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https://www.readbyqxmd.com/read/29342133/a-myc-enhancer-cluster-regulates-normal-and-leukaemic-haematopoietic-stem-cell-hierarchies
#1
Carsten Bahr, Lisa von Paleske, Veli V Uslu, Silvia Remeseiro, Naoya Takayama, Stanley W Ng, Alex Murison, Katja Langenfeld, Massimo Petretich, Roberta Scognamiglio, Petra Zeisberger, Amelie S Benk, Ido Amit, Peter W Zandstra, Mathieu Lupien, John E Dick, Andreas Trumpp, François Spitz
The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a 'super-enhancer' is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29339053/upregulation-of-nlrp3-via-stat3-dependent-histone-acetylation-contributes-to-painful-neuropathy-induced-by-bortezomib
#2
Cui-Cui Liu, Zhu-Xi Huang, Xiao Li, Kai-Feng Shen, Meng Liu, Han-Dong Ouyang, Su-Bo Zhang, Yu-Ting Ruan, Xiao-Long Zhang, Shao-Ling Wu, Wen-Jun Xin, Chao Ma
Painful neuropathy, as a severe side effect of chemotherapeutic bortezomib, is the most common reason for treatment discontinuation. However, the mechanism by which administration of bortezomib leads to painful neuropathy remains unclear. In the present study, we found that application of bortezomib significantly increased the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) and phosphorylated signal transducer and activator of transcription-3 (STAT3) in dorsal root ganglion (DRG). Intrathecal injection of NLRP3 siRNA significantly prevented the mechanical allodynia induced by bortezomib treatment, and intrathecal injection of recombinant adeno-associated virus vector encoding NLRP3 markedly decreased paw withdrawal threshold of naive rats...
January 12, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29338039/stat3-expression-by-myeloid-cells-is-detrimental-for-the-t-cell-mediated-control-of-infection-with-mycobacterium-tuberculosis
#3
Yu Gao, Juan Ignacio Basile, Cajsa Classon, Dolores Gavier-Widen, Akihiko Yoshimura, Berit Carow, Martin E Rottenberg
STAT3 is a master regulator of the immune responses. Here we show that M. tuberculosis-infected stat3fl/fl lysm cre mice, defective for STAT3 in myeloid cells, contained lower bacterial load in lungs and spleens, reduced granuloma extension but higher levels of pulmonary neutrophils. STAT3-deficient macrophages showed no improved control of intracellular mycobacterial growth. Instead, protection associated to elevated ability of stat3fl/fl lysm cre antigen-presenting cells (APCs) to release IL-6 and IL-23 and to stimulate IL-17 secretion by mycobacteria-specific T cells...
January 16, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29337050/impairments-in-social-novelty-recognition-and-spatial-memory-in-mice-with-conditional-deletion-of-scn1a-in-parvalbumin-expressing-cells
#4
Tetsuya Tatsukawa, Ikuo Ogiwara, Emi Mazaki, Atsushi Shimohata, Kazuhiro Yamakawa
Loss of function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1, have been described in the majority of Dravet syndrome patients presenting with epileptic seizures, hyperactivity, autistic traits, and cognitive decline. We previously reported predominant Nav1.1 expression in parvalbumin-expressing (PV+) inhibitory neurons in juvenile mouse brain and observed epileptic seizures in mice with selective deletion of Scn1a in PV+ cells mediated by PV-Cre transgene expression (Scn1afl/+/PV-Cre-TG)...
January 11, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29329320/atypical-e2f-functions-are-critical-for-pancreas-polyploidization
#5
Ramadhan B Matondo, Eva Moreno, Mathilda J M Toussaint, Peter C J Tooten, Saskia C van Essen, Elsbeth A van Liere, Sameh A Youssef, Laura Bongiovanni, Alain de Bruin
The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8...
2018: PloS One
https://www.readbyqxmd.com/read/29324782/mafb-is-dispensable-for-the-fetal-testis-morphogenesis-and-the-maintenance-of-spermatogenesis-in-adult-mice
#6
Hossam H Shawki, Hisashi Oishi, Toshiaki Usui, Yu Kitadate, Walaa A Basha, Ahmed M Abdellatif, Kazunori Hasegawa, Risa Okada, Keiji Mochida, Hany A El-Shemy, Masafumi Muratani, Atsuo Ogura, Shosei Yoshida, Satoru Takahashi
The transcription factor MAFB is an important regulator of the development and differentiation of various organs and tissues. Previous studies have shown that MAFB is expressed in embryonic and adult mouse testes and is expected to act as the downstream target of retinoic acid (RA) to initiate spermatogenesis. However, its exact localization and function remain unclear. Here, we localized MAFB expression in embryonic and adult testes and analyzed its gene function using Mafb-deficient mice. We found that MAFB and c-MAF are the only large MAF transcription factors expressed in testes, while MAFA and NRL are not...
2018: PloS One
https://www.readbyqxmd.com/read/29322219/sirt6-mediated-transcriptional-suppression-of-txnip-is-critical-for-pancreatic-beta-cell-function-and-survival-in-mice
#7
Kunhua Qin, Ning Zhang, Zhao Zhang, Michael Nipper, Zhenxin Zhu, Jake Leighton, Kexin Xu, Nicolas Musi, Pei Wang
AIMS/HYPOTHESIS: Better understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase sirtuin 6 (SIRT6) in beta cell development and homeostasis. METHODS: Sirt6 endocrine progenitor cell conditional knockout and beta cell-specific knockout mice were generated using the Cre-loxP system...
January 10, 2018: Diabetologia
https://www.readbyqxmd.com/read/29304157/conditional-deletion-of-rb1-in-the-tie2-lineage-leads-to-aortic-valve-regurgitation
#8
Marina Freytsis, Lauren Baugh, Zhiyi Liu, Irene Georgakoudi, Philip W Hinds, Lauren D Black, Gordon S Huggins
OBJECTIVE: Aortic valve disease is a complex process characterized by valve interstitial cell activation, disruption of the extracellular matrix culminating in valve mineralization occurring over many years. We explored the function of the retinoblastoma protein (pRb) in aortic valve disease, given its critical role in mesenchymal cell differentiation including bone development and mineralization. APPROACH AND RESULTS: We generated a mouse model of conditional pRb knockout (cKO) in the aortic valve regulated by Tie2-Cre-mediated excision of floxed RB1 alleles...
2018: PloS One
https://www.readbyqxmd.com/read/29282324/biphasic-functions-for-the-gdnf-ret-signaling-pathway-in-chemosensory-neuron-development-and-diversification
#9
Christopher R Donnelly, Amol A Shah, Charlotte M Mistretta, Robert M Bradley, Brian A Pierchala
The development of the taste system relies on the coordinated regulation of cues that direct the simultaneous development of both peripheral taste organs and innervating sensory ganglia, but the underlying mechanisms remain poorly understood. In this study, we describe a novel, biphasic function for glial cell line-derived neurotrophic factor (GDNF) in the development and subsequent diversification of chemosensory neurons within the geniculate ganglion (GG). GDNF, acting through the receptor tyrosine kinase Ret, regulates the expression of the chemosensory fate determinant Phox2b early in GG development...
December 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29274472/protein-phosphatase-2ac%C3%AE-gene-knock-out-results-in-cortical-atrophy-through-activating-hippo-cascade-in-neuronal-progenitor-cells
#10
Bo Liu, Li-Hua Sun, Yan-Fei Huang, Li-Jun Guo, Li-Shu Luo
Protein phosphatase 2ACα (PP2ACα), a vital member of the protein phosphatase family, has been studied primarily as a regulator for the development, growth and protein synthesis of a lot of cell types. Dysfunction of PP2ACα protein results in neurodegenerative disease; however, this finding has not been directly confirmed in the mouse model with PP2ACα gene knock-out. Therefore, in this study presented here, we generated the PP2ACα gene knock-out mouse model by the Cre-loxP targeting gene system, with the purpose to directly observe the regulatory role of PP2ACα gene in the development of mouse's cerebral cortex...
December 20, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29246798/dlx3-dependent-stat3-signaling-in-keratinocytes-regulates-skin-immune-homeostasis
#11
Shreya Bhattacharya, Jin-Chul Kim, Youichi Ogawa, Gaku Nakato, Veronica Nagle, Stephen R Brooks, Mark C Udey, Maria I Morasso
Epidermal specific deletion of the homeobox transcription regulator DLX3 disrupts keratinocyte differentiation and results in an IL-17-linked psoriasis-like skin inflammation. To identify the epidermal initiating signals produced by DLX3-null keratinocytes, we performed acute deletion of DLX3 in adult epidermis using a tamoxifen-inducible Krt14-cre/ERT system. K14CreERT;DLX3fl/fl (icKO) skin exhibited dysregulated expression of differentiation-associated genes, upregulation of proinflammatory cytokines, and accumulation of Langerhans cells and macrophages within 3 days of tamoxifen-induced DLX3 ablation...
December 12, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29239831/factors-associated-with-in-hospital-mortality-among-critically-ill-surgical-patients-with-multidrug-resistant-gram-negative-infections
#12
Andrew S Jarrell, Rachel M Kruer, Loredana Diana Berescu, Peter J Pronovost, Julie B Trivedi
PURPOSE: Multidrug-resistant (MDR) Gram-negative infection increases risk of mortality, other complications, and costs. The objective of this study was to determine the prevalence of and identify factors associated with in-hospital mortality among critically ill surgical patients. MATERIALS AND METHODS: This case-control study included critically ill surgical patients from 2011 to 2014 who had a carbapenem-resistant Enterobacteriaceae (CRE), MDR P. aeruginosa, or MDR Acinetobacter spp...
November 24, 2017: Journal of Critical Care
https://www.readbyqxmd.com/read/29232705/etv2-mir-130a-jarid2-cascade-regulates-vascular-patterning-during-embryogenesis
#13
Bhairab N Singh, Naoyuki Tahara, Yasuhiko Kawakami, Satyabrata Das, Naoko Koyano-Nakagawa, Wuming Gong, Mary G Garry, Daniel J Garry
Remodeling of the primitive vasculature is necessary for the formation of a complex branched vascular architecture. However, the factors that modulate these processes are incompletely defined. Previously, we defined the role of microRNAs (miRNAs) in endothelial specification. In the present study, we further examined the Etv2-Cre mediated ablation of DicerL/L and characterized the perturbed vascular patterning in the embryo proper and yolk-sac. We mechanistically defined an important role for miR-130a, an Etv2 downstream target, in the mediation of vascular patterning and angiogenesis in vitro and in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/29228157/gut-epithelial-vitamin-d-receptor-regulates-microbiota-dependent-mucosal-inflammation-by-suppressing-intestinal-epithelial-cell-apoptosis
#14
Lei He, Tianjing Liu, Yongyan Shi, Feng Tian, Huiyuan Hu, Dilip K Deb, Yinyin Chen, Marc Bissonnette, Yan Chun Li
Recent studies show that colonic vitamin D receptor (VDR) signaling protects the mucosal epithelial barrier and suppresses colonic inflammation, but the underlying molecular mechanism remains to be fully understood. To investigate the implication of colonic VDR down-regulation seen in patients with inflammatory bowel disease, we assessed the effect of gut epithelial VDR deletion on colonic inflammatory responses in an experimental colitis model. In 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model, mice carrying VDR deletion in gut epithelial cells (VDRf/f;Villin-Cre or VDRΔIEC) or in colonic epithelial cells (VDRf/f;CDX2-Cre or VDRΔCEC) developed more severe clinical colitis than VDRf/f control mice, characterized by more robust TH1 and TH17 responses, with greater increases in mucosal IFN-γ+, IL-17+ and IFN-γ+IL-17+ T cells...
December 7, 2017: Endocrinology
https://www.readbyqxmd.com/read/29220094/osteocytes-play-an-important-role-in-experimental-periodontitis-in-healthy-and-diabetic-mice-through-expression-of-rankl
#15
Dana T Graves, Ahmed Alshabab, Mayra Laino Albiero, Marcelo Mattos, Joice Dias Correa, Shanshan Chen, Yang Yang
AIM: Periodontitis results from bacteria induced inflammation. A key cytokine, RANKL is produced by a number of cell types. The cellular source of RANKL critical for periodontitis has not been established. METHODS: We induced periodontal bone loss by oral inoculation of Porphyromonas gingivalis and Fusobacterium nucleatum in both normoglycemic and streptozotocin induced type 1 diabetic mice. Experimental transgenic mice had osteocyte specific deletion of floxed RANKL mediated by DMP-1 driven Cre recombinase...
December 8, 2017: Journal of Clinical Periodontology
https://www.readbyqxmd.com/read/29214672/region-specific-deletions-of-the-glutamate-transporter-glt1-differentially-affect-seizure-activity-and-neurodegeneration-in-mice
#16
Junya Sugimoto, Moeko Tanaka, Kaori Sugiyama, Yukiko Ito, Hidenori Aizawa, Miho Soma, Tomoko Shimizu, Akira Mitani, Kohichi Tanaka
Glial glutamate transporter GLT1 plays a key role in the maintenance of extracellular glutamate homeostasis. Recent human genetic studies have suggested that de novo mutations in GLT1 (EAAT2) cause early-onset epilepsy with multiple seizure types. Consistent with these findings, global GLT1 null mice show lethal spontaneous seizures. The consequences of GLT1 dysfunction vary between different brain regions, suggesting that the role of GLT1 dysfunction in epilepsy may also vary with brain regions. In this study, we generated region-specific GLT1 knockout mice by crossing floxed-GLT1 mice with mice that express the Cre recombinase in a particular domain of the ventricular zone...
December 6, 2017: Glia
https://www.readbyqxmd.com/read/29214635/kv4-2-channel-activity-controls-intrinsic-firing-dynamics-of-arcuate-kisspeptin-neurons
#17
Philipe R F Mendonça, Victoria Kyle, Shel-Hwa Yeo, William H Colledge, Hugh P C Robinson
Kisspeptin neurons in the hypothalamus are critically involved in reproductive function, via their effect on GnRH neuron activity and consequent gonadotropin release. Kisspeptin neurons show an intrinsic irregularity of firing, but the mechanism of this remains unclear. To address this, we carried out targeted whole-cell patch-clamp recordings of kisspeptin neurons in the arcuate nucleus (Kiss1Arc ), in brain slices isolated from adult male Kiss-Cre:tdTomato mice. Cells fired irregularly in response to constant current stimuli, with a wide range of spike time variability, and prominent subthreshold voltage fluctuations...
December 6, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29207258/macrophage-dependent-cytoplasmic-transfer-during-melanoma-invasion-in%C3%A2-vivo
#18
Minna Roh-Johnson, Arish N Shah, Jason A Stonick, Kumud R Poudel, Julia Kargl, Grace H Yang, Julie di Martino, Rafael E Hernandez, Charles E Gast, Luai R Zarour, Susumu Antoku, A McGarry Houghton, Jose Javier Bravo-Cordero, Melissa H Wong, John Condeelis, Cecilia B Moens
Interactions between tumor cells and tumor-associated macrophages play critical roles in the initiation of tumor cell motility. To capture the cellular interactions of the tumor microenvironment with high-resolution imaging, we directly visualized tumor cells and their interactions with macrophages in zebrafish. Live imaging in zebrafish revealed that macrophages are dynamic, yet maintain sustained contact with tumor cells. In addition, the recruitment of macrophages to tumor cells promotes tumor cell dissemination...
December 4, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29180723/neuromodulation-of-orexin-neurons-reduces-diet-induced-adiposity
#19
A N Zink, P E Bunney, A A Holm, C J Billington, C M Kotz
BACKGROUND/OBJECTIVES: Low levels of orexin are associated with obesity and reduced physical activity in humans and animals. SUBJECTS/METHODS: Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) selectively activated orexin neurons in mouse lateral hypothalamus (LH) to measure effects on spontaneous physical activity (SPA). DREADD targeting was achieved by stereotaxic injection of AAV vectors into caudal lateral LH of heterozygous orexin Cre or C57/B6J mice...
November 28, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/29176755/baculovirus-mediated-mir-214-knockdown-shifts-osteoporotic-ascs-differentiation-and-improves-osteoporotic-bone-defects-repair
#20
Kuei-Chang Li, Yu-Han Chang, Mu-Nung Hsu, Shih-Chun Lo, Wan-Hua Li, Yu-Chen Hu
Osteoporotic patients often suffer from bone fracture but its healing is compromised due to impaired osteogenesis potential of bone marrow-derived mesenchymal stem cells (BMSCs). Here we aimed to exploit adipose-derived stem cells from ovariectomized rats (OVX-ASCs) for bone healing. We unraveled that OVX-ASCs highly expressed miR-214 and identified 2 miR-214 targets: CTNNB1 (β-catenin) and TAB2. We demonstrated that miR-214 targeting of these two genes blocked the Wnt pathway, led to preferable adipogenesis and hindered osteogenesis...
November 24, 2017: Scientific Reports
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