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https://www.readbyqxmd.com/read/29235363/phenotypic-screening-approaches-for-chagas-disease-drug-discovery
#1
Eric Chatelain, Jean-Robert Ioset
Introduction- Chagas disease, caused by the parasite Trypanosoma cruzi, is a global public health issue. Current treatments targeting the parasite are limited to two old nitroheterocyclic drugs with serious side effects. The need for new and safer drugs has prompted numerous drug discovery efforts to identify compounds suitable for parasitological cure in the last decade. Areas covered- Target-based drug discovery has been limited by the small number of well validated targets - the latest example being the failure of azoles, T...
December 13, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29232215/pulmonary-tumor-thrombotic-microangiopathy-case-report-and-review-of-literature
#2
Josh Curtis Hutchinson, James W Fulcher, Jeff Hanna, Michael E Ward
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare rapidly progressive fatal disease that is difficult to diagnosis antemortem. Activation of the coagulation cascade and fibrocellular intimal thickening caused by embolism of tumor cells into pulmonary vasculature leads to extensive pulmonary hypertension and eventually death. We describe a case of PTTM with association of a presumed lung adenocarcinoma primary. Although rare in nature, PTTM should be a considered diagnosis with chronic dyspnea of unknown origin, severe pulmonary hypertension coupled with right-side heart failure, in the absence of pulmonary embolism...
December 11, 2017: American Journal of Forensic Medicine and Pathology
https://www.readbyqxmd.com/read/29225802/effective-immunosuppressive-management-with-belatacept-and-eculizumab-in-post-transplant-ahus-due-to-a-homozygous-deletion-of-cfhr1-cfhr3-and-the-presence-of-cfh-antibodies
#3
Johannes Münch, Anette Bachmann, Maik Grohmann, Christof Mayer, Michael Kirschfink, Tom H Lindner, Carsten Bergmann, Jan Halbritter
Atypical haemolytic uraemic syndrome (aHUS) may clinically present as acute renal graft failure resulting from excessive activation of the complement cascade. While mutations of complement-encoding genes predispose for aHUS, it is generally thought to require an additional insult (e.g. drugs) to trigger and manifest the full-blown clinical syndrome. Calcineurin inhibitors (CNIs) used for immunosuppression act as potential triggers, especially in the post-transplantation setting. Therefore, CNI-free immunosuppressive regimens may be beneficial...
December 2017: Clinical Kidney Journal
https://www.readbyqxmd.com/read/29211014/lipopolysaccharide-induced-nitric-oxide-prostaglandin-e2-and-cytokine-production-of-mouse-and-human-macrophages-are-suppressed-by-pheophytin-b
#4
Chun-Yu Lin, Wen-Hung Wang, Shin-Huei Chen, Yu-Wei Chang, Ling-Chien Hung, Chung-Yi Chen, Yen-Hsu Chen
Sepsis is an overwhelming systemic response to infection that frequently results in tissue damage, organ failure, and even death. Nitric oxide (NO), prostaglandin E2 (PGE2), and cytokine overproduction are thought to be associated with the immunostimulatory cascade in sepsis. In the present study, we analyzed the anti-inflammatory efficacy of the pheophytin-b on both RAW 264.7 murine macrophage and purified human CD14⁺ monocytes stimulated with lipopolysaccharide (LPS) and elucidated the mechanisms by analyzing the cell signaling pathways known to be activated in sepsis...
December 6, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29210631/uterine-function-from-normal-to-polycystic-ovarian-syndrome-alterations
#5
Silvana Rocio Ferreira, Alicia Beatriz Motta
BACKGROUND: The endometrium is one of the most important female reproductive organs. Polycystic ovarian syndrome (PCOS) is a reproductive and endocrine pathology that affect women of reproductive age. PCOS negatively affects the endometrium, leading to implantation failure and proliferative aberrations. METHODS: We conducted a search at the http://www.ncbi.nlm.nhi.gov/pubmed/electronic database using the following key words: endometrial steroid receptors, endometrium, uterine function, endometrium and PCOS, implantation window, implantation and PCOS, implantation markers, inflammation, oxidative stress...
December 5, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29196654/cascading-collapse-of-online-social-networks
#6
János Török, János Kertész
Online social networks have increasing influence on our society, they may play decisive roles in politics and can be crucial for the fate of companies. Such services compete with each other and some may even break down rapidly. Using social network datasets we show the main factors leading to such a dramatic collapse. At early stage mostly the loosely bound users disappear, later collective effects play the main role leading to cascading failures. We present a theory based on a generalised threshold model to explain the findings and show how the collapse time can be estimated in advance using the dynamics of the churning users...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29177767/membrane-aging-as-the-real-culprit-of-alzheimer-s-disease-modification-of-a-hypothesis
#7
REVIEW
Qiujian Yu, Chunjiu Zhong
Our previous studies proposed that Alzheimer's disease (AD) is a metabolic disorder and hypothesized that abnormal brain glucose metabolism inducing multiple pathophysiological cascades contributes to AD pathogenesis. Aging is one of the great significant risk factors for AD. Membrane aging is first prone to affect the function and structure of the brain by impairing glucose metabolism. We presume that risk factors of AD, including genetic factors (e.g., the apolipoprotein E ε4 allele and genetic mutations) and non-genetic factors (such as fat, diabetes, and cardiac failure) accelerate biomembrane aging and lead to the onset and development of the disease...
November 24, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/29173808/epigenetic-and-microenvironmental-alterations-in-bone-marrow-associated-with-ros-in-experimental-aplastic-anemia
#8
Ritam Chatterjee, Sujata Law
Aplastic anemia or bone marrow failure often develops as an effect of chemotherapeutic drug application for the treatment of various pathophysiological conditions including cancer. The long-term bone marrow injury affects the basic hematopoietic population including hematopoietic stem/progenitor cells (HSPCs). The present study aimed in unearthing the underlying mechanisms of chemotherapeutics mediated bone marrow aplasia with special focus on altered redox status and associated effects on hematopoietic microenvironment and epigenetic status of hematopoietic cells...
November 22, 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/29171478/-enteral-failure-and-metabolic-syndrome-common-neurohormonal-mechanisms-of-development-possibilities-of-their-rational-therapy
#9
Ya M Vakhrushev, M V Lyapina
The paper deals with small bowel (SB) functional disorders in metabolic syndrome (MS). The main components of a cascade of metabolic abnormalities in MS are closely due to SB functional changes. This is associated to some extent with the presence of common neurohormonal mechanisms in the development of enteropathy and MS. The paper gives the physical, laboratory and instrumental methods for identifying SB dysfunctions in patients with MS. Therapy for the latter is of particular interest in the context of SB functional recovery...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/29161832/a-simple-model-of-hiv-epidemic-in-italy-the-role-of-the-antiretroviral-treatment
#10
Federico Papa, Francesca Binda, Giovanni Felici, Marco Franzetti, Alberto Gandolfi, Carmela Sinisgalli, Claudia Balotta
In the present paper we propose a simple time-varying ODE model to describe the evolution of HIV epidemic in Italy. The model considers a single population of susceptibles, without distinction of high-risk groups within the general population, and accounts for the presence of immigration and emigration, modelling their effects on both the general demography and the dynamics of the infected subpopulations. To represent the intra-host disease progression, the untreated infected population is distributed over four compartments in cascade according to the CD4 counts...
February 1, 2018: Mathematical Biosciences and Engineering: MBE
https://www.readbyqxmd.com/read/29154687/pyruvate-enhancement-of-cardiac-performance-cellular-mechanisms-and-clinical-application
#11
Robert T Mallet, Albert H Olivencia-Yurvati, Rolf Bünger
Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/29150840/longitudinal-pathways-between-mental-health-difficulties-and-academic-performance-during-middle-childhood-and-early-adolescence
#12
Jessica Deighton, Neil Humphrey, Jay Belsky, Jan Boehnke, Panos Vostanis, Praveetha Patalay
There is a growing appreciation that child functioning in different domains, levels, or systems are interrelated over time. Here, we investigate links between internalizing symptoms, externalizing problems, and academic attainment during middle childhood and early adolescence, drawing on two large data sets (child: mean age 8.7 at enrolment, n = 5,878; adolescent: mean age 11.7, n = 6,388). Using a 2-year cross-lag design, we test three hypotheses - adjustment erosion, academic incompetence, and shared risk - while also examining the moderating influence of gender...
November 18, 2017: British Journal of Developmental Psychology
https://www.readbyqxmd.com/read/29148534/genetic-testing-of-complement-and-coagulation-pathways-in-patients-with-severe-hypertension-and-renal-microangiopathy
#13
Christopher P Larsen, Jon D Wilson, Alejandro Best-Rocha, Marjorie L Beggs, Randolph A Hennigar
A diagnosis of thrombotic microangiopathy on kidney biopsy in a patient presenting with hypertensive emergency has historically elicited the diagnosis of malignant hypertension-associated thrombotic microangiopathy. Recent studies, however, have raised awareness that a number of these patients may actually represent atypical hemolytic uremic syndrome. To further investigate this premise, we performed next-generation sequencing to interrogate the coding regions of 29 complement and coagulation cascade genes associated with atypical hemolytic uremic syndrome in 100 non-elderly patients presenting with severe hypertension, renal failure and a kidney biopsy showing microangiopathic changes limited to the classic accelerated hypertension-associated lesion of arterial intimal edema ('mucoid intimal hyperplasia') in isolation and without accompanying glomerular microthrombi...
November 17, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29148236/emerging-roles-of-er-stress-in-the-aetiology-and-pathogenesis-of-alzheimer-s-disease
#14
REVIEW
Yannis Gerakis, Claudio Hetz
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synaptic dysfunction and accumulation of abnormal aggregates formed by amyloid-β peptides or phophorylated Tau proteins. Accumulating evidence suggests that alterations in the buffering capacity of the proteostasis network is a salient feature of AD. The endoplasmic reticulum (ER) is the main compartment involved in protein folding and secretion and is drastically affected in AD neurons. ER stress triggers the activation of the Unfolded Protein Response (UPR), a signal transduction pathway that enforces adaptive programs to recover homeostasis or trigger apoptosis of irreversibly damaged cells...
November 17, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29146792/curtailing-cascading-failures
#15
Raissa M D'Souza
No abstract text is available yet for this article.
November 17, 2017: Science
https://www.readbyqxmd.com/read/29146778/small-vulnerable-sets-determine-large-network-cascades-in-power-grids
#16
Yang Yang, Takashi Nishikawa, Adilson E Motter
The understanding of cascading failures in complex systems has been hindered by the lack of realistic large-scale modeling and analysis that can account for variable system conditions. Using the North American power grid, we identified, quantified, and analyzed the set of network components that are vulnerable to cascading failures under any out of multiple conditions. We show that the vulnerable set consists of a small but topologically central portion of the network and that large cascades are disproportionately more likely to be triggered by initial failures close to this set...
November 17, 2017: Science
https://www.readbyqxmd.com/read/29141899/atypical-g-protein-%C3%AE-5-promotes-cardiac-oxidative-stress-apoptosis-and-fibrotic-remodeling-in-response-to-multiple-cancer-chemotherapeutics
#17
Biswanath Maity, Sreemoyee Chakraborti, Arnab Pramanick, Sudipta Saha, Somnath Singha Roy, Arnab Ray Chaudhuri, Madhusudan Das, Sujoy Ghosh, Adele Stewart
The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. We report here that, though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gβ5 in the myocardium, correlating with oxidative stress, myocyte apoptosis, and the accumulation of pro-inflammatory and pro-fibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII pro-apoptotic signaling cascades...
November 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/29138863/therapeutic-effect-of-ulinastatin-on-pulmonary-fibrosis-via-downregulation-of-tgf%C3%A2-%C3%AE-1-tnf%C3%A2-%C3%AE-and-nf%C3%A2-%C3%AE%C2%BAb
#18
Dejun Li, Hongsheng Ji, Bao Zhao, Chunyang Xu, Wenjun Xia, Lihui Han, Dongqing Yu, Yuanrong Ju, Changjun Jin
Pulmonary fibrosis is a chronic, progressive, lethal lung disease characterized by alveolar cell necrosis and dysplasia of interstitial fibrotic tissue, resulting in loss of lung function and eventual respiratory failure. Previously, glucocorticoid drugs were used to treat this lung disorder. However, positive responses were recorded in less than half of treated patients and the cytotoxicity caused by high dosage treatment is still a concern. The present study investigated whether ulinastatin, a typical urinary trypsin inhibitor that mitigates numerous inflammatory responses, could be a treatment option for lung fibrosis...
November 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29130601/scaling-up-hiv-viral-load-lessons-from-the-large-scale-implementation-of-hiv-early-infant-diagnosis-and-cd4-testing
#19
Trevor Peter, Clement Zeh, Zachary Katz, Ali Elbireer, Bereket Alemayehu, Lara Vojnov, Alex Costa, Naoko Doi, Ilesh Jani
INTRODUCTION: The scale-up of effective HIV viral load (VL) testing is an urgent public health priority. Implementation of testing is supported by the availability of accurate, nucleic acid based laboratory and point-of-care (POC) VL technologies and strong WHO guidance recommending routine testing to identify treatment failure. However, test implementation faces challenges related to the developing health systems in many low-resource countries. The purpose of this commentary is to review the challenges and solutions from the large-scale implementation of other diagnostic tests, namely nucleic-acid based early infant HIV diagnosis (EID) and CD4 testing, and identify key lessons to inform the scale-up of VL...
November 2017: Journal of the International AIDS Society
https://www.readbyqxmd.com/read/29118418/cascading-failures-in-interdependent-networks-with-multiple-supply-demand-links-and-functionality-thresholds
#20
M A Di Muro, L D Valdez, H H Aragão Rêgo, S V Buldyrev, H E Stanley, L A Braunstein
Various social, financial, biological and technological systems can be modeled by interdependent networks. It has been assumed that in order to remain functional, nodes in one network must receive the support from nodes belonging to different networks. So far these models have been limited to the case in which the failure propagates across networks only if the nodes lose all their supply nodes. In this paper we develop a more realistic model for two interdependent networks in which each node has its own supply threshold, i...
November 8, 2017: Scientific Reports
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