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Aims/hypothesis Acetyl coenzyme A acetyltransferase (ACAT), also known as acetoacetyl-CoA thiolase, catalyses the formation of acetoacetyl-CoA from acetyl-CoA and forms part of the isoprenoid biosynthesis pathway. Thus, ACAT plays a central role in cholesterol metabolism in a variety of cells. Here, we aimed to assess the effect of hepatic Acat2 overexpression on cholesterol metabolism and systemic energy metabolism. Methods We generated liver-targeted adeno-associated virus 9 (AAV9) to achieve hepatic Acat2 overexpression in mice. Mice were injected with AAV9 through the tail vein and subjected to morphological, physiological (body composition, indirect calorimetry, treadmill, GTT, blood biochemistry, cardiac ultrasonography and ECG), histochemical, gene expression and metabolomic analysis under normal diet or feeding with high-fat diet to investigate the role of ACAT2 in the liver. Results Hepatic Acat2 overexpression reduced body weight and total fat mass, elevated the metabolic rate, improved glucose tolerance and lowered the serum cholesterol level of mice. In addition, the overexpression of Acat2 inhibited fatty acid, glucose and ketone metabolic pathways but promoted cholesterol metabolism and changed the bile acid pool and composition of the liver. Hepatic Acat2 overexpression also decreased the size of white adipocytes and promoted lipid metabolism in white adipose tissue. Furthermore, hepatic Acat2 overexpression protected mice from high-fat-diet-induced weight gain and metabolic defects Conclusions/interpretation Our study identifies an essential role for ACAT2 in cholesterol metabolism and systemic energy expenditure and provides key insights into the metabolic benefits of hepatic Acat2 overexpression. Thus, adenoviral Acat2 overexpression in the liver may be a potential therapeutic tool in the treatment of obesity and hypercholesterolaemia. Graphical abstract

Tissue specificity is a fundamental property of an organ that affects numerous biological processes, including aging and longevity, and is regulated by the circadian clock. However, the distinction between circadian-affected tissue specificity and other tissue specificities remains poorly understood. Here, using multi-omics data on circadian rhythms in mice, we discovered that approximately 35% of tissue-specific genes are directly affected by circadian regulation. These circadian-affected tissue-specific genes have higher expression levels and are associated with metabolism in hepatocytes. They also exhibit specific features in long-reads sequencing data. Notably, these genes are associated with aging and longevity at both the gene level and at the network module level. The expression of these genes oscillates in response to caloric restricted feeding regimens, which have been demonstrated to promote longevity. In addition, aging and longevity genes are disrupted in various circadian disorders. Our study indicates that the modulation of circadian-affected tissue specificity is essential for understanding the circadian mechanisms that regulate aging and longevity at the genomic level. A multi-omics study on circadian rhythms in mice suggests that ~35% of tissue-specific genes may be influenced by circadian regulation, and these genes are linked to aging and longevity.

Exploring the functions of human-specific genes (HSGs) is challenging due to the lack of a tractable genetic model system. Testosterone is essential for maintaining human spermatogenesis and fertility, but the underlying mechanism is unclear. Here, we identified Cancer/Testis Antigen gene family 47 (CT47) as an essential regulator of human-specific spermatogenesis by stabilizing arginine methyltransferase 5 (PRMT5). A humanized mouse model revealed that CT47 functions to arrest spermatogenesis by interacting with and regulating CT47/PRMT5 accumulation in the nucleus during the leptotene/zygotene-to-pachytene transition of meiosis. We demonstrate that testosterone induces nuclear depletion of CT47/PRMT5 and rescues leptotene-arrested spermatocyte progression in humanized testes. Loss of CT47 in human embryonic stem cells (hESCs) by CRISPR/Cas9 led to an increase in haploid cells but blocked the testosterone-induced increase in haploid cells when hESCs were differentiated into haploid spermatogenic cells. Moreover, CT47 levels were decreased in nonobstructive azoospermia. Together, these results established CT47 as a crucial regulator of human spermatogenesis by preventing meiosis initiation before the testosterone surge.

The circadian clock is the inner rhythm of life activities and is controlled by a self-sustained and endogenous molecular clock, which maintains a ~ 24 h internal oscillation. As the core element of the circadian clock, BMAL1 is susceptible to degradation through the ubiquitin-proteasome system (UPS). Nevertheless, scant information is available regarding the UPS enzymes that intricately modulate both the stability and transcriptional activity of BMAL1, affecting the cellular circadian rhythm. In this work, we identify and validate UBR5 as a new E3 ubiquitin ligase that interacts with BMAL1 by using affinity purification, mass spectrometry, and biochemical experiments. UBR5 overexpression induced BMAL1 ubiquitination, leading to diminished stability and reduced protein level of BMAL1, thereby attenuating its transcriptional activity. Consistent with this, UBR5 knockdown increases the BMAL1 protein. Domain mapping discloses that the C-terminus of BMAL1 interacts with the N-terminal domains of UBR5. Similarly, cell-line-based experiments discover that HYD, the UBR5 homolog in Drosophila , could interact with and downregulate CYCLE, the BMAL1 homolog in Drosophila . PER2 -luciferase bioluminescence real-time reporting assay in a mammalian cell line and behavioral experiments in Drosophila reveal that UBR5 or hyd knockdown significantly reduces the period of the circadian clock. Therefore, our work discovers a new ubiquitin ligase UBR5 that regulates BMAL1 stability and circadian rhythm and elucidates the underlying molecular mechanism. This work provides an additional layer of complexity to the regulatory network of the circadian clock at the post-translational modification level, offering potential insights into the modulation of the dysregulated circadian rhythm.

Circadian systems provide a fitness advantage to organisms by allowing them to adapt to daily changes of environmental cues, such as light/dark cycles. The molecular mechanism underlying the circadian clock has been well characterized. However, how internal circadian clocks are entrained with regular daily light/dark cycles remains unclear. By collecting and analyzing indirect calorimetry (IC) data from more than 2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC), we show that the onset time and peak phase of activity and food intake rhythms are reliable parameters for screening defects of circadian misalignment. We developed a machine learning algorithm to quantify these two parameters in our misalignment screen (SyncScreener) with existing datasets and used it to screen 750 mutant mouse lines from five IMPC phenotyping centres. Mutants of five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) were found to be associated with altered patterns of activity or food intake. By further studying the Slc7a11tm1a/tm1a mice, we confirmed its advanced activity phase phenotype in response to a simulated jetlag and skeleton photoperiod stimuli. Disruption of Slc7a11 affected the intercellular communication in the suprachiasmatic nucleus, suggesting a defect in synchronization of clock neurons. Our study has established a systematic phenotype analysis approach that can be used to uncover the mechanism of circadian entrainment in mice.

Sweat sensors play a significant role in personalized healthcare by dynamically monitoring biochemical markers to detect individual physiological status. The specific response to the target biomolecules usually depends on natural oxidase, but it is susceptible to external interference. In this work, we report tryptophan- and histidine-treated copper metal-organic frameworks (Cu-MOFs). This amino-functionalized copper-organic framework shows highly selective activity for ascorbate oxidation and can serve as an efficient ascorbate oxidase-mimicking material in sensitive sweat sensors. Experiments and calculation results elucidate that the introduced tryptophan/histidine fundamentally regulates the adsorption behaviors of biomolecules, enabling ascorbate to be selectively captured from complex sweat and further efficiently electrooxidized. This work provides not only a paradigm for specifically sweat sensing but also a significant understanding of natural oxidase-inspired MOF nanoenzymes for sensing technologies and beyond. Sweat sensors are important in personalized healthcare using natural oxidase to target biomolecules but these reactions are susceptible to external interference. Here, the authors report tryptophan- and histidine-treated copper metal-organic frameworks which show highly selective activity for ascorbate oxidation and can serve as an efficient ascorbate oxidase-mimicking material in sensitive sweat sensors.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic inflammatory disorder characterized by alcohol-independent hepatic lipid accumulation, remains poorly understood in terms of PANoptosis involvement. Methods: We integrated high-throughput sequencing data with bioinformatics to profile differentially expressed genes (DEGs) and immune infiltration patterns in MASLD, identifying PANoptosis-associated DEGs (PANoDEGs). Machine learning algorithms prioritized key PANoDEGs, while ROC curves assessed their diagnostic efficacy. Cellular, animal, and clinical validations confirmed target expression. Results: Three PANoDEGs (SNHG16, Caspase-6, and Dynamin-1-like protein) exhibited strong MASLD associations and diagnostic significance. Immune profiling revealed elevated M1 macrophages, naïve B cells, and activated natural killer cells in MASLD tissues versus controls. Further experiments verified the expression of the key PANoDEGs. Conclusions: This study provides new insights for further studies on the pathogenesis and treatment strategies of PANoptosis in MASLD.

Keloids, characterized by skin fibrosis and excessive accumulation of extracellular matrix, remain a therapeutic challenge. In this study, we systematically capture the cellular composition of keloids by the single-cell RNA sequencing technique. Our results indicated that there are significant differences in most cell types present between 12 pairs of keloid and adjacent normal tissue. We found that fibroblasts, endothelial cells, mast cells, mural cells, and Schwann cells increased significantly in keloid. The proportion of mesenchymal fibroblast subpopulations in keloids was markedly higher than those in the surrounding normal skin tissue. Furthermore, we found that the immune profiles between two groups varied significantly. The proportion of macrophages in the keloid was significantly elevated compared to the surrounding normal tissue, while cDC2 cells significantly decreased. Hotspot and pseudotime trajectory analysis indicated two modules of macrophage cells (Module2: highly expresses RNASE1, C1QA, CD163, CD14, C1QC, FCGRT, MS4A7; Module10: highly expresses APOC1, CTSB, CTSL, TYROBP), which exhibited the characteristics of tumor-associated macrophages, were upregulated in more-advanced keloid cells. Subsequently, the analysis of cellular communication networks suggested that a macrophage-centered communication regulatory network may exist in keloids and that fibroblasts in keloids may facilitate the transition and proliferation of M2 macrophages, which contributes to further comprehension of the immunological features of keloids. Overall, we delineate the immunology landscape of keloids and present new insights into the mechanisms involved in its formation in this study.

The Jiangmen Underground Neutrino Observatory (JUNO) is a multi-purpose experiment, under construction in southeast China, that is designed to determine the neutrino mass ordering and precisely measure neutrino oscillation parameters. Monte Carlo simulation plays an important role for JUNO detector design, detector commissioning, offline data processing, and physics processing. The JUNO experiment has the world’s largest liquid scintillator detector instrumented with many thousands of PMTs. The broad energy range of interest, long lifetime, and the large scale present data processing challenges across all areas. This paper describes the JUNO simulation software, highlighting the challenges of JUNO simulation and solutions to meet these challenges, including such issues as support for time-correlated analysis, event mixing, event correlation and handling the simulation of many millions of optical photons.

Chemokines and their receptors play a pivotal role in shaping the tumor microenvironment (TME) and modulating immune responses by orchestrating immune cell recruitment, spatial positioning, and facilitating cell-cell interactions. However, the exact mechanisms underlying chemokine signaling across different cell populations within the TME remain poorly understood. In this study, we utilized multiple-omics approaches to explore the relationship between CCR1 + macrophages, CD8 + exhausted T (Tex) cells, and immune checkpoint blockade (ICB) therapy response, as well as the role of chemokine signaling in the formation of CCR1 + macrophage and CD8 + Tex cell niches. We found that CCR1 + macrophages were closely associated with ICB outcomes in melanoma. Additionally, combination therapy with a CCR1 antagonist and anti-PD-1 monoclonal antibody significantly reduced tumor burden in melanoma mouse models, which was attributed to the substantial depletion of CD8 + Tex cells. Further, CCR1 + macrophages were found to co-localize with CD8 + Tex cells in human melanoma tissue, and the CCR1 + macrophage-CD8 + Tex cell niche was correlated with ICB treatment response in mice. Importantly, the CCR1-CCL3 axis was identified as a critical mediator in the formation of this niche. Overall, our study underscores the spatial relationship between CCR1 + macrophages and CD8 + Tex cells in ICB therapy, providing a promising strategy to overcome ICB resistance in melanoma.