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https://www.readbyqxmd.com/read/28637242/yap-and-wwtr1-regulate-the-expression-of-sex-determining-genes-in-sertoli-cells-but-their-inactivation-does-not-cause-sex-reversal
#1
Adrien Levasseur, Marilène Paquet, Derek Boerboom, Alexandre Boyer
Yes-associated protein (YAP) and WW containing transcription regulator 1 (WWTR1) are two functionally redundant transcriptional regulators that are downstream effectors of the Hippo signaling pathway, and that act as major regulators of cell growth and differentiation. To elucidate their role in Sertoli cells, primary Sertoli cell culture from Yapflox/flox; Wwtr1flox/flox animals were infected with a Cre recombinase-expressing adenovirus. Concomitant inactivation of Yap and Wwtr1 resulted in a decrease in the mRNA levels of the male sex differentiation genes Dhh, Dmrt1, Sox9 and Wt1, whereas those of genes involved in female differentiation (Wnt4, Rspo1 and Foxl2) were induced...
June 16, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28637199/first-ex-vivo-and-preliminary-sheep-model-results-of-the-new-tribio-aortic-valve-bioprosthesis-in-small-aortic-annuli
#2
Sina Stock, Hans-Hinrich Sievers, Doreen Richardt, Michael Scharfschwerdt
OBJECTIVES: : Small aortic annuli are challenging in aortic valve replacement. Prosthesis-patient mismatch, accompanied by high transvalvular gradients and small orifice area, is an often faced problem impairing postoperative outcome. The new TRIBIO bioprosthesis aims to enable enhanced haemodynamics, being increasingly important with decreasing annular size. This study compares ex vivo hydrodynamics of TRIBIO with 2 established bioprostheses in small annuli at different stroke volumes, simulating 'rest' and 'exercise', and evaluates haemodynamics of TRIBIO in a sheep model...
June 20, 2017: Interactive Cardiovascular and Thoracic Surgery
https://www.readbyqxmd.com/read/28636992/acetylsalicylic-acid-inhibits-the-growth-of-melanoma-tumors-via-sox2-dependent-paf-r-independent-signaling-pathway
#3
Anita Thyagarajan, Jeremiah Saylae, Ravi P Sahu
Acquired resistance to standard therapies remains a serious challenge, requiring novel therapeutic approaches that incorporate potential factors involved in tumor resistance. As cancers including melanoma express inflammatory cyclooxygenases generating prostaglandins implicated in tumor growth, we investigated mechanism of anti-inflammatory drug, acetylsalicylic acid (ASA) which has been shown to inhibit various tumor types, however, its effects against highly aggressive melanoma model are unclear. Given our reports that an activation of platelet-activating factor-receptor (PAF-R) augments the growth and impede efficacies of therapeutic agents in experimental melanoma, we also sought to determine if PAF-R mediates anti-melanoma activity of ASA...
June 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636932/ubiquitination-linked-phosphorylation-of-the-fanci-s-tq-cluster-contributes-to-activation-of-the-fanconi-anemia-i-d2-complex
#4
Ronald S Cheung, Maria Castella, Antonio Abeyta, Philip R Gafken, Nyka Tucker, Toshiyasu Taniguchi
Repair of interstrand crosslinks by the Fanconi anemia (FA) pathway requires both monoubiquitination and de-ubiquitination of the FANCI/FANCD2 (FANCI/D2) complex. In the standing model, the phosphorylation of six sites in the FANCI S/TQ cluster domain occurs upstream of, and promotes, FANCI/D2 monoubiquitination. We generated phospho-specific antibodies against three different S/TQ cluster sites (serines 556, 559, and 565) on human FANCI and found that, in contrast to the standing model, distinct FANCI sites were phosphorylated either predominantly upstream (ubiquitination independent; serine 556) or downstream (ubiquitination-linked; serines 559 and 565) of FANCI/D2 monoubiquitination...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28636924/epithelial-folding-driven-by-apical-or-basal-lateral-modulation-geometric-features-mechanical-inference-and-boundary-effects
#5
Fu-Lai Wen, Yu-Chiun Wang, Tatsuo Shibata
During embryonic development, epithelial sheets fold into complex structures required for tissue and organ functions. Although substantial efforts have been devoted to identifying molecular mechanisms underlying epithelial folding, far less is understood about how forces deform individual cells to sculpt the overall sheet morphology. Here we describe a simple and general theoretical model for the autonomous folding of monolayered epithelial sheets. We show that active modulation of intracellular mechanics along the basal-lateral as well as the apical surfaces is capable of inducing fold formation in the absence of buckling instability...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636912/channeling-of-camp-in-pde-pka-complexes-promotes-signal-adaptation
#6
Nikhil Kumar Tulsian, Srinath Krishnamurthy, Ganesh Srinivasan Anand
Spatiotemporal control of the cAMP signaling pathway is governed by both hormonal stimulation of cAMP generation by adenylyl cyclases (activation phase) and cAMP hydrolysis by phosphodiesterases (PDEs) (termination phase). The termination phase is initiated by PDEs actively targeting the protein kinase A (PKA) R-subunit through formation of a PDE-PKAR-cyclic adenosine monophosphate (cAMP) complex (the termination complex). Our results using PDE8 as a model PDE, reveal that PDEs mediate active hydrolysis of cAMP bound to its receptor RIα by enhancing the enzymatic activity...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636876/tissue-alignment-enhances-remodeling-potential-of-tendon-derived-cells-lessons-from-a-novel-microtissue-model-of-tendon-scarring
#7
Jasper Foolen, Stefania L Wunderli, Sandra Loerakker, Jess G Snedeker
Tendinopathy is a widespread and unresolved clinical challenge, in which associated pain and hampered mobility present a major cause for work-related disability. Tendinopathy associates with a change from a healthy tissue with aligned extracellular matrix (ECM) and highly polarized cells that are connected head-to-tail, towards a diseased tissue with a disorganized ECM and randomly distributed cells, scar-like features that are commonly attributed to poor innate regenerative capacity of the tissue. A fundamental clinical dilemma with this scarring process is whether treatment strategies should focus on healing the affected (disorganized) tissue or strengthen the remaining healthy (anisotropic) tissue...
June 18, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/28636654/characterization-of-human-fcrl4-positive-b-cells
#8
Michel Jourdan, Nicolas Robert, Maïlys Cren, Coraline Thibaut, Christophe Duperray, Alboukadel Kassambara, Michel Cogné, Karin Tarte, Bernard Klein, Jérôme Moreaux
FCRL4 is an immunoregulatory receptor that belongs to the Fc receptor-like (FCRL) family. In healthy individuals, FCRL4 is specifically expressed by memory B cells (MBCs) localized in sub-epithelial regions of lymphoid tissues. Expansion of FCRL4+ B cells has been observed in blood and other tissues in various infectious and autoimmune disorders. Currently, the mechanisms involved in pathological FCRL4+ B cell generation are actively studied, but they remain elusive. As in vivo FCRL4+ cells are difficult to access and to isolate, here we developed a culture system to generate in vitro FCRL4+ B cells from purified MBCs upon stimulation with soluble CD40 ligand and/or CpG DNA to mimic T-cell dependent and/or T-cell independent activation, respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28636592/quantifiable-predictive-features-define-epitope-specific-t-cell-receptor-repertoires
#9
Pradyot Dash, Andrew J Fiore-Gartland, Tomer Hertz, George C Wang, Shalini Sharma, Aisha Souquette, Jeremy Chase Crawford, E Bridie Clemens, Thi H O Nguyen, Katherine Kedzierska, Nicole L La Gruta, Philip Bradley, Paul G Thomas
T cells are defined by a heterodimeric surface receptor, the T cell receptor (TCR), that mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs). TCRs are generated by genomic rearrangement of the germline TCR locus, a process termed V(D)J recombination, that has the potential to generate marked diversity of TCRs (estimated to range from 10(15) (ref. 1) to as high as 10(61) (ref. 2) possible receptors). Despite this potential diversity, TCRs from T cells that recognize the same pMHC epitope often share conserved sequence features, suggesting that it may be possible to predictively model epitope specificity...
June 21, 2017: Nature
https://www.readbyqxmd.com/read/28636533/microrna-149-suppresses-hepatic-inflammatory-response-through-antagonizing-stat3-signaling-pathway
#10
Qiqi Zhang, Jia Su, Ziwei Wang, Hui Qi, Zeyong Ge, Zhijun Li, Wei-Dong Chen, Yan-Dong Wang
Chronic inflammation is increasingly recognized as an important component of tumorigenesis and metabolic diseases. The roles of microRNA149* (miRNA149*) in inflammation remain poorly understood. Here, we demonstrate that miR-149* is a suppressor of STAT3-mediated inflammation. MiR-149*-/- mice were generated with CRISPR/CAS9 technique. In a lipopolysaccharide (LPS)-induced inflammation model, miR-149*-/- mice show more severe liver injury and inflammation, compared with wild-type (WT) mice. MiR-149*-/- mice also displayed elevated messenger RNA (mRNA) levels of interleukin (IL)-6, inducible nitric oxide synthase (iNOS), complement C3 (C3) and IL-4 in response to LPS...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636491/atherosclerosis-induced-by-a-high-cholesterol-and-high-fat-diet-in-the-inbred-strain-of-the-wuzhishan-miniature-pig
#11
Yuqiong Zhao, Lei Xiang, Yaqian Liu, Miaomiao Niu, Jifang Yuan, Hua Chen
Coronary artery disease has a significant genetic predisposition, which mainly results from atherosclerosis. Miniature pig is an excellent model to investigate atherosclerosis. This study investigated whether the occurrence and development of atherosclerosis in the Wuzhishan miniature pigs (WZSPs) that were closely bred 12 generations had better consistency. The WZSPs (n = 9) were fed a high-cholesterol and high-fat diet (HCFD). After continuous feeding, 3 WZSPs each were sacrificed at 6, 8, and 12 months, respectively, and the general clinical manifestations and serological indexes were detected...
June 21, 2017: Animal Biotechnology
https://www.readbyqxmd.com/read/28636361/a-machine-learning-assisted-approach-for-discovering-novel-inhibitors-targeting-bromodomain-containing-protein-4
#12
Jing Xing, Wenchao Lu, Rongfeng Liu, Yulan Wang, Yiqian Xie, Hao Zhang, Zhe Shi, Hao Jiang, Yu-Chih Liu, Kaixian Chen, Hualiang Jiang, Cheng Luo, Mingyue Zheng
Bromodomain-containing protein 4 (BRD4) is implicated in the pathogenesis of a number of different cancers, inflammatory diseases and heart failure. Much effort has been dedicated toward discovering novel scaffold BRD4 inhibitors (BRD4is) with different selectivity profiles and potential anti-resistance properties. Structure-based drug design (SBDD) and virtual screening (VS) are the most frequently used approaches. Here, we demonstrate a novel, structure-based VS approach that uses machine-learning algorithms trained on the priori structure and activity knowledge to predict the likelihood that a compound is a BRD4i based on its binding pattern with BRD4...
June 21, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28636358/transferable-atom-centered-potentials-for-the-correction-of-basis-set-incompleteness-errors-in-density-functional-theory
#13
Alberto Otero-de-la-Roza, Gino A DiLabio
Recent progress in the accurate calculation of non-covalent interactions has enabled density-functional theory (DFT) to model systems relevant in biological and supramolecular chemistry. The application of DFT methods using atom-centered Gaussian basis sets to large systems is limited by the number of basis functions required to accurately model thermochemistry and, in particular, weak intermolecular interactions. Basis-set incompleteness error (BSIE) arising from the use of incomplete basis sets leads to erroneous intermolecular energies, bond dissociation energies, and structures...
June 21, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28636354/rational-design-of-lithium-sulfur-battery-cathodes-based-on-experimentally-determined-maximum-active-material-thickness
#14
Michael J Klein, Gabriel M Veith, Arumugam Manthiram
Rational design of conductive carbon hosts for high energy density lithium-sulfur batteries requires an understanding of the fundamental limitations to insulating active material loading. In this work, we investigate the electrochemistry of lithium sulfide films ranging in thickness from 30 to 3500 nm. We show that films thicker than approximately 40 nm cannot be charged at local charge densities above 1 μA cm-2, and by implication, the maximum useful pore diameter is near 60 nm in a practical cathode. 'Activation' overpotentials for Li2S are identified in thicker films, resulting from polysulfide generation, but are shown not to improve the fundamental areal charge limitations...
June 21, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28636338/contributions-of-local-farming-to-urban-sustainability-in-the-northeast-united-states
#15
Benjamin P Goldstein, Michael Z Hauschild, John E Fernández, Morten Birkved
Food consumption is an important contributor to a city's environmental impacts (carbon emissions, land occupation, water use, etc.) Urban farming (UF) has been advocated as a means to increase urban sustainability by reducing food-related transport and tapping into local resources. Taking Boston as an illustrative Northeast U.S. city, we developed a novel method to estimate sub-urban, food-borne carbon and land footprints using multiregion-input-output modeling and nutritional surveys. Computer simulations utilizing primary data explored UF's ability to reduce these footprints using select farming technologies, building on previous city-scale UF assessments which have hitherto been dependent on proxy data for UF...
June 21, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#16
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28636276/covariate-selection-with-group-lasso-and-doubly-robust-estimation-of-causal-effects
#17
Brandon Koch, David M Vock, Julian Wolfson
The efficiency of doubly robust estimators of the average causal effect (ACE) of a treatment can be improved by including in the treatment and outcome models only those covariates which are related to both treatment and outcome (i.e., confounders) or related only to the outcome. However, it is often challenging to identify such covariates among the large number that may be measured in a given study. In this article, we propose GLiDeR (Group Lasso and Doubly Robust Estimation), a novel variable selection technique for identifying confounders and predictors of outcome using an adaptive group lasso approach that simultaneously performs coefficient selection, regularization, and estimation across the treatment and outcome models...
June 21, 2017: Biometrics
https://www.readbyqxmd.com/read/28635362/costs-and-effectiveness-of-fingolimod-versus-alemtuzumab-in-the-treatment-of-highly-active-relapsing-remitting-multiple-sclerosis-in-the-uk-retreatment-discount-and-disutility
#18
Stephen M Montgomery, Jeanette Kusel, Richard Nicholas, Nicholas Adlard
OBJECTIVE: Patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease modifying therapies (DMTs) who continue to experience disease activity may be considered for escalation therapies such as fingolimod or may be considered for alemtuzumab. Previous economic modelling used Markov models; applying one alternative technique, discrete event simulation (DES) modelling, allows retreatment and long-term adverse events (AEs) to be included in the analysis. METHODS: A DES was adapted to model relapse-triggered retreatment with alemtuzumab and the effect of including ongoing quality-adjusted life year (QALY) decrements for AEs that extend beyond previous one year Markov cycles...
June 21, 2017: Journal of Medical Economics
https://www.readbyqxmd.com/read/28635300/pyridine-dinucleotides-from-molecules-to-man
#19
Joshua P Fessel, William M Oldham
SIGNIFICANCE: Pyridine dinucleotides, NAD and NADP, were discovered over 100 years ago as necessary cofactors for fermentation in yeast extracts. Since that time, these molecules have been recognized as fundamental players in a variety of cellular processes, including energy metabolism, redox homeostasis, cellular signaling, and gene transcription, among many others. Given their critical role as mediators of cellular responses to metabolic perturbations, it is unsurprising that dysregulation of NAD and NADP metabolism has been associated with the pathobiology of many chronic human diseases...
June 21, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28635291/fractal-model-for-wettability-of-rough-surfaces
#20
Rahul Jain, Ranga Pitchumani
This paper presents a fractal model to describe wettability on multiscale randomly rough surfaces. Hydrophobic or superhydrophobic surfaces produced using processes such as electrodeposition and etching lead to the creation of random roughness at multiple length scales on the surface. This paper considers the description of such surfaces with a fractal asperity model based on the Weierstrass-Mandelbrot (W-M) function, where the fractal parameters are uniquely determined from a power spectrum of the surface...
June 21, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
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