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The master DNA damage repair histone protein, H2AX, is essential for orchestrating the recruitment of downstream mediator and effector proteins at damaged chromatin. The phosphorylation of H2AX at S139, γH2AX, is well-studied for its DNA repair function. However, the extended C-terminal tail is not characterized. Here, we define the minimal motif on H2AX for the canonical function in activating the MDC1-RNF8-RNF168 phosphorylation-ubiquitination pathway that is important for recruiting repair proteins, such as 53BP1 and BRCA1. Interestingly, H2AX recruits 53BP1 independently from the MDC1-RNF8-RNF168 pathway through its evolved C-terminal linker region with S139 phosphorylation. Mechanistically, 53BP1 recruitment to damaged chromatin is mediated by the interaction between the H2AX C-terminal tail and the 53BP1 Oligomerization-Tudor domains. Moreover, γH2AX-linker mediated 53BP1 recruitment leads to camptothecin resistance in H2AX knockout cells. Overall, our study uncovers an evolved mechanism within the H2AX C-terminal tail for regulating DNA repair proteins at damaged chromatin.

Objective: Response surface methodology was used to optimize the extraction process of steroidal glycosides from Cynanchum auriculatum Royle ex Wight by complex enzymatic method, and its effects on alcohol dehydrogenase activity and human hepatoma cell HepG2 were analyzed. Methods: Four experimental factors; enzymolysis duration, temperature, compound enzyme dose and pH were used as responses to a single-factor experiment of the Response Surface Methodology on the steroidal glycoside yields, using perennial C. auriculatum as the target material. The alcohol-induced hepatocyte damage model of HepG2 was used to investigate the contents of ALT, LDH, and GSH and changes in cell shape. Results: The results show that the optimum extraction conditions of steroidal glycoside enzyme were obtained at an enzymolysis duration of 100 min, a temperature of 46 ℃, enzyme dose of 1.30% and pH of 5.0. Consequently, the actual extraction rate of （2.80±0.04）% was achieved using the optimized process conditions, which was close to the expected value. Compared with the model group, it significantly suppresses the growth of ALT and LDH while increasing the amount of intracellular GSH, and the cell damage was restored. Conclusion: The compound enzyme method can effectively extract the steroidal glycosides of Cynanchum auriculatum Royle ex Wight; steroidal glycosides of C. auriculatum have hepatoprotective effect.

Introduction: Atherosclerotic complications represent the leading cause of cardiovascular mortality globally. Dysfunction of endothelial cells (ECs) often initiates the pathological events in atherosclerosis. Objectives: In this study, we sought to investigate the transcriptional profile of atherosclerotic aortae, identify novel regulator in dysfunctional ECs and hence provide mechanistic insights into atherosclerotic progression. Methods: We applied single-cell RNA sequencing (scRNA-seq) on aortic cells from Western diet-fed apolipoprotein E-deficient (ApoE−/−) mice to explore the transcriptional landscape and heterogeneity of dysfunctional ECs. In vivo validation of SOX4 upregulation in ECs were performed in atherosclerotic tissues, including mouse aortic tissues, human coronary arteries, and human renal arteries. Single-cell analysis on human aortic aneurysmal tissue was also performed. Downstream vascular abnormalities induced by EC-specific SOX4 overexpression, and upstream modulators of SOX4 were revealed by biochemical assays, immunostaining, and wire myography. Effects of shear stress on endothelial SOX4 expression was investigated by in vitro hemodynamic study. Results: Among the compendium of aortic cells, mesenchymal markers in ECs were significantly enriched. Two EC subsets were subsequently distinguished, as the ‘endothelial-like’ and ‘mesenchymal-like’ subsets. Conventional assays consistently identified SOX4 as a novel atherosclerotic marker in mouse and different human arteries, additional to a cancer marker. EC-specific SOX4 overexpression promoted atherogenesis and endothelial-to-mesenchymal transition (EndoMT). Importantly, hyperlipidemia-associated cytokines and oscillatory blood flow upregulated, whereas the anti-diabetic drug metformin pharmacologically suppressed SOX4 level in ECs. Conclusion: Our study unravels SOX4 as a novel phenotypic regulator during endothelial dysfunction, which exacerbates atherogenesis. Our study also pinpoints hyperlipidemia-associated cytokines and oscillatory blood flow as endogenous SOX4 inducers, providing more therapeutic insights against atherosclerotic diseases.

A technique is developed to identify the types of atmosphere-ocean interaction during El Niño-Southern Oscillation events using sea surface temperature, sea level pressure (SLP), and outgoing longwave radiation (OLR) data. Two pairs of indices are derived that separate the interactions into tropical and subtropical types and basin-wide and local types. The dominant interaction type for the observed El Niño events since 1980 is identified and shown to shift with time from the tropical to subtropical and from basin-wide to local. Thus, the 21st century El Niños have become dominated by subtropical and local interactions, in strong contrast to the 20th century El Niños that were dominated by the tropical and basin-wide interactions. These changes result in the 1997-98 and 2015-16 extreme El Niños being different in their evolutions and global impacts, despite having similar intensities. SLP is the key variable for separating the tropical and subtropical types of interactions, while OLR is the key variable for separating the basin-wide and local types of interactions.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT-induced pathology while reducing Polycomb Repressive Complex2 core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

Abstract We study the thermodynamics of spherically symmetric, neutral and non-rotating black holes in conformal (Weyl) gravity. To this end, we apply different methods: (i) the evaluation of the specific heat; (ii) the study of the entropy concavity; (iii) the geometrical approach to thermodynamics known as thermodynamic geometry; (iv) the Poincaré method that relates equilibrium and out-of-equilibrium thermodynamics. We show that the thermodynamic geometry approach can be applied to conformal gravity too, because all the key thermodynamic variables are insensitive to Weyl scaling. The first two methods, (i) and (ii), indicate that the entropy of a de Sitter black hole is always in the interval $$2/3\le S\le 1$$ 2 / 3 ≤ S ≤ 1 , whereas thermodynamic geometry suggests that, at $$S=1$$ S = 1 , there is a second order phase transition to an Anti de Sitter black hole. On the other hand, we obtain from the Poincaré method (iv) that black holes whose entropy is $$S < 4/3$$ S < 4 / 3 are stable or in a saddle-point, whereas when $$S>4/3$$ S > 4 / 3 they are always unstable, hence there is no definite answer on whether such transition occurs. Since thermodynamics geometry takes the view that the entropy is an extensive quantity, while the Poincaré method does not require extensiveness, it is valuable to present here the analysis based on both approaches, and so we do.

Tricuspid regurgitation (TR) may occur late after left-sided valve surgery (LSVS). Isolated tricuspid regurgitation after left-sided valve surgery (iTR-LSVS) refers to isolated TR without significant lesions in the mitral and/or aortic position late after mitral and/or aortic replacement or repair. Severe TR has a negative impact on long-term prognosis and requires surgical or transcatheter treatment. However, there is no clear recommendation on when and how intervention should be performed for patients with iTR-LSVS in the current guidelines for the management of valvular heart disease. The historically high operative mortality may be reduced by current minimally invasive techniques and transcatheter therapy. To further understand iTR-LSVS, standardize the treatment, improve the prognosis, and promote the collaboration, the Chinese Minimally Invasive Cardiovascular Surgery Committee (CMICS) wrote this expert consensus on the management of iTR-LSVS from the aspects of etiology, preoperative evaluation, indications for intervention, surgical treatment, transcatheter therapy, and postoperative management.