This work elucidates the molecular binding mechanism of CO2 in C4C1IMPF6 ionic liquid (IL) and its interplay with the CO2 asymmetric stretch frequency ν3, and establishes computational protocols for ...the reliable construction of spectroscopic maps for simulating ultrafast 2D-IR data of CO2 solvated in ILs. While charge transfer drives the static frequency shift between different ionic liquids ( J. Chem. Phys. 2015, 142, 212425 ), we find here that electrostatic and Pauli repulsion effects dominate the dynamical frequency shift between different geometries sampled from the finite-temperature dynamics within a single ionic liquid. This finding is also surprising because dispersion interactions dominate the CO2–IL interaction energies, but are comparably constant across different geometries. An important practical consequence of this finding is that density functional theory is expected to be sufficiently accurate for constructing potential energy surfaces for CO2 in C4C1IMPF6, as needed for accurate anharmonic calculations to construct a reliable spectroscopic map. Similarly, we established appropriate computational and chemical models for treating the extended solvent environment. We found that a QM/MM treatment including at least 2 cation-ion pairs at the QM level and at least 32 pairs at the MM level is necessary to converge vibrational frequencies to within 1 cm–1. Using these insights, this work identifies a computational protocol as well as a chemical model necessary to construct accurate spectroscopic maps from first principles.
Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate ...that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.
Background: In skeletal muscle, diverse stresses induce the transcription factor ATF4, which promotes muscle atrophy by an unknown mechanism.
Results: ATF4 causes muscle atrophy by inducing Gadd45a, which reprograms myonuclear gene expression to repress anti-atrophy mechanisms and induce pro-atrophy mechanisms.
Conclusion: Gadd45a is a critical stress-induced mediator of muscle atrophy.
Significance: The ATF4/Gadd45a pathway is a potential therapeutic target in atrophic muscle.
Genetic Factors and Orofacial Clefting Lidral, Andrew C; Moreno, Lina M; Bullard, Steven A
Seminars in orthodontics,
06/2008, Letnik:
14, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Cleft lip with or without cleft palate is the most common facial birth defect and it is caused by a complex interaction between genetic and environmental factors. The purpose of this review is to ...provide an overview of the spectrum of the genetic causes for cleft lip and cleft palate using both syndromic and nonsyndromic forms of clefting as examples. Although the gene identification process for orofacial clefting in humans is in the early stages, the pace is rapidly accelerating. Recently, several genes have been identified that have a combined role in up to 20% of all clefts. Although this is a significant step forward, it is apparent that additional cleft-causing genes have yet to be identified. Ongoing human genome-wide linkage studies have identified regions in the genome that likely contain genes that when mutated cause orofacial clefting, including a major gene on chromosome 9 that is positive in multiple racial groups. Currently, efforts are focused to identify which genes are mutated in these regions. In addition, parallel studies are also evaluating genes involved in environmental pathways. Furthermore, statistical geneticists are developing new methods to characterize both gene-gene and gene-environment interactions to build better models for pathogenesis of this common birth defect. The ultimate goal of these studies is to provide knowledge for more accurate risk counseling and the development of preventive therapies.
Double strand breaks (DSBs) have been found at several meiotic recombination hot spots in Saccharomyces cerevisiae; more global studies have found that they occur at many places along several yeast ...chromosomes during meiosis. Indeed, the number of breaks found is consistent with the number of recombination events predicted from the genetic map. We have previously demonstrated that the HIS2 gene is a recombination hot spot, exhibiting a high frequency of gene conversion and associated crossing over. This paper shows that DSBs occur in meiosis at a site in the coding region and at a site downstream of the HIS2 gene and that the DSBs are dependent upon genes required for recombination. The frequency of DSBs at HIS2 increases when the gene conversion frequency is increased by alterations in the DNA around HIS2, and vice versa. A deletion that increases both DSBs and conversion can stimulate both when heterozygous; that is, it is semidominant and acts to stimulate DSBs in trans. These data are consistent with the view that homologous chromosomes associate with each other before the formation of the DSBs
Early exchange (EE) genes are required for the initiation of meiotic recombination in Saccharomyces cerevisiae. Cells with mutations in several EE genes undergo an earlier reductional division (MI), ...which suggests that the initiation of meiotic recombination is involved in determining proper timing of the division. The different effects of null mutations on the timing of reductional division allow EE genes to be assorted into three classes: mutations in RAD50 or REC102 that confer a very early reductional division; mutations in REC104 or REC114 that confer a division earlier than that of wild-type (WT) cells, but later than that of mutants of the first class; and mutations in MEI4 that do not significantly alter the timing of MI. The very early mutations are epistatic to mutations in the other two classes. We propose a model that accounts for the epistatic relationships and the communication between recombination initiation and the first division. Data in this article indicate that double-strand breaks (DSBs) are not the signal for the normal delay of reductional division; these experiments also confirm that MEI4 is required for the formation of meiotic DSBs. Finally, if a DSB is provided by the HO endonuclease, recombination can occur in the absence of MEI4 and REC104.
Abstract only
Skeletal muscle atrophy is a common and debilitating condition that requires widespread changes in skeletal muscle gene expression. However, the transcriptional regulatory factors that ...mediate muscle atrophy are incompletely understood. Here, we examined the potential role of ATF4, a stress‐responsive bZIP transcription factor that is induced in atrophying muscle. We found that ATF4 overexpression in mouse skeletal muscle was sufficient to induce muscle fiber atrophy. To determine if ATF4 is required for muscle atrophy, we generated and studied mice lacking ATF4 specifically in striated muscle (ATF4 mKO mice). ATF4 mKO mice were phenotypically normal under baseline conditions, however they lost ≈ 50% less muscle in response to two distinct muscle atrophy stimuli (fasting and hindlimb immobilization), indicating resistance to muscle atrophy. To determine if ATF4 promotes muscle atrophy by altering protein metabolism, we performed metabolic labeling studies in C2C12 skeletal myotubes, and found that ATF4 reduced protein synthesis and increased proteolysis, leading to myotube atrophy. Collectively, these data indicate that ATF4 is an essential mediator of muscle atrophy, and suggest that ATF4 reduces protein synthesis, induces proteolysis and promotes muscle atrophy by inducing one or more downstream target genes. This work was supported by the NIH and Department of Veterans Affairs.
In the yeast Saccharomyces cerevisiae at least 10 genes are required to begin meiotic recombination. A new early recombination gene REC103 is described in this paper. It was initially defined by the ...rec103-1 mutation found in a selection for mutations overcoming the spore inviability of a rad52 spo13 haploid strain. Mutations in REC103 also rescue rad52 in spo13 diploids. rec103 spo13 strains produce viable spores; these spores show no evidence of meiotic recombination. rec103 SPO13 diploids produce no viable spores, consistent with loss of recombination. Mutations in REC103 do not affect mitotic recombination, growth, or repair. These phenotypes are identical to those conferred by mutations in several other early meiotic recombination genes (e.g., REC102, REC104, REC114, ME14, MER2, and SPO11). REC103 maps to chromosome VII between ADE5 and RAD54. Cloning and sequencing of REC103 reveals that REC103 is identical to SK18, a gene that depresses the expression of yeast double-stranded ("killer") (ds)RNA viruses. REC103/SK18 is transcribed in mitotic cells and is induced approximately 15-fold in meiosis. REC103 has 26% amino acid identity to the Schizasaccharomyces pombe rec14+ gene; mutations in both genes confer similar meiotic phenotypes, suggesting that they may play similar roles in meiotic recombination.
Recombination is an essential part of meiosis: in almost all organisms, including Saccharomyces cerevisiae, proper chromosome segregation and the viability of meiotic products is dependent upon ...normal levels of recombination. In this article we examine the kinetics of the meiotic divisions in four mutants defective in the initiation of recombination. We find that mutations in any of three Early Exchange genes (REC104, REC114 or REC102) confer a phenotype in which the reductional division occurs earlier than in an isogenic wild-type diploid. We also present data confirming previous reports that strains with a mutation in the Early Exchange gene. MEI4 undergo the first division at about the same time as wild-type cells. The rec104 mutation is epistatic to the mei4 mutation for the timing of the first division. These observations suggest a possible relationship between the initiation of recombination and the timing of the reductional division. These data also allow these four Early Exchange genes examined to be distinguished in terms of their role in coordinating recombination with the reductional division.
The aetiological agents of red sore disease (RSD) reportedly comprise a taxonomically ambiguous stalked ciliate (a species of Epistylis) and Aeromonas hydrophila. The taxonomic identity of each ...pathogen remains provisional: using supra‐specific morphological features for the ciliate and culture‐based methods that cannot delineate bacterial strain. On 7 and 9 November 2017 and 28 May 2020, biologists and anglers reported a local epizootic (Hiwassee and Chattahoochee river basins; Georgia) wherein some moribund fish presented RSD‐like lesions. The ciliates were assigned to Epistylis by morphology. The ciliate is regarded as Epistylis cf wuhanensis, as nucleotide sequences from its small subunit ribosomal DNA were identical to those of Epistylis wuhanensis. The bacterium was identified as Aeromonas hydrophila by phenotypic markers and nucleotide sequences from the DNA gyrase subunit B; our sequences comprised 3 strains and phylogenetically were recovered sister to strains of Eurasian origin. Histological sections of lesions revealed effacement or partial deterioration of the epithelium covering scales, scale loss, haemorrhaging, necrosis, oedema, and extensive inflammatory infiltrate in the dermis. This is the first nucleotide sequence information for the symbionts implicated in RSD.
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