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https://www.readbyqxmd.com/read/28633205/advancing-the-science-of-myocardial-recovery-with-mechanical-circulatory-support-a-working-group-of-the-national-heart-lung-and-blood-institute
#1
EDITORIAL
Stavros G Drakos, Francis D Pagani, Martha S Lundberg, Timothy J Baldwin
The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts from June 2 to 3, 2016, in Bethesda, Maryland, to develop NHLBI recommendations aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MCS devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling...
July 2017: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/28630153/membrane-spanning-%C3%AE-helical-barrels-as-tractable-protein-design-targets
#2
REVIEW
Ai Niitsu, Jack W Heal, Kerstin Fauland, Andrew R Thomson, Derek N Woolfson
The rational (de novo) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of 'scaffolds' for protein design, and the means to garner sequence-to-structure relationships to guide the design process...
August 5, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28624514/bromodomain-containing-proteins-in-prostate-cancer
#3
REVIEW
Alfonso Urbanucci, Ian G Mills
Several oncogenic factors have been involved in prostate cancer progression. However, therapeutic approaches still focus on suppression of androgen receptor (AR) signaling. In fact, whereas the full-length AR incorporates a ligand-binding domain, which has become a drug target for competitive inhibitors, other transcription factors often do not have tractable binding pockets that aid drug development. Consequently drug development efforts have turned to transcription co-regulators, often chromatin-modifying enzymes or factors that bind to epigenetic modifications to chromatin...
June 14, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28619757/cdk4-6-inhibitors-sensitize-rb-positive-sarcoma-cells-to-wee1-kinase-inhibition-through-reversible-cell-cycle-arrest
#4
Ashleigh M Francis, Angela Alexander, Yanna Liu, Smruthi Vijayaraghavan, Kwang Hui Low, Dong Yang, Tuyen Bui, Neeta Somaiah, Vinod Ravi, Khandan Keyomarsi, Kelly K Hunt
Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28574981/a-motor-unit-based-model-of-muscle-fatigue
#5
Jim R Potvin, Andrew J Fuglevand
Muscle fatigue is a temporary decline in the force and power capacity of skeletal muscle resulting from muscle activity. Because control of muscle is realized at the level of the motor unit (MU), it seems important to consider the physiological properties of motor units when attempting to understand and predict muscle fatigue. Therefore, we developed a phenomenological model of motor unit fatigue as a tractable means to predict muscle fatigue for a variety of tasks and to illustrate the individual contractile responses of MUs whose collective action determines the trajectory of changes in muscle force capacity during prolonged activity...
June 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28560482/integrated-in-silico-fragment-based-drug-design-case-study-with-allosteric-modulators-on-metabotropic-glutamate-receptor-5
#6
Yuemin Bian, Zhiwei Feng, Peng Yang, Xiang-Qun Xie
GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases...
May 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28557180/targeting-g-protein-coupled-receptors-by-capture-compound-mass-spectrometry-ccms-a-case-study-with-sertindole
#7
Christian Blex, Simon Michaelis, Anna K Schrey, Jens Furkert, Jenny Eichhorst, Kathrin Bartho, Frederick G Quast, Anett Marais, Matthias Hakelberg, Uschi Gruber, Sylvia Niquet, Oliver Popp, Friedrich Kroll, Michael Sefkow, Ralf Schülein, Dreger Mathias, Hubert Köster
Unbiased chemoproteomic profiling of small molecule interactions with endogenous proteins is important for drug discovery. For meaningful results, all protein classes have to be tractable, including G-protein coupled receptors (GPCRs). These are hardly tractable by affinity pulldown from lysates. We report a Capture Compound (CC)-based strategy to target and identify GPCRs directly from living cells. We synthesized CCs with sertindole attached to the CC scaffold in different orientations to target the dopamine D2 receptor (DRD2) heterologously expressed in HEK293 cells...
May 29, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28542189/mir-277-4989-regulate-transcriptional-landscape-during-juvenile-to-adult-transition-in-the-parasitic-helminth-schistosoma-mansoni
#8
Anna V Protasio, Stijn van Dongen, Julie Collins, Leonor Quintais, Diogo M Ribeiro, Florian Sessler, Martin Hunt, Gabriel Rinaldi, James J Collins, Anton J Enright, Matthew Berriman
Schistosomes are parasitic helminths that cause schistosomiasis, a disease affecting circa 200 million people, primarily in underprivileged regions of the world. Schistosoma mansoni is the most experimentally tractable schistosome species due to its ease of propagation in the laboratory and the high quality of its genome assembly and annotation. Although there is growing interest in microRNAs (miRNAs) in trematodes, little is known about the role these molecules play in the context of developmental processes...
May 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28538159/long-term-stochastic-editing-of-regenerative-anatomy-via-targeting-endogenous-bioelectric-gradients
#9
Fallon Durant, Junji Morokuma, Christopher Fields, Katherine Williams, Dany Spencer Adams, Michael Levin
We show that regenerating planarians' normal anterior-posterior pattern can be permanently rewritten by a brief perturbation of endogenous bioelectrical networks. Temporary modulation of regenerative bioelectric dynamics in amputated trunk fragments of planaria stochastically results in a constant ratio of regenerates with two heads to regenerates with normal morphology. Remarkably, this is shown to be due not to partial penetrance of treatment, but a profound yet hidden alteration to the animals' patterning circuitry...
May 23, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28498102/chimeric-origins-of-ochrophytes-and-haptophytes-revealed-through-an-ancient-plastid-proteome
#10
Richard G Dorrell, Gillian Gile, Giselle McCallum, Raphaël Méheust, Eric P Bapteste, Christen M Klinger, Loraine Brillet-Guéguen, Katalina D Freeman, Daniel J Richter, Chris Bowler
Plastids are supported by a wide range of proteins encoded within the nucleus and imported from the cytoplasm. These plastid-targeted proteins may originate from the endosymbiont, the host, or other sources entirely. Here, we identify and characterise 770 plastid-targeted proteins that are conserved across the ochrophytes, a major group of algae including diatoms, pelagophytes and kelps, that possess plastids derived from red algae. We show that the ancestral ochrophyte plastid proteome was an evolutionary chimera, with 25% of its phylogenetically tractable nucleus-encoded proteins deriving from green algae...
May 12, 2017: ELife
https://www.readbyqxmd.com/read/28489574/targeting-neurokinin-3-receptor-a-novel-anti-angiogenesis-strategy-for-cancer-treatment
#11
Ting Wang, Siwei Chen, Shihui Wang, Liang Shi, Chenggong Wang, Jingxin Zhang, Yanfeng Gao, Guodong Li, Yuanming Qi, Xiuli An, Lixiang Chen
Angiogenesis is essential for tumor growth and metastasis, controlling angiogenesis is a promising strategy in cancer treatment. However, thus farther severe side effects of anti-angiogenic drugs have been rather demonstrated, stimulating interest in seeking novel targets of anti-angiogenesis. Neurokinin receptors, also known as tachykinin receptors, are usually considered as drug targets due to diverse physiological functions and their tractability. Although Neurokinin B, the selective natural agonist of neurokinin-3 receptor, have been shown to exhibit anti-angiogenesis activity, the effect and mechanism of neurokinin-3 receptor-mediated angiogenesis still remains unclear...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28488276/cntnap2-is-a-direct-foxp2-target-in-vitro-and-in-vivo-in-zebra-finches-complex-regulation-by-age-and-activity
#12
Iris Adam, Ezequiel Mendoza, Ursula Kobalz, Sandra Wohlgemuth, Constance Scharff
Mutations of FOXP2 are associated with altered brain structure, including the striatal part of the basal ganglia, and cause a severe speech and language disorder. Songbirds serve as a tractable neurobiological model for speech and language research. Experimental downregulation of FoxP2 in zebra finch Area X, a nucleus of the striatal song control circuitry, affects synaptic transmission and spine densities. It also renders song learning and production inaccurate and imprecise, similar to the speech impairment of patients carrying FOXP2 mutations...
May 10, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/28487472/bioinformatics-in-translational-drug-discovery
#13
Sarah K Wooller, Graeme Benstead-Hume, Xiangrong Chen, Yusuf Ali, Frances Pearl
Bioinformatics approaches are becoming ever more essential in translational drug discovery both in academia and within the pharmaceutical industry. Computational exploitation of the increasing volumes of data generated at all phases of drug discovery is enabling key challenges of the process to be addressed. Here we highlight some of the areas in which bioinformatics resources and methods are being developed to support drug discovery. These include the creation of large data warehouses, bioinformatics algorithms to analyse 'big data' that identify novel drug targets and/or biomarkers, programs to assess the tractability of targets, and the prediction of repositioning opportunities that use licensed drugs to treat additional indications...
May 9, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28486691/combined-kinase-inhibitors-of-mek1-2-and-either-pi3k-or-pdgfr-are-efficacious-in-intracranial-triple-negative-breast-cancer
#14
Amanda E D Van Swearingen, Maria J Sambade, Marni B Siegel, Shivani Sud, Robert S McNeill, Samantha M Bevill, Xin Chen, Ryan E Bash, Louisa Mounsey, Brian T Golitz, Charlene Santos, Allison Deal, Joel S Parker, Naim Rashid, C Ryan Miller, Gary L Johnson, Carey K Anders
Background: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases...
May 9, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28485964/potent-pan-raf-and-rtks-inhibitors-based-on-cyclopropyl-formamide-fragment-overcome-resistance
#15
Yanmin Zhang, Lu Wang, Qing Zhang, Gaoyuan Zhu, Zhimin Zhang, Zhou Xiang, Yadong Chen, Tao Lu, Weifang Tang
While selective BRafV600E inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of MAPK pathway. Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by cyclopropyl formamide group afforded I-01 as a novel multi-targeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and RTKs. Based on the binding mode of I-01, analogues I-02~I-18 were designed and synthesized...
May 9, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28476773/genome-stability-in-engineered-strains-of-the-extremely-thermophilic-lignocellulose-degrading-bacterium-caldicellulosiruptor-bescii
#16
Amanda M Williams-Rhaesa, Farris L Poole, Jessica T Dinsmore, Gina L Lipscomb, Gabriel M Rubinstein, Israel M Scott, Jonathan M Conway, Laura L Lee, Piyum A Khatibi, Robert M Kelly, Michael W W Adams
Caldicellulosiruptor bescii is the most thermophilic cellulose-degrader known and is of great interest because of its ability to degrade non-pretreated plant biomass. For biotechnological applications, an efficient genetic system is required to engineer it to convert plant biomass into desired products. To date, two different genetically-tractable lineages of C. bescii strains have been generated. The first (JWCB005) is based on a random deletion within the pyrimidine biosynthesis genes pyrFA, and the second (MACB1018) is based on the targeted deletion of pyrE making use of a kanamycin resistance marker...
May 5, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28471759/advancing-the-science-of-myocardial-recovery-with-mechanical-circulatory-support-a-working-group-of-the-national-heart-lung-and-blood-institute
#17
Stavros G Drakos, Francis D Pagani, Martha S Lundberg, J Timothy Baldwin
The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts from June 2 to 3, 2016, in Bethesda, Maryland, to develop NHLBI recommendations aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MCS devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling...
April 29, 2017: ASAIO Journal: a Peer-reviewed Journal of the American Society for Artificial Internal Organs
https://www.readbyqxmd.com/read/28470611/expression-of-prokaryotic-integral-membrane-proteins-in-e-coli
#18
James D Love
Production of prokaryotic membrane proteins for structural and functional studies in E. coli can be parallelized and miniaturized. All stages from cloning, expression, purification to detergent selection can be investigated using high-throughput techniques to rapidly and economically find tractable targets.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28467046/a-targeted-mass-spectrometry-assay-for-detection-of-hiv-gag-protein-following-induction-of-latent-viral-reservoirs
#19
Daniela Schlatzer, Aiman A Haqqani, Xiaolin Li, Curtis Dobrowolski, Mark R Chance, John C Tilton
During early infection, HIV-1 establishes a reservoir of latently infected cells that persist during antiretroviral therapy. These reservoirs are considered the primary obstacle to eradicating HIV-1 from patients, and multiple strategies are being investigated to eliminate latently infected cells. Measuring the reservoir size using an affordable and scalable assay is critical as these approaches move into clinical trials: the current "gold-standard" viral outgrowth assay is costly, labor-intensive, and requires large numbers of cells...
May 3, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28458126/genetic-susceptibility-to-neuroblastoma
#20
REVIEW
Vanessa P Tolbert, Grace E Coggins, John M Maris
Until recently, the genetic basis of neuroblastoma, a heterogeneous neoplasm arising from the developing sympathetic nervous system, remained undefined. The discovery of gain-of-function mutations in the ALK receptor tyrosine kinase gene as the major cause of familial neuroblastoma led to the discovery of identical somatic mutations and rapid advancement of ALK as a tractable therapeutic target. Inactivating mutations in a master regulator of neural crest development, PHOX2B, have also been identified in a subset of familial neuroblastomas...
February 2017: Current Opinion in Genetics & Development
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