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https://www.readbyqxmd.com/read/29753164/a-novel-approach-of-virulome-based-reverse-vaccinology-for-exploring-and-validating-peptide-based-vaccine-candidates-against-the-most-troublesome-nosocomial-pathogen-acinetobacter-baumannii
#1
Sajjad Ahmad, Syed Sikander Azam
Acinetobacter baumannii is one of the major cause of nosocomial infections around the globe. The emergence of hyper-virulent strains of the pathogen greatly narrows down therapeutic options for patients infected with this red alert superbug. Development of a peptide-based vaccine can offers an alternative, attractive, and cost-effective remedy for multidrug-resistant A. baumannii associated complications. Herein, we introduced a novel virulome based Reverse Vaccinology for screening peptide based vaccine candidates against A...
May 5, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29728854/improved-l-ornithine-production-in-corynebacterium-crenatum-by-introducing-an-artificial-linear-transacetylation-pathway
#2
Qunfeng Shu, Meijuan Xu, Jing Li, Taowei Yang, Xian Zhang, Zhenghong Xu, Zhiming Rao
L-Ornithine is a non-protein amino acid with extensive applications in the food and pharmaceutical industries. In this study, we performed metabolic pathway engineering of an L-arginine hyper-producing strain of Corynebacterium crenatum for L-ornithine production. First, we amplified the L-ornithine biosynthetic pathway flux by blocking the competing branch of the pathway. To enhance L-ornithine synthesis, we performed site-directed mutagenesis of the ornithine-binding sites to solve the problem of L-ornithine feedback inhibition for ornithine acetyltransferase...
May 4, 2018: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/29697047/rev7-and-53bp1-crb2-prevent-recq-helicase-dependent-hyper-resection-of-dna-double-strand-breaks
#3
Bryan A Leland, Angela C Chen, Amy Y Zhao, Robert C Wharton, Megan C King
Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5' ends of a DSB. For example, loss of 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2...
April 26, 2018: ELife
https://www.readbyqxmd.com/read/29615404/the-tumor-suppressive-tgf-%C3%AE-smad1-s1pr2-signaling-axis-is-recurrently-inactivated-in-diffuse-large-b-cell-lymphoma
#4
Anna Stelling, Hind Hashwah, Katrin Bertram, Markus G Manz, Alexandar Tzankov, Anne Müller
The sphingosine-1-phosphate receptor S1PR2 and its downstream signaling pathway is commonly silenced in diffuse large B-cell lymphoma (DLBCL), either by mutational inactivation or through negative regulation by the oncogenic transcription factor FOXP1. In this study, we have examined the upstream regulators of S1PR2 expression and have newly identified the TGF-β/TGF-βR2/SMAD1 axis as critically involved in S1PR2 transcriptional activation. Phosphorylated SMAD1 directly binds to regulatory elements in the S1PR2 locus as assessed by chromatin immunoprecipitation, and the CRISPR-mediated genomic editing of S1PR2 , SMAD1 or TGFBR2 in DLBCL cell lines renders cells unresponsive to TGF-β-induced apoptosis...
April 3, 2018: Blood
https://www.readbyqxmd.com/read/29558460/p53-as-a-dichotomous-regulator-of-liver-disease-the-dose-makes-the-medicine
#5
REVIEW
Jelena Krstic, Markus Galhuber, Tim J Schulz, Michael Schupp, Andreas Prokesch
Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues...
March 20, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29507606/mn-2-modulates-the-expression-of-cellulase-genes-in-trichoderma-reesei-rut-c30-via-calcium-signaling
#6
Yumeng Chen, Yaling Shen, Wei Wang, Dongzhi Wei
Background: The filamentous fungus Trichoderma reesei Rut-C30 is one of the most vital fungi for the production of cellulases, which can be used for biofuel production from lignocellulose. Nevertheless, the mechanism of transmission of external stimuli and signals in modulating cellulase production in T. reesei Rut-C30 remains unclear. Calcium is a known second messenger regulating cellulase gene expression in T. reesei . Results: In this study, we found that a biologically relevant extracellular Mn2+ concentration markedly stimulates cellulase production, total protein secretion, and the intracellular Mn2+ concentration of Rut-C30, a cellulase hyper-producing strain of T...
2018: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/29483281/differential-synaptic-remodeling-by-dopamine-in-direct-and-indirect-striatal-projection-neurons-in-pitx3-mice-a-genetic-model-of-parkinson-s-disease
#7
Luz M Suarez, Samuel Alberquilla, Jose R García-Montes, Rosario Moratalla
In toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SPNs (iSPNs), whereas spine loss and hyperexcitability persist in direct pathway SPNs (dSPNs). These alterations have only been characterized in toxin-based models of PD, raising the possibility that they are an artifact of exposure to the toxin, which may engage compensatory mechanisms independent of the PD-like pathology or due to the loss of dopaminergic afferents...
April 11, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29357448/propagation-of-beta-gamma-rhythms-in-the-cortico-basal-ganglia-circuits-of-the-parkinsonian-rat
#8
Timothy Owen West, Luc Berthouze, David M Halliday, Vladimir Litvak, Andrew Sharott, Peter J Magill, Simon F Farmer
Much of the motor impairment associated with Parkinson's disease is thought to arise from pathological activity in the networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in Parkinsonism, we investigated changes to the directed connectivity in BG networks following dopamine depletion. We recorded local field potentials (LFPs) in the cortex and basal ganglia of rats rendered Parkinsonian by injection of 6-hydroxydopamine (6-OHDA) and in dopamine-intact controls...
January 10, 2018: Journal of Neurophysiology
https://www.readbyqxmd.com/read/29351448/extracellular-oxidation-in-cystic-fibrosis-airway-epithelium-causes-enhanced-egfr-adam17-activity
#9
Marta Stolarczyk, Guido Veit, Andrea Schnúr, Mieke Veltman, Gergely L Lukacs, Bob J Scholte
The EGF receptor (EGFR)/a disintegrin and metalloproteinase 17 (ADAM17) signaling pathway mediates the shedding of growth factors and secretion of cytokines and is involved in chronic inflammation and tissue remodeling. Since these are hallmarks of cystic fibrosis (CF) lung disease, we hypothesized that CF transmembrane conductance regulator (CFTR) deficiency enhances EGFR/ADAM17 activity in human bronchial epithelial cells. In CF bronchial epithelial CFBE41o- cells lacking functional CFTR (iCFTR- ) cultured at air-liquid interface (ALI) we found enhanced ADAM17-mediated shedding of the EGFR ligand amphiregulin (AREG) compared with genetically identical cells with induced CFTR expression (iCFTR+ )...
April 1, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29343707/sensory-neuronal-p2rx4-receptors-controls-bdnf-signaling-in-inflammatory-pain
#10
Sarah Lalisse, Jennifer Hua, Manon Lenoir, Nathalie Linck, François Rassendren, Lauriane Ulmann
Chronic inflammatory and neuropathic pains are major public health concerns. Potential therapeutic targets include the ATP-gated purinergic receptors (P2RX) that contribute to these pathological types of pain in several different cell types. The purinergic receptors P2RX2 and P2RX3 are expressed by a specific subset of dorsal root ganglion neurons and directly shape pain processing by primary afferents. In contrast the P2RX4 and P2RX7 are mostly expressed in myeloid cells, where activation of these receptors triggers the release of various pro-inflammatory molecules...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343547/molecular-pathways-for-immune-recognition-of-preproinsulin-signal-peptide-in-type-1-diabetes
#11
Deborah Kronenberg-Versteeg, Martin Eichmann, Mark A Russell, Arnoud de Ru, Beate Hehn, Norkhairin Yusuf, Peter A van Veelen, Sarah J Richardson, Noel G Morgan, Marius K Lemberg, Mark Peakman
The signal peptide region of preproinsulin (PPI) contains epitopes targeted by human leucocyte antigen-A (HLA-A)-restricted (HLA-A0201, A2402) cytotoxic T-cells as part of the pathogenesis of β-cell destruction in type 1 diabetes. We extended PPI epitope discovery to disease-associated HLA-B*1801 and HLA-B*3906 (risk) and HLA-A*1101 and HLA-B*3801 (protective) alleles revealing that 4/6 alleles present epitopes derived from the signal peptide region. During co-translational translocation of PPI, its signal peptide is cleaved and retained within the endoplasmic reticulum (ER) membrane, implying it is processed for immune recognition outside of the canonical, proteasome-directed pathway...
January 17, 2018: Diabetes
https://www.readbyqxmd.com/read/29324765/brassinosteroids-regulate-root-growth-by-controlling-reactive-oxygen-species-homeostasis-and-dual-effect-on-ethylene-synthesis-in-arabidopsis
#12
Bingsheng Lv, Huiyu Tian, Feng Zhang, Jiajia Liu, Songchong Lu, Mingyi Bai, Chuanyou Li, Zhaojun Ding
The brassinosteroids (BRs) represent a class of phytohormones, which regulate numerous aspects of growth and development. Here, a det2-9 mutant defective in BR synthesis was identified from an EMS mutant screening for defects in root length, and was used to investigate the role of BR in root development in Arabidopsis. The det2-9 mutant displays a short-root phenotype, which is result from the reduced cell number in root meristem and decreased cell size in root maturation zone. Ethylene synthesis is highly increased in the det2-9 mutant compared with the wild type, resulting in the hyper-accumulation of ethylene and the consequent inhibition of root growth...
January 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29321253/role-of-the-hof1-cyk3-interaction-in-cleavage-furrow-ingression-and-primary-septum-formation-during-yeast-cytokinesis
#13
Meng Wang, Ryuichi Nishihama, Masayuki Onishi, John R Pringle
In Saccharomyces cerevisiae, it is well established that Hof1, Cyk3, and Inn1 contribute to septum formation and cytokinesis. Because hof1∆ and cyk3∆ single mutants have relatively mild defects but hof1∆ cyk3∆ double mutants are nearly dead, it has been hypothesized that these proteins contribute to parallel pathways. However, there is also evidence that they interact physically. In this study, we examined this interaction and its functional significance in detail. Our data indicate that the interaction 1) is mediated by a direct binding of the Hof1 SH3 domain to a proline-rich motif in Cyk3; 2) occurs specifically at the time of cytokinesis but is independent of the (hyper)phosphorylation of both proteins that occurs at about the same time; 3) is dispensable for the normal localization of both proteins; 4) is essential for normal primary-septum formation and a normal rate of cleavage-furrow ingression; and 5) becomes critical for growth when either Inn1 or the type II myosin Myo1 (a key component of the contractile actomyosin ring) is absent...
March 1, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29236724/the-role-of-cortical-oscillations-in-a-spiking-neural-network-model-of-the-basal-ganglia
#14
Zafeirios Fountas, Murray Shanahan
Although brain oscillations involving the basal ganglia (BG) have been the target of extensive research, the main focus lies disproportionally on oscillations generated within the BG circuit rather than other sources, such as cortical areas. We remedy this here by investigating the influence of various cortical frequency bands on the intrinsic effective connectivity of the BG, as well as the role of the latter in regulating cortical behaviour. To do this, we construct a detailed neural model of the complete BG circuit based on fine-tuned spiking neurons, with both electrical and chemical synapses as well as short-term plasticity between structures...
2017: PloS One
https://www.readbyqxmd.com/read/29212878/a-complex-molecular-switch-directs-stress-induced-cyclin-c-nuclear-release-through-scf-grr1-mediated-degradation-of-med13
#15
David C Stieg, Stephen D Willis, Vidyaramanan Ganesan, Kai Li Ong, Joseph Scuorzo, Mia Song, Julianne Grose, Randy Strich, Katrina F Cooper
In response to oxidative stress, cells decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module, which, with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In Saccharomyces cerevisiae , oxidative stress triggers Med13 destruction, which thereafter releases cyclin C into the cytoplasm. Cytoplasmic cyclin C associates with mitochondria, where it induces hyperfragmentation and regulated cell death...
February 1, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29177441/de-novo-mutations-in-caudal-type-homeo-box-transcription-factor-2-cdx2-in-patients-with-persistent-cloaca
#16
Jacob S J Hsu, Manting So, Clara S M Tang, Anwarul Karim, Robert M Porsch, Carol Wong, Michelle Yu, Fanny Yeung, Huimin Xia, Ruizhong Zhang, Stacey S Cherny, Patrick H Y Chung, Kenneth K Y Wong, Pak C Sham, Ngoc Diem Ngo, Miaoxin Li, Paul K H Tam, Vincent C H Lui, Maria-Mercè Garcia-Barcelo
The cloaca is an embryonic cavity that is divided into the urogenital sinus and rectum upon differentiation of the cloacal epithelium triggered by tissue-specific transcription factors including CDX2. Defective differentiation leads to persistent cloaca in humans (PC), a phenotype recapitulated in Cdx2 mutant mice. PC is linked to hypo/hyper-vitaminosis A. Although no gene has ever been identified, there is a strong evidence for a genetic contribution to PC. We applied whole-exome sequencing and copy-number-variants analyses to 21 PC patients and their unaffected parents...
January 15, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29167757/amino-acid-catabolism-directed-biofuel-production-in-clostridium-sticklandii-an-insight-into-model-driven-systems-engineering
#17
REVIEW
C Sangavai, P Chellapandi
Model-driven systems engineering has been more fascinating process for the microbial production of biofuel and bio-refineries in chemical and pharmaceutical industries. Genome-scale modeling and simulations have been guided for metabolic engineering of Clostridium species for the production of organic solvents and organic acids. Among them, Clostridium sticklandii is one of the potential organisms to be exploited as a microbial cell factory for biofuel production. It is a hyper-ammonia producing bacterium and is able to catabolize amino acids as important carbon and energy sources via Stickland reactions and the development of the specific pathways...
December 2017: Biotechnology Reports
https://www.readbyqxmd.com/read/29046870/-salmonella-populations-inside-host-cells
#18
REVIEW
Sónia Castanheira, Francisco García-Del Portillo
Bacteria of the Salmonella genus cause diseases ranging from gastroenteritis to life-threatening typhoid fever and are among the most successful intracellular pathogens known. After the invasion of the eukaryotic cell, Salmonella exhibits contrasting lifestyles with different replication rates and subcellular locations. Although Salmonella hyper-replicates in the cytosol of certain host cell types, most invading bacteria remain within vacuoles in which the pathogen proliferates at moderate rates or persists in a dormant-like state...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29018800/asthma-endotypes-and-an-overview-of-targeted-therapy-for-asthma
#19
REVIEW
Sarah Svenningsen, Parameswaran Nair
Guidelines for the management of severe asthma do not emphasize the measurement of the inflammatory component of airway disease to indicate appropriate treatments or to monitor response to treatment. Inflammation is a central component of asthma and contributes to symptoms, physiological, and structural abnormalities. It can be assessed by a number of endotyping strategies based on "omics" technology such as proteomics, transcriptomics, and metabolomics. It can also be assessed using simple cellular responses by quantitative cytometry in sputum...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28972144/resistance-to-pyridine-based-inhibitor-kf116-reveals-an-unexpected-role-of-integrase-in-hiv-1-gag-pol-polyprotein-proteolytic-processing
#20
Ashley C Hoyte, Augusta V Jamin, Pratibha C Koneru, Matthew J Kobe, Ross C Larue, James R Fuchs, Alan N Engelman, Mamuka Kvaratskhelia
The pyridine-based multimerization selective HIV-1 integrase (IN) inhibitors (MINIs) are a distinct subclass of allosteric IN inhibitors. MINIs potently inhibit HIV-1 replication during virion maturation by inducing hyper- or aberrant IN multimerization but are largely ineffective during the early steps of viral replication. Here, we investigated the mechanism for the evolution of a triple IN substitution (T124N/V165I/T174I) that emerges in cell culture with a representative MINI, KF116. We show that HIV-1 NL4-3(IN T124N/V165I/T174I) confers marked (>2000-fold) resistance to KF116...
December 1, 2017: Journal of Biological Chemistry
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