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https://www.readbyqxmd.com/read/29348121/endothelial-cell-derived-von-willebrand-factor-but-not-platelet-derived-promotes-atherosclerosis-in-apolipoprotein-e-deficient-mice
#1
Prakash Doddapattar, Nirav Dhanesha, Mehul R Chorawala, Chandler Tinsman, Manish Jain, Manasa K Nayak, Janice M Staber, Anil K Chauhan
OBJECTIVE: VWF (von Willebrand factor) is synthesized by endothelial cells and megakaryocytes and is known to contribute to atherosclerosis. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically and functionally different from endothelial cell-derived VWF (EC-VWF). We determined the role of different pools of VWF in the pathophysiology of atherosclerosis. APPROACH AND RESULTS: Using bone marrow transplantation, we generated chimeric Plt-VWF, EC-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 in platelets and plasma on apolipoprotein E-deficient (Apoe-/-) background...
January 18, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29343767/blockade-of-trpv1-inhibits-methamphetamine-induced-rewarding-effects
#2
Yu-Hua Tian, Shi-Xun Ma, Kwang-Wook Lee, Sunmee Wee, George F Koob, Seok-Yong Lee, Choon-Gon Jang
Methamphetamine (MAP) is the most widely used psychostimulant in the world, but the exact mechanisms underlying MAP addiction are not yet fully understood. Recent studies have identified the distribution of TRPV1 in several brain regions that are related to drug addiction, including nucleus accumbens (NAc) and dorsal striatum (DSt). In the present study, we performed conditioned place preference (CPP) and self-administration tests to examine the effects of capsazepine (CPZ) and SB366791 (SB) on MAP reward. We found that both CPZ and SB significantly inhibited MAP-induced CPP and self-administration; in contrast, TRPV1 knock-out (KO) mice did not develop MAP-induced CPP...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343749/testosterone-boosts-physical-activity-in-male-mice-via-dopaminergic-pathways
#3
Ferran Jardí, Michaël R Laurent, Nari Kim, Rougin Khalil, Dimitri De Bundel, Ann Van Eeckhaut, Lawrence Van Helleputte, Ludo Deboel, Vanessa Dubois, Dieter Schollaert, Brigitte Decallonne, Geert Carmeliet, Ludo Van den Bosch, Rudi D'Hooge, Frank Claessens, Dirk Vanderschueren
Low testosterone (T) in men, especially its free fraction, has been associated with loss of energy. In accordance, orchidectomy (ORX) in rodents results in decreased physical activity. Still, the mechanisms through which T stimulates activity remain mostly obscure. Here, we studied voluntary wheel running behavior in three different mouse models of androgen deficiency: ORX, androgen receptor (AR) knock-out (ARKO) and sex hormone binding globulin (SHBG)-transgenic mice, a novel mouse model of "low free T". Our results clearly show a fast and dramatic action of T stimulating wheel running, which is not explained by its action on muscle, as evidenced by neuromuscular studies and in a muscle-specific conditional ARKO mouse model...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29338841/the-starch-utilization-system-assembles-around-stationary-starch-binding-proteins
#4
Hannah H Tuson, Matthew H Foley, Nicole M Koropatkin, Julie S Biteen
Bacteroides thetaiotaomicron (Bt) is a prominent member of the human gut microbiota with an extensive capacity for glycan harvest. This bacterium expresses a five-protein complex in the outer membrane, called the starch utilization system (Sus), which binds, degrades, and imports starch into the cell. Sus is a model system for the many glycan-targeting polysaccharide utilization loci found in Bt and other members of the Bacteroidetes phylum. Our previous work has shown that SusG, a lipidated amylase in the outer membrane, explores the entire cell surface but diffuses more slowly as it interacts with starch...
January 12, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29330493/development-of-versatile-non-homologous-end-joining-based-knock-in-module-for-genome-editing
#5
Shun Sawatsubashi, Yudai Joko, Seiji Fukumoto, Toshio Matsumoto, Shigeo S Sugano
CRISPR/Cas9-based genome editing has dramatically accelerated genome engineering. An important aspect of genome engineering is efficient knock-in technology. For improved knock-in efficiency, the non-homologous end joining (NHEJ) repair pathway has been used over the homology-dependent repair pathway, but there remains a need to reduce the complexity of the preparation of donor vectors. We developed the versatile NHEJ-based knock-in module for genome editing (VIKING). Using the consensus sequence of the time-honored pUC vector to cut donor vectors, any vector with a pUC backbone could be used as the donor vector without customization...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29327641/generation-of-an-arrayed-crispr-cas9-library-targeting-epigenetic-regulators-from-high-content-screens-to-in-vivo-assays
#6
Tristan Henser-Brownhill, Josep Monserrat, Paola Scaffidi
The CRISPR-Cas9 system has revolutionized genome engineering, allowing precise modification of DNA in various organisms. The most popular method for conducting CRISPR-based functional screens involves the use of pooled lentiviral libraries in selection screens coupled with next-generation sequencing. Screens employing genome-scale pooled small guide RNA (sgRNA) libraries are demanding, particularly when complex assays are used. Furthermore, pooled libraries are not suitable for microscopy-based high-content screens or for systematic interrogation of protein function...
January 12, 2018: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/29311600/depdc5-deficiency-contributes-to-resistance-to-leucine-starvation-via-p62-accumulation-in-hepatocellular-carcinoma
#7
Yuki Mizuno, Shu Shimada, Yoshimitsu Akiyama, Shuichi Watanabe, Tomomi Aida, Kosuke Ogawa, Hiroaki Ono, Yusuke Mitsunori, Daisuke Ban, Atsushi Kudo, Shigeki Arii, Shoji Yamaoka, Minoru Tanabe, Shinji Tanaka
Decrease in blood concentration of branched-chain amino acids, especially leucine, is known to promote liver carcinogenesis in patients with chronic liver disease, but the mechanism is unclear. We herein established hepatocellular carcinoma (HCC) cells knocked out for DEPDC5 by using the CRISPR/Cas9 system, and elucidated that cell viability of the DEPDC5 knockout (DEPDC5-KO) cells was higher than that of the DEPDC5 wild-type (DEPDC5-WT) under leucine starvation. Considering that autophagy deficiency might be involved in acquired resistance to leucine deprivation, we observed reduction of LC3-II followed by accumulation of p62 in the DEPDC5-KO, which induced reactive oxygen species (ROS) tolerance...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29304082/striated-muscle-gene-therapy-for-the-treatment-of-lipoprotein-lipase-deficiency
#8
Katherine E Gadek, Hong Wang, Monica N Hall, Mitchell Sungello, Andrew Libby, Drew MacLaskey, Robert H Eckel, Bradley B Olwin
Excessive circulating triglycerides due to reduction or loss of lipoprotein lipase activity contribute to hypertriglyceridemia and increased risk for pancreatitis. The only gene therapy treatment for lipoprotein lipase deficiency decreases pancreatitis but minimally reduces hypertriglyceridemia. Synthesized in multiple tissues including striated muscle and adipose tissue, lipoprotein lipase is trafficked to blood vessel endothelial cells where it is anchored at the plasma membrane and hydrolyzes triglycerides into free fatty acids...
2018: PloS One
https://www.readbyqxmd.com/read/29298325/conditional-ablation-of-the-rfx4-isoform-1-transcription-factor-allele-dosage-effects-on-brain-phenotype
#9
Ping Xu, James P Morrison, Julie F Foley, Deborah J Stumpo, Toni Ward, Darryl C Zeldin, Perry J Blackshear
Regulatory factor X4 (RFX4) isoform 1 is a recently discovered isoform of the winged helix transcription factor RFX4, which can bind to X-box consensus sequences that are enriched in the promoters of cilia-related genes. Early insertional mutagenesis studies in mice first identified this isoform, and demonstrated that it was crucial for mouse brain development. RFX4 isoform 1 is the only RFX4 isoform significantly expressed in the mouse fetal and adult brain. In this study, we evaluated conditional knock-out (KO) mice in which one or two floxed alleles of Rfx4 were deleted early in development through the use of a Sox2-Cre transgene...
2018: PloS One
https://www.readbyqxmd.com/read/29279301/inositol-polyphosphate-multikinase-inhibits-angiogenesis-via-inositol-pentakisphosphate-induced-hif-1%C3%AE-degradation
#10
Chenglai Fu, Richa Tyagi, Alfred C Chin, Tomas Rojas, Ruo-Jing Li, Prasun Guha, Isaac A Bernstein, Feng Rao, Risheng Xu, Jiyoung Y Cha, Jing Xu, Adele M Snowman, Gregg L Semenza, Solomon H Snyder
Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. Objective: We have investigated the role of IPMK in regulating angiogenesis. Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of vascular endothelial growth factor (VEGF), which mediates the regulation of angiogenesis by IPMK...
December 26, 2017: Circulation Research
https://www.readbyqxmd.com/read/29246262/ebi2-receptor-regulates-myelin-development-and-inhibits-lpc-induced-demyelination
#11
Aleksandra Rutkowska, Andreas W Sailer, Kumlesh K Dev
BACKGROUND: The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7α, 25-dihydroxycholesterol (7α25HC) and plays a role in T cell-dependant antibody response and B cell migration. Abnormal EBI2 signaling is implicated in a range of autoimmune disorders; however, its role in the CNS remains poorly understood. METHODS: Here we characterize the role of EBI2 in myelination under normal and pathophysiological conditions using organotypic cerebellar slice cultures and EBI2 knock-out (KO) animals...
December 16, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29231847/natural-knockouts-natural-selection-knocked-out
#12
Peter Borger
In functional genomics studies, research is dedicated to unveiling the function of genes using gene-knockouts, model organisms in which a gene is artificially inactivated. The idea is that, by knocking out the gene, the provoked phenotype would inform us about the function of the gene. Still, the function of many genes cannot be elucidated, because disruption of conserved sequences, including protein-coding genes, often does not directly affect the phenotype. Since the phenomenon was first observed in the early nineties of the last century, these so-called 'no-phenotype knockouts' have met with great skepticism and resistance by died-in-the-wool selectionists...
December 12, 2017: Biology
https://www.readbyqxmd.com/read/29213330/renewable-synthesis-of-n-butyraldehyde-from-glucose-by-engineered-escherichia-coli
#13
Jason T Ku, Wiwik Simanjuntak, Ethan I Lan
Background: n-Butyraldehyde is a high-production volume chemical produced exclusively from hydroformylation of propylene. It is a versatile chemical used in the synthesis of diverse C4-C8 alcohols, carboxylic acids, esters, and amines. Its high demand and broad applications make it an ideal chemical to be produced from biomass. Results: An Escherichia coli strain was engineered to produce n-butyraldehyde directly from glucose by expressing a modified Clostridium CoA-dependent n-butanol production pathway with mono-functional Coenzyme A-acylating aldehyde dehydrogenase (Aldh) instead of the natural bifunctional aldehyde/alcohol dehydrogenase...
2017: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/29212945/refining-the-roles-of-neuroligins-in-synapse-development-and-function-a-reductionist-conditional-knock-out-approach
#14
Hunter S Shaw, Christopher K Salmon
No abstract text is available yet for this article.
December 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29203887/age-dependent-increase-of-oxidative-stress-regulates-microrna-29-family-preserving-cardiac-health
#15
Johanna Heid, Chiara Cencioni, Roberto Ripa, Mario Baumgart, Sandra Atlante, Giuseppina Milano, Alessandro Scopece, Carsten Kuenne, Stefan Guenther, Valerio Azzimato, Antonella Farsetti, Giacomo Rossi, Thomas Braun, Giulio Pompilio, Fabio Martelli, Andreas M Zeiher, Alessandro Cellerino, Carlo Gaetano, Francesco Spallotta
The short-lived turquoise killifish Nothobranchius furzeri (Nfu) is a valid model for aging studies. Here, we investigated its age-associated cardiac function. We observed oxidative stress accumulation and an engagement of microRNAs (miRNAs) in the aging heart. MiRNA-sequencing of 5 week (young), 12-21 week (adult) and 28-40 week (old) Nfu hearts revealed 23 up-regulated and 18 down-regulated miRNAs with age. MiR-29 family turned out as one of the most up-regulated miRNAs during aging. MiR-29 family increase induces a decrease of known targets like collagens and DNA methyl transferases (DNMTs) paralleled by 5´methyl-cytosine (5mC) level decrease...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29194125/nav1-7-and-pain-contribution-of-peripheral-nerves
#16
Tal Hoffmann, Ohad Sharon, Jürgen Wittmann, Richard W Carr, Alina Vyshnevska, Roberto De, Mohammed A Nassar, Peter W Reeh, Christian Weidner
The sodium channel NaV1.7 contributes to action potential generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to CNS the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. With single-fiber recordings from isolated skin we found (1) a significantly lower prevalence of heat responsiveness to in normally mechanosensitive C-fibers, although (2) the rare heat responses appeared quite vigorous and (3) heat-induced CGRP release was normal...
November 24, 2017: Pain
https://www.readbyqxmd.com/read/29186920/rna-chaperone-function-of-a-universal-stress-protein-in-arabidopsis-confers-enhanced-cold-stress-tolerance-in-plants
#17
Sarah Mae Boyles Melencion, Yong Hun Chi, Thuy Thi Pham, Seol Ki Paeng, Seong Dong Wi, Changyu Lee, Seoung Woo Ryu, Sung Sun Koo, Sang Yeol Lee
The physiological function of Arabidopsis thaliana universal stress protein (AtUSP) in plant has remained unclear. Thus, we report here the functional role of the Arabidopsis universal stress protein, AtUSP (At3g53990). To determine how AtUSP affects physiological responses towards cold stress, AtUSP overexpression (AtUSP OE) and T-DNA insertion knock-out (atusp, SALK_146059) mutant lines were used. The results indicated that AtUSP OE enhanced plant tolerance to cold stress, whereas atusp did not. AtUSP is localized in the nucleus and cytoplasm, and cold stress significantly affects RNA metabolism such as by misfolding and secondary structure changes of RNA...
November 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29171003/inhibition-of-monoacylglycerol-lipase-terminates-diazepam-resistant-status-epilepticus-in-mice-and-its-effects-are-potentiated-by-a-ketogenic-diet
#18
Gaetano Terrone, Alberto Pauletti, Alessia Salamone, Massimo Rizzi, Bianca R Villa, Luca Porcu, Mark J Sheehan, Edward Guilmette, Christopher R Butler, Justin R Piro, Tarek A Samad, Annamaria Vezzani
OBJECTIVE: Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures...
November 24, 2017: Epilepsia
https://www.readbyqxmd.com/read/29163080/behavioral-and-neurochemical-phenotyping-of-mice-incapable-of-homer1a-induction
#19
Michael C Datko, Jia-Hua Hu, Melanie Williams, Cindy M Reyes, Kevin D Lominac, Georg von Jonquieres, Matthias Klugmann, Paul F Worley, Karen K Szumlinski
Immediate early and constitutively expressed products of the Homer1 gene regulate the functional assembly of post-synaptic density proteins at glutamatergic synapses to influence excitatory neurotransmission and synaptic plasticity. Earlier studies of Homer1 gene knock-out (KO) mice indicated active, but distinct, roles for IEG and constitutively expressed Homer1 gene products in regulating cognitive, emotional, motivational and sensorimotor processing, as well as behavioral and neurochemical sensitivity to cocaine...
2017: Frontiers in Behavioral Neuroscience
https://www.readbyqxmd.com/read/29161318/loss-of-mtorc2-signaling-in-oligodendrocyte-precursor-cells-delays-myelination
#20
Mark D Grier, Kathryn L West, Nathaniel D Kelm, Cary Fu, Mark D Does, Brittany Parker, Eleanor McBrier, Andre H Lagrange, Kevin C Ess, Robert P Carson
Myelin abnormalities are increasingly being recognized as an important component of a number of neurologic developmental disorders. The integration of many signaling pathways and cell types are critical for correct myelinogenesis. The PI3-K and mechanistic target of rapamycin (mTOR) pathways have been found to play key roles. mTOR is found within two distinct complexes, mTORC1 and mTORC2. mTORC1 activity has been shown to play a major role during myelination, while the role of mTORC2 is not yet well understood...
2017: PloS One
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