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https://www.readbyqxmd.com/read/28749574/design-synthesis-pharmacological-evaluation-and-docking-studies-of-glun2b-selective-nmda-receptor-antagonists-with-a-benzo-7-annulen-7-amine-scaffold
#1
Sandeep Gawaskar, Louisa Temme, Julian A Schreiber, Dirk Schepmann, Alessandro Bonifazi, Dina Robaa, Wolfgang Sippl, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
Antagonists that selectively target GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen-7-amines and their GluN2B affinity were investigated. 2-Nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (8) represents the central building block for the introduction of various substituents at the 2-position and various 7-amino moieties. N-(3-Phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amines with a 2-NO2 (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (Ki =1...
July 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28749240/epigenetic-dysregulation-of-the-erythropoietic-transcription-factor-klf1-and-the-beta-like-globin-locus-in-juvenile-myelomonocytic-leukemia
#2
Silvia Fluhr, Christopher Felix Krombholz, Angelina Meier, Thomas Epting, Oliver Mücke, Christoph Plass, Charlotte M Niemeyer, Christian Flotho
Increased levels of fetal hemoglobin (HbF) are a hallmark of more than half of the children diagnosed with juvenile myelomonocytic leukemia (JMML). Elevated HbF levels in JMML are associated with DNA hypermethylation of distinct gene promoter regions in leukemic cells. Since the regulation of globin gene transcription is known to be under epigenetic control, we set out to study the relation of DNA methylation patterns at β-/γ-globin promoters, mRNA and protein expression of globins, and epigenetic modifications of genes encoding the globin-regulatory transcription factors BCL11A and KLF1 in nucleated erythropoietic precursor cells of patients with JMML...
July 27, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28748916/conformation-and-dynamics-of-the-c-terminal-region-in-human-phosphoglycerate-mutase-1
#3
Shi-En Liu, Jun-Chi Hu, Hao Zhang, Pan Xu, Wei Wan, Ming-Yue Zheng, Kun-Qian Yu, Hong Ding, Hua-Liang Jiang, Lu Zhou, Cheng Luo
Phosphoglycerate mutase 1 (PGAM1), an important enzyme in glycolysis, is overexpressed in a number of human cancers, thus has been proposed as a promising metabolic target for cancer treatments. The C-terminal portion of the available crystal structures of PGAM1 and its homologous proteins is partially disordered, as evidenced by weak electron density. In this study, we identified the conformational behavior of the C-terminal region of PGAM1 as well as its role during the catalytic cycle. Using the PONDR-FIT server, we demonstrated that the C-terminal region was intrinsically disordered...
July 27, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28748857/effect-of-high-fat-diet-induced-disorders-on-rat-with-endometrial-hyperplasia-and-adiponectin-system-in-circulation-and-uterus
#4
Chen-Guang Shang, Zhao-Hui Liu, Xiao-Hui Wang, Zong-Hao Feng, Yan Zhang
BACKGROUND: Epidemiologic and genetic studies suggest a link between insulin resistance (IR) and endometrial cancer, and endometrial hyperplasia (EH) is a precancerous stage of endometrial cancer. Adiponectin is an adipokine which previously shown to be a risk factor for endometrial cancer. The aim of the study was to develop a rat model of IR and EH and evaluate adiponectin system in circulation and uterus. METHODS: This study was a 46-week animal trial from February 2014 to January 2015...
August 5, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28748765/biomarkers-in-aortic-valve-stenosis-and-their-clinical-significance-in-transcatheter-aortic-valve-implantation
#5
Konstantinos Toutouzas, Konstantinos Stathogiannis, George Latsios, Andreas Synetos, Maria Drakopoulou, Vicky Penesopoulou, Archontoula Michelongona, Eleftherios Tsiamis, Dimitris Tousoulis
Aortic valve stenosis is one of the most common valvular heart disorders and the prevalence will rise as the population ages. Once symptomatic, patients with aortic valve stenosis tend to fare worse with high mortality rates. Aortic valve replacement is indicated in these patients and besides the standard surgical replacement; a less invasive approach, transcatheter aortic valve implantation, has gained momentum and has showed promising and solid results in patients with high surgical risk. An important aspect of evaluating patients with aortic valve stenosis is the ability to choose the best possible candidate for the procedure...
July 27, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28748761/tyrosinase-electrochemical-biosensors-monitoring-medicinally-significant-substances
#6
Milan Sýs, Karel Vytřas
Nowadays in biosensing, development of analytical techniques is focused on improvement for monitoring biologically active species in living organisms, especially in real time analysis. This article provides an overview of applications of electrochemical tyrosinase biosensors in analysis of medicinally significant substances, otherwise also known as biomarkers. At the beginning, special attention is paid to characterisation of the tyrosinase enzyme, explanation of reaction mechanisms of tyrosinase with various types of electrochemical transducers and techniques needed for stable immobilization of this biocatalyst on the transducer surface used...
July 27, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28748217/mechanisms-and-applications-of-the-anti-inflammatory-effects-of-photobiomodulation
#7
Michael R Hamblin
Photobiomodulation (PBM) also known as low-level level laser therapy is the use of red and near-infrared light to stimulate healing, relieve pain, and reduce inflammation. The primary chromophores have been identified as cytochrome c oxidase in mitochondria, and calcium ion channels (possibly mediated by light absorption by opsins). Secondary effects of photon absorption include increases in ATP, a brief burst of reactive oxygen species, an increase in nitric oxide, and modulation of calcium levels. Tertiary effects include activation of a wide range of transcription factors leading to improved cell survival, increased proliferation and migration, and new protein synthesis...
2017: AIMS Biophysics
https://www.readbyqxmd.com/read/28748185/novel-actions-of-growth-hormone-in-podocytes-implications-for-diabetic-nephropathy
#8
REVIEW
Dhanunjay Mukhi, Rajkishor Nishad, Ram K Menon, Anil Kumar Pasupulati
The kidney regulates water, electrolyte, and acid-base balance and thus maintains body homeostasis. The kidney's potential to ensure ultrafiltered and almost protein-free urine is compromised in various metabolic and hormonal disorders such as diabetes mellitus (DM). Diabetic nephropathy (DN) accounts for ~20-40% of mortality in DM. Proteinuria, a hallmark of renal glomerular diseases, indicates injury to the glomerular filtration barrier (GFB). The GFB is composed of glomerular endothelium, basement membrane, and podocytes...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28747912/acquired-senescent-t-cell-phenotype-correlates-with-clinical-severity-in-gata-binding-protein-2-deficient-patients
#9
Raquel Ruiz-García, Carmen Rodríguez-Vigil, Francisco Manuel Marco, Fernando Gallego-Bustos, María José Castro-Panete, Laura Diez-Alonso, Carlos Muñoz-Ruiz, Jesús Ruiz-Contreras, Estela Paz-Artal, Luis Ignacio González-Granado, Luis Miguel Allende
GATA binding protein 2 (GATA2) deficiency is a rare disorder of hematopoiesis, lymphatics, and immunity caused by spontaneous or autosomal dominant mutations in the GATA2 gene. Clinical manifestations range from neutropenia, lymphedema, deafness, to severe viral and mycobacterial infections, bone marrow failure, and acute myeloid leukemia. Patients also present with monocytopenia, dendritic cell, B- and natural killer (NK)-cell deficiency. We studied the T-cell and NK-cell compartments of four GATA2-deficient patients to assess if changes in these lymphocyte populations could be correlated with clinical phenotype...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28747872/l-3-n-butylphthalide-protects-hspb8-k141n-mutation-induced-oxidative-stress-by-modulating-the-mitochondrial-apoptotic-and-nrf2-pathways
#10
Xiao-Dong Yang, Zhi-Dong Cen, Hai-Peng Cheng, Kai Shi, Jie Bai, Fei Xie, Hong-Wei Wu, Bei-Bei Li, Wei Luo
Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is the most common inherited peripheral nerve disorder. Missense mutations, such as K141N, in the small heat shock protein HSPB8 are known to cause distal hereditary motor neuropathy 2A (dHMN2A) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). However, of critical clinical significance, very few specific therapies for this disease exist. In the present study, we investigated the impact of mutant K141N HSPB8 on mitochondrial distribution and function in a cellular model of CMT2L...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28747709/trimethylamine-n-oxide-abolishes-the-chaperone-activity-of-%C3%AE-casein-an-intrinsically-disordered-protein
#11
Mohd Younus Bhat, Laishram Rajendrakumar Singh, Tanveer Ali Dar
Osmolytes (small molecules that help in circumventing stresses) are known to promote protein folding and prevent aggregation in the case of globular proteins. However, the effect of such osmolytes on the structure and function of intrinsically disordered proteins (IDPs) has not been clearly understood. Here we have investigated the effect of methylamine osmolytes on α-casein (an IDP present in mammalian milk) and discovered that TMAO (Trimethylamine-N-oxide) but not other methylamines renders α-casein functionless...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28747448/movement-disorder-in-gnao1-encephalopathy-associated-with-gain-of-function-mutations
#12
Huijie Feng, Benita Sjögren, Behirda Karaj, Vincent Shaw, Aysegul Gezer, Richard R Neubig
OBJECTIVE: To define molecular mechanisms underlying the clinical spectrum of epilepsy and movement disorder in individuals with de novo mutations in the GNAO1 gene. METHODS: We identified all GNAO1 mutations reported in individuals with epilepsy (early infantile epileptiform encephalopathy 17) or movement disorders through April 2016; 15 de novo mutant alleles from 25 individuals were introduced into the Gαo subunit by site-directed mutagenesis in a mammalian expression plasmid...
July 26, 2017: Neurology
https://www.readbyqxmd.com/read/28747251/serca-control-of-cell-death-and-survival
#13
REVIEW
Elie R Chemaly, Luca Troncone, Djamel Lebeche
Intracellular calcium (Ca(2+)) is a critical coordinator of various aspects of cellular physiology. It is increasingly apparent that changes in cellular Ca(2+) dynamics contribute to the regulation of normal and pathological signal transduction that controls cell growth and survival. Aberrant perturbations in Ca(2+) homeostasis have been implicated in a range of pathological conditions, such as cardiovascular diseases, diabetes, tumorigenesis and steatosis hepatitis. Intracellular Ca(2+) concentrations are therefore tightly regulated by a number of Ca(2+) handling enzymes, proteins, channels and transporters located in the plasma membrane and in Ca(2+) storage organelles, which work in concert to fine tune a temporally and spatially precise Ca(2+) signal...
July 12, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28747201/intravenous-superoxide-dismutase-as-a-protective-agent-to-prevent-impairment-of-lung-function-induced-by-high-tidal-volume-ventilation
#14
Nan-Chun Wu, Fan-Ting Liao, Hao-Min Cheng, Shih-Hsien Sung, Yu-Chun Yang, Jiun-Jr Wang
BACKGROUND: Positive-pressure mechanical ventilation is essential in assisting patients with respiratory failure in the intensive care unit and facilitating oxygenation in the operating room. However, it was also recognized as a primary factor leading to hospital-acquired pulmonary dysfunction, in which pulmonary oxidative stress and lung inflammation had been known to play important roles. Cu/Zn superoxide dismutase (SOD) is an important antioxidant, and possesses anti-inflammatory capacity...
July 26, 2017: BMC Pulmonary Medicine
https://www.readbyqxmd.com/read/28746987/cytosolic-redox-components-regulate-protein-homeostasis-via-additional-localisation-in-the-mitochondrial-intermembrane-space
#15
REVIEW
Mauricio Cardenas-Rodriguez, Kostas Tokatlidis
Oxidative protein folding is confined to the bacterial periplasm, endoplasmic reticulum and the mitochondrial intermembrane space. Maintaining a redox balance requires the presence of reductive pathways. The major thiol-reducing pathways engage the thioredoxin and the glutaredoxin systems which are involved in removal of oxidants, protein proofreading and folding. Alterations in redox balance likely affect the flux of these redox pathways and are related to ageing and diseases such as neurodegenerative disorders and cancer...
July 26, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28746897/parkinsonian-features-in-aging-gfap-hmox1-transgenic-mice-overexpressing-human-ho-1-in-the-astroglial-compartment
#16
Wei Song, Marisa Cressatti, Hillel Zukor, Adrienne Liberman, Carmela Galindez, Hyman M Schipper
Epigenetic influences mediating brain iron deposition, oxidative mitochondrial injury, and macroautophagy in Parkinson disease and related conditions remain enigmatic. Here, we show that selective overexpression of the stress protein, heme oxygenase-1 (HO-1) in astrocytes of GFAP.HMOX1 transgenic mice between 8.5 and 19 months of age results in nigrostriatal hypodopaminergia associated with locomotor incoordination and stereotypy; downregulation of tyrosine hydroxylase, DAT, LMX1B, Nurr1, Pitx3 and DJ-1 mRNA and/or protein; overproduction of α-synuclein and ubiquitin; oxidative stress; basal ganglia siderosis; mitochondrial damage/mitophagy; and augmented GABAergic systems (increased GABA, GAD67 and reelin)...
June 28, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28746876/wbscr16-is-a-guanine-nucleotide-exchange-factor-important-for-mitochondrial-fusion
#17
Guorui Huang, Dawiyat Massoudi, Alison M Muir, Dinesh C Joshi, Chuan-Li Zhang, Shing Yan Chiu, Daniel S Greenspan
Regulated inter-mitochondrial fusion/fission is essential for maintaining optimal mitochondrial respiration and control of apoptosis and autophagy. In mammals, mitochondrial fusion is controlled by outer membrane GTPases MFN1 and MFN2 and by inner membrane (IM) GTPase OPA1. Disordered mitochondrial fusion/fission contributes to various pathologies, and MFN2 or OPA1 mutations underlie neurodegenerative diseases. Here, we show that the WBSCR16 protein is primarily associated with the outer face of the inner mitochondrial membrane and is important for mitochondrial fusion...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28746872/aberrant-proteostasis-of-bmal1%C3%A2-underlies-circadian-abnormalities-in-a-paradigmatic-mtor-opathy
#18
Jonathan O Lipton, Lara M Boyle, Elizabeth D Yuan, Kevin J Hochstrasser, Fortunate F Chifamba, Ashwin Nathan, Peter T Tsai, Fred Davis, Mustafa Sahin
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28746870/identification-of-a-genetic-variation-in-erap1-aminopeptidase-that-prevents-human-cytomegalovirus-mir-ul112-5p-mediated-immunoevasion
#19
Paolo Romania, Loredana Cifaldi, Benedetta Pignoloni, Nadia Starc, Valerio D'Alicandro, Ombretta Melaiu, Giuseppina Li Pira, Ezio Giorda, Rosalba Carrozzo, Monika Bergvall, Tomas Bergström, Lars Alfredsson, Tomas Olsson, Ingrid Kockum, Ilkka Seppälä, Terho Lehtimäki, Mikko A Hurme, Hartmut Hengel, Angela Santoni, Cristina Cerboni, Franco Locatelli, Mauro D'Amato, Doriana Fruci
Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65495-503 peptide to specific CTLs. In addition, we show that the rs17481334 G variant, naturally occurring in the ERAP1 3' UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 3' UTR of ERAP1 A variant, but not the 3' UTR of ERAP1 G variant, and, accordingly, ERAP1 expression is reduced both at RNA and protein levels only in human fibroblasts homozygous for the A variant...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28746862/generation-of-monoclonal-antibodies-and-development-of-an-immunofluorometric-assay-for-the-detection-of-cuzd1-in-tissues-and-biological-fluids
#20
Sofia Farkona, Antoninus Soosaipillai, Panagiota Filippou, Dimitrios Korbakis, Stefano Serra, Felix Rückert, Eleftherios P Diamandis, Ivan M Blasutig
BACKGROUND: CUB and zona pellucida-like domain-containing protein 1 (CUZD1) was identified as a pancreas-specific protein and was proposed as a candidate biomarker for pancreatic related disorders. CUZD1 protein levels in tissues and biological fluids have not been extensively examined. The purpose of the present study was to generate specific antibodies targeting CUZD1 to assess CUZD1 expression within tissues and biological fluids. METHODS: Mouse monoclonal antibodies against CUZD1 were generated and used to perform immunohistochemical analyses and to develop a sensitive and specific enzyme-linked immunosorbent assay (ELISA)...
July 23, 2017: Clinical Biochemistry
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