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https://www.readbyqxmd.com/read/28803710/intrathecal-2-hydroxypropyl-%C3%AE-cyclodextrin-decreases-neurological-disease-progression-in-niemann-pick-disease-type-c1-a-non-randomised-open-label-phase-1-2-trial
#1
Daniel S Ory, Elizabeth A Ottinger, Nicole Yanjanin Farhat, Kelly A King, Xuntian Jiang, Lisa Weissfeld, Elizabeth Berry-Kravis, Cristin D Davidson, Simona Bianconi, Lee Ann Keener, Ravichandran Rao, Ariane Soldatos, Rohini Sidhu, Kimberly A Walters, Xin Xu, Audrey Thurm, Beth Solomon, William J Pavan, Bernardus N Machielse, Mark Kao, Steven A Silber, John C McKew, Carmen C Brewer, Charles H Vite, Steven U Walkley, Christopher P Austin, Forbes D Porter
BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. METHODS: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA...
August 10, 2017: Lancet
https://www.readbyqxmd.com/read/28802167/induction-of-senescence-in-cancer-cells-by-5-aza-2-deoxycytidine-bioinformatics-and-experimental-insights-to-its-targets
#2
Jayarani F Putri, Nashi Widodo, Kazuichi Sakamoto, Sunil C Kaul, Renu Wadhwa
5'-Aza-2'-deoxycytidine (5-Aza-dC) is a demethylating drug that causes genome-wide hypomethylation resulting in the expression of several tumor suppressor genes causing growth arrest of cancer cells. Cancer is well established as a multifactorial disease and requires multi-module therapeutics. Search for new drugs and their approval by FDA takes a long time. Keeping this in view, research on new functions of FDA-approved anticancer drugs is desired to expand the list of multi-module functioning drugs for cancer therapy...
August 2, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28800512/metabotropic-glutamate-receptors-as-emerging-research-targets-in-bipolar-disorder
#3
REVIEW
Caren J Blacker, Charles P Lewis, Mark A Frye, Marin Veldic
Glutamatergic dysregulation is implicated in the neuropathology of bipolar disorder (BD). There is increasing interest in investigating the role of metabotropic glutamate receptors (mGluRs) in BD and as a target for treatment intervention. Bipolar mGluR studies (published January 1992-April 2016) were identified via PubMed, Embase, Web of Science, and Scopus. Full-text screening, data extraction, and quality appraisal were conducted in duplicate, with strict inclusion and exclusion criteria. The initial literature search for mGluRs in BD, including non-bipolar mood disorders and primary psychotic disorders, identified 1544 articles...
July 31, 2017: Psychiatry Research
https://www.readbyqxmd.com/read/28796515/optimal-length-of-conformational-transition-region-in-protein-search-for-targets-on-dna
#4
Maria P Kochugaeva, Alexander M Berezhkovskii, Anatoly B Kolomeisky
The starting point of many fundamental biological processes is associated with protein molecules finding and recognizing specific sites on DNA. However, despite a large number of experimental and theoretical studies on protein search for targets on DNA, many molecular aspects of underlying mechanisms are still not well understood. Experiments show that proteins bound to DNA can switch between slow recognition and fast search conformations. However, from a theoretical point of view, such conformational transitions should slow down the protein search for specific sites on DNA, in contrast to available experimental observations...
August 10, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28791911/targeting-species-specific-trace-amine-associated-receptor-1-ligands-to-date-perspective-of-the-rational-drug-design-process
#5
Elena Cichero, Michele Tonelli
G-protein-coupled receptors represent main targets of several clinically relevant drugs, playing nowadays a leading part for further drug discovery process. Trace amine-associated receptor's family (TAARs) assumed an intriguing role as druggable target in medicinal chemistry, being TAAR1 the most investigated. Indeed, related ligands proved to be intertwined in several circuits involved in pathological pathways or therapeutic routes. Herein, we highlight relevant efforts in the search of novel agonists, focusing on responsiveness featured by different chemotypes toward rodent and human TAAR1, in order to explore species-specificity preferences...
August 9, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28790856/role-of-downregulated-mir-133a-3p-expression-in-bladder-cancer-a-bioinformatics-study
#6
Li Gao, Sheng-Hua Li, Yi-Xin Tian, Qing-Qing Zhu, Gang Chen, Yu-Yan Pang, Xiao-Hua Hu
It has been discovered that miR-133a-3p acts as a tumor suppressor in bladder cancer (BC). Nevertheless, the function of miR-133a-3p in BC remains unclarified. Thus, we carried out this study to validate the expression of miR-133a-3p in BC and provide insights into the molecular mechanism underlying it. To assess the expression of miR-133a-3p in BC, we searched eligible studies from literature and Gene expression Omnibus (GEO) to perform a meta-analysis. We also plotted the summary receiver operating characteristic (SROC) curve to evaluate the diagnostic ability of miR-133a-3p in BC...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28790851/identification-of-the-anticancer-effects-of-a-novel-proteasome-inhibitor-ixazomib-on-colorectal-cancer-using-a-combined-method-of-microarray-and-bioinformatics-analysis
#7
Qiaowei Fan, Bingrong Liu
PURPOSE: The study aimed to explore the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer (CRC) using a combined method of microarray and bioinformatics analysis. MATERIALS AND METHODS: Cell proliferation was tested by Cell Counting Kit-8 (CCK-8) assay for SW620 cells treated with different concentrations of ixazomib and different treatment times. The microarray analysis was conducted for six samples, including three samples of SW620 cells untreated with ixazomib and three samples of SW620 cells treated with ixazomib...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28789673/gene-and-transcript-abundances-of-bacterial-type-iii-secretion-systems-from-the-rumen-microbiome-are-correlated-with-methane-yield-in-sheep
#8
Janine Kamke, Priya Soni, Yang Li, Siva Ganesh, William J Kelly, Sinead C Leahy, Weibing Shi, Jeff Froula, Edward M Rubin, Graeme T Attwood
BACKGROUND: Ruminants are important contributors to global methane emissions via microbial fermentation in their reticulo-rumens. This study is part of a larger program, characterising the rumen microbiomes of sheep which vary naturally in methane yield (g CH4/kg DM/day) and aims to define differences in microbial communities, and in gene and transcript abundances that can explain the animal methane phenotype. METHODS: Rumen microbiome metagenomic and metatranscriptomic data were analysed by Gene Set Enrichment, sparse partial least squares regression and the Wilcoxon Rank Sum test to estimate correlations between specific KEGG bacterial pathways/genes and high methane yield in sheep...
August 8, 2017: BMC Research Notes
https://www.readbyqxmd.com/read/28783594/antigenic-characterization-of-52-55kda-protein-isolated-from-trypanosoma-evansi-and-its-application-in-detection-of-equine-trypanosomosis
#9
S C Yadav, Ritesh Kumar, Jaideep Kumar, Meetali Singh, B C Bera, Rajender Kumar, U Tatu, Kanika Tehri
Trypanosoma evansi is a haemo-protozoan parasite responsible for the disease surra, an economically important disease of wide range of domestic and wild animals. The present diagnostic methods using soluble antigens have inherent problems like lack of standardized and reproducible antigens, as well as ethical issues. This entails further efforts for search of defined antigenic molecules with satisfying sensitivity and specificity for sero-epidemiology of trypanosomosis. In present investigation, we have identified and purified 52-55kDa immuno-dominant protein cluster in molecular mass ranges by preparatory SDS-PAGE methods from T...
August 1, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28783195/murine-cutaneous-leishmaniasis-investigated-by-maldi-mass-spectrometry-imaging
#10
Fernanda Negrão, Daniele F de O Rocha, Caroline F Jaeeger, Francisca J S Rocha, Marcos N Eberlin, Selma Giorgio
Imaging mass spectrometry (IMS) is recognized as a powerful tool to investigate the spatial distribution of untargeted or targeted molecules of a wide variety of samples including tissue sections. Leishmania is a protozoan parasite that causes different clinical manifestations in mammalian hosts. Leishmaniasis is a major public health risk in different continents and represents one of the most important neglected diseases. Cutaneous lesions from mice experimentally infected with Leishmania spp. were investigated by matrix-assisted laser desorption ionization MS using the SCiLS Lab software for statistical analysis...
August 7, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28768860/zinc-finger-containing-cellular-transcription-corepressor-zbtb25-promotes-influenza-virus-rna-transcription-and-is-a-target-for-zinc-ejector-drugs
#11
Shu-Chuan Chen, King-Song Jeng, Michael M C Lai
Influenza A virus (IAV) replication relies on an intricate interaction between virus and host cells. How the cellular proteins are usurped for IAV replication remains largely obscure. The aim of this study was to search for novel and potential cellular factors that participate in IAV replication. ZBTB25, a transcription repressor of a variety of cellular genes, was identified by an RNAi genomic library screening. Depletion of ZBTB25 significantly reduced IAV production. Conversely, overexpression of ZBTB25 enhanced it...
August 2, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28761153/pla2r-binds-to-the-annexin-a2-s100a10-complex-in-human-podocytes
#12
Maryline Fresquet, Thomas A Jowitt, Edward A McKenzie, Matthew D Ball, Michael J Randles, Rachel Lennon, Paul E Brenchley
Phospholipase A2 receptor (PLA2R) is a member of the mannose receptor family found in podocytes in human kidney. PLA2R is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLA2R autoantibodies which bind to the podocyte. However the function of PLA2R in health and in disease remains unclear. To gain insight into the molecular mechanisms of PLA2R function, we searched for its endogenous binding partners. Proteomic analysis identified annexinA2 as a potential interactor with the extracellular domains of PLA2R...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28760695/structural-and-functional-analyses-of-a-timp-and-mmp-in-the-ligament-of-pinctada-fucata
#13
Kazuki Kubota, Yasushi Tsuchihashi, Toshihiro Kogure, Kaoru Maeyama, Fumihiro Hattori, Shigeharu Kinoshita, Shohei Sakuda, Hiromichi Nagasawa, Etsuro Yoshimura, Michio Suzuki
The bivalve hinge ligament is the hard tissue that functions to open and close shells. The ligament contains fibrous structures consisting of aragonite crystals surrounded by a dense organic matrix. This organic matrix may contribute to the formation of fibrous aragonite crystals, but the mechanism underlying this formation remains unclear. In this study, we identified a novel ligament-specific protein, Pinctada fucata tissue inhibitor of metalloproteinase (PfTIMP), from the fibrous organic matrix between aragonite crystals in the ligament using the amino acid sequence and cDNA cloning methods...
July 29, 2017: Journal of Structural Biology
https://www.readbyqxmd.com/read/28758227/standardization-approaches-in-absolute-quantitative-proteomics-with-mass-spectrometry
#14
REVIEW
Francisco Calderón-Celis, Jorge Ruiz Encinar, Alfredo Sanz-Medel
Mass spectrometry-based approaches have enabled important breakthroughs in quantitative proteomics in the last decades. This development is reflected in the better quantitative assessment of protein levels as well as to understand post-translational modifications and protein complexes and networks. Nowadays, the focus of quantitative proteomics shifted from the relative determination of proteins (ie, differential expression between two or more cellular states) to absolute quantity determination, required for a more-thorough characterization of biological models and comprehension of the proteome dynamism, as well as for the search and validation of novel protein biomarkers...
July 31, 2017: Mass Spectrometry Reviews
https://www.readbyqxmd.com/read/28756483/identification-of-structure-stabilizing-interactions-in-enzymes-a-novel-mechanism-to-impact-enzyme-activity
#15
Marisol Serrano, Veronica Gonzalez, Supriyo Ray, Maria D Chavez, Mahesh Narayan
Cruzain, a cysteine protease in the cathepsin family, is pivotal to the life-cycle of Trypanosoma cruzi, the etiological agent in Chagas disease. Current inhibitors of cruzain suffer from drawbacks involving gastrointestinal and neurological side effects and as a result have spurred the search for alternative anti-trypanocidals. Through sequence alignment studies and intra-residue interaction analysis of the pro-protein of cruzain (pro-cruzain), we have identified a host of non-active site residues that are conserved among the cathepsins...
July 29, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28756307/identification-and-comparison-of-candidate-odorant-receptor-genes-in-the-olfactory-and-non-olfactory-organs-of-holotrichia-oblita-faldermann-by-transcriptome-analysis
#16
Kebin Li, Hongshuang Wei, Changlong Shu, Shuai Zhang, Yazhong Cao, Chen Luo, Jiao Yin
A sophisticated olfactory system is part of the explanation for the prominence of insects among animals because of the essential roles of the olfactory system in foraging, host seeking, mating, ovipositing and avoiding toxic substances. In this study, we sequenced and analysed the transcriptomes of olfactory tissue (antennae) and non-olfactory tissue (legs) of the scarab beetle, Holotrichia oblita Faldermann, which is a serious underground pest in China. We obtained approximately 80.2 million 150bp reads that were assembled into 61,038 unigenes with an average length of 890bp...
July 24, 2017: Comparative Biochemistry and Physiology. Part D, Genomics & Proteomics
https://www.readbyqxmd.com/read/28754563/changes-in-gene-expression-variability-reveal-a-stable-synthetic-lethal-interaction-network-in-brca2-ovarian-cancers
#17
Raymund Bueno, Jessica C Mar
Synthetic lethal interactions (SLIs) are robust mechanisms that provide cells with the ability to sustain viability despite having mutations in genes critical to the DNA damage response, a core cellular process. Studies in model organisms such as S. cerevisiae showed that thousands of genes important in maintaining DNA integrity cooperated in a SLI network. Two genes participate in a SLI when mutation in one gene has no effect on the cell, but mutations in both interacting genes are lethal. Furthermore in C...
July 25, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28754127/predictive-biomarkers-of-resistance-to-hypofractionated-radiotherapy-in-high-grade-glioma
#18
Julian Biau, Emmanuel Chautard, Leanne De Koning, Frank Court, Bruno Pereira, Pierre Verrelle, Marie Dutreix
BACKGROUND: Radiotherapy plays a major role in the management of high grade glioma. However, the radioresistance of glioma cells limits its efficiency and drives recurrence inside the irradiated tumor volume leading to poor outcome for patients. Stereotactic hypofractionated radiotherapy is one option for recurrent high grade gliomas. Optimization of hypofractionated radiotherapy with new radiosensitizing agents requires the identification of robust druggable targets involved in radioresistance...
July 28, 2017: Radiation Oncology
https://www.readbyqxmd.com/read/28750054/assisted-design-of-antibody-and-protein-therapeutics-adapt
#19
Victor Vivcharuk, Jason Baardsnes, Christophe Deprez, Traian Sulea, Maria Jaramillo, Christopher R Corbeil, Alaka Mullick, Joanne Magoon, Anne Marcil, Yves Durocher, Maureen D O'Connor-McCourt, Enrico O Purisima
Effective biologic therapeutics require binding affinities that are fine-tuned to their disease-related molecular target. The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform aids in the selection of mutants that improve/modulate the affinity of antibodies and other biologics. It uses a consensus z-score from three scoring functions and interleaves computational predictions with experimental validation, significantly enhancing the robustness of the design and selection of mutants. The platform was tested on three antibody Fab-antigen systems that spanned a wide range of initial binding affinities: bH1-VEGF-A (44 nM), bH1-HER2 (3...
2017: PloS One
https://www.readbyqxmd.com/read/28749667/bace-1-inhibitors-from-recent-single-target-molecules-to-multitarget-compounds-for-alzheimer-s-disease
#20
Federica Prati, Giovanni Bottegoni, Maria Laura Bolognesi, Andrea Cavalli
The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment...
August 8, 2017: Journal of Medicinal Chemistry
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