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https://www.readbyqxmd.com/read/28533521/hepatocyte-shp-1-is-a-critical-modulator-of-inflammation-during-endotoxemia
#1
Anupam Adhikari, Caroline Martel, André Marette, Martin Olivier
Liver hepatocytes (Hep) are known to be central players during the inflammatory response to systemic infection. Interestingly, the protein tyrosine phosphatases (PTP) SHP-1, has been recognized as a major regulator of inflammation; however their implication in the control of Hep-mediated inflammatory response is still unknown. To study its implication in the regulation of the Hep-mediated inflammatory response during endotoxemia, Cre-Lox mice with a Hep-specific Ptpn6 deletion (Ptpn6 (H-KO) ) were injected with LPS...
May 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28522687/integrin-linked-kinase-signaling-promotes-cyst-growth-and-fibrosis-in-polycystic-kidney-disease
#2
Archana Raman, Gail A Reif, Yuqiao Dai, Aditi Khanna, Xiaogang Li, Lindsay Astleford, Stephen C Parnell, James P Calvet, Darren P Wallace
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by innumerous fluid-filled cysts and progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is markedly overexpressed by cyst epithelial cells. Periostin promotes cell proliferation, cyst growth, interstitial fibrosis, and the decline in renal function in PKD mice. Here, we investigated the regulation of these processes by the integrin-linked kinase (ILK), a scaffold protein that links the extracellular matrix to the actin cytoskeleton and is stimulated by periostin...
May 18, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28520872/glucocerebrosidase-deficiency-in-dopaminergic-neurons-induces-microglial-activation-without-neurodegeneration
#3
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/28520214/mtorc1-inhibits-nf-%C3%AE%C2%BAb-nfatc1-signaling-and-prevents-osteoclast-precursor-differentiation-in-vitro-and-in-mice
#4
Yue Zhang, Song Xu, Kai Li, Kang Tan, Kangyan Liang, Jian Wang, Junhui Shen, Wenchong Zou, Le Hu, Daozhang Cai, Changhai Ding, Mangmang Li, Guozhi Xiao, Bin Liu, Anling Liu, Xiaochun Bai
The mechanistic target of rapamycin complex 1 (mTORC1) is a critical sensor for bone homeostasis and bone formation; however, the role of mTORC1 in osteoclast development and the underlying mechanisms have not yet been fully established. Here, we found that mTORC1 activity declined during osteoclast precursors differentiation in vitro and in vivo. We further targeted deletion of Raptor (mTORC1 key component) or Tsc1 (mTORC1 negative regulator) to constitutively inhibit or activate mTORC1 in osteoclast precursors (monocytes/macrophages), using LyzM-cre mice...
May 18, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28515282/talin-plays-a-critical-role-in-the-maintenance-of-the-regulatory-t-cell-pool
#5
Jane E Klann, Kelly A Remedios, Stephanie H Kim, Patrick J Metz, Justine Lopez, Lauren A Mack, Ye Zheng, Mark H Ginsberg, Brian G Petrich, John T Chang
Talin, a cytoskeletal protein essential in mediating integrin activation, has been previously shown to be involved in the regulation of T cell proliferation and function. In this study, we describe a role for talin in maintaining the homeostasis and survival of the regulatory T (Treg) cell pool. T cell-specific deletion of talin in Tln1(fl/fl)Cd4(Cre) mice resulted in spontaneous lymphocyte activation, primarily due to numerical and functional deficiencies of Treg cells in the periphery. Peripheral talin-deficient Treg cells were unable to maintain high expression of IL-2Rα, resulting in impaired IL-2 signaling and ultimately leading to increased apoptosis through downregulation of prosurvival proteins Bcl-2 and Mcl-1...
May 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28512117/the-interaction-of-mc3r-and-mc4r-with-mrap2-acth-%C3%AE-msh-and-agrp-in-chickens
#6
Jiannan Zhang, Xin Li, Yawei Zhou, Lin Cui, Jing Li, Chenlei Wu, Yiping Wan, Juan Li, Yajun Wang
The interaction of melanocortin-4 (MC4R) and melanocortin-3 (MC3R) receptors with proopiomelanocortin (POMC)-derived peptides (e.g. α-MSH), agouti-related protein (AgRP), and melanocortin-2 receptor accessory protein 2 (MRAP2) is suggested to play critical roles in energy balance of vertebrates. However, evidence on their interaction in birds remains scarce. Our study aims to reveal their interaction in chickens and the results showed that: 1) chicken (c-)MC3R and cMC4R expressed in CHO cells can be activated by α-MSH and ACTH1-39 equipotently, monitored by a pGL3-CRE-luciferase reporter system; 2) cMC3R and cMC4R, when co-expressed with cMRAP2 (or cMRAP, a cMRAP2 homolog), show increased sensitivity to ACTH treatment and thus likely act as ACTH-preferring receptors, and the interaction between cMC3R/cMC4R and cMRAP2 was demonstrated by co-immunoprecipitation assay; 3) both cMC3R and cMC4R display constitutive activity when expressed in CHO cells, as monitored by Dual-luciferase reporter assay, and cMRAP2 (and cMRAP) can modulate their constitutive activity; 4) AgRP inhibits the constitutive activity of cMC3R/cMC4R, and it also antagonizes ACTH/α-MSH action on cMC4R/cMC3R, indicating that AgRP functions as the inverse agonist and antagonist for both receptors...
May 16, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28506985/histone-acetyltransferase-kat8-is-essential-for-mouse-oocyte-development-by-regulating-ros-levels
#7
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/28500076/stat5-is-required-for-cd103-dendritic-cell-and-alveolar-macrophage-development-and-protection-from-lung-injury
#8
William E Eddy, Ke-Qin Gong, Bryan Bell, William C Parks, Steven F Ziegler, Anne M Manicone
We tested the role of Stat5 in dendritic cell and alveolar macrophage (AM) homeostasis in the lung using CD11c-cre mediated deletion (Cre(+)5(f/f)). We show that Stat5 is required for CD103(+) dendritic cell and AM development. We found that fetal monocyte maturation into AMs was impaired in Cre(+)5(f/f) mice, and we also confirmed impaired AM development of progenitor cells using mixed chimera experiments. In the absence of Stat5 signaling in AMs, mice developed alveolar proteinosis with altered lipid homeostasis...
May 12, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28494939/cardiosphere-derived-cells-require-endoglin-for-paracrine-mediated-angiogenesis
#9
Rachael E Redgrave, Simon Tual-Chalot, Benjamin J Davison, Esha Singh, Darroch Hall, Muhammad M Amirrasouli, Derek Gilchrist, Alexander Medvinsky, Helen M Arthur
Clinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Small benefits occur via paracrine mechanisms that include stimulating angiogenesis, and increased understanding of these mechanisms would help to improve patient outcomes. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor β (TGFβ) family ligands, including bone morphogenetic protein 9 (BMP9)...
May 9, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28481036/generation-and-characterization-of-a-conditional-allele-of-interferon-regulatory-factor-6
#10
Arianna L Smith, Youssef A Kousa, Akira Kinoshita, Kate Fodor, Baoli Yang, Brian C Schutte
Interferon Regulatory Factor 6 (IRF6) is a critical regulator of differentiation, proliferation and migration of keratinocytes. Mutations in IRF6 cause two autosomal dominant disorders characterized by cleft lip with or without cleft palate. In addition, DNA variation in IRF6 confers significant risk for non-syndromic cleft lip and palate. IRF6 is also implicated in adult onset development and disease processes, including mammary gland development and squamous cell carcinoma. Mice homozygous for a null allele of Irf6 die shortly after birth due to severe skin, limb, and craniofacial defects, thus impeding the study of gene function after birth...
May 8, 2017: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/28469167/interplay-between-ccn1-and-wnt5a-in-endothelial-cells-and-pericytes-determines-the-angiogenic-outcome-in-a-model-of-ischemic-retinopathy
#11
Sangmi Lee, Menna Elaskandrany, Lester F Lau, Douglas Lazzaro, Maria B Grant, Brahim Chaqour
CYR61-CTGF-NOV (CCN)1 is a dynamically expressed extracellular matrix (ECM) protein with critical functions in cardiovascular development and tissue repair. Angiogenic endothelial cells (ECs) are a major cellular source of CCN1 which, once secreted, associates with the ECM and the cell surface and tightly controls the bidirectional flow of information between cells and the surrounding matrix. Endothelium-specific CCN1 deletion in mice using a cre/lox strategy induces EC hyperplasia and causes blood vessels to coalesce into large flat hyperplastic sinuses with no distinctive hierarchical organization...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28461470/grp78-haploinsufficiency-suppresses-acinar-to-ductal-metaplasia-signaling-and-mutant-kras-driven-pancreatic-tumorigenesis-in-mice
#12
Jieli Shen, Dat P Ha, Genyuan Zhu, Daisy F Rangel, Agnieszka Kobielak, Parkash S Gill, Susan Groshen, Louis Dubeau, Amy S Lee
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras(G12D/+);p53(f/+) (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth...
May 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28430966/decreased-thromboembolic-stroke-but-not-atherosclerosis-or-vascular-remodeling-in-mice-with-rock2-deficient-platelets
#13
Nikola Sladojevic, Goo Taeg Oh, Hyung-Hwan Kim, Lea M Beaulieu, Hervé Falet, Karol Kaminski, Jane E Freedman, James K Liao
Aims: Rho-associated coiled-coil containing kinase (ROCK)-2 is an important mediator of the actin cytoskeleton. Because changes in the actin cytoskeleton are critical for platelet function, we hypothesized that ROCK2 in platelets will play important role in thrombosis and can be potentially a target for therapeutic intervention in thromboembolic stroke. Methods and Results: We generated platelet-specific ROCK2-deficient mice (ROCK2 Plt-/- ) from conditional ROCK2 fl°x/fl°x and platelet factor (PF)-4-Cre transgenic mice...
April 14, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28430962/ulk1-prevents-cardiac-dysfunction-in-obesity-through-autophagy-meditated-regulation-of-lipid-metabolism
#14
Minae An, Dong-Ryeol Ryu, Jang Won Park, Ji Ha Choi, Eun-Mi Park, Kyung Eun Lee, Minna Woo, Minsuk Kim
Aims: Autophagy is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Whereas many studies support the importance of autophagy in the mechanisms underlying obesity-related cardiac dysfunction, the role of autophagy in cardiac lipid metabolism remains unclear. In the heart, lipotoxicity is exacerbated by cardiac lipoprotein lipase (LPL), which mediates accumulation of fatty acids to the heart through intravascular triglyceride (TG) hydrolysis...
April 17, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28396503/correlation-of-meiotic-dsb-formation-and-transcription-initiation-around-fission-yeast-recombination-hotspots
#15
Shintaro Yamada, Mika Okamura, Arisa Oda, Hiroshi Murakami, Kunihiro Ohta, Takatomi Yamada
Meiotic homologous recombination, a critical event for ensuring faithful chromosome segregation and creating genetic diversity, is initiated by programed DNA double strand breaks (DSBs) formed at recombination hotspots. Meiotic DSB formation is likely to be influenced by other DNA-templated processes including transcription, but how DSB formation and transcription interact with each other has not been understood well. In this study, we used fission yeast to investigate a possible interplay of these two events...
April 10, 2017: Genetics
https://www.readbyqxmd.com/read/28394187/using-critical-realistic-evaluation-to-support-translation-of-research-into-clinical-practice
#16
Michelle C Swift, Marilyn Langevin, Alexander M Clark
A challenge that speech-language pathologists (SLPs) face is the translation of research into clinical practice. While randomised controlled trials (RCTs) are often touted as the "gold standard" of efficacy research, much valuable information is lost through the process; RCTs by nature are designed to wash out individual client factors and contexts that might influence the outcome in order to present the "true" impact of the intervention. However, in the area of behavioural interventions, the interaction of client factors and contexts with the treatment agent can substantially influence the outcome...
April 10, 2017: International Journal of Speech-language Pathology
https://www.readbyqxmd.com/read/28391161/the-mvmp-p4-promoter-is-a-host-cell-type-range-determinant-in-vivo
#17
Chen Meir, Michal Mincberg, Irina Rostovsky, Saar Tal, Ellen M Vollmers, Adi Levi, Peter Tattersall, Claytus Davis
The protoparvovirus early promoters, e.g. P4 of Minute Virus of Mice (MVM), play a critical role during infection. Initial P4 activity depends on the host transcription machinery only. Since this is cell-type dependent, it is hypothesized that P4 is a host cell-type range determinant. Yet host range determinants have mapped mostly to capsid, never P4. Here we test the hypothesis using the mouse embryo as a model system. Disruption of the CRE element of P4 drastically decreased infection levels without altering range...
June 2017: Virology
https://www.readbyqxmd.com/read/28385723/fabp4-cre-mediated-sirt6-deletion-impairs-adipose-tissue-function-and-metabolic-homeostasis-in-mice
#18
Xiwen Xiong, Cuicui Zhang, Yang Zhang, Rui Fan, Xinlai Qian, Xiaocheng Charlie Dong
SIRT6 is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis, and anti-inflammation. However, its function in the adipose tissue is not well understood. To examine the metabolic function of SIRT6 in the adipose tissue, we generated two mouse models that are deficient in Sirt6 using the Cre-lox approach. Two commonly used Cre lines that are driven by either the mouse Fabp4 or Adipoq gene promoter were chosen for this study. The Sirt6 knockout mice generated by the Fabp4-Cre line (Sirt6f/f:Fabp4-Cre) had a significant increase in both body weight and fat mass, and exhibited glucose intolerance and insulin resistance as compared with the control wildtype mice...
April 6, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28383552/experimental-atopic-dermatitis-depends-on-il-33r-signaling-via-myd88-in-dendritic-cells
#19
Changwei Li, Isabelle Maillet, Claire Mackowiak, Camille Viala, Franco Di Padova, Mei Li, Dieudonnée Togbe, Valérie Quesniaux, Yuping Lai, Bernhard Ryffel
Atopic dermatitis (AD) is a chronic Th2 type inflammatory skin disorder. Here we report that MyD88 signaling is crucial in the pathogenesis of experimental AD induced by vitamin D3 analog MC903. The clinical signs and inflammation caused by MC903 are drastically reduced in MyD88(-/-) mice with diminished eosinophil, neutrophil infiltration and Th2 cytokine expression. The biological effect of interleukin-1 (IL-1) family members relies on MyD88 signaling. We observed a strong upregulation of IL-1 family cytokine expression, including IL-1α, IL-1β, IL-33, IL-18, IL-36α, IL-36β, IL-36γ and IL-36Ra...
April 6, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28375030/aminoglycosides-against-carbapenem-resistant-enterobacteriaceae-in-the-critically-ill-the-pitfalls-of-aminoglycoside-susceptibility
#20
Alexandre P Zavascki, Brandon O Klee, Jürgen B Bulitta
The emergence of carbapenem-resistant Enterobacteriaceae (CRE) has brought aminoglycosides to the frontline since an aminoglycoside may be the only antimicrobial to which CRE isolates show in vitro susceptibility. The appropriateness of aminoglycoside-based therapies for severe infections by CRE is discussed considering the current breakpoints and recent pharmacokinetic (PK) studies in critically ill patients. Areas covered: Many aminoglycoside-susceptible CRE isolates present minimal inhibitory concentrations (MICs) at or slightly below the breakpoint of amikacin or gentamicin...
April 17, 2017: Expert Review of Anti-infective Therapy
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