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Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E‐deficient (ApoE−/−) mouse with CKD (CKD/ApoE−/− mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD‐associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE−/− mice are comprehensively investigated. Using multi‐omics analysis and targeted and VSMC‐specific gene knockout mice, VSMCs are identified as both type‐I‐interferon (IFN‐I)‐responsive and IFN‐I‐productive cells. Mechanistically, mitochondrial damage resulting from CKD‐induced oxidative stress primes the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway to trigger IFN‐I response in VSMCs. Enhanced IFN‐I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN‐I response remarkably attenuates CKD‐associated plaque vulnerability. These findings reveal that IFN‐I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD‐associated plaque vulnerability. Mitigating IFN‐I response may hold promise for the treatment of CKD‐associated cardiovascular diseases. Oxidative stress‐induced mitochondrial damage under chronic kidney disease (CKD) milieu primes the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway in vascular smooth muscle cells (VSMCs) to trigger type‐I‐interferon response, which induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner and finally results in plaque vulnerability.

Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S . aureus infection led to S . aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S . aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S . aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S . aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S . aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.

Background The relationship between human gut microbiota and high-altitude hypoxia acclimatization remains highly controversial. This stems primarily from uncertainties regarding both the potential temporal changes in the microbiota under such conditions and the existence of any dominant or core bacteria that may assist in host acclimatization. Results To address these issues, and to control for variables commonly present in previous studies which significantly impact the results obtained, namely genetic background, ethnicity, lifestyle, and diet, we conducted a 108-day longitudinal study on the same cohort comprising 45 healthy Han adults who traveled from lowland Chongqing, 243 masl, to high-altitude plateau Lhasa, Xizang, 3658 masl, and back. Using shotgun metagenomic profiling, we study temporal changes in gut microbiota composition at different timepoints. The results show a significant reduction in the species and functional diversity of the gut microbiota, along with a marked increase in functional redundancy. These changes are primarily driven by the overgrowth of Blautia A , a genus that is also abundant in six independent Han cohorts with long-term duration in lower hypoxia environment in Shigatse, Xizang, at 4700 masl. Further animal experiments indicate that Blautia A -fed mice exhibit enhanced intestinal health and a better acclimatization phenotype to sustained hypoxic stress. Conclusions Our study underscores the importance of Blautia A species in the gut microbiota’s rapid response to high-altitude hypoxia and its potential role in maintaining intestinal health and aiding host adaptation to extreme environments, likely via anti-inflammation and intestinal barrier protection.

Metal-centered chirality has been recognized for over one century, and stereogenic-at-metal complexes where chirality is exclusively attributed to the metal center due to the specific coordination pattern of achiral ligands around the metal ion, has been broadly utilized in diverse areas of natural science. However, synthesis of these molecules remains constrained. Notably, while asymmetric catalysis has played a crucial role in the production of optically active organic molecules, its application to stereogenic-at-metal complexes is less straightforward. In this study, we introduce a kinetic resolution strategy employing a Pd-catalyzed asymmetric Suzuki-Miyaura cross-coupling reaction that efficiently produces optically active stereogenic-at-iridium complexes from racemic mixtures with high selectivity (achieving an s -factor of up to 133). This method enables further synthesis of complexes relevant to chiral metallodrugs and photosensitizers, underscoring the practical utility of our approach. Mechanistic studies suggest that reductive elimination is likely the turnover-limiting step over the Suzuki-Miyaura cross-coupling. Asymmetric catalysis plays a crucial role in the synthesis of optically active organic molecules, but its application to stereogenic-at-metal complexes is more challenging. Here, the authors report the asymmetric synthesis of stereogenic-at-iridium complexes through kinetic resolution via a Pd-catalyzed Suzuki-Miyaura cross-coupling reaction.

Over the past two decades, many studies have shown that the yam storage protein dioscorin, which is abundant in the wastewater of starch processing, exhibits many biological activities both in vitro and in vivo . In the present study, the acid-precipitation method was optimized using Box-Behnken design (BBD) combined with response surface methodology (RSM) for the recovery of yam soluble protein (YSP) from wastewater. The experimental yield of YSP reached 57.7%. According to relative quantitative proteomics (LC-MS/MS), the crude YSP was mainly composed of 15 dioscorin isoforms, which was further verified by anion-exchange and size-exclusion chromatography. YSP was found to be rich in glutamic acid and aspartic acid, and the eight essential acids made up approximately 33.7% of the YSP. Moreover, the YSP demonstrated antioxidant activity, including scavenging DPPH, hydroxyl and superoxide anion radicals, and the possible structure-activity relationships were discussed. These results indicated that YSP produced by acid precipitation may be used as a protein source with antioxidant properties.

Soil acidification has always been a substantial eco-environmental problem restricting agricultural development in the red soil region of southern China. It is necessary to determine the dynamic change in soil pH in this area to formulate regional agricultural and environmental management measures. Yujiang County, a typical county with red soil acidification in southern China, was selected as the study area. Based on soil data from 1982, 2007, and 2018, the spatiotemporal variation characteristics and the latest changes in soil pH in the county were analyzed. The results show that the soil pH in Yujiang County decreased from 5.66 to 4.74 and then increased to 4.96 from 1982 to 2018, showing a trend of first decreasing and then increasing. According to the spatial distribution characteristics of soil pH, the low soil pH values in the three periods were mainly distributed in the northern mountainous areas with more forestland and dry land area and some southern hilly areas, while the paddy soil pH values in the middle low hilly areas were relatively higher. The soil pH decreased rapidly from 1982 to 2007, showing a large area of acidification. In 2007, the proportions of acidic (4.5 < pH < 5.5) and strongly acidic (pH < 4.5) soils increased by 67.37% and 10.6%, respectively, compared with that in 1982. However, from 2007 to 2018, the soil pH of the whole county increased, and the acidification trend was alleviated, which is of great significance to the regional red soil ecological environment. Through the analysis of the main factors affecting the change in soil pH, it was found that the sharp decline in soil pH in Yujiang County during 1982–2007 was mainly caused by acid rain and excessive nitrogen application. From 2007 to 2018, no significant reduction in nitrogen fertilizer in this area occurred, and although the increase in soil organic matter contributed to alleviating soil acidification, the analysis showed that the decrease in acid rain was the main reason for the rise in soil pH in Yujiang County. At the same time, notably, there is a large area of soil in the area that is still acidic, and effective control of soil acidification is still an important ecological and environmental issue in this area. In order to further improve the pH value of soil in red soil region, it is suggested that on the basis of continuous improvement of acid rain, in addition to increasing soil organic matter by returning straw to field and other measures, appropriate amount of lime or alkaline biochar can be applied to better improve the soil ecological environment in red soil hilly region.

The rise of antibiotic resistance poses a significant public health crisis, particularly due to limited antimicrobial options for the treatment of infections with Gram‐negative pathogens. Here, an antimicrobial peptide (AMP) SR25 is characterized, which effectively kills both Gram‐negative and Gram‐positive bacteria through a unique dual‐targeting mechanism without detectable resistance. Meanwhile, an SR25‐functionalized hydrogel is developed for the efficient treatment of infected diabetic wounds. SR25 is obtained through genome mining from an uncultured bovine enteric actinomycete named Nonomuraea Jilinensis sp. nov. Investigations reveal that SR25 has two independent cellular targets, disrupting bacterial membrane integrity and restraining the activity of succinate:quinone oxidoreductase (SQR). In a diabetic mice wound infection model, the SR25‐incorporated hydrogel exhibits high efficacy against mixed infections of Escherichia coli (E. coli) and methicillin‐resistant Staphylococcus aureus (MRSA), accelerating wound healing. Overall, these findings demonstrate the therapeutic potential of SR25 and highlight the value of mining drugs with multiple mechanisms from uncultured animal commensals for combating challenging bacterial pathogens. The previously uncultured bacterium presents a viable strategy for the discovery of novel antimicrobial peptides. The antimicrobial peptide SR25 operates through a dual mechanism, targeting both the bacterial cell membrane and succinate:quinone oxidoreductase. It exhibits outstanding antibacterial efficacy and promotes the recovery of infected diabetes wounds.

The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging to investigate the complex relationship between these epigenetic marks across the genome. Here we describe a nanopore-sequencing-based-method, nanoHiMe-seq, for interrogating the genome-wide localization of histone modifications and DNA methylation from single DNA molecules. nanoHiMe-seq leverages a nonspecific methyltransferase to exogenously label adenine bases proximal to antibody-targeted modified nucleosomes in situ. The labelled adenines and the endogenous methylated CpG sites are simultaneously detected on individual nanopore reads using a hidden Markov model, which is implemented in the nanoHiMe software package. We demonstrate the utility, robustness and sensitivity of nanoHiMe-seq by jointly profiling DNA methylation and histone modifications at low coverage depths, concurrently determining phased patterns of DNA methylation and histone modifications, and probing the intrinsic connectivity between these epigenetic marks across the genome. The interplay between histone modifications and DNA methylation plays a crucial role in establishing and maintaining the epigenomic landscape. Here, the authors develop a nanopore sequencing based method for mapping histone modifications and DNA methylation from native, long, single DNA molecules.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that frequently presents at an advanced stage with limited effective treatment options and a dismal prognosis. It is a highly heterogenous disease driven by various genetic and epigenetic alterations. Recent advances in sequencing modalities have significantly improved our understanding of the genetics of PDAC, which could lead to promising and novel therapeutic strategies. In this review, we summarize the most up-to-date literature on the molecular landscape of PDAC and its precursor lesions, as well as recent advances in targeted therapy.

As an alternative gravitational theory to General Relativity (GR), Conformal Gravity (CG) can be verified through astronomical observations. Currently, Mannheim and Kazanas have provided vacuum solutions for cosmological and local gravitational systems, and these solutions may resolve the dark matter and dark energy issues encountered in GR, making them particularly valuable. For static, spherically symmetric systems, CG predicts an additional linear potential generated by luminous matter in addition to the conventional Newtonian potential. This extra potential is expected to account for the observations of galaxies and galaxy clusters without the need of dark matter. It is characterized by the parameter γ*, which corresponds to the linear potential generated by the unit of the solar mass, and it is thus a universal constant. The value of γ* was determined by fitting the rotation curve data of spiral galaxies. These predictions of CG should also be verified by the observations of strong gravitational lensing. To date, in the existing literature, the observations of strong lensing employed to test CG have been limited to a few galaxy clusters. It has been found that the value of γ* estimated from strong lensing is several orders of magnitude greater than that obtained from fitting rotation curves. In this study, building upon the previous research, we tested CG via strong lensing statistics. We used a well-defined sample that consisted of both galaxies and galaxy clusters. This allowed us to test CG through statistical strong lensing in a way similar to the conventional approach in GR. As anticipated, our results were consistent with previous studies, namely that the fitted γ* is much larger than that from rotation curves. Intriguingly, we further discovered that, in order to fit the strong lensing data of another sample, the value of γ* cannot be a constant, as is required in CG. Instead, we derived a formula for γ* as a function of the stellar mass M* of the galaxies or galaxy clusters. It was found that γ* decreases as M* increases.