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https://www.readbyqxmd.com/read/29792848/subthalamic-nucleus-deep-brain-stimulation-protects-neurons-by-activating-autophagy-via-pp2a-inactivation-in-a-rat-model-of-parkinson-s-disease
#1
Ting-Ting Du, Ying-Chuan Chen, Yong-Quan Lu, Fan-Gang Meng, Hui Yang, Jian-Guo Zhang
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for alleviating disability in patients with moderate to severe Parkinson's disease (PD). Preclinical studies have shown that stimulation of the rat STN can protect against nigral dopaminergic neuron loss. However, the underlying mechanism is unclear. To investigate the molecular basis of the neuroprotective effects of STN stimulation, a rat model of PD was established by unilaterally injecting 6-hydroxydopamine (6-OHDA) into the striatum...
May 21, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29792714/docking-screens-for-dual-inhibitors-of-disparate-drug-targets-for-parkinson-s-disease
#2
Mariama Jaiteh, Alexey Zeifman, Marcus Saarinen, Per Svenningsson, José M Brea, Maria Isabel Loza, Jens Carlsson
Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A2A adenosine receptor (A2AAR) and monoamine oxidase B (MAO-B)...
May 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29792674/partial-intrinsic-disorder-governs-the-dengue-capsid-protein-conformational-ensemble
#3
Priscilla L S Boon, Wuan Geok Saw, Xin Xiang Lim, Palur Venkata Raghuvamsi, Roland G Huber, Jan K Marzinek, Daniel A Holdbrook, Ganesh S Anand, Gerhard Grüber, Peter J Bond
The 11 kDa, positively charged dengue capsid protein (C protein) exists stably as a homodimer and co-localizes with the viral genome within mature viral particles. Its core is composed of four alpha helices encompassing a small hydrophobic patch that may interact with lipids, but approximately 20% of the protein at the N-terminus is intrinsically disordered, making it challenging to elucidate its conformational landscape. Here, we combine small-angle X-ray scattering (SAXS), amide hydrogen-deuterium exchange mass spectrometry (HDXMS), and atomic-resolution molecular dynamics (MD) simulations to probe the dynamics of dengue C proteins...
May 24, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29792024/metabotropic-glutamate-receptors-in-alcohol-use-disorder-physiology-plasticity-and-promising-pharmacotherapies
#4
Max E Joffe, Samuel W Centanni, Anel A Jaramillo, Danny G Winder, P Jeffrey Conn
Developing efficacious treatments for alcohol use disorder (AUD) has proven difficult. The insidious nature of the disease necessitates a deep understanding of its underlying biology as well as innovative approaches to ameliorate ethanol-related pathophysiology. Excessive ethanol-seeking and relapse are generated by long-term changes to membrane properties, synaptic physiology, and plasticity throughout the limbic system and associated brain structures. Each of these factors can be modulated by metabotropic glutamate (mGlu) receptors, a diverse set of G protein-coupled receptors highly expressed throughout the central nervous system...
May 23, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29791992/role-of-the-duodenum-in-the-pathogenesis-of-functional-dyspepsia-a-paradigm-shift
#5
REVIEW
Hye-Kyung Jung, Nicholas J Talley
Functional dyspepsia (FD) is a common disorder characterized by chronic epigastric pain or burning, or bothersome postprandial fullness or early satiation, without a definitive organic cause. The pathogenesis of FD is likely heterogeneous. Classically, motor disorders, visceral hypersensitivity, and brain-gut interactions have been implicated in the pathophysiology of FD, but recently an important role for chronic low-grade inflammation and post-infectious gastroenteritis in FD has been reported and confirmed...
May 23, 2018: Journal of Neurogastroenterology and Motility
https://www.readbyqxmd.com/read/29791910/melatonin-attenuates-histopathological-changes-in-the-hippocampus-of-infantile-rats-with-kaolin-induced-hydrocephalus
#6
Mehmet Turgut, Meral Baka, Yiğit Uyanıkgil
OBJECTIVE/AIM: Hydrocephalus is defined as an incapacitating neurological disorder characterized by ventricular enlargement in children, but the effects of melatonin on this hydrocephalus have not yet been fully elucidated. In the present experiment, we attempted to investigate the effects of exogenous melatonin administration on hydrocephalus-induced hippocampal changes in infantile rats. METHODS: In this study, we randomly divided 45 Swiss albino rats aged 2 weeks into 3 groups: group I, the control group received a sham injection with needle insertion only; groups II and III were given kaolin injections before treatment - group II, the hydrocephalus group, was treated with an isotonic NaCl solution, and group III, the hydrocephalus plus melatonin group, was treated with 0...
May 23, 2018: Pediatric Neurosurgery
https://www.readbyqxmd.com/read/29791766/protein-regulation-by-intrinsically-disordered-regions-a-role-for-subdomains-in-the-idr-of-the-hiv-1-rev-protein
#7
Ofrah Faust, Dana Grunhaus, Odelia Shimshon, Eylon Yavin, Assaf Friedler
Intrinsically disordered regions (IDRs) in proteins are highly abundant, but they are still commonly viewed as long stretches of polar, solvent accessible residues. Here we show that the disordered C-terminal domain of HIV-1 Rev has two sub-regions that carry out two distinct complementary roles of regulating oligomerization and contributing to stability. We propose this is carried out by a delicate balance between charged and hydrophobic residues within the IDR. We suggest that intrinsically disordered regions in proteins should be divided to sub domains similarly to structured regions, rather than being viewed as a long flexible stretches...
May 23, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29791652/inflammatory-myopathy-in-the-context-of-an-unusual-overlapping-laminopathy
#8
Cristina Guillín-Amarelle, Sofía Sánchez-Iglesias, Antonio Mera, Elena Pintos, Ana Castro-Pais, Leticia Rodríguez-Cañete, Julio Pardo, Felipe F Casanueva, David Araújo-Vilar
Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported...
May 17, 2018: Archives of Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29791485/alterations-in-the-brain-interactome-of-the-intrinsically-disordered-n-terminal-domain-of-the-cellular-prion-protein-prpc-in-alzheimer-s-disease
#9
Sarah Ulbrich, Petra Janning, Ralf Seidel, Jakob Matschke, Anika Gonsberg, Sebastian Jung, Markus Glatzel, Martin Engelhard, Konstanze F Winklhofer, Jörg Tatzelt
The cellular prion protein (PrPC) is implicated in neuroprotective signaling and neurotoxic pathways in both prion diseases and Alzheimer's disease (AD). Specifically, the intrinsically disordered N-terminal domain (N-PrP) has been shown to interact with neurotoxic ligands, such as Aβ and Scrapie prion protein (PrPSc), and to be crucial for the neuroprotective activity of PrPC. To gain further insight into cellular pathways tied to PrP, we analyzed the brain interactome of N-PrP. As a novel approach employing recombinantly expressed PrP and intein-mediated protein ligation, we used N-PrP covalently coupled to beads as a bait for affinity purification...
2018: PloS One
https://www.readbyqxmd.com/read/29790812/-express-nav1-7-is-phosphorylated-by-fyn-tyrosine-kinase-which-modulates-channel-expression-and-gating-in-a-cell-type-dependent-manner
#10
Yangyang Li, Tengteng Zhu, Huan Yang, Sulayman Dib-Hajj, Stephen Waxman, Ye Yu, Tian-Le Xu, Xiaoyang Cheng
Voltage-gated sodium channel Nav1.7 is a key molecule in nociception, and its dysfunction has been associated with various pain disorders. Here, we investigated the regulation of Nav1.7 biophysical properties by Fyn, a Src family tyrosine kinase. Nav1.7 was coexpressed with either constitutively active (FynCA) or dominant negative (FynDN) variants of Fyn kinase. FynCA elevated protein expression and tyrosine phosphorylation of Nav1.7 channels. Site-directed mutagenesis analysis identified two tyrosine residues (Y1470 and Y1471) located within the Nav1...
January 1, 2018: Molecular Pain
https://www.readbyqxmd.com/read/29790640/prolines-fingerprint-in-intrinsically-disordered-proteins
#11
Maria Grazia Murrali, Alessandro Piai, Wolfgang Bermel, Isabella C Felli, Roberta Pierattelli
NMR spectroscopy is one of the main techniques for high resolution studies of intrinsically disordered proteins (IDPs). Indeed, it permits to map the structural and dynamical features of all the amino acids constituting the polypeptide at atomic resolution. Only proline residues are less straightforward to be characterized, as they lack the amide proton, rendering them not directly visible in the commonly-used 2D ¹H-¹⁵N correlation experiments. However, these residues are highly abundant in IDPs and can mediate important functions...
May 23, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29790601/a-method-for-partitioning-the-information-contained-in-a-protein-sequence-between-its-structure-and-function
#12
Andrea Possenti, Michele Vendruscolo, Carlo Camilloni, Guido Tiana
Proteins employ the information stored in the genetic code and translated into their sequences to carry out well-defined functions in the cellular environment. The possibility to encode for such functions is controlled by the balance between the amount of information supplied by the sequence and that left after that the protein has folded into its structure. We study the amount of information necessary to specify the protein structure, providing an estimate that keeps into account the thermodynamic properties of protein folding...
May 23, 2018: Proteins
https://www.readbyqxmd.com/read/29790589/genotype-phenotype-correlation-of-hereditary-erythrocytosis-mutations-a-single-center-experience
#13
Jennifer L Oliveira, Lea M Coon, Lori A Frederick, Molly Hein, Kenneth C Swanson, Michelle E Savedra, Tavanna R Porter, Mrinal M Patnaik, Ayalew Tefferi, Animesh Pardanani, Stefan K Grebe, David S Viswanatha, James D Hoyer
Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3-bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen-sensing pathway proteins PHD, HIF2α, and VHL. Our laboratory has 40 years of experience with hemoglobin disorder testing and we have characterized HOAs using varied protein and molecular techniques including functional assessment by p50 analysis. In addition, we have more recently commenced adding the assessment of clinically relevant regions of the VHL, BPGM, EPOR, EGLN1 (PHD2), and EPAS1 (HIF2A) genes in a more comprehensive hereditary erythrocytosis panel of tests...
May 23, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29790085/white-matter-microstructure-in-bipolar-disorder-is-influenced-by-the-interaction-between-a-glutamate-transporter-eaat1-gene-variant-and-early-stress
#14
Sara Poletti, Irene Bollettini, Cristina Lorenzi, Alice Vitali, Silvia Brioschi, Alessandro Serretti, Cristina Colombo, Francesco Benedetti
Glutamate is the principal excitatory neurotransmitter in the central nervous system. In mature brains, it is critically involved in neuroplasticity and, at high levels, neurotoxicity. The concentrations of glutamate in the extracellular space are maintained at low physiological levels by molecular glutamate transporters (excitatory amino acid transporters-EAATs). Adverse childhood experiences (ACEs) are highly reported in bipolar disorder (BD) and interact with the glutamatergic system in the brain. The aim of the study is to investigate the effect of a glutamate transporter polymorphism EAAT2-181A > C (rs4354668) and exposure to ACE on white matter microstructure in patients with BD...
May 22, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29790000/o-glcnac-cycling-in-the-developing-adult-and-geriatric-brain
#15
REVIEW
Olof Lagerlöf
Hundreds of proteins in the nervous system are modified by the monosaccharide O-GlcNAc. A single protein is often O-GlcNAcylated on several amino acids and the modification of a single site can play a crucial role for the function of the protein. Despite its complexity, only two enzymes add and remove O-GlcNAc from proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Global and local regulation of these enzymes make it possible for O-GlcNAc to coordinate multiple cellular functions at the same time as regulating specific pathways independently from each other...
May 22, 2018: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/29789966/beh%C3%A3-et-s-syndrome-and-nervous-system-involvement
#16
REVIEW
Uğur Uygunoğlu, Aksel Siva
PURPOSE OF REVIEW: Although Behçet's syndrome (BS) is classified as a rare disease in European countries and the USA, its neurologic involvement "neuro-Behçet's syndrome (NBS)" is commonly included in the differential diagnosis of many inflammatory and vascular central nervous system (CNS) disorders. Clinical and neuroimaging findings support two major forms of NBS: parenchymal NBS (p-NBS) and an extra-parenchymal form that presents with cerebral venous sinus thrombosis (CVST)...
May 23, 2018: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/29789935/potential-use-of-stem-cells-as-a-therapy-for-cystinosis
#17
REVIEW
Celine J Rocca, Stephanie Cherqui
Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders (LSDs). Initial symptoms of cystinosis correspond to the renal Fanconi syndrome. Patients then develop chronic kidney disease and multi-organ failure due to accumulation of cystine in all tissue compartments. LSDs are commonly characterized by a defective activity of lysosomal enzymes. Hematopoietic stem and progenitor cell (HSPC) transplantation is a treatment option for several LSDs based on the premise that their progeny will integrate in the affected tissues and secrete the functional enzyme, which will be recaptured by the surrounding deficient cells and restore physiological activity...
May 22, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/29789568/deficiency-of-prkd2-triggers-hyperinsulinemia-and-metabolic-disorders
#18
Yao Xiao, Can Wang, Jia-Yu Chen, Fujian Lu, Jue Wang, Ning Hou, Xiaomin Hu, Fanxin Zeng, Dongwei Ma, Xueting Sun, Yi Ding, Yan Zhang, Wen Zheng, Yuli Liu, Haibao Shang, Wenzhen Zhu, Chensheng Han, Yulin Zhang, Kunfu Ouyang, Liangyi Chen, Ju Chen, Rui-Ping Xiao, Chuan-Yun Li, Xiuqin Zhang
Hyperinsulinemia is the earliest symptom of insulin resistance (IR), but a causal relationship between the two remains to be established. Here we show that a protein kinase D2 (PRKD2) nonsense mutation (K410X) in two rhesus monkeys with extreme hyperinsulinemia along with IR and metabolic defects by using extreme phenotype sampling and deep sequencing analyses. This mutation reduces PRKD2 at both the mRNA and the protein levels. Taking advantage of a PRKD2-KO mouse model, we demonstrate that PRKD2 deletion triggers hyperinsulinemia which precedes to IR and metabolic disorders in the PRKD2 ablation mice...
May 22, 2018: Nature Communications
https://www.readbyqxmd.com/read/29789464/role-of-mtor-complexes-in-neurogenesis
#19
REVIEW
Francesca LiCausi, Nathaniel W Hartman
Dysregulation of neural stem cells (NSCs) is associated with several neurodevelopmental disorders, including epilepsy and autism spectrum disorder. The mammalian target of rapamycin (mTOR) integrates the intracellular signals to control cell growth, nutrient metabolism, and protein translation. mTOR regulates many functions in the development of the brain, such as proliferation, differentiation, migration, and dendrite formation. In addition, mTOR is important in synaptic formation and plasticity. Abnormalities in mTOR activity is linked with severe deficits in nervous system development, including tumors, autism, and seizures...
May 22, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29789348/gestational-low-protein-intake-enhances-whole-kidney-mir-192-and-mir-200-family-expression-and-epithelial-to-mesenchymal-transition-in-rat-adult-male-offspring
#20
Letícia B Sene, Victor Hugo Gonçalves Rizzi, José A R Gontijo, Patricia A Boer
Studies have shown that adult offspring of mothers fed a protein-restricted diet during pregnancy present a pronounced reduction of nephron number associated with decreased fractional urinary sodium excretion and arterial hypertension. Additionally, recent advances in our understanding of the molecular pathways that govern the association of gestational nutritional restriction, intrauterine growth retardation and inflammation with impaired nephrogenesis, nephron underdosing and kidney fibrosis point to the epithelial to mesenchymal transition (EMT) as a common factor...
May 22, 2018: Journal of Experimental Biology
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