The role of haploinsufficiency of RPS14 and p53 activation in the molecular pathogenesis of the 5q- syndrome

In recent years we have gained great insight into the molecular pathogenesis of the 5q- syndrome, a distinct subtype of myelodysplasia. The demonstration of haploinsufficiency of the ribosomal gene RPS14 (mapping to the commonly deleted region) and the finding that this is the cause of the erythroid defect in the 5qsyndrome represent major advances. A mouse model of the human 5q- syndrome generated by large-scale deletion of the Cd74-Nid67 interval (containing RPS14) further supports a critical role for RPS14 haploinsufficiency. It is widely accepted that ribosomal deficiency results in p53 activation and defective erythropoiesis and the crossing of the ‘5q- mice’ with p53 deficient mice ameliorated the erythroid progenitor defect. Emerging data suggests that the p53 activation observed in the mouse model may also apply to the human 5q- syndrome.

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Advances in the 5q− syndrome

Blood ◽

10.1182/blood-2010-04-273771 ◽

2010 ◽

Vol 116 (26) ◽

pp. 5803-5811 ◽

Cited By ~ 81

Author(s):

Jacqueline Boultwood ◽

Andrea Pellagatti ◽

Andrew N. J. McKenzie ◽

James S. Wainscoat

Keyword(s):

Mouse Model ◽

Large Scale ◽

Ribosomal Gene ◽

Functional Screening ◽

Erythroid Progenitor ◽

P53 Activation ◽

Modeling Data ◽

Mouse Modeling ◽

Microrna Genes

AbstractThe 5q− syndrome is the most distinct of all the myelodysplastic syndromes with a clear genotype/phenotype relationship. The significant progress made during recent years has been based on the determination of the commonly deleted region and the demonstration of haploinsufficiency for the ribosomal gene RPS14. The functional screening of all the genes in the commonly deleted region determined that RPS14 haploinsufficiency is the probable cause of the erythroid defect in the 5q− syndrome. A mouse model of the human 5q− syndrome has now been created by chromosomal engineering involving a large-scale deletion of the Cd74-Nid67 interval (containing RPS14). A variety of lines of evidence support the model of ribosomal deficiency causing p53 activation and defective erythropoiesis, including most notably the crossing of the “5q− mice” with p53-deficient mice, thereby ameliorating the erythroid progenitor defect. Emerging evidence supports the notion that the p53 activation observed in the mouse model may also apply to the human 5q− syndrome. Other mouse modeling data suggest that haploinsufficiency of the microRNA genes miR-145 and miR-146a may contribute to the thrombocytosis seen in the 5q− syndrome. Lenalidomide has become an established therapy for the 5q− syndrome, although its precise mode of action remains uncertain.

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Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice

Neural Plasticity ◽

10.1155/2017/4526417 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Hua Yang ◽

Mengjie Zhang ◽

Jiahao Shi ◽

Yunhe Zhou ◽

Zhipeng Wan ◽

...

Keyword(s):

Cerebral Cortex ◽

Mouse Model ◽

Glutamate Release ◽

Critical Role ◽

Conditional Knockout ◽

Snare Complex ◽

Extracellular Glutamate ◽

Glutamate Level

Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.

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Camel whey protein enhances diabetic wound healing in a streptozotocin-induced diabetic mouse model: the critical role of β-Defensin-1, -2 and -3

Lipids in Health and Disease ◽

10.1186/1476-511x-12-46 ◽

2013 ◽

Vol 12 (1) ◽

Cited By ~ 42

Author(s):

Gamal Badr

Keyword(s):

Wound Healing ◽

Mouse Model ◽

Whey Protein ◽

Critical Role ◽

Diabetic Mouse ◽

Diabetic Wound ◽

Diabetic Wound Healing

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Abstract 636: Gut Microflora Influences Pathology in the Kawasaki Disease (KD) Vasculitis Mouse Model

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.636 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Daiko Wakita ◽

Yosuke Kurashima ◽

Yoshihiro Takasato ◽

Youngho Lee ◽

Kenichi Shimada ◽

...

Keyword(s):

Mouse Model ◽

Immune Responses ◽

Critical Role ◽

Gut Microflora ◽

Vascular Abnormalities ◽

Coronary Arteritis ◽

Specific Pathogen ◽

New Perspective ◽

Bacteria And Fungi

Background: KD is the leading cause of acquired heart disease in the US. We have demonstrated the critical role of innate immune responses via IL-1R/MyD88 signaling in the Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model. The diversity and composition of microflora (both bacterial and fungal) have been associated with the regulation and alterations of immune responses and various pathologies. However, the role of gut microbiota in immunopathology of KD has not been investigated. Objective: To evaluate the role of gut microflora in development of coronary arteritis, and vascular abnormalities in KD mouse model. Methods and Results: We investigated the role of gut microflora in the LCWE-induced KD mouse model, using Specific-Pathogen Free (SPF) and Germ Free (GF) mice (C57BL/6). GF mice showed a significant decrease of KD lesions, including coronary arteritis compared with SPF mice. The development of LCWE-induced AAA, which we recently discovered in this mouse model, was also markedly diminished in GF mice. In addition to GF mice, we also investigated the specific role of commensal bacteria and/or fungi, and determined whether altered microorganism burden in this KD mouse model contributes to disease severity. To deplete bacteria and/or fungi in the gut microflora, we exposed pregnant SPF mice and their offspring to antibiotics cocktail (Abx) or antifungal drug (fluconazole; Fluc) in their drinking water for 5 wks and induced KD. The mice treated with Abx or Fluc had significantly reduced coronary arteritis and AAA compared to controls. The Abx plus Fluc administration showed marked decrease of KD vasculitis. Conclusions: We demonstrate here that gut microflora play a critical role in the development of KD vasculitis in LCWE-induced mouse model. Our results suggest that both bacteria and fungi in the intestinal microbiota may control the induction and severity of KD vasculitis. These findings provide a new perspective on the potential role of the microbiome in KD pathogenesis and may offer new diagnostic and therapeutic strategies for KD patients.

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Lipotoxicity-Induced mtDNA Release Promotes Diabetic Cardiomyopathy by Activating the cGAS-STING Pathway in Obesity Related Diabetes

10.21203/rs.3.rs-695715/v1 ◽

2021 ◽

Author(s):

Xiu Mei Ma ◽

Kang Geng ◽

Betty Yuen-Kwan Law ◽

Peng Wang ◽

Yue Li Pu ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Cell Model ◽

Critical Role ◽

Kidney Tissue ◽

H9c2 Cells ◽

Downstream Targets ◽

Sting Pathway

Abstract Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissue. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was resulted from PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.

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Trust in scientists in times of pandemic: Panel evidence from 12 countries

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2108576118 ◽

2021 ◽

Vol 118 (40) ◽

pp. e2108576118

Author(s):

Yann Algan ◽

Daniel Cohen ◽

Eva Davoine ◽

Martial Foucault ◽

Stefanie Stantcheva

Keyword(s):

Large Scale ◽

Social Trust ◽

Critical Role ◽

Individual Level ◽

Individual Support ◽

Compliant Behavior ◽

Paradoxical Effects ◽

The Government ◽

Nonpharmaceutical Interventions

This article analyzes the specific and critical role of trust in scientists on both the support for and compliance with nonpharmaceutical interventions (NPIs) during the COVID-19 pandemic. We exploit large-scale, longitudinal, and representative surveys for 12 countries over the period from March to December 2020, and we complement the analysis with experimental data. We find that trust in scientists is the key driving force behind individual support for and compliance with NPIs and for favorable attitudes toward vaccination. The effect of trust in government is more ambiguous and tends to diminish support for and compliance with NPIs in countries where the recommendations from scientists and the government were not aligned. Trust in others also has seemingly paradoxical effects: in countries where social trust is high, the support for NPIs is low due to higher expectations that others will voluntary social distance. Our individual-level longitudinal data also allows us to evaluate the effects of within-person changes in trust over the pandemic: we show that trust levels and, in particular, trust in scientists have changed dramatically for individuals and within countries, with important subsequent effects on compliant behavior and support for NPIs. Such findings point out the challenging but critical need to maintain trust in scientists during a lasting pandemic that strains citizens and governments.

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The critical role of magnetic helicity in astrophysical large-scale dynamos

Plasma Physics and Controlled Fusion ◽

10.1088/0741-3335/51/12/124043 ◽

2009 ◽

Vol 51 (12) ◽

pp. 124043 ◽

Cited By ~ 19

Author(s):

Axel Brandenburg

Keyword(s):

Large Scale ◽

Critical Role ◽

Magnetic Helicity

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Critical role of c-Kit in beta cell function: increased insulin secretion and protection against diabetes in a mouse model

Diabetologia ◽

10.1007/s00125-012-2566-5 ◽

2012 ◽

Vol 55 (8) ◽

pp. 2214-2225 ◽

Cited By ~ 29

Author(s):

Z. C. Feng ◽

J. Li ◽

B. A. Turco ◽

M. Riopel ◽

S. P. Yee ◽

...

Keyword(s):

Insulin Secretion ◽

Mouse Model ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Critical Role

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The Carnegie Uaxactun Project and the Development of Maya Archaeology

Ancient Mesoamerica ◽

10.1017/s0956536100000298 ◽

1990 ◽

Vol 1 (2) ◽

pp. 257-276 ◽

Cited By ~ 7

Author(s):

Stephen L. Black

Keyword(s):

Large Scale ◽

Critical Role ◽

Carnegie Institution ◽

Field Methods ◽

Maya Archaeology ◽

History Of ◽

Maya Area

AbstractThe Carnegie Institution of Washington's 1924–1937. Uaxactun Project, one of the first large-scale excavations in the Maya area, established the role of dirt archaeology in Maya studies. The archaeologists who worked on this pioneering project developed many field methods and approaches that remain in use today. A review of the project and of the careers of its participants shows the critical role the Carnegie Uaxactun Project has played in the history of Maya archaeology.

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