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Liver transplantation is the ultimate method for treating end-stage liver disease. With the increasing prevalence of obesity, the number of patients with non-alcoholic fatty liver, a common cause of chronic liver disease, is on the rise and may become the main cause of liver transplantation in the future. With the increasing gap between the number of donor livers and patients waiting for liver transplantation and the increasing prevalence of non-alcoholic fatty liver, the proportion of steatosis livers among non-standard donor organs is also increasing. Ischemia-reperfusion injury has historically been the focus of attention in the liver transplantation process, and severe ischemia-reperfusion injury leads to adverse outcomes of liver transplantation. Studies have shown that the production of reactive oxygen species and subsequent oxidative stress play a key role in the pathogenesis of hepatic ischemia and reperfusion injury and non-alcoholic fatty liver. Furthermore, the sensitivity of fatty liver transplantation to ischemia-reperfusion injury has been suggested to be related to the production of reactive oxygen species (ROS) and oxidative stress. In ischemia-reperfusion injury, Kupffer cell and macrophage activation along with mitochondrial damage and the xanthine/xanthine oxidase system promote marked reactive oxygen species production and the inflammatory response and apoptosis, resulting in liver tissue injury. The increased levels of ROS and lipid peroxidation products, vicious circle of ROS and oxidative stress along with mitochondrial dysfunction promoted the progress of non-alcoholic fatty liver. In contrast to the non-fatty liver, a non-alcoholic fatty liver produces more reactive oxygen species and suffers more serious oxidative stress when subjected to ischemia-reperfusion injury. We herein review the effects of reactive oxygen species on ischemia-reperfusion injury and non-alcoholic fatty liver injury as well as highlight several treatment approaches.

Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. In this phase 2, single-arm, prospective study, we recruited patients aged 18–70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1–14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956. Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6–71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2–78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. None.

The emergence of 3D Gaussian splatting (3DGS) has greatly accelerated rendering in novel view synthesis. Unlike neural implicit representations like neural radiance fields (NeRFs) that represent a 3D scene with position and viewpoint-conditioned neural networks, 3D Gaussian splatting utilizes a set of Gaussian ellipsoids to model the scene so that efficient rendering can be accomplished by rasterizing Gaussian ellipsoids into images. Apart from fast rendering, the explicit representation of 3D Gaussian splatting also facilitates downstream tasks like dynamic reconstruction, geometry editing, and physical simulation. Considering the rapid changes and growing number of works in this field, we present a literature review of recent 3D Gaussian splatting methods, which can be roughly classified by functionality into 3D reconstruction, 3D editing, and other downstream applications. Traditional point-based rendering methods and the rendering formulation of 3D Gaussian splatting are also covered to aid understanding of this technique. This survey aims to help beginners to quickly get started in this field and to provide experienced researchers with a comprehensive overview, aiming to stimulate future development of the 3D Gaussian splatting representation.

Background Parkinson’s disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. Results The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. Conclusions Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. CoKvBsES-WQ_2hkhyhEj9X Video abstract

Several recent studies have shown the presence of genes for the key enzyme associated with archaeal methane/alkane metabolism, methyl-coenzyme M reductase (Mcr), in metagenome-assembled genomes (MAGs) divergent to existing archaeal lineages. Here, we study the mcr -containing archaeal MAGs from several hot springs, which reveal further expansion in the diversity of archaeal organisms performing methane/alkane metabolism. Significantly, an MAG basal to organisms from the phylum Thaumarchaeota that contains mcr genes, but not those for ammonia oxidation or aerobic metabolism, is identified. Together, our phylogenetic analyses and ancestral state reconstructions suggest a mostly vertical evolution of mcrABG genes among methanogens and methanotrophs, along with frequent horizontal gene transfer of mcr genes between alkanotrophs. Analysis of all mcr -containing archaeal MAGs/genomes suggests a hydrothermal origin for these microorganisms based on optimal growth temperature predictions. These results also suggest methane/alkane oxidation or methanogenesis at high temperature likely existed in a common archaeal ancestor. Methane metabolism by some lineages of Archaea contributes to the cycling of carbon on Earth. Here, the authors show high diversity of methyl-coenzyme M reductase (Mcr), a key enzyme associated with archaeal methane/alkane metabolism, in hot spring Archaea, and investigate their ecological roles and evolution.

Itaconate has been recently recognized as an anti-inflammatory metabolite involved in the pathogen–macrophage interface. Due to its weak electrophilicity, itaconate could modify cysteines of the protein KEAP1 and glutathione, which contribute to its anti-inflammatory effect. However, the substrates of itaconate modification in macrophages have not been systematically profiled, which largely impedes the understanding of its roles in immune responses. Here, we developed a specific thiol-reactive probe, 1-OH-Az, for quantitative chemoproteomic profiling of cysteine modifications by itaconate, and provided a global portrait of its proteome reactivity. We found that itaconate covalently modifies key glycolytic enzymes and impairs glycolytic flux mainly through inhibition of fructose-bisphosphate aldolase A (ALDOA). Moreover, itaconate attenuates the inflammatory response in stimulated macrophages by impairing the glycolysis. Our study provides a valuable resource of protein targets of itaconate in macrophages and establishes a negative-feedback link between glycolysis and itaconate, elucidating new functional insights for this anti-inflammatory metabolite. Using a thiol-reactive probe, chemoproteomic profiling of cysteine targets of itaconate reveals the covalent modification of glycolytic enzymes, impairing glycolytic flux and contributing to attenuation of the inflammatory response in macrophages.

A bstract We study gapped boundaries characterized by “fermionic condensates” in 2+1 d topological order. Mathematically, each of these condensates can be described by a super commutative Frobenius algebra. We systematically obtain the species of excitations at the gapped boundary/junctions, and study their endomorphisms (ability to trap a Majorana fermion) and fusion rules, and generalized the defect Verlinde formula to a twisted version. We illustrate these results with explicit examples. We also connect these results with topological defects in super modular invariant CFTs. To render our discussion self-contained, we provide a pedagogical review of relevant mathematical results, so that physicists without prior experience in tensor category should be able to pick them up and apply them readily.

Background Long non-coding RNAs (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been shown to be associated with liver fibrosis. Nevertheless, the role of PVT1 in atrial fibrosis remains undefined. This study aims to elucidate the pathophysiological role of lncRNA PVT1 in the regulation of atrial fibrosis and to explore the underlying mechanism. Methods Expression of PVT1, miR-128-sp, and Sp1 were examined in human atrial muscle tissues and angiotensin-II (Ang-II)-induced human atrial fibroblasts. Furthermore, the role of PVT1 in regulating atrial fibrosis in Ang-II-treated human atrial fibroblasts and Ang-II-induced atrial fibrosis in mice was investigated. Moreover, the interaction among PVT1, miR-128-3p, and Sp1 were examined using bioinformatics, expression correlation analysis, gain- or loss-of-function assays, RIP assays, and luciferase reporter assays. The involvement of transforming growth factor beta 1 (TGF-β1)/Smad pathway in this process was also explored. Results PVT1 was increased in atrial muscle tissues from AF patients and positively with collagen I and collagen III. In vitro assay revealed that PVT1 overexpression facilitated the Ang-II-induced atrial fibroblasts proliferation, collagen production, and TGF-β1/Smad signaling activation, whereas PVT1 knockdown caused the opposite effect. In vivo assay further confirmed that PVT1 knockdown attenuated the Ang-II-induced mouse atrial fibrosis. Mechanically, PVT1 acted as a sponge for miR-128-3p to facilitate Sp1 expression, thereby activating the TGF-β1/Smad signaling pathway. Conclusion LncRNA PVT1 promotes atrial fibrosis via miR-128-3p-SP1-TGF-β1-Smad axis in atrial fibrillation.

We examine holographic entanglement entropy with higher curvature gravity in the bulk. We show that in general Wald’s formula for horizon entropy does not yield the correct entanglement entropy. However, for Lovelock gravity, there is an alternate prescription which involves only the intrinsic curvature of the bulk surface. We verify that this prescription correctly reproduces the universal contribution to the entanglement entropy for CFT’s in four and six dimensions. We also make further comments on gravitational theories with more general higher curvature interactions.