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Husum Curry posted an update 6 months, 2 weeks ago
BACKGROUND Juvenile myoclonic epilepsy (JME) is a classic epileptic syndrome that lacks consensus on the possibility of suspending treatment with antiepileptic drugs (AD). METHOD Retrospective observational study of a series of patients diagnosed with JME with 20 years or more of evolution, focusing on those with withdrawal from AD. RESULTS The study involved twenty patients (average age 44.1 years, 55% men) with JME of 30 years average evolution and average age at its outset of 14.2 years. The most frequent type of motor crisis was the combination of myoclonic and tonic-clonic seizures (70%); 60% of the patients have been free of seizures for more than five years. Four patients (20%) were withdrawn from AD, two of them with an average age of 23 years and an average time free of seizures of 7.5 years, who relapsed, and the other two with an average age of 39 years and following 23.5 years free of seizures, who currently have been without seizures for two and nine years. CONCLUSIONS The possibility of withdrawing AD in patients with JME who have been free of seizures over an extended time seems feasible. We suggest taking into account age at withdrawal and prior existence of a prolonged period of time free of seizures.An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.Mutations in enzymes that modify histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) have been linked to human disease, yet the role of these residues in mammals is unclear. We mutated K4 or K36 to alanine in the histone variant H3.3 and showed that the K4A mutation in mouse embryonic stem cells (ESCs) impaired differentiation and induced widespread gene expression changes. K4A resulted in substantial H3.3 depletion, especially at ESC promoters; it was accompanied by reduced remodeler binding and increased RNA polymerase II (Pol II) activity. Regulatory regions depleted of H3.3K4A showed histone modification alterations and changes in enhancer activity that correlated with gene expression. In contrast, the K36A mutation did not alter H3.3 deposition and affected gene expression at the later stages of differentiation. Thus, H3K4 is required for nucleosome deposition, histone turnover and chromatin remodeler binding at regulatory regions, where tight regulation of Pol II activity is necessary for proper ESC differentiation.Most therapeutics are designed to alter the activities of proteins. From metabolic enzymes to cell surface receptors, connecting the function of a protein to a cellular phenotype, to the activity of a drug and to a clinical outcome represents key mechanistic milestones during drug development. Yet, even for therapeutics with exquisite specificity, the sequence of events following target engagement can be complex. Interconnected communities of structural, metabolic and signalling proteins modulate diverse downstream effects that manifest as interindividual differences in efficacy, adverse effects and resistance to therapy. GW280264X Recent advances in mass spectrometry proteomics have made it possible to decipher these complex relationships and to understand how factors such as genotype, cell type, local environment and external perturbations influence them. In this Review, we explore how proteomic technologies are expanding our understanding of protein communities and their responses to large- and small-molecule therapeutics.An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The elevated expression of poly(ADP-ribose) polymerase-1 (PARP1) and increased PARP1 activity, namely, poly(ADP-ribosyl)ation (PARylation), have been observed in cardiac remodeling, leading to extreme energy consumption and myocardial damage. However, the mechanisms underlying the regulation of PARP1 require further study. WWP2, a HECT-type E3 ubiquitin ligase, is highly expressed in the heart, but its function there is largely unknown. Here, we clarified the role of WWP2 in the regulation of PARP1 and the impact of this regulatory process on cardiac remodeling. We determined that the knockout of WWP2 specifically in myocardium decreased the level of PARP1 ubiquitination and increased the effects of isoproterenol (ISO)-induced PARP1 and PARylation, in turn aggravating ISO-induced myocardial hypertrophy, heart failure, and myocardial fibrosis. Similar findings were obtained in a model of ISO-induced H9c2 cells with WWP2 knockdown, while the reexpression of WWP2 significantly increased PARP1 ubiquitination and decreased PAPR1 and PARylation levels. Mechanistically, coimmunoprecipitation results identified that WWP2 is a novel interacting protein of PARP1 and mainly interacts with its BRCT domain, thus mediating the degradation of PARP1 through the ubiquitin-proteasome system. In addition, lysine 418 (K418) and lysine 249 (K249) were shown to be of critical importance in regulating PARP1 ubiquitination and degradation by WWP2. These findings reveal a novel WWP2-PARP1 signal transduction pathway involved in controlling cardiac remodeling and may provide a basis for exploring new strategies for treating heart disorders related to cardiac remodeling.
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