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https://www.readbyqxmd.com/read/29446724/inhibitors-of-er-aminopeptidase-1-and-2-from-design-to-clinical-application
#1
Dimitris Georgiadis, Anastasia Mpakali, Despoina Koumantou, Efstratios Stratikos
Endoplasmic Reticulum aminopeptidase 1 and 2 are two homologous enzymes that help generate peptide ligands for presentation by Major Histocompatibility Class I molecules. Their enzymatic activity influences the antigenic peptide repertoire and indirectly controls adaptive immune responses. Accumulating evidence suggests that these two enzymes are tractable targets for the regulation of immune responses with possible applications ranging from cancer immunotherapy to treating inflammatory autoimmune disease. Here, we review the state-of-the-art in the development of inhibitors of ERAP1 and ERAP2 as well as their potential and limitations for clinical applications...
February 13, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29441692/a-conservation-planning-tool-for-greater-sage-grouse-using-indices-of-species-distribution-resilience-and-resistance
#2
Mark A Ricca, Peter S Coates, K Benjamin Gustafson, Brianne E Brussee, Jeanne C Chambers, Shawn P Espinosa, Scott C Gardner, Sherri Lisius, Pilar Ziegler, David J Delehanty, Michael L Casazza
Managers require quantitative yet tractable tools that can identify areas for restoration yielding effective benefits for targeted wildlife species and the ecosystems they inhabit. As a contemporary example of high national significance for conservation, the persistence of greater sage-grouse (Centrocercus urophasianus, hereafter 'sage-grouse') in the Great Basin ecoregion is compromised, in part, by strongly interacting stressors of conifer encroachment, annual grass invasion, and larger and more frequent wildfires occurring in sagebrush ecosystems...
February 14, 2018: Ecological Applications: a Publication of the Ecological Society of America
https://www.readbyqxmd.com/read/29438671/the-structure-of-the-biofilm-controlling-response-regulator-bfmr-from-acinetobacter-baumannii-reveals-details-of-its-dna-binding-mechanism
#3
G Logan Draughn, Morgan E Milton, Erik A Feldmann, Benjamin G Bobay, Braden M Roth, Andrew L Olson, Richele J Thompson, Luis A Actis, Christopher Davies, John Cavanagh
The rise of drug-resistant bacterial infections coupled with decreasing antibiotic efficacy poses a significant challenge to global healthcare. Acinetobacter baumannii is an insidious, emerging bacterial pathogen responsible for severe nosocomial infections aided by its ability to form biofilms. The response regulator BfmR, from the BfmR/S two-component system, is the master regulator of biofilm initiation in A. baumannii and is a tractable therapeutic target. Here we present the structure of A. baumannii BfmR using a hybrid approach combining X-ray crystallography, nuclear magnetic resonance spectroscopy, chemical crosslinking mass spectrometry, and molecular modeling...
February 10, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29434668/quantitative-trait-loci-for-cell-wall-composition-traits-measured-using-near-infrared-spectroscopy-in-the-model-c4-perennial-grass-panicum-hallii
#4
Elizabeth R Milano, Courtney E Payne, Ed Wolfrum, John Lovell, Jerry Jenkins, Jeremy Schmutz, Thomas E Juenger
Background: Biofuels derived from lignocellulosic plant material are an important component of current renewable energy strategies. Improvement efforts in biofuel feedstock crops have been primarily focused on increasing biomass yield with less consideration for tissue quality or composition. Four primary components found in the plant cell wall contribute to the overall quality of plant tissue and conversion characteristics, cellulose and hemicellulose polysaccharides are the primary targets for fuel conversion, while lignin and ash provide structure and defense...
2018: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/29432245/evaluation-of-the-child-with-developmental-impairments
#5
Clara D M van Karnebeek
PURPOSE OF REVIEW: This article discusses the diagnostic evaluation of intellectual developmental disorder, comprising global developmental delay and intellectual disability in children. RECENT FINDINGS: With a prevalence of 1% to 3% and substantial comorbidity, high lifetime costs, and emotional burden, intellectual developmental disorder is characterized by limitations in both intellectual functioning (IQ less than 70) and adaptive behavior starting before 18 years of age...
February 2018: Continuum: Lifelong Learning in Neurology
https://www.readbyqxmd.com/read/29426225/%C3%AF-2r-tmem97-binding-ligands-reduce-age-dependent-neurodegeneration-in-c-elegans-sc_app-model-using-a-high-content-microfluidic-screening-platform
#6
Sudip Mondal, Evan Hegarty, James J Sahn, Luisa L Scott, Sertan K Gökçe, Christopher Martin, Navid Ghorashian, Praveen Navoda Satarasinghe, Sangeetha Iyer, Wisath Sae-Lee, Timothy Hodges, Jonathan T Pierce, Stephen F Martin, Adela Ben-Yakar
The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently we developed a model of amyloid precursor protein-induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons...
February 9, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29411967/drosophila-as-a-model-system-for-neurotransmitter-measurements
#7
Mimi Shin, Jeffrey M Copeland, B Jill Venton
Drosophila melanogaster, the fruit fly, is an important, simple model organism for studying the effects of genetic mutations on neuronal activity and behavior. Biologists use Drosophila for neuroscience studies because of its genetic tractability, complex behaviors, well-known and simple neuroanatomy, and many orthologs to human genes. Neurochemical measurements in Drosophila are challenging due to the small size of the central nervous system. Recently, methods have been developed to measure real-time neurotransmitter release and clearance in both larvae and adults using electrochemistry...
February 7, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29384054/toll-like-receptor-4-a-new-target-for-preterm-labour-pharmacotherapies
#8
Sarah A Robertson, Hanan H Wahid, Peck Yin Chin, Mark R Hutchinson, Lachlan M Moldenhauer, Jeffrey A Keelan
Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered ≤34 weeks' gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage...
January 30, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29381485/ire1%C3%AE-rnase-dependent-lipid-homeostasis-promotes-survival-in-myc-transformed-cancers
#9
Hong Xie, Chih-Hang Anthony Tang, Jun H Song, Anthony Mancuso, Juan R Del Valle, Jin Cao, Yan Xiang, Chi V Dang, Roy Lan, Danielle J Sanchez, Brian Keith, Chih-Chi Andrew Hu, M Celeste Simon
Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the IRE1α-XBP1 pathway through multiple molecular mechanisms in a variety of c-Myc- and N-Myc-dependent cancers. In particular, Myc-overexpressing cells require IRE1α-XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity...
January 30, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29374774/the-alk-receptor-in-sympathetic-neuron-development-and-neuroblastoma
#10
REVIEW
Isabelle Janoueix-Lerosey, Lucille Lopez-Delisle, Olivier Delattre, Hermann Rohrer
The ALK gene encodes a tyrosine kinase receptor characterized by an expression pattern mainly restricted to the developing central and peripheral nervous systems. In 2008, the discovery of ALK activating mutations in neuroblastoma, a tumor of the sympathetic nervous system, represented a breakthrough in the understanding of the pathogenesis of this pediatric cancer and established mutated ALK as a tractable therapeutic target for precision medicine. Subsequent studies addressed the identity of ALK ligands, as well as its physiological function in the sympathoadrenal lineage, its role in neuroblastoma development and the signaling pathways triggered by mutated ALK...
January 27, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29367405/diversity-of-internal-sensory-neuron-axon-projection-patterns-is-controlled-by-the-pou-domain-protein-pdm3-in-drosophila-larvae
#11
Cheng Sam Qian, Margarita Kaplow, Jennifer K Lee, Wesley B Grueber
Internal sensory neurons innervate body organs and provide information about internal state to the central nervous system to maintain physiological homeostasis. Despite their conservation across species, the anatomy, circuitry, and development of internal sensory systems are still relatively poorly understood. A largely unstudied population of larval Drosophila sensory neurons, termed tracheal dendrite (td) neurons, innervate internal respiratory organs and may serve as a model for understanding the sensing of internal states...
January 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29366319/molecular-toolkit-for-gene-expression-control-and-genome-modification-in-rhodococcus-opacus-pd630
#12
Drew M DeLorenzo, Austin G Rottinghaus, William R Henson, Tae Seok Moon
Rhodococcus opacus PD630 is a non-model Gram-positive bacterium that possesses desirable traits for lignocellulosic biomass conversion. In particular, it has a relatively rapid growth rate, exhibits genetic tractability, produces high quantities of lipids, and can tolerate and consume toxic lignin-derived aromatic compounds. Despite these unique, industrially relevant characteristics, R. opacus has been underutilized because of a lack of reliable genetic parts and engineering tools. In this work, we developed a molecular toolbox for reliable gene expression control and genome modification in R...
February 16, 2018: ACS Synthetic Biology
https://www.readbyqxmd.com/read/29364884/the-cost-effectiveness-of-alternative-vaccination-strategies-for-polyvalent-meningococcal-vaccines-in-burkina-faso-a-transmission-dynamic-modeling-study
#13
Reza Yaesoubi, Caroline Trotter, Caroline Colijn, Maziar Yaesoubi, Anaïs Colombini, Stephen Resch, Paul A Kristiansen, F Marc LaForce, Ted Cohen
BACKGROUND: The introduction of a conjugate vaccine for serogroup A Neisseria meningitidis has dramatically reduced disease in the African meningitis belt. In this context, important questions remain about the performance of different vaccine policies that target remaining serogroups. Here, we estimate the health impact and cost associated with several alternative vaccination policies in Burkina Faso. METHODS AND FINDINGS: We developed and calibrated a mathematical model of meningococcal transmission to project the disability-adjusted life years (DALYs) averted and costs associated with the current Base policy (serogroup A conjugate vaccination at 9 months, as part of the Expanded Program on Immunization [EPI], plus district-specific reactive vaccination campaigns using polyvalent meningococcal polysaccharide [PMP] vaccine in response to outbreaks) and three alternative policies: (1) Base Prime: novel polyvalent meningococcal conjugate (PMC) vaccine replaces the serogroup A conjugate in EPI and is also used in reactive campaigns; (2) Prevention 1: PMC used in EPI and in a nationwide catch-up campaign for 1-18-year-olds; and (3) Prevention 2: Prevention 1, except the nationwide campaign includes individuals up to 29 years old...
January 2018: PLoS Medicine
https://www.readbyqxmd.com/read/29363766/the-role-of-autophagy-in-the-regulation-of-yeast-life-span
#14
REVIEW
Jessica K Tyler, Jay E Johnson
The goal of the aging field is to develop novel therapeutic interventions that extend human health span and reduce the burden of age-related disease. While organismal aging is a complex, multifactorial process, a popular theory is that cellular aging is a significant contributor to the progressive decline inherent to all multicellular organisms. To explore the molecular determinants that drive cellular aging, as well as how to retard them, researchers have utilized the highly genetically tractable budding yeast Saccharomyces cerevisiae...
January 24, 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29358719/investigation-of-candida-parapsilosis-virulence-regulatory-factors-during-host-pathogen-interaction
#15
Renáta Tóth, Vitor Cabral, Ernst Thuer, Flóra Bohner, Tibor Németh, Csaba Papp, Leonardo Nimrichter, Gergő Molnár, Csaba Vágvölgyi, Toni Gabaldón, Joshua D Nosanchuk, Attila Gácser
Invasive candidiasis is among the most life-threatening infections in patients in intensive care units. Although Candida albicans is the leading cause of candidaemia, the incidence of Candida parapsilosis infections is also rising, particularly among the neonates. Due to differences in their biology, these species employ different antifungal resistance and virulence mechanisms and also induce dissimilar immune responses. Previously, it has been suggested that core virulence effecting transcription regulators could be attractive ligands for future antifungal drugs...
January 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29356495/the-translation-termination-factor-gspt1-is-a-phenotypically-relevant-off-target-of-heterobifunctional-phthalimide-degraders
#16
Mette Ishoey, Someth Chorn, Natesh Singh, Martin G Jaeger, Matthias Brand, Joshiawa Paulk, Sophie Bauer, Michael A Erb, Katja Parapatics, André C Müller, Keiryn L Bennett, Gerhard F Ecker, James E Bradner, Georg E Winter
Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752...
January 22, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29348631/dynamic-all-optical-drug-screening-on-cardiac-voltage-gated-ion-channels
#17
Jonas Streit, Sonja Kleinlogel
Voltage-gated ion channels (VGCs) are prime targets for the pharmaceutical industry, but drug profiling on VGCs is challenging, since drug interactions are confined to specific conformational channel states mediated by changes in transmembrane potential. Here we combined various optogenetic tools to develop dynamic, high-throughput drug profiling assays with defined light-step protocols to interrogate VGC states on a millisecond timescale. We show that such light-induced electrophysiology (LiEp) yields high-quality pharmacological data with exceptional screening windows for drugs acting on the major cardiac VGCs, including hNav1...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29324456/targeted-knockdown-of-bone-morphogenetic-protein-signaling-within-neural-progenitors-protects-the-brain-and-improves-motor-function-following-postnatal-hypoxia-ischemia
#18
Robert W Dettman, Derin Birch, Augusta Fernando, John A Kessler, Maria L V Dizon
Hypoxic-ischemic injury (HI) to the neonatal human brain results in myelin loss that, in some children, can manifest as cerebral palsy. Previously, we had found that neuronal overexpression of the bone morphogenic protein (BMP) inhibitor noggin during development increased oligodendroglia and improved motor function in an experimental model of HI utilizing unilateral common carotid artery ligation followed by hypoxia. As BMPs are known to negatively regulate oligodendroglial fate specification of neural stem cells and alter differentiation of committed oligodendroglia, BMP signaling is likely an important mechanism leading to myelin loss...
January 12, 2018: Developmental Neuroscience
https://www.readbyqxmd.com/read/29321164/kras-oncoprotein-expression-is-regulated-by-a-self-governing-eif5a-peak1-feed-forward-regulatory-loop
#19
Ken Fujimura, Huawei Wang, Felicia Watson, Richard L Klemke
There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic adenocarcinoma (PDAC) and other cancers which overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A-PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis...
January 10, 2018: Cancer Research
https://www.readbyqxmd.com/read/29320160/efforts-aimed-to-reduce-attrition-in-antimalarial-drug-discovery-a-systematic-evaluation-of-current-antimalarial-targets-portfolio
#20
María Jesus Chaparro, Felix Calderon, Pablo Castañeda, Elena Fernandez Alvaro, Raquel Gabarro, Francisco-Javier Gamo, María G Gómez-Lorenzo, Julio Martín, Esther Fernandez
Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (Artemisinin Combination Therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits...
January 10, 2018: ACS Infectious Diseases
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