, Sandro Banfi, Francesca Simonelli
We performed a clinical and genetic characterization of a pediatric cohort of patients with inherited retinal dystrophy (IRD) to identify the most suitable cases for gene therapy. The cohort comprised 43 patients, aged between 2 and 18 years, with severe isolated IRD at the time of presentation. The ophthalmological characterization also included assessment of the photoreceptor layer integrity in the macular region (ellipsoid zone (EZ) band). In parallel, we carried out a targeted, next-generation sequencing (NGS)-based analysis using a panel that covers over 150 genes with either an established or a candidate role in IRD pathogenesis...
October 20, 2017: Genes
https://www.readbyqxmd.com/read/29053596/elucidating-the-role-of-host-long-non-coding-rna-during-viral-infection-challenges-and-paths-forward
#14
REVIEW
David J Lemler, Hayden N Brochu, Fang Yang, Erin A Harrell, Xinxia Peng
Research over the past decade has clearly shown that long non-coding RNAs (lncRNAs) are functional. Many lncRNAs can be related to immunity and the host response to viral infection, but their specific functions remain largely elusive. The vast majority of lncRNAs are annotated with extremely limited knowledge and tend to be expressed at low levels, making ad hoc experimentation difficult. Changes to lncRNA expression during infection can be systematically profiled using deep sequencing; however, this often produces an intractable number of candidate lncRNAs, leaving no clear path forward...
October 20, 2017: Vaccines
https://www.readbyqxmd.com/read/29053592/platelets-and-multi-organ-failure-in-sepsis
#15
REVIEW
Elisabetta Greco, Enrico Lupia, Ornella Bosco, Barbara Vizio, Giuseppe Montrucchio
Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis...
October 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29053481/programmed-death-ligand-1-expression-among-700-consecutive-endometrial-cancers-strong-association-with-mismatch-repair-protein-deficiency
#16
Zaibo Li, Amy S Joehlin-Price, Jennifer Rhoades, Martins Ayoola-Adeola, Karin Miller, Anil V Parwani, Floor J Backes, Ashley S Felix, Adrian A Suarez
OBJECTIVE: This study aims to determine the prevalence of programmed death ligand 1 (PD-L1) expression in endometrial carcinoma (EC) and determine clinical and pathological associations. METHODS: Immunohistochemistry for PD-L1 was performed on sections of a triple-core tissue microarray of 700 ECs. Positive PD-L1 expression, defined as 1% of cells staining positive, was evaluated in tumor and stromal compartments. Using age-adjusted logistic regression, we estimated odds ratios and 95% confidence intervals for associations between PD-L1 expression (overall and by staining compartment) with clinical and tumor characteristics...
October 20, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/29053277/utilizing-inverse-emulsion-polymerization-to-generate-responsive-nanogels-for-cytosolic-protein-delivery
#17
Kishore Raghupathi, Scott J Eron, Francesca Anson, Jeanne A Hardy, S Thayumanavan
Therapeutic biologics have various advantages over synthetic drugs in terms of selectivity, their catalytic nature and thus, therapeutic efficacy. These properties offer the potential for more effective treatments that may also overcome the undesirable side effects observed due to off-target toxicities of small-molecule drugs. Unfortunately, systemic administration of biologics is challenging due to cellular penetration, renal clearance and enzymatic degradation difficulties. A delivery vehicle that can overcome these challenges and deliver biologics to specific cellular populations has the potential for significant therapeutic impact...
October 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29053254/a-versatile-tool-for-the-analysis-of-metal-protein-interactions-reveals-the-promiscuity-of-metallodrug-protein-interactions
#18
Ronald Fook Seng Lee, Laure Menin, Luc Patiny, Daniel Ortiz, Paul J Dyson
Metallodrug-protein interactions contribute to their therapeutic effect (even when DNA is the dominant target), side-effects and are implicit in drug resistance. Here, we provide mass spectrometric-based evidence to show that metallodrug interactions with proteins are considerably more complex than current literature would suggest. Using native incubation and electrospray conditions together with an automated tool we designed for exhaustive mass spectra matching, the promiscuity of binding of cisplatin to ubiquitin is revealed, with 14 different binding sites observed...
October 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29053138/mir-31a-5p-promotes-postnatal-cardiomyocyte-proliferation-by-targeting-rhobtb1
#19
Junjie Xiao, Hui Liu, Dragos Cretoiu, Daniela Oana Toader, Nicolae Suciu, Jing Shi, Shutong Shen, Yihua Bei, Joost Pg Sluijter, Saumya Das, Xiangqing Kong, Xinli Li
A limited number of microRNAs (miRNAs, miRs) have been reported to control postnatal cardiomyocyte proliferation, but their strong regulatory effects suggest a possible therapeutic approach to stimulate regenerative capacity in the diseased myocardium. This study aimed to investigate the miRNAs responsible for postnatal cardiomyocyte proliferation and their downstream targets. Here, we compared miRNA profiles in cardiomyocytes between postnatal day 0 (P0) and day 10 (P10) using miRNA arrays, and found that 21 miRNAs were upregulated at P10, whereas 11 were downregulated...
October 20, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29052968/non-steroidal-estrogen-receptor-isoform-selective-biphenyls
#20
Seema Bhatnagar, Anjali Soni, Swati Kaushik, Megha Rikhi, T R Santhosh Kumar, B Jayaram
Estrogen receptor (ER) has been a therapeutic target to treat ER positive breast cancer, most notably by agents known as selective estrogen receptor modulators (SERMs). However, resistance and severe adverse effects of known drugs gave impetus to the search for newer agents with better therapeutic profile. ERα and ERβ are two isoforms sharing 56% identity, and having different physiological functions and expressions in various tissues. Only two residues differ in the active sites of the two isoforms motivating us to design isoform selective ligands...
October 20, 2017: Chemical Biology & Drug Design
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