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https://www.readbyqxmd.com/read/28550640/endogenous-tissue-factor-pathway-inhibitor-in-vascular-smooth-muscle-cells-inhibits-arterial-thrombosis
#1
Jichun Yang, Kaiyue Jin, Jiajun Xiao, Jing Ma, Duan Ma
Tissue factor pathway inhibitor (TFPI) is the main inhibitor of tissue factor-mediated coagulation. TFPI is expressed by endothelial and smooth muscle cells in the vasculature. Endothelium-derived TFPI has been reported to play a regulatory role in arterial thrombosis. However, the role of endogenous TFPI in vascular smooth muscle cells (VSMCs) in thrombosis and vascular disease development has yet to be elucidated. In this TFPI(Flox) mice crossbred with Sma-Cre mice were utilized to establish TFPI conditional knockout mice and to examine the effects of VSMC-directed TFPI deletion on development, hemostasis, and thrombosis...
May 27, 2017: Frontiers of Medicine
https://www.readbyqxmd.com/read/28545714/anticystogenic-activity-of-a-small-molecule-pak4-inhibitor-may-be-a-novel-treatment-for-autosomal-dominant-polycystic-kidney-disease
#2
Vicki J Hwang, Xia Zhou, Xiaonan Chen, Josephine Trott, Omran Abu Aboud, Kyuhwan Shim, Lai Kuan Dionne, Kenneth J Chmiel, William Senapedis, Erkan Baloglu, Moe R Mahjoub, Xiaogang Li, Robert H Weiss
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD...
May 23, 2017: Kidney International
https://www.readbyqxmd.com/read/28539333/endothelial-markers-expressing-stromal-cells-are-critical-for-kidney-formation
#3
Elina Mukherjee, Katherine Virginia Maringer, Emily Papke, Daniel S Bushnell, Caitlin M Schaefer, Rafael Kramann, Jacqueline Ho, Benjamin D Humphreys, Carlton M Bates, Sunder Sims-Lucas
Kidneys are highly vascularized and contain many distinct vascular beds. However, the origins and roles of developing renal endothelial cells in the formation of the kidney are unclear. We have shown that the Foxd1-positive renal stroma gives rise to endothelial marker expressing progenitors that are incorporated within a subset of peritubular capillaries; however, the significance of these cells is unclear. The purpose of this study was to determine whether deletion of Flk1 in the Foxd1 stroma was important for renal development...
May 24, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28520915/ovary-specific-depletion-of-the-nuclear-receptor-nr5a2-compromises-expansion-of-the-cumulus-oophorus-but-not-fertilization-by-icsi
#4
Kalyne Bertolin, Marie-Charlotte Meinsohn, João Suzuki, Jan Gossen, Kristina Schoonjans, Rajesha Duggavathi, Bruce D Murphy
The orphan nuclear receptor, liver receptor homolog-1 (Nr5a2) is widely expressed in mammalian tissues, its ovarian expression is restricted to granulosa cells of activated follicles. We employed the floxed Nr5a2 (Nr5a2f/f) mutant mouse line and two granulosa-specific Cre lines, Amhr2Cre and tgCyp19Cre, to develop two tissue- and time-specific Nr5a2 depletion models, Nr5a2Amhr2-/- and Nr5a2Cyp19-/-. In the Nr5a2Cyp19-/- ovaries, Nr5a2 was depleted in mural granulosa, but not cumulus cells. We induced follicular development in mutant and wild type (control, CON) mice with equine chorionic gonadotropin (eCG) followed 44h later treatment with human chorionic gonadotropin (hCG) to induce ovulation...
May 18, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28520872/glucocerebrosidase-deficiency-in-dopaminergic-neurons-induces-microglial-activation-without-neurodegeneration
#5
Federico N Soria, Michel Engeln, Marta Martinez-Vicente, Christelle Glangetas, María José López-González, Sandra Dovero, Benjamin Dehay, Elisabeth Normand, Miquel Vila, Alexandre Favereaux, François Georges, Christophe Lo Bianco, Erwan Bezard, Pierre-Olivier Fernagut
Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation while elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remains elusive, partially because of lack of aged models of GBA1 deficiency. Since knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons...
May 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28512198/novel-role-of-rac-mid1-signaling-in-medial-cerebellar-development
#6
Takashi Nakamura, Takehiko Ueyama, Yuzuru Ninoyu, Hirofumi Sakaguchi, Narantsog Choijookhuu, Yoshitaka Hishikawa, Hiroshi Kiyonari, Masaaki Kohta, Mizuho Sakahara, Ivan de Curtis, Eiji Kohmura, Yasuo Hisa, Atsu Aiba, Naoaki Saito
Rac signaling impacts a relatively large number of downstream targets; however, few studies have established an association between Rac pathways and pathological conditions. In the present study, we generated mice with double knockout of Rac1 and Rac3 (Atoh1-Cre;Rac1(flox/flox);Rac3(-/-) ) in cerebellar granule neurons (CGNs). We observed impaired tangential migration at E16.5, as well as numerous apoptotic CGNs at the deepest layer of the external granule layer (EGL) in the medial cerebellum of Atoh1-Cre;Rac1(flox/flox);Rac3(-/-) mice at P8...
May 15, 2017: Development
https://www.readbyqxmd.com/read/28510629/fibroblast-growth-factor-receptor-2-fgfr2-is-required-for-meibomian-gland-homeostasis-in-the-adult-mouse
#7
Lixing W Reneker, Lanlan Wang, Rebecca T Irlmeier, Andrew J W Huang
Purpose: Little is known about the signaling mechanisms controlling meibomian gland (MG) homeostasis and the pathogenic processes leading to MG atrophy and dysfunction in dry eye disease (DED). We investigated the role of fibroblast growth factor receptor 2 (FGFR2) in the MG homeostasis of adult mice. Methods: A triple transgenic mouse strain (Krt14-rtTA; tetO-Cre; Fgfr2flox/flox), referred to as Fgfr2CKO mice, was generated in which the Fgfr2 gene is ablated by Cre recombinase in keratin 14 (Krt14)-expressing epithelial cells on doxycycline (Dox) induction...
May 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28506985/histone-acetyltransferase-kat8-is-essential-for-mouse-oocyte-development-by-regulating-ros-levels
#8
Shi Yin, Xiaohua Jiang, Hanwei Jiang, Qian Gao, Fang Wang, Suixing Fan, Teka Khan, Nazish Jabeen, Manan Khan, Asim Ali, Peng Xu, Tej K Pandita, Heng-Yu Fan, Yuanwei Zhang, Qinghua Shi
Proper oocyte development is critical for female fertility and requires timely and accurate control of gene expression. K (Lysine) Acetyltransferase 8 (KAT8), an important component of the X chromosome dosage compensation system in Drosophila, regulates gene activity by acetylating histone H4 preferentially at lysine 16. To explore the function of Kat8 during mouse oocyte development, we crossed Kat8(flox/flox) mice with Gdf9-Cre mice to specifically delete Kat8 in oocytes. Oocyte Kat8 deletion resulted in female infertility with follicle development failure in the secondary and preantral follicle stages...
May 15, 2017: Development
https://www.readbyqxmd.com/read/28504114/a-shortened-tamoxifen-induction-scheme-to-induce-creer-recombinase-without-side-effects-on-the-male-mouse-skeleton
#9
Ferran Jardí, Michaël R Laurent, Vanessa Dubois, Rougin Khalil, Ludo Deboel, Dieter Schollaert, Ludo Van Den Bosch, Brigitte Decallonne, Geert Carmeliet, Frank Claessens, Dirk Vanderschueren
The selective estrogen receptor modulator tamoxifen exerts estrogen agonistic or antagonistic actions on several tissues, including bone. The off-target effects of tamoxifen are one of the most widely recognized pitfalls of tamoxifen-inducible Cre recombinases (CreERs), potentially confounding the phenotypic findings. Still, the validation of tamoxifen induction schemes that minimize the side effects of the drug has not been addressed. Here, we compared the side effects on the skeleton and other androgen-responsive targets of a shortened tamoxifen regimen (2 doses of 190 mg/kg body weight by oral gavage) to a standard protocol (4 doses) and determined their efficiency in inducing CreER-mediated gene deletion...
May 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28502476/purkinje-cells-are-more-vulnerable-to-the-specific-depletion-of-cathepsin-d-than-to-that-of-atg7
#10
Masato Koike, Masahiro Shibata, Takehiko Sunabori, Junji Yamaguchi, Kenji Sakimura, Masaaki Komatsu, Keiji Tanaka, Yasuo Uchiyama
Neurologic phenotypes of cathepsin D (CTSD)-deficient mice, a murine model of neuronal ceroid lipofuscinoses, indicate the importance of CTSD for the maintenance of metabolism in central nervous system neurons. To further understand the role of CTSD in central nervous system neurons, we generated mice with a CTSD deficiency specifically in the Purkinje cells (PCs) (CTSD(Flox/Flox);GRID2-Cre) and compared their phenotypes with those of PC-selective Atg7-deficient (Atg7(Flox/Flox);GRID2-Cre) mice. In both strains of mice, PCs underwent degeneration, but the CTSD-deficient PCs disappeared more rapidly than their Atg7-deficient counterparts...
May 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28488815/hypomorphic-conditional-deletion-of-e11-podoplanin-reveals-a-role-in-osteocyte-dendrite-elongation
#11
Katherine A Staines, Behzad Javaheri, Peter Hohenstein, Robert Fleming, Ekele Ikpegbu, Erin Unger, Mark Hopkinson, David J Buttle, Andrew A Pitsillides, Colin Farquharson
The transmembrane glycoprotein E11/Podoplanin (Pdpn) has been implicated in the initial stages of osteocyte differentiation. However, its precise function and regulatory mechanisms are still unknown. Due to the known embryonic lethality induced by global Pdpn deletion, we have herein explored the effect of bone specific Pdpn knockdown on osteocyte form and function in the post-natal mouse. Extensive skeletal phenotyping of male and female 6-week-old Oc-cre;Pdpn(flox/flox) (cKO) mice and their Pdpn(flox/flox) controls (fl/fl) has revealed that Pdpn deletion significantly compromises tibial cortical bone microarchitecture in both sexes, albeit to different extents (P < 0...
May 10, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28488329/phosphodiesterase-1b-deletion-confers-depression-like-behavioral-resistance-separate-from-stress-related-effects-in-mice
#12
Jillian R Hufgard, Michael T Williams, Charles V Vorhees
Phosphodiesterase-1b (Pde1b) is highly expressed in striatum, dentate gyrus, CA3, and substantia nigra. In a new Floxed Pde1b x Cre(CMV) global knock-out (KO) mouse model we show an immobility resistance phenotype that recapitulates that found in constitutive Pde1b KO mice. We use this new mouse model to show that the resistance to acute stress-induced depression-like phenotype is not the product of changes in locomotor activity or reactivity to other stressors (learned helplessness, novelty suppressed feeding, or dexamethasone suppression), and is not associated with anhedonia using the sucrose preference test...
May 10, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/28475592/lsl-krasg12d-lsl-trp53r172h-ink4flox-ptf1-p48-cre-mice-are-an-applicable-model-for-locally-invasive-and-metastatic-pancreatic-cancer
#13
Lixiang Ma, Hexige Saiyin
Pancreatic cancer (PC) accumulates multiple genetic mutations, including activating KRAS mutations and inactivating TP53, SMAD4 and CDKN2A mutations, during progression. The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (GEMMs) showed that these mutations exert different synergistic effects in PC. However, the effect of the combination of TP53, CDKN2A and KRAS mutations on the trajectory of PC progression is unknown. Here, we report a GEMM that harbors KRAS (KrasG12D), TP53 (Trp53R172H/+), CDKN2A (Ink4flox/+) and Ptf1/p48-Cre (KPIC) mutations...
2017: PloS One
https://www.readbyqxmd.com/read/28465655/early-amd-like-defects-in-the-rpe-and-retinal-degeneration-in-aged-mice-with-rpe-specific-deletion-of-atg5-or-atg7
#14
Youwen Zhang, Samuel D Cross, James B Stanton, Alan D Marmorstein, Yun Zheng Le, Lihua Y Marmorstein
PURPOSE: To examine the effects of autophagy deficiency induced by RPE-specific deletion of Atg5 or Atg7 in mice as a function of age. METHODS: Conditional knockout mice with a floxed allele of Atg5 or Atg7 were crossed with inducible VMD2-rtTA/Cre transgenic mice. VMD2-directed RPE-specific Cre recombinase expression was induced with doxycycline feeding in the resulting mice. Cre-mediated deletion of floxed Atg5 or Atg7 resulted in RPE-specific inactivation of the Atg5 or Atg7 gene...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28462391/the-impact-of-electrographic-seizures-on-developing-hippocampal-dendrites-is-calcineurin-dependent
#15
Masataka Nishimura, J R Casanova, John W Swann
Neurobehavioral abnormalities are commonly associated with intractable childhood epilepsy. Studies from numerous labs have demonstrated cognitive and socialization deficits in rats and mice that have experienced early-life seizures. However, the cellular and molecular mechanisms underlying these effects are unknown. Previously, experiments have shown that recurrent seizures in infancy suppress the growth of hippocampal dendrites at the same time they impair learning and memory. Experiments in slice cultures have also demonstrated dendrite growth suppression...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28461605/selective-nrf2-gene-deletion-in-the-rostral-ventrolateral-medulla-evokes-hypertension-and-sympathoexcitation-in-mice
#16
Lie Gao, Matthew C Zimmerman, Shyam Biswal, Irving H Zucker
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcriptional regulator of redox homeostasis that impacts antioxidant gene expression. Central oxidative stress and reduced antioxidant enzyme expression in the rostral ventrolateral medulla (RVLM) contributed to sympathoexcitation in chronic heart failure. In the current study, we hypothesized that deletion of Nrf2 in the RVLM would increase sympathetic drive and blood pressure. Experiments were performed in Nrf2-floxed mice treated with microinjection of lentiviral-Cre-GFP or lentiviral-GFP into the RVLM...
June 2017: Hypertension
https://www.readbyqxmd.com/read/28456865/lipoprotein-lipase-in-hypothalamus-is-a-key-regulator-of-body-weight-gain-and-glucose-homeostasis-in-mice
#17
Elise Laperrousaz, Valentine S Moullé, Raphaël G Denis, Nadim Kassis, Chloé Berland, Benoit Colsch, Xavier Fioramonti, Erwann Philippe, Amélie Lacombe, Charlotte Vanacker, Noémie Butin, Kimberley D Bruce, Hong Wang, Yongping Wang, Yuanqing Gao, Cristina Garcia-Caceres, Vincent Prévot, Matthias H Tschöp, Robert H Eckel, Hervé Le Stunff, Serge Luquet, Christophe Magnan, Céline Cruciani-Guglielmacci
AIMS/HYPOTHESIS: Regulation of energy balance involves the participation of many factors, including nutrients, among which are circulating lipids, acting as peripheral signals informing the central nervous system of the energy status of the organism. It has been shown that neuronal lipoprotein lipase (LPL) participates in the control of energy balance by hydrolysing lipid particles enriched in triacylglycerols. Here, we tested the hypothesis that LPL in the mediobasal hypothalamus (MBH), a well-known nucleus implicated in the regulation of metabolic homeostasis, could also contribute to the regulation of body weight and glucose homeostasis...
April 29, 2017: Diabetologia
https://www.readbyqxmd.com/read/28454887/trends-in-pulmonary-hypertension-over-a-period-of-30-years-experience-from-a-single-referral-centre
#18
Carlos Andrés Quezada Loaiza, María Teresa Velázquez Martín, Carmen Jiménez López-Guarch, María José Ruiz Cano, Paula Navas Tejedor, Patricia Esmeralda Carreira, Ángela Flox Camacho, Alicia de Pablo Gafas, Juan Francisco Delgado Jiménez, Miguel Ángel Gómez Sánchez, Pilar Escribano Subías
INTRODUCTION AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, right ventricular dysfunction and death. Despite scientific advances, is still associated with high morbidity and mortality. The aim is to describe the clinical approach and determine the prognostic factors of patients with PAH treated in a national reference center over 30 years. METHODS: Three hundred and seventy nine consecutive patients with PAH (January 1984 to December 2014) were studied...
April 25, 2017: Revista Española de Cardiología
https://www.readbyqxmd.com/read/28451635/efficient-remyelination-requires-dna-methylation
#19
Sarah Moyon, Dan Ma, Jimmy L Huynh, David J C Coutts, Chao Zhao, Patrizia Casaccia, Robin J M Franklin
Oligodendrocyte progenitor cells (OPCs) are the principal source of new myelin in the central nervous system. A better understanding of how they mature into myelin-forming cells is of high relevance for remyelination. It has recently been demonstrated that during developmental myelination, the DNA methyltransferase 1 (DNMT1), but not DNMT3A, is critical for regulating proliferation and differentiation of OPCs into myelinating oligodendrocytes (OLs). However, it remains to be determined whether DNA methylation is also critical for the differentiation of adult OPCs during remyelination...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28446632/dietary-methionine-restriction-regulates-liver-protein-synthesis-and-gene-expression-independently-of-eukaryotic-initiation-factor-2-phosphorylation-in-mice
#20
Ashley P Pettit, William O Jonsson, Albert R Bargoud, Emily T Mirek, Frederick F Peelor, Yongping Wang, Thomas W Gettys, Scot R Kimball, Benjamin F Miller, Karyn L Hamilton, Ronald C Wek, Tracy G Anthony
Background: The phosphorylation of eukaryotic initiation factor 2 (p-eIF2) during dietary amino acid insufficiency reduces protein synthesis and alters gene expression via the integrated stress response (ISR).Objective: We explored whether a Met-restricted (MR) diet activates the ISR to reduce body fat and regulate protein balance.Methods: Male and female mice aged 3-6 mo with either whole-body deletion of general control nonderepressible 2 (Gcn2) or liver-specific deletion of protein kinase R-like endoplasmic reticulum kinase (Perk) alongside wild-type or floxed control mice were fed an obesogenic diet sufficient in Met (0...
April 26, 2017: Journal of Nutrition
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