The Role of Protein-coding and Regulatory Evolution in Speciation of Wild Yeast

The evolutionary processes leading to the generation of new species has been studied extensively in plants and animals; however, due to the challenges of studying microbes, microbial speciation has received less attention. This project aims to thoroughly characterize a case of eukaryotic microbial speciation on the genetic level, specifically, the effects of migration and divergence on the wild yeast, Saccharomyces paradoxus. Previous studies have shown there are two isolated populations— one in North America, and one in Europe— and a third migrant population that originally came from Eurasia but is currently inhabiting North America. The migrant population has been genetically diverging since its arrival and now avoids mating with the North American population, suggesting an on-going speciation process. This research used publically available genomic data, as well as data collected in our lab, to quantify genetic differences between the three populations. I investigated all of the protein- coding genes in the wild yeast genome to determine the effects of migration and adaptation to a new environment. The results showed that the European and migrant populations are undergoing the very beginning of speciation. One nuclear gene, PET111, which encodes a mitochondrial regulatory protein, appears to have been under significant positive selection, indicating the possibility of mito-nuclear coevolution. The importance of adaptive mutations in protein-coding vs. regulatory regions of the genome has been a hotly-debated topic in evolutionary developmental biology (“evo devo”). To address this controversial question, for each gene in the genome, I quantified neutral genetic divergence within the gene and compared it to the nucleotide diversity of the adjacent cis- regulatory regions. Confirming the “evo-devo” tenet, the results showed that more changes are accumulating in the cis-regulatory regions than in the protein-coding regions under neutral, and that the regulatory variation may be under selection in the diverging migrant population

Sutterella and its metabolic pathways positively correlate with vaccine-elicited antibody responses in infant rhesus macaques

IntroductionIt is becoming clearer that the microbiota helps drive responses to vaccines; however, little is known about the underlying mechanism. In this study, we aimed to identify microbial features that are associated with vaccine immunogenicity in infant rhesus macaques.MethodsWe analyzed 16S rRNA gene sequencing data of 215 fecal samples collected at multiple timepoints from 64 nursery-reared infant macaques that received various HIV vaccine regimens. PERMANOVA tests were performed to determine factors affecting composition of the gut microbiota throughout the first eight months of life in these monkeys. We used DESeq2 to identify differentially abundant bacterial taxa, PICRUSt2 to impute metagenomic information, and mass spectrophotometry to determine levels of fecal short-chain fatty acids and bile acids.ResultsComposition of the early-life gut microbial communities in nursery-reared rhesus macaques from the same animal care facility was driven by age, birth year, and vaccination status. We identified a Sutterella and a Rodentibacter species that positively correlated with vaccine-elicited antibody responses, with the Sutterella species exhibiting more robust findings. Analysis of Sutterella-related metagenomic data revealed five metabolic pathways that significantly correlated with improved antibody responses following HIV vaccination. Given these pathways have been associated with short-chain fatty acids and bile acids, we quantified the fecal concentration of these metabolites and found several that correlated with higher levels of HIV immunogen-elicited plasma IgG.DiscussionOur findings highlight an intricate bidirectional relationship between the microbiota and vaccines, where multiple aspects of the vaccination regimen modulate the microbiota and specific microbial features facilitate vaccine responses. An improved understanding of this microbiota–vaccine interplay will help develop more effective vaccines, particularly those that are tailored for early life

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Structural Changes of the Interface Material of Scallop Adductor under Ultra-High Pressure

Because of their high nutritional value, the demand for scallops is increasing year by year. In the process of improving people’s living standards, the ready-to-eat characteristics and dry sales characteristics of this product make its shelling process particularly important in the production process. However, the mechanism of ultra-high pressure shelling has not yet been clarified. Therefore, in-depth study of the structural change of the scallop connection interface is of vital importance to explore the mechanism of ultra-high pressure shelling and the development of intelligent equipment from the mechanical point of view. The obturator muscle fibers and the inner surface materials of the shell at the obturator muscle scar of the scallop at 100, 200 and 300 MPa were obtained for Raman spectrum, Fourier-transform infrared spectrum and scanning electron microscopy analysis. The results showed that under the pressure of 200 MPa, the degree of protein denaturation of scallop adductor muscle increased, the elasticity disappeared, and the fiber was stretched; The deformation of the organic plasma membrane connected by the inorganic–organic interface weakens the binding force of the interface material and increases the possibility of the composite interface failure. To sum up, ultra-high pressure can effectively weaken the interface adhesion of scallop organic-inorganic composite materials, and is one of the effective ways of shelling. The research results can provide a basis for the in-depth analysis of ultra-high pressure mechanisms and the development of intelligent equipment, and provide technical support for the realization of ultra-high-pressure industrial production

Real‐world comprehensive diagnosis and “Surgery + X” treatment strategy of early‐stage synchronous multiple primary lung cancer

Abstract Background Diagnosing and treating synchronous multiple primary lung cancers (sMPLC) are complex and challenging. This study aimed to report real‐world data on the comprehensive diagnosis and treatment of patients with early‐stage sMPLC. Materials and Methods A single‐center cohort study was carried out and a large number of patients with early‐stage sMPLC were included. A single‐ or two‐stage surgery was performed to remove the primary and co‐existing lesions. The “X” strategies, including ablation, SBRT, and EGFR‐TKIs treatment, were applied to treat the high‐risk residual lesions. Wide panel‐genomic sequencing was performed to assess the genetic heterogeneity of the co‐existing lesions. Results A total of 465 early‐stage sMPLC patients with 1198 resected lesions were included. Despite most patients being histologically different or harboring different genetic alternations, about 7.5% of the patients had the same histological type and driver gene mutation changes, comprehensive re‐evaluation is thus needed. The “Surgery + X” strategy showed remarkable efficacy and safety in treating multiple lesions. Follow‐up data revealed that the T2 stage (p = 0.014) and the solid presence of a primary lesion (p < 0.001) were significantly related to tumor recurrence. And a T2‐stage primary tumor had a significantly higher rate of developing new lesions after the initial surgery (p < 0.001). Conclusions In real‐world practice, histopathological and radiological evaluation combined with genetic analyses could be a robust diagnostic approach for sMPLC. The “Surgery + X” treatment strategy showed remarkable efficacy, superiority, and safety in the clinical treatment of early‐stage sMPLC

Effect of Low-Dose Vitamin D Supplementation on Serum 25(OH)D in School Children and White-Collar Workers

Objective: Our study aimed to investigate the nutritional vitamin D status of school children aged 9–15 years and white-collar workers in Zhejiang province, and evaluate the efficacy of low-dose-oral vitamin D supplementation in both populations. Methods: We conducted a prospective controlled trial during March 2014 to November 2015, comparing the efficacy of vitamin D supplements (400 IU/day) with non-intervention for 18 months in school children aged 9–15 years. Meanwhile, a before-after study was conducted among white-collar workers for 1 year. Serum 25(OH)D concentration was measured at baseline and after vitamin D supplementation, respectively. Results: At the baseline, 95% of school children and 84% of adult participants had vitamin D deficiency (&lt;20 ng/mL). In school children, no difference was observed between the intervention and control groups with regard to anthropometric data. Serum 25(OH)D concentrations of the school children intervention group, school children control group and white-collar workers were 12.77 ± 3.01 ng/mL, 14.17 ± 3.59 ng/mL and 16.58 ± 3.66 ng/mL at baseline and increased to 17.34 ± 3.78 ng/mL, 18.04 ± 4.01 ng/mL and 17.75 ± 5.36 ng/mL after vitamin D supplementation, respectively. Although, after adjusting for potential confounders, the 400 IU oral vitamin D supplementation increased serum 25(OH)D concentration in school children (β = 0.81, p = 0.0426) as well as in white-collar workers (p = 0.0839), the prevalence of vitamin D deficiency was still very high among school children (79.23% in intervention group and 72.38% in control group) and white-collar workers (76.00%). Conclusions: High prevalence of vitamin D deficiency was common in these two study populations. Daily doses of 400 IU oral vitamin D supplementation was not able to adequately increase serum 25(OH)D concentrations. A suitable recommendation regarding the level of vitamin D supplementation is required for this Chinese population

Oncostatin M and TNF-α Induce Alpha-1 Antitrypsin Production in Undifferentiated Adipose Stromal Cells

Alpha-1 antitrypsin (A1AT), a circulating acute-phase reactant antiprotease, is produced and secreted by cells of endodermal epithelial origin, primarily hepatocytes, and by immune cells. Deficiency of A1AT is associated with increased risk of excessive lung inflammation and injury, especially following chronic cigarette smoke (CS) exposure. Exogenous administration of mesenchymal progenitor cells, including adipose tissue-derived stromal/stem cells (ASC), alleviates CS-induced lung injury through paracrine effectors such as growth factors. It is unknown, however, if mesodermal ASC can secrete functional A1AT and if CS exposure affects their A1AT production. Human ASC collected via liposuction from nonsmoking or smoking donors were stimulated by inflammatory cytokines tumor necrosis alpha (TNFα), oncostatin M (OSM), and/or dexamethasone (DEX) or were exposed to sublethal concentrations of ambient air control or CS extract (0.5%-2%). We detected minimal expression and secretion of A1AT by cultured ASC during unstimulated conditions, which significantly increased following stimulation with TNFα or OSM. Furthermore, TNFα and OSM synergistically enhanced A1AT expression and secretion, which were further increased by DEX. The A1AT transcript variant produced by stimulated ASC resembled that produced by bronchial epithelial cells rather than the variant produced by monocytes/macrophages. While the cigarette smoking status of the ASC donor had no measurable effect on the ability of ASC to induce A1AT expression, active exposure to CS extract markedly reduced A1AT expression and secretion by cultured ASC, as well as human tracheobronchial epithelial cells. ASC-secreted A1AT covalently complexed with neutrophil elastase in control ASC, but not in cells transfected with A1AT siRNA. Undifferentiated ASC may require priming to secrete functional A1AT, a potent antiprotease that may be relevant to stem cell therapeutic effects