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https://www.readbyqxmd.com/read/28098815/replication-fork-protection-factors-controlling-r-loop-bypass-and-suppression
#1
REVIEW
Emily Yun-Chia Chang, Peter C Stirling
Replication-transcription conflicts have been a well-studied source of genome instability for many years and have frequently been linked to defects in RNA processing. However, recent characterization of replication fork-associated proteins has revealed that defects in fork protection can directly or indirectly stabilize R-loop structures in the genome and promote transcription-replication conflicts that lead to genome instability. Defects in essential DNA replication-associated activities like topoisomerase, or the minichromosome maintenance (MCM) helicase complex, as well as fork-associated protection factors like the Fanconi anemia pathway, both appear to mitigate transcription-replication conflicts...
January 14, 2017: Genes
https://www.readbyqxmd.com/read/28098160/a-zip6-zip10-heteromer-controls-ncam1-phosphorylation-and-integration-into-focal-adhesion-complexes-during-epithelial-to-mesenchymal-transition
#2
Dylan Brethour, Mohadeseh Mehrabian, Declan Williams, Xinzhu Wang, Farinaz Ghodrati, Sepehr Ehsani, Elizabeth A Rubie, James R Woodgett, Jean Sevalle, Zhengrui Xi, Ekaterina Rogaeva, Gerold Schmitt-Ulms
The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs 5, 6 and 10, raising the prospect that the study of these ZIPs may reveal insights relevant for understanding the function of PrP. Building on data which suggested PrP and ZIP6 are critical during epithelial-to-mesenchymal transition (EMT), we investigated ZIP6 in an EMT paradigm using ZIP6 knockout cells, mass spectrometry and bioinformatic methods. Reminiscent of PrP, ZIP6 levels are five-fold upregulated during EMT and the protein forms a complex with NCAM1...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28096518/structural-basis-for-guanidine-sensing-by-the-ykkc-family-of-riboswitches
#3
Robert A Battaglia, Ian R Price, Ailong Ke
Regulation of gene expression by cis-encoded riboswitches is a prevalent theme in bacteria. Of the hundreds of riboswitch families identified, the majority of them remain as orphans, without a clear ligand assignment. The ykkC orphan family was recently characterized as guanidine-sensing riboswitches. Herein we present a 2.04 Å crystal structure of the guanidine-bound ykkC riboswitch from Dickeya dadantii. The riboswitch folds into a boot-shaped structure, with a co-axially stacked P1/P2 stem forming the boot, and a 3'-P3 stem-loop forming the heel...
January 17, 2017: RNA
https://www.readbyqxmd.com/read/28096435/regulation-of-aldosterone-secretion-by-mineralocorticoid-receptor-mediated-signaling
#4
Cherish Chong, Anis Hamid, Tham Yao, Amanda Garza, Luminita Pojoga, Gail K Adler, Jose R Romero, Gordon H Williams
We posit the existence of a paracrine/autocrine negative feedback loop, mediated by the mineralocorticoid receptor (MR), regulating aldosterone secretion. To assess this hypothesis we asked whether altering MR activity in zona glomerulosa (ZG) cells affects aldosterone production. To this end, we studied ex vivo ZG cells isolated from male Wistar rats fed chow containing either high (1.6% Na+ [HS]) or low (0.03% Na+ [LS]) amount of sodium. Western blot analyses demonstrated that MR was present in both the ZG and zona fasciculata/zona reticularis (ZF/ZR/ZR)...
January 17, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28094136/day-and-night-glycaemic-control-with-closed-loop-insulin-delivery-versus-conventional-insulin-pump-therapy-in-free-living-adults-with-well-controlled-type-1-diabetes-an-open-label-randomised-crossover-study
#5
Lia Bally, Hood Thabit, Harald Kojzar, Julia K Mader, Jehona Qerimi-Hyseni, Sara Hartnell, Martin Tauschmann, Janet M Allen, Malgorzata E Wilinska, Thomas R Pieber, Mark L Evans, Roman Hovorka
BACKGROUND: Tight control of blood glucose concentration in people with type 1 diabetes predisposes to hypoglycaemia. We aimed to investigate whether day-and-night hybrid closed-loop insulin delivery can improve glucose control while alleviating the risk of hypoglycaemia in adults with HbA1c below 7·5% (58 mmol/mol). METHODS: In this open-label, randomised, crossover study, we recruited adults (aged ≥18 years) with type 1 diabetes and HbA1c below 7·5% from Addenbrooke's Hospital (Cambridge, UK) and Medical University of Graz (Graz, Austria)...
January 13, 2017: Lancet Diabetes & Endocrinology
https://www.readbyqxmd.com/read/28092538/spatio-temporal-closed-loop-object-detection
#6
Leonardo Galteri, Lorenzo Seidenari, Marco Bertini, Alberto Del Bimbo
Object detection is one of the most important tasks of computer vision. It is usually performed by evaluating a subset of the possible locations of an image that are more likely to contain the object of interest. Exhaustive approaches have now been superseded by object proposal methods. The interplay of detectors and proposal algorithms has not been fully analyzed and exploited up to now, although this is a very relevant problem for object detection in video sequences. We propose to connect, in a closed-loop, detectors and object proposal generator functions exploiting the ordered and continuous nature of video sequences...
January 10, 2017: IEEE Transactions on Image Processing: a Publication of the IEEE Signal Processing Society
https://www.readbyqxmd.com/read/28092267/cryo-em-structure-of-the-atp-sensitive-potassium-channel-illuminates-mechanisms-of-assembly-and-gating
#7
Gregory M Martin, Craig Yoshioka, Emily A Rex, Jonathan F Fay, Qing Xie, Matthew R Whorton, James Z Chen, Show-Ling Shyng
KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic β-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6Å resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0)...
January 16, 2017: ELife
https://www.readbyqxmd.com/read/28079137/x-ray-structure-and-enzymatic-activity-profile-of-a-core-papain-like-protease-of-mers-coronavirus-with-utility-for-structure-based-drug-design
#8
Jozlyn R Clasman, Yahira M Báez-Santos, Robert C Mettelman, Amornrat O'Brien, Susan C Baker, Andrew D Mesecar
Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the papain-like protease (PLpro) domain in coronavirus polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection. However, our recent cellular studies reveal that removing the Ubl2 domain from MERS PLpro has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins. Here, we test the hypothesis that the Ubl2 domain is not required for the catalytic function of MERS PLpro in vitro...
January 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28078474/clinical-audit-effectively-bridges-the-evidence-practice-gap-in-chronic-subdural-haematoma-management
#9
Jignesh Tailor, D Fernando, Z Sidhu, R Foley, K D Abeysinghe, D C Walsh
BACKGROUND: Placement of a subdural drain after drainage of chronic subdural haematoma (CSDH) has been shown to reduce the rate of recurrence in several randomised controlled trials (RCT). The most recently published RCT was from Cambridge, UK, in 2009. Despite class I evidence for the use of subdural drains, it is unclear whether these results have been translated into clinical practice. In this clinical audit we review the use of subdural drains in our institution before and after the publication of the 2009 RCT results...
January 11, 2017: Acta Neurochirurgica
https://www.readbyqxmd.com/read/28077651/bromodomain-containing-4-brd4-couples-nf%C3%AE%C2%BAb-rela-with-airway-inflammation-and-the-irf-rig-i-amplification-loop-in-respiratory-syncytial-virus-infection
#10
Bing Tian, Jun Yang, Yingxin Zhao, Teodora Ivanciuc, Hong Sun, Roberto P Garofalo, Allan R Brasier
: The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to Respiratory Syncytial Virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) in mediating this innate immune response in human small airway epithelial cells. We observe that RSV induces BRD4 to complex with NFκB/RelA. BRD4 is functionally required for expression of the NFκB-dependent inflammatory gene regulatory network (GRN), including the IFN Response Factor (IRFs)-1 and -7 that mediate a cross-talk pathway for RIG-I upregulation...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28077635/virion-structure-of-black-queen-cell-virus-a-common-honeybee-pathogen
#11
Radovan Spurny, Antonín Přidal, Lenka Pálková, Hoa Khanh Tran Kiem, Joachim R de Miranda, Pavel Plevka
: Viral diseases are a major threat to honeybee (Apis mellifera) populations world-wide and therefore an important factor in reliable crop pollination and food security. Black queen cell virus (BQCV) is the etiological agent of a fatal disease of honeybee queen larvae and pupae. The virus belongs to the genus Triatovirus from the family Dicistroviridae that is part of the order Picornavirales Here we present a crystal structure of BQCV determined to a resolution of 3.4 Å. The virion is formed by sixty copies of each of the major capsid proteins VP1, VP2, and VP3, however there is no density corresponding to a 75-residue-long minor capsid protein VP4 encoded by the BQCV genome...
11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28076827/new-diphenylmethane-derivatives-as-peroxisome-proliferator-activated-receptor-alpha-gamma-dual-agonists-endowed-with-anti-proliferative-effects-and-mitochondrial-activity
#12
Luca Piemontese, Carmen Cerchia, Antonio Laghezza, Pamela Ziccardi, Sabina Sblano, Paolo Tortorella, Vito Iacobazzi, Vittoria Infantino, Paolo Convertini, Fabrizio Dal Piaz, Angelo Lupo, Vittorio Colantuoni, Antonio Lavecchia, Fulvio Loiodice
We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers...
December 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28076779/transcription-dynamics-prevent-rna-mediated-genomic-instability-through-srpk2-dependent-ddx23-phosphorylation
#13
Sreerama Chaitanya Sridhara, Sílvia Carvalho, Ana Rita Grosso, Lina Marcela Gallego-Paez, Maria Carmo-Fonseca, Sérgio Fernandes de Almeida
Genomic instability is frequently caused by nucleic acid structures termed R-loops that are formed during transcription. Despite their harmful potential, mechanisms that sense, signal, and suppress these structures remain elusive. Here, we report that oscillations in transcription dynamics are a major sensor of R-loops. We show that pausing of RNA polymerase II (RNA Pol II) initiates a signaling cascade whereby the serine/arginine protein kinase 2 (SRPK2) phosphorylates the DDX23 helicase, culminating in the suppression of R-loops...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076681/computational-modeling-of-neurotransmitter-release-evoked-by-electrical-stimulation-non-linear-approaches-to-predicting-stimulation-evoked-dopamine-release
#14
James K Trevathan, Ali Yousefi, Hyung Ook Park, John J Bartoletta, Kip A Ludwig, Kendall H Lee, J Luis Lujan
Neurochemical changes evoked by electrical stimulation of the nervous system have been linked to both therapeutic and undesired effects of neuromodulation therapies used to treat obsessive-compulsive disorder, depression, epilepsy, Parkinson's disease, stroke, hypertension, tinnitus, and many other indications. In fact, interest in better understanding the role of neurochemical signaling in neuromodulation therapies has been a focus of recent government- and industry-sponsored programs whose ultimate goal is to usher in an era of personalized medicine by creating neuromodulation therapies that respond to real-time changes in patient status...
January 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28076415/structure-and-recognition-of-a-novel-hiv-1-gp120-gp41-interface-antibody-that-caused-mper-exposure-through-viral-escape
#15
Constantinos Kurt Wibmer, Jason Gorman, Gabriel Ozorowski, Jinal N Bhiman, Daniel J Sheward, Debra H Elliott, Julie Rouelle, Ashley Smira, M Gordon Joyce, Nonkululeko Ndabambi, Aliaksandr Druz, Mangai Asokan, Dennis R Burton, Mark Connors, Salim S Abdool Karim, John R Mascola, James E Robinson, Andrew B Ward, Carolyn Williamson, Peter D Kwong, Lynn Morris, Penny L Moore
A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28069814/muc2-mucin-and-butyrate-contribute-to-the-synthesis-of-the-antimicrobial-peptide-cathelicidin-in-response-to-e-histolytica-and-dss-induced-colitis
#16
Eduardo R Cobo, Vanessa Kissoon-Singh, France Moreau, Ravi Holani, Kris Chadee
Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP), LL-37/hCAP-18 and Cramp respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity against Entamoeba histolytica (Eh) are not well characterized...
January 9, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28068996/non-linear-parameters-of-specific-resistance-loops-to-characterise-obstructive-airways-diseases
#17
Marko Topalovic, Vasileios Exadaktylos, Thierry Troosters, Geert Celis, Jean-Marie Aerts, Wim Janssens
BACKGROUND: Specific resistance loops appear in different shapes influenced by different resistive properties of the airways, yet their descriptive ability is compressed to a single parameter - its slope. We aimed to develop new parameters reflecting the various shapes of the loop and to explore their potential in the characterisation of obstructive airways diseases. METHODS: Our study included 134 subjects: Healthy controls (N = 22), Asthma with non-obstructive lung function (N = 22) and COPD of all disease stages (N = 90)...
January 9, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28065739/r-loop-depletion-by-over-expressed-rnase-h1-in-mouse-b-cells-increases-activation-induced-deaminase-access-to-the-transcribed-strand-without-altering-frequency-of-isotype-switching
#18
Robert W Maul, Hyongi Chon, Kiran Sakhuja, Susana M Cerritelli, Lina A Gugliotti, Patricia J Gearhart, Robert J Crouch
R-loops, three-strand structures consisting of mRNA hybridized to the complementary DNA and a single-stranded DNA loop, are formed in switch regions on the heavy-chain immunoglobulin locus. To determine if R-loops have a direct effect on any of the steps involved in isotype switching, we generated a transgenic mouse that over-expressed RNase H1, an enzyme that cleaves the RNA of RNA/DNA hybrids in B cells. R-loops in the switch μ region were depleted by 70% in ex vivo activated splenic B cells. Frequencies of isotype switching to IgG1, IgG2b, IgG2c, and IgG3 were the same as C57BL/6 control cells...
January 6, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28064285/unusual-duplication-in-the-pericentromeric-region-of-chromosome-9-in-a-patient-with-phenotypic-alterations
#19
Andréa C M Malinverni, Mileny E Colovati, Ana B A Perez, Thamy P Caneloi, Hélio R Oliveira, Nadezda Kosyakova, Thomas Liehr, Ahmed B Hamid, Maria I Melaragno
Several alterations involving the pericentromeric region of chromosome 9 are considered as normal population variants. These heterochromatic variants or heteromorphisms can include 9qh+, 9cen+, 9ph+, 9ph-, inv(9)(p11q13), and other patterns which can only be defined by FISH studies. However, some heteromorphisms have been found more frequently in patients with several clinical disorders. Here, we report on a patient with intellectual disability, language and neurodevelopmental delay, as well as facial dysmorphism and an unusual chromosome 9...
January 7, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28063499/analysis-of-phosphatidic-acid-binding-and-regulation-of-pipki-in-vitro-and-in-intact-cells
#20
L W R Tay, Z Wang, G Du
Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is a lipid second messenger that regulates a wide array of essential cellular events, such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, adhesion, and motility. To control the spatiotemporal production of PI(4,5)P2, the activity of type 1 phosphotidylinositol-4-phosphate-5-kinases (PIPKIs) is tightly regulated by small GTPases and another signaling lipid, phosphatidic acid (PA). It is of interest that PI(4,5)P2 is also a critical cofactor for the activation of the PA-generating enzyme, phospholipase D (PLD)...
2017: Methods in Enzymology
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