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https://read.qxmd.com/read/30763969/-impairment-of-the-visual-system-in-glaucoma
#1
Manuel A Schmidt, Tobias Engelhorn, Arnd Dörfler, Georg Michelson
MR Diffusion Tensor Imaging (DTI) enables visualisation of the visual system in glaucoma; it has been shown that the atrophy of the optic radiation is more pronounced in glaucoma than in age-matched controls. The atrophy of the optic radiation thereby correlates with OCT and visual field measures. Diffusion tensor imaging permits quantification of the axonal integrity of the optic radiation by calculation of fractional anisotropy (FA) and radial diffusivity (RD). Both within and also outside the visual system, there are substantial changes in FA and RD, changes suggesting a complex neurodegenerative disease...
February 2019: Klinische Monatsblätter Für Augenheilkunde
https://read.qxmd.com/read/30763888/deployment-of-dna-polymerases-beta-and-lambda-in-single-nucleotide-and-multinucleotide-pathways-of-mammalian-base-excision-dna-repair
#2
Upasna Thapar, Bruce Demple
There exist two major base excision DNA repair (BER) pathways, namely single-nucleotide or "short-patch" (SP-BER), and "long-patch" BER (LP-BER). Both pathways appear to be involved in the repair of small base lesions such as uracil, abasic sites and oxidized bases. In addition to DNA polymerase β (Polβ) as the main BER enzyme for repair synthesis, there is evidence for a minor role for DNA polymerase lambda (Polλ) in BER. In this study we explore the potential contribution of Polλ to both SP- and LP-BER in cell-free extracts...
February 4, 2019: DNA Repair
https://read.qxmd.com/read/30763806/intact-protein-mass-spectrometry-reveals-intraspecies-variations-in-venom-composition-of-a-local-population-of-vipera-kaznakovi-in-northeastern-turkey
#3
Daniel Petras, Benjamin-Florian Hempel, Bayram Göçmen, Mert Karis, Gareth Whiteley, Simon C Wagstaff, Paul Heiss, Nicholas R Casewell, Ayse Nalbantsoy, Roderich D Süssmuth
We report on the variable venom composition of a population of the Caucasus viper (Vipera kaznakovi) in Northeastern Turkey. We applied a combination of venom gland transcriptomics, and de-complexing bottom-up and top-down venomics. In contrast to sole bottom-up venomics approaches and gel or chromatography based venom comparison, our combined approach enables a faster and more detailed comparison of venom proteomes from multiple individuals. In total, we identified peptides and proteins from 15 toxin families, including snake venom metalloproteinases (svMP; 37...
February 11, 2019: Journal of Proteomics
https://read.qxmd.com/read/30763671/genomic-structural-diversity-in-criollo-argentino-horses-analysis-of-copy-number-variations
#4
Claudia M Corbi-Botto, Hernán Morales-Durand, María E Zappa, Sebastián A Sadaba, Pilar Peral-García, Guillermo Giovambattista, Silvina Díaz
Copy number variation (CNV) has been proved to be widespread in human, animal and plant genomes. Together with single nucleotide polymorphisms (SNPs), CVNs play a key role in genetic diversity. In this study, genome-wide detection of CNVs was performed based on SNP data from 24 Criollo Argentino horses genotyped with the GGP Equine70k array. Overall, 165 CNVs meeting stringent quality control criteria were identified and then aggregated into 87 CNV regions (CNVRs), representing a horse genome coverage of 13...
February 11, 2019: Gene
https://read.qxmd.com/read/30763650/%C3%AE-secretase-and-its-modulators-twenty-years-and-beyond
#5
REVIEW
Weiming Xia
Twenty years ago, Wolfe, Xia, and Selkoe identified two aspartate residues in Alzheimer's presenilin protein that constitute the active site of the γ-secretase complex. Mutations in the genes encoding amyloid precursor protein (APP) or presenilin (PS) cause early onset familial Alzheimer's disease (AD), and sequential cleavages of the APP by β-secretase and γ-secretase/presenilin generate amyloid β protein (Aβ), the major component of pathological hallmark, neuritic plaques, in brains of AD patients. Therapeutic strategies centered on targeting γ-secretase/presenilin to reduce amyloid were implemented and led to several high profile clinical trials...
February 11, 2019: Neuroscience Letters
https://read.qxmd.com/read/30763642/two-mechanisms-involving-the-autophagic-and-proteasomal-pathways-process-the-metastasis-suppressor-protein-n-myc-downstream-regulated-gene-1
#6
Sumit Sahni, Kyung Chan Park, Zaklina Kovacevic, Des R Richardson
N-myc downstream regulated gene 1 (NDRG1) is an intriguing metastasis suppressor protein, which plays an important role in suppressing multiple oncogenic signaling pathways. Interestingly, multiple isoforms of NDRG1 have been identified, although the molecular mechanisms involved in their generation remains elusive. Herein, we demonstrate the role of two mechanisms involving autophagic and proteasomal machinery as part of an intricate system to generate different NDRG1 isoforms. Examining multiple pancreatic cancer cell-types using immunoblotting demonstrated three major isoforms of NDRG1 at approximately 41-, 46- and 47-kDa...
February 11, 2019: Biochimica et biophysica acta. Molecular basis of disease
https://read.qxmd.com/read/30763594/cathepsins-potent-regulators-in-carcinogenesis
#7
Tejinder Pal Khaket, Taeg Kyu Kwon, Sun Chul Kang
Cathepsins (CTS) are mainly lysosomal acid hydrolases extensively involved in the prognosis of different diseases, and having a distinct role in tumor progression by regulating cell proliferation, autophagy, angiogenesis, invasion, and metastasis. As all these processes conjunctively lead to cancer progression, their site-specific regulation might be beneficial for cancer treatment. CTS regulate activation of the proteolytic cascade and protein turnover, while extracellular CTS is involved in promoting extracellular matrix degradation and angiogenesis, thereby stimulating invasion and metastasis...
February 11, 2019: Pharmacology & Therapeutics
https://read.qxmd.com/read/30763317/evolutionary-rate-covariation-analysis-of-e-cadherin-identifies-raskol-as-a-regulator-of-cell-adhesion-and-actin-dynamics-in-drosophila
#8
Qanber Raza, Jae Young Choi, Yang Li, Roisin M O'Dowd, Simon C Watkins, Maria Chikina, Yang Hong, Nathan L Clark, Adam V Kwiatkowski
The adherens junction couples the actin cytoskeletons of neighboring cells to provide the foundation for multicellular organization. The core of the adherens junction is the cadherin-catenin complex that arose early in the evolution of multicellularity to link actin to intercellular adhesions. Over time, evolutionary pressures have shaped the signaling and mechanical functions of the adherens junction to meet specific developmental and physiological demands. Evolutionary rate covariation (ERC) identifies proteins with correlated fluctuations in evolutionary rate that can reflect shared selective pressures and functions...
February 2019: PLoS Genetics
https://read.qxmd.com/read/30763280/cyclin-dependent-kinase-21-is-a-novel-regulator-of-proliferation-and-meiosis-in-the-male-germ-line-of-zebrafish
#9
Kaitlyn A Webster, Katrin Henke, Delaney M Ingalls, Adeeba Nahrin, Matthew P Harris, Kellee R Siegfried
Germ cell differentiation and maintenance relies on complex regulation of mitotic and meiotic progression. Cyclin-dependent kinases (Cdks) and their activating Cyclin partners are known to have specialized roles in regulating cell-cycle progression across tissues, including in germ cells. Very little is known about Cdk/Cyclin function in zebrafish, or the regulation of germ cell maintenance and differentiation. In a forward genetic screen for gonadogenesis defects in zebrafish, a mutation disrupting cdk21 (cyclin-dependent kinase 21) was identified, which caused gonad hypoplasia, reduced fertility, and failure of female sex specification...
February 1, 2019: Reproduction: the Official Journal of the Society for the Study of Fertility
https://read.qxmd.com/read/30763090/design-of-n-benzoxaborole-benzofuran-gsk8175-optimization-of-human-pk-inspired-by-metabolites-of-a-failed-clinical-hcv-inhibitor
#10
Pek Yoke Chong, J Brad Shotwell, John F Miller, Daniel J Price, Andy Maynard, Christian Voitenleitner, Amanda Mathis, Shawn Williams, Jeffrey Pouliot, Katrina Creech, Feng Wang, Jing M Fang, Huichang Zhang, Vincent Tai, Elizabeth Turner, Kristen M Kahler, Renae Crosby, Andrew J Peat
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which a N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein we describe second generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons...
February 14, 2019: Journal of Medicinal Chemistry
https://read.qxmd.com/read/30763087/open-boundary-molecular-mechanics-coarse-grained-framework-for-simulations-of-low-resolution-g-protein-coupled-receptor-ligand-complexes
#11
Thomas Tarenzi, Vania Calandrini, Raffaello Potestio, Paolo Carloni
G-protein-coupled receptors (GPCRs) constitute as much as 30% of the overall proteins targeted by FDA-approved drugs. However, paucity of structural experimental information and low sequence identity between members of the family impair the reliability of traditional docking approaches and atomistic molecular dynamics simulations for in silico pharmacological applications. We present here a dual-resolution approach tailored for such low-resolution models. It couples a hybrid Molecular Mechanics/Coarse-Grained (MM/CG) scheme, previously developed by us for GPCR/ligand complexes, with a Hamiltonian-based Adaptive Resolution Scheme (H-AdResS) for the solvent...
February 14, 2019: Journal of Chemical Theory and Computation
https://read.qxmd.com/read/30763067/discovery-and-structural-characterization-of-atp-site-ligands-for-the-wild-type-and-v617f-mutant-jak2-pseudokinase-domain
#12
Randall McNally, Qing Li, Kunhua Li, Carien Dekker, Eric Vangrevelinghe, Matthew Jones, Patrick Chene, Rainer Machauer, Thomas Radimerski, Michael J Eck
The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Exploration of analogs of screening hit BI-D1870 led to the identification of compound 2, a 123 nM ligand for the pseudokinase domain...
February 14, 2019: ACS Chemical Biology
https://read.qxmd.com/read/30763066/an-autoinducer-analog-reveals-an-alternative-mode-of-ligand-binding-for-the-lasr-quorum-sensing-receptor
#13
Jon E Paczkowski, Amelia R McCready, Jian-Ping Cong, Zhijie Li, Philip D Jeffrey, Chari D Smith, Brad R Henke, Frederick M Hughson, Bonnie L Bassler
Bacteria use a cell-cell communication process called quorum sensing to coordinate collective behaviors. Quorum sensing relies on production and group-wide detection of extracellular signal molecules called autoinducers. Here, we probe the activity of the Pseudomonas aeruginosa LasR quorum-sensing receptor using synthetic agonists based on the structure of the native homoserine lactone autoinducer. The synthetic compounds range from low to high potency, and agonist activity tracks with the ability of the agonist to stabilize the LasR protein...
February 14, 2019: ACS Chemical Biology
https://read.qxmd.com/read/30762928/bioinformatic-analysis-of-cacybp-associated-proteins-using-human-glioma-databases
#14
Chengmin Xuan, Yong Gao, Mingwei Jin, Shumei Xu, Lei Wang, Yuan Wang, Rui Han, Kunpeng Shi, Xincheng Chen, Qi An
The ubiquitin-proteasome system is the primary cellular pathway for protein degradation, mediating 80% of intracellular protein degradation. Because of the widespread presence of ubiquitin-modified protein substrates, ubiquitination can regulate a variety of cellular activities including cell proliferation, apoptosis, autophagy, endocytosis, DNA damage repair, and immune responses. With the continuous generation of genomics data in recent years it has become particularly important to analyze these data effectively and reasonably...
February 14, 2019: IUBMB Life
https://read.qxmd.com/read/30762924/spironolactone-induced-xpb-degradation-depends-on-cdk7-kinase-and-scf-fbxl-18-e3-ligase
#15
Masanobu Ueda, Kenkyo Matsuura, Hidehiko Kawai, Mitsuo Wakasugi, Tsukasa Matsunaga
The multi-subunit complex transcription factor IIH (TFIIH) has dual functions in transcriptional initiation and nucleotide excision repair (NER). TFIIH is comprised of two subcomplexes, the core subcomplex (7 subunits) including XPB and XPD helicases and the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex (3 subunits) containing CDK7 kinase. Recently, it has been reported that spironolactone, an anti-aldosterone drug, inhibits cellular NER by inducing proteasomal degradation of XPB and potentiates the cytotoxicity of platinum-based drugs in cancer cells, suggesting possible drug repositioning...
February 14, 2019: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://read.qxmd.com/read/30762606/the-role-of-somatic-mutational-events-in-the-pathogenesis-of-epilepsy
#16
Philip H Iffland, Peter B Crino
PURPOSE OF REVIEW: There has been rapid progress in defining novel causative gene variants responsible for a large spectrum of human epilepsy syndromes and subtypes. Of particular interest is the discovery that somatic mutations, for example, noninherited mutations occurring in neuroglial progenitor cells during embryonic brain development, are highly linked to malformations of cortical development (MCD) such as focal cortical dysplasia (FCD) type II and hemimegalencephaly. RECENT FINDINGS: Somatic gene variants have been identified in genes encoding regulatory proteins within the mechanistic target of rapamycin (mTOR) signaling cascade and have thus comprised the group classified as mTORopathies...
February 11, 2019: Current Opinion in Neurology
https://read.qxmd.com/read/30762520/the-structure-of-the-ctf19c-ccan-from-budding-yeast
#17
Stephen M Hinshaw, Stephen C Harrison
Eukaryotic kinetochores connect spindle microtubules to chromosomal centromeres. A group of proteins called the Ctf19 complex (Ctf19c) in yeast and the constitutive centromere associated network (CCAN) in other organisms creates the foundation of a kinetochore. The Ctf19c/CCAN influences the timing of kinetochore assembly, sets its location by associating with a specialized nucleosome containing the histone H3 variant Cse4/CENP-A, and determines the organization of the microtubule attachment apparatus. We present here the structure of a reconstituted 13-subunit Ctf19c determined by cryo-electron microscopy at ~4 Å resolution...
February 14, 2019: ELife
https://read.qxmd.com/read/30762367/complexation-behavior-of-%C3%AE-lactoglobulin-with-surface-active-ionic-liquids-in-aqueous-solutions-an-experimental-and-computational-approach
#18
Gagandeep Singh, Gurbir Singh, Srinivasarao Kancharla, Tejwant Singh Kang
The nature of functionalization of alkyl chain of imidazolium based surface active ionic liquids (SAILs) with amide- of ester-moiety led to contrasting complexation behavior towards globular protein, bovine serum albumin (BSA). This prompted us to further investigate the SAIL dependent colloidal behavior of another globular protein, -lactoglobulin (LG) to probe the origin of varying structural transformations in globular proteins induced by SAILs. Herein, we investigated the colloidal systems of βLG, rich in β-sheet structure, in the presence of four structurally different SAILs using a multi-technique approach...
February 14, 2019: Journal of Physical Chemistry. B
https://read.qxmd.com/read/30762072/nuclear-pore-protein-tpr-associates-with-lamin-b1-and-affects-nuclear-lamina-organization-and-nuclear-pore-distribution
#19
Jindřiška Fišerová, Miloslava Maninová, Tomáš Sieger, Jana Uhlířová, Lenka Šebestová, Michaela Efenberková, Martin Čapek, Karel Fišer, Pavel Hozák
The organization of the nuclear periphery is crucial for many nuclear functions. Nuclear lamins form dense network at the nuclear periphery and play a substantial role in chromatin organization, transcription regulation and in organization of nuclear pore complexes (NPCs). Here, we show that TPR, the protein located preferentially within the nuclear baskets of NPCs, associates with lamin B1. The depletion of TPR affects the organization of lamin B1 but not lamin A/C within the nuclear lamina as shown by stimulated emission depletion microscopy...
February 14, 2019: Cellular and Molecular Life Sciences: CMLS
https://read.qxmd.com/read/30762052/direct-observation-of-the-fast-and-robust-folding-of-a-slipknotted-protein-by-optical-tweezers
#20
Chengzhi He, Shuai Li, Xiaoqing Gao, Adam Xiao, Chunguang Hu, Xiaodong Hu, Xiaotang Hu, Hongbin Li
Understanding the folding mechanism of knotted and slipknotted proteins has attracted considerable interest. Due to their topological complexity, knotted and slipknotted proteins are predicted to fold slowly and involve large topological barriers. Molecular dynamics simulation studies suggest that a slipknotted conformation can serve as an important intermediate to help greatly reduce the topological difficulty during the folding of some knotted proteins. Here we use a single molecule optical tweezers technique to directly probe the folding of a small slipknotted protein AFV3-109...
February 14, 2019: Nanoscale
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