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Background: To date, numerous studies have investigated the relationship between the triglyceride glucose (TyG) index and carotid plaques, but the impact of gender on this relationship has not been explored. Therefore, this study aims to investigate gender-specific differences in the relationship between the TyG index and carotid plaques in a high cardiovascular risk population in China., Methods: This cross-sectional study's data were derived from a longitudinal pilot study involving 1,085 high-risk cardiovascular subjects. A multivariable logistic regression model was used to analyze the relationship between the TyG index and carotid plaques. A generalized additive model combined with a stratified regression model was employed to assess the nonlinear relationship between the TyG index and carotid plaques across different genders. In the nonlinear relation, the inflection point was calculated by a two-piecewise linear regression model., Results: After adjusting for confounders such as age, sex, BMI, SBP, DBP, AST/ALT, TC, LDL-c, HDL-c, creatinine, smoking, and antilipemic medication, the generalized additive model results revealed a nonlinear relationship between the TyG index and carotid plaque formation, with significant differences across genders. In males, the relationship between the TyG index and carotid plaques was S-shaped. The two-piecewise linear regression model identified two inflection points: TyG = 8.39 ( P  = 0.017) and TyG = 10.2 ( P  = 0.009)., Conclusion: The relationship between the TyG index and the formation of carotid plaques is nonlinear, and there are significant differences in the correlation between males and females., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Lin, Xu, Zheng, Sun, Yan, Chen and Lin.)

The blood-brain barrier (BBB) is a selective, semi-permeable layer of endothelial cells that protects the central nervous system from harmful substances circulating in blood. It is one of the important barriers of the nervous system. BBB dysfunction is an early pathophysiological change observed in nervous system diseases. There are few treatments for BBB dysfunction, so this motivates the review. Ferroptosis is a novel cell death mode caused by iron-mediated lipid peroxidation accumulation, which has recently attracted more attention due to its possible role in nervous system disorders. Studies have shown that lipid peroxidation and iron accumulation are related to the barrier dysfunction, especially the expression of tight junction proteins. Therefore, examination of the relationship between ferroptosis and BBB dysfunction may reveal new targets for the treatment of brain diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Pang, Yeo, Xie, Xiang, Shi, Yu and Li.)

The antibiotic resistance crisis continues to threaten human health. Better predictions of the evolution of antibiotic resistance genes could contribute to the design of more sustainable treatment strategies. However, comprehensive prediction of antibiotic resistance gene evolution via laboratory approaches remains challenging. By combining site-specific integration and high-throughput sequencing, we quantified relative growth under the respective selection of cefotaxime or ceftazidime selection in ∼23,000 Escherichia coli MG1655 strains that each carried a unique, single-copy variant of the extended-spectrum β-lactamase gene blaCTX-M-14 at the chromosomal att HK022 site. Significant synergistic pleiotropy was observed within four subgenic regions, suggesting key regions for the evolution of resistance to both antibiotics. Moreover, we propose PEARP and PEARR, two deep-learning models with strong clinical correlations, for the prospective and retrospective prediction of blaCTX-M-14 evolution, respectively. Single to quintuple mutations of blaCTX-M-14 predicted to confer resistance by PEARP were significantly enriched among the clinical isolates harboring blaCTX-M-14 variants, and the PEARR scores matched the minimal inhibitory concentrations obtained for the 31 intermediates in all hypothetical trajectories. Altogether, we conclude that the measurement of local fitness landscape enables prediction of the evolutionary trajectories of antibiotic resistance genes, which could be useful for a broad range of clinical applications, from resistance prediction to designing novel treatment strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Objective to evaluate the clinical efficacy and safety of sacubitril valsartan in the treatment of heart failure (HF) with midrange ejection fraction after acute myocardial infarction (AMI) in diabetic patients. From January 2015 to July 2020, HF patients with diabetes mellitus complicated with AMI were retrospectively analyzed. According to the medication, they were divided into 2 groups, that is, sacubitril valsartan group (84 cases) and valsartan group (86 cases). Valsartan group took valsartan capsule (80 mg/capsule, Beijing Novartis Pharmaceutical Co., Ltd) 80 mg, qd, on the basis of routine treatment. On the basis of routine treatment, the sacubitril valsartan group took sacubitril valsartan sodium tablets (50 mg/tablet, Beijing Novartis Pharmaceutical Co., Ltd), the initial dose was 25 mg, bid, and gradually increased to the target dose according to the patient's blood pressure. After 12 months of treatment, the independent sample t test showed that the left ventricular end diastolic dimension in the sacubitril valsartan group was lower than that in the valsartan group [(47.26 ± 4.71) mm vs (50.05 ± 5.62) mm, P < .001]. The left ventricular ejection fraction in the sacubitril valsartan group was higher than that in the valsartan group [(54.76 ± 4.24)% vs (49.28 ± 3.74)%, P < .001]. χ2 inspection showed that the readmission rate in the sacubitril valsartan group was lower than that in the valsartan group (7.14% vs 18.60%, P < .05). Sacubitril valsartan has good safety and tolerability in patients with diabetes mellitus complicated with AMI who have HF with midrange ejection fraction. Compared with valsartan, sacubitril valsartan can improve the left ventricular function better and reduce the readmission rate due to HF in these patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The phenotypic consequence of a genetic mutation depends on many factors including the expression level of a gene. However, a comprehensive quantification of this expression effect is still lacking, as is a further general mechanistic understanding of the effect. Here, we measured the fitness effect of almost all (>97.5%) single-nucleotide mutations in GFP, an exogenous gene with no physiological function, and URA3, a conditionally essential gene. Both genes were driven by two promoters whose expression levels differed by around tenfold. The resulting fitness landscapes revealed that the fitness effects of at least 42% of all single-nucleotide mutations within the genes were expression dependent. Although only a small fraction of variation in fitness effects among different mutations can be explained by biophysical properties of the protein and messenger RNA of the gene, our analyses revealed that the avoidance of stochastic molecular errors generally underlies the expression dependency of mutational effects and suggested protein misfolding as the most important type of molecular error among those examined. Our results therefore directly explained the slower evolution of highly expressed genes and highlighted cytotoxicity due to stochastic molecular errors as a non-negligible component for understanding the phenotypic consequence of mutations., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

A full understanding of the developmental process requires fine-scale characterization of cell divisions and cell types, which are naturally organized as the developmental cell lineage tree (CLT). Technological breakthroughs facilitated determination of more CLTs, but complete comprehension of the data remains difficult without quantitative comparison among CLTs. We hereby quantified phenotypic similarity between CLTs using a novel computational method that exhaustively searches for optimal correspondence between individual cells meanwhile retaining their topological relationships. The revealed CLT similarities allowed us to infer functional similarity at the transcriptome level, identify cell fate transformations, predict functional relationships between mutants, and find evolutionary correspondence between cell types of different species. By allowing quantitative comparison between CLTs, our work is expected to greatly enhance the interpretability of relevant data and help answer the myriad of questions surrounding the developmental process., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The six-minute walking test (6MWT) is a tool that plays a key role in evaluating the functional exercise capacity, prognosis and evaluation of treatment response of patients with various cardiopulmonary diseases. However, standard reference equations are currently unavailable for the six-minute walking distance (6MWD) for people aged 60-85 years in China. The purpose of this study was to 1) measure the 6MWD of healthy Chinese people aged 60-85 years, 2) establish reference equations for predicting the 6MWD, and 3) compare our reference equations with equations reported in previously published studies., Method: We obtained informed consent from each participant prior to the test, and the research design was approved by the Ethics Committee of Wenzhou People's Hospital. The demographic and anthropometric data and the 6MWD of healthy Chinese subjects aged 60-85 years old were measured using a standardized protocol. Every subject completed two 6MWTs, and the longest 6MWD further analyzed., Results: Two hundred sixty-six subjects (128 males and 138 females) completed the 6MWT, and the mean walking distance was 518 ± 72 m. Males achieved a longer walking distance than females (518 ± 72 m vs. 487 ± 70 m; p < 0.0001), and active subjects achieved a longer walking distance than nonactive subjects (512 ± 76 m vs. 485 ± 63 m; p < 0.0001). According to the univariate analysis, the 6MWD was significantly associated with age, height, body mass index (BMI), heart rate and blood pressure after exercise and changes in heart rate before and after exercise. The stepwise multivariate regression analysis identified age, height and BMI as independent predictors of the 6MWD. The reference equations for Caucasians and South Americans tended to overestimate the 6MWD of our subjects, while the equations for Asian and African populations tended to underestimate the 6MWD., Conclusions: This study is the first to describe the 6MWD of healthy Chinese people aged 60-85 years, and reference prediction equations were proposed. These findings will help to improve the evaluation of Chinese patients with diseases that affect exercise capacity.

Eighteen of the 20 amino acids are each encoded by more than one synonymous codon. Due to differential transfer RNA supply within the cell, synonymous codons are not used with equal frequency, a phenomenon termed codon usage bias (CUB). Previous studies have demonstrated that CUB of endogenous genes trans-regulates the translational efficiency of other genes. We hypothesized similar effects for CUB of exogenous genes on host translation, and tested it in the case of viral infection, a common form of naturally occurring exogenous gene translation. We analysed public Ribo-Seq datasets from virus-infected yeast and human cells and showed that virus CUB trans-regulated tRNA availability, and therefore the relative decoding time of codons. Manipulative experiments in yeast using 37 synonymous fluorescent proteins confirmed that an exogenous gene with CUB more similar to that of the host would apply decreased translational load on the host per unit of expression, whereas expression of the exogenous gene was elevated. The combination of these two effects was that exogenous genes with CUB overly similar to that of the host severely impeded host translation. Finally, using a manually curated list of viruses and natural and symptomatic hosts, we found that virus CUB tended to be more similar to that of symptomatic hosts than that of natural hosts, supporting a general deleterious effect of excessive CUB similarity between virus and host. Our work revealed repulsion between virus and host CUBs when they are overly similar, a previously unrecognized complexity in the coevolution of virus and host.

Background: During the evolution of mammalian sex chromosomes, the degeneration of Y-linked homologs has led to a dosage imbalance between X-linked and autosomal genes. The evolutionary resolution to such dosage imbalance, as hypothesized by Susumu Ohno fifty years ago, should be doubling the expression of X-linked genes. Recent studies have nevertheless shown that the X to autosome expression ratio equals ~ 1 in haploid human parthenogenetic embryonic stem (pES) cells and ~ 0.5 in diploid pES cells, suggesting no doubled expression for X-linked genes and refuting Ohno's hypothesis., Results: Here, by reanalyzing an RNA-seq-based single-cell transcriptome dataset of human embryos, we found that from the 8-cell stage until the time-point just prior to implantation, the expression levels of X-linked genes are not two-fold upregulated in male cells and gradually decrease from two-fold in female cells. Additional analyses of gene expression noise further suggest that the dosage sensitivity of X-linked genes is weaker than that of autosomal genes in differentiated female cells, which contradicts a key assumption in Ohno's hypothesis, that most X-linked genes are dosage sensitive. Moreover, the dosage-sensitive housekeeping genes are preferentially located on autosomes, implying selection against X-linkage for dosage-sensitive genes., Conclusions: We observed dosage imbalance between X-linked and autosomal genes, as well as relatively high expression noise from X-linked genes. These results collectively suggest that X-linked genes are less dosage sensitive than autosomal genes, putting one primary assumption of Ohno's hypothesis in question.

Background: Mutation rates vary across the genome. Many trans factors that influence mutation rates have been identified, as have specific sequence motifs at the 1-7-bp scale, but cis elements remain poorly characterized. The lack of understanding regarding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis., Results: Here, we use a combination of synthetic genes and sequences of thousands of isolated yeast colonies to show that intrinsic DNA curvature is a major cis determinant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast and humans accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity and not due to differences in the local activity of DNA repair., Conclusions: Our study establishes a framework for understanding the cis properties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.

We present a novel plasmonic antenna structure, a split-wedge antenna, created by splitting an ultrasharp metallic wedge with a nanogap perpendicular to its apex. The nanogap can tightly confine gap plasmons and boost the local optical field intensity in and around these opposing metallic wedge tips. This three-dimensional split-wedge antenna integrates the key features of nanogaps and sharp tips, i.e., tight field confinement and three-dimensional nanofocusing, respectively, into a single platform. We fabricate split-wedge antennas with gaps that are as small as 1 nm in width at the wafer scale by combining silicon V-grooves with template stripping and atomic layer lithography. Computer simulations show that the field enhancement and confinement are stronger at the tip-gap interface compared to what standalone tips or nanogaps produce, with electric field amplitude enhancement factors exceeding 50 when near-infrared light is focused on the tip-gap geometry. The resulting nanometric hotspot volume is on the order of λ 3 /10 6 . Experimentally, Raman enhancement factors exceeding 10 7 are observed from a 2 nm gap split-wedge antenna, demonstrating its potential for sensing and spectroscopy applications.

Ideally, both ecosystem service and human development policies should improve human well-being through the conservation of ecosystems that provide valuable services. However, program costs and benefits to multiple stakeholders, and how they change through time, are rarely carefully analyzed. We examine one of China's new ecosystem service protection and human development policies: the Relocation and Settlement Program of Southern Shaanxi Province (RSP), which pays households who opt voluntarily to resettle from mountainous areas. The RSP aims to reduce disaster risk, restore important ecosystem services, and improve human well-being. We use household surveys and biophysical data in an integrated economic cost-benefit analysis for multiple stakeholders. We project that the RSP will result in positive net benefits to the municipal government, and to cross-region and global beneficiaries over the long run along with environment improvement, including improved water quality, soil erosion control, and carbon sequestration. However, there are significant short-run relocation costs for local residents so that poor households may have difficulty participating because they lack the resources to pay the initial costs of relocation. Greater subsidies and subsequent supports after relocation are necessary to reduce the payback period of resettled households in the long run. Compensation from downstream beneficiaries for improved water and from carbon trades could be channeled into reducing relocation costs for the poor and sharing the burden of RSP implementation. The effectiveness of the RSP could also be greatly strengthened by early investment in developing human capital and environment-friendly jobs and establishing long-term mechanisms for securing program goals. These challenges and potential solutions pervade ecosystem service efforts globally.

The cause of the tremendous among-protein variation in the rate of sequence evolution is a central subject of molecular evolution. Expression level has been identified as a leading determinant of this variation among genes encoded in the same genome, but the underlying mechanisms are not fully understood. We here propose and demonstrate that a requirement for stronger folding of more abundant mRNAs results in slower evolution of more highly expressed genes and proteins. Specifically, we show that: (i) the higher the expression level of a gene, the greater the selective pressure for its mRNA to fold; (ii) random mutations are more likely to decrease mRNA folding when occurring in highly expressed genes than in lowly expressed genes; and (iii) amino acid substitution rate is negatively correlated with mRNA folding strength, with or without the control of expression level. Furthermore, synonymous (d(S)) and nonsynonymous (d(N)) nucleotide substitution rates are both negatively correlated with mRNA folding strength. However, counterintuitively, d(S) and d(N) are differentially constrained by selection for mRNA folding, resulting in a significant correlation between mRNA folding strength and d(N)/d(S), even when gene expression level is controlled. The direction and magnitude of this correlation is determined primarily by the G+C frequency at third codon positions. Together, these findings explain why highly expressed genes evolve slowly, demonstrate a major role of natural selection at the mRNA level in constraining protein evolution, and reveal a previously unrecognized and unexpected form of nonprotein-level selection that impacts d(N)/d(S).

It is unknown how the composition and structure of DNA within the cell affect spontaneous mutations. Theory suggests that in eukaryotic genomes, nucleosomal DNA undergoes fewer C→T mutations because of suppressed cytosine hydrolytic deamination relative to nucleosome-depleted DNA. Comparative genomic analyses and a mutation accumulation experiment showed that nucleosome occupancy nearly eliminated cytosine deamination, resulting in an ~50% decrease of the C→T mutation rate in nucleosomal DNA. Furthermore, the rates of G→T and A→T mutations were also about twofold suppressed by nucleosomes. On the basis of these results, we conclude that nucleosome-dependent mutation spectra affect eukaryotic genome structure and evolution and may have implications for understanding the origin of mutations in cancers and in induced pluripotent stem cells.

According to the safety assessments of all vitamins and minerals intake undertaken by the US Institute of Medicine's Food and Nutrition Board (FNB), UK MAFF Expert Group on Safety and European Scientific Committee on Food, we are reviewing that the rationale of making ULs (the risk of experiencing adverse effects, assessment for dosage and reaction and Uncertainty Factors); comparing ULs of main vitamins and minerals between Chinese and American, and introducing new concepts of ULs on vitamin A, D, Ca, Cu, I, P, Se, Fe and V.