174 research outputs found
Author Correction: Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome (Scientific Reports, (2020), 10, 1, (18051), 10.1038/s41598-020-74650-4)
No full text\ua9 2021, The Author(s).Ivan P. Moskowitz was omitted from the author list in the original version of this Article
Non-muscle Myosin IIB (Myh10) Is Required for Epicardial Function and Coronary Vessel Formation During Mammalian Development
No full textThe coronary vasculature is an essential vessel network providing the blood supply to the heart. Disruptions in coronary blood flow contribute to cardiac disease, a major cause of premature death worldwide. The generation of treatments for cardiovascular disease will be aided by a deeper understanding of the developmental processes that underpin coronary vessel formation. From an ENU mutagenesis screen, we have isolated a mouse mutant displaying embryonic hydrocephalus and cardiac defects (EHC). Positional cloning and candidate gene analysis revealed that the EHC phenotype results from a point mutation in a splice donor site of the Myh10 gene, which encodes NMHC IIB. Complementation testing confirmed that the Myh10 mutation causes the EHC phenotype. Characterisation of the EHC cardiac defects revealed abnormalities in myocardial development, consistent with observations from previously generated NMHC IIB null mouse lines. Analysis of the EHC mutant hearts also identified defects in the formation of the coronary vasculature. We attribute the coronary vessel abnormalities to defective epicardial cell function, as the EHC epicardium displays an abnormal cell morphology, reduced capacity to undergo epithelial-mesenchymal transition (EMT), and impaired migration of epicardial-derived cells (EPDCs) into the myocardium. Our studies on the EHC mutant demonstrate a requirement for NMHC IIB in epicardial function and coronary vessel formation, highlighting the importance of this protein in cardiac development and ultimately, embryonic survival
The effect of pH on rates of reaction and hydrogen generation during serpentinization
No full text© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in McCollom, T. M., Klein, F., Solheid, P., & Moskowitz, B. The effect of pH on rates of reaction and hydrogen generation during serpentinization. Philosophical Transactions.Series A, Mathematical, Physical, and Engineering Sciences, 378(2165), (2020): 20180428, doi: 10.1098/rsta.2018.0428.A series of three laboratory experiments were conducted to investigate how pH affects reaction pathways and rates during serpentinization. Two experiments were conducted under strongly alkaline conditions using olivine as reactant at 200 and 230°C, and the results were compared with previous studies performed using the same reactants and methods at more neutral pH. For both experiments, higher pH resulted in more rapid serpentinization of the olivine and generation of larger amounts of H2 for comparable reaction times. Proportionally greater amounts of Fe were partitioned into brucite and chrysotile and less into magnetite in the experiments conducted at higher pH. In a third experiment, alkaline fluids were injected into an ongoing experiment containing olivine and orthopyroxene to raise the pH from circumneutral to strongly alkaline conditions. Increasing the pH of the olivine-orthopyroxene experiment resulted in an immediate and steep increase in H2 production, and led to far more extensive reaction of the primary minerals compared to a similar experiment conducted under more neutral conditions. The results suggest that the development of strongly alkaline conditions in actively serpentinizing systems promotes increased rates of reaction and H2 production, enhancing the flux of H2 available to support biological activity in these environments.This research was supported by the NASA Astrobiology Institute through Cooperative Agreement no. NNA15BB02A and NASA Solar Systems Workings program grant no. NNX16AL74G. The IRM is supported by the Instruments and Facilities Program of the NSF Division of Earth Science
Inducible recombination in the cardiac conduction system of minK: CreERT2 BAC transgenic mice
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Depolymerized lamins link nuclear envelope breakdown to mitotic transcriptional quiescence
No full textABSTRACTThe nuclear envelope, a defining feature of eukaryotic cells, restricts DNA-dependent processes including gene transcription to the nucleus. The nuclear lamina is an integral component of the animal nuclear envelope, composed of polymers of nuclear lamin proteins1,2. Upon mitosis, the nuclear lamina disassembles, the nuclear envelope breaks down, and transcription becomes quiescent3,4. We report here a direct molecular link between nuclear lamina disassembly and mitotic transcriptional quiescence. We found that, at the G2 cell-cycle phase immediately preceding mitosis, nuclear lamin A/C (LMNA) became phosphorylated at Ser22 and depolymerized from the nuclear lamina. Depolymerized LMNA accumulated in the nuclear interior and physically associated with active cis-regulatory elements genome-wide. Depolymerized LMNA-associated sites were overrepresented near genes repressed by LMNA, suggesting that depolymerized LMNA participates in transcriptional repression at G2. Consistently, depolymerized LMNA-target genes underwent a steep expression decline from S to G2/M. Furthermore, LMNA deletion caused inappropriate RNA Polymerase II (Pol II) accumulation downstream of Pol II pause sites at promoters and enhancers genome-wide, leading to inappropriate and excessive transcriptional elongation. A subset of depolymerized LMNA-target genes were upregulated in fibroblasts of patients with Hutchinson-Gilford progeria, a premature aging disorder caused by LMNA mutations5, raising the possibility that defects in depolymerized LMNA-mediated mitotic transcriptional quiescence contribute to progeria pathogenesis. These observations support a model in which depolymerized LMNA targets active regulatory elements to promote RNA Pol II pausing preceding mitosis, coupling nuclear envelope breakdown to mitotic transcriptional quiescence.</jats:p
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