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The deep population history of East Asia remains poorly understood owing to a lack of ancient DNA data and sparse sampling of present-day people1,2. Here we report genome-wide data from 166 East Asian individuals dating to between 6000 BC and AD 1000 and 46 present-day groups. Hunter-gatherers from Japan, the Amur River Basin, and people of Neolithic and Iron Age Taiwan and the Tibetan Plateau are linked by a deeply splitting lineage that probably reflects a coastal migration during the Late Pleistocene epoch. We also follow expansions during the subsequent Holocene epoch from four regions. First, hunter-gatherers from Mongolia and the Amur River Basin have ancestry shared by individuals who speak Mongolic and Tungusic languages, but do not carry ancestry characteristic of farmers from the West Liao River region (around 3000 BC), which contradicts theories that the expansion of these farmers spread the Mongolic and Tungusic proto-languages. Second, farmers from the Yellow River Basin (around 3000 BC) probably spread Sino-Tibetan languages, as their ancestry dispersed both to Tibet-where it forms approximately 84% of the gene pool in some groups-and to the Central Plain, where it has contributed around 59-84% to modern Han Chinese groups. Third, people from Taiwan from around 1300 BC to AD 800 derived approximately 75% of their ancestry from a lineage that is widespread in modern individuals who speak Austronesian, Tai-Kadai and Austroasiatic languages, and that we hypothesize derives from farmers of the Yangtze River Valley. Ancient people from Taiwan also derived about 25% of their ancestry from a northern lineage that is related to, but different from, farmers of the Yellow River Basin, which suggests an additional north-to-south expansion. Fourth, ancestry from Yamnaya Steppe pastoralists arrived in western Mongolia after around 3000 BC but was displaced by previously established lineages even while it persisted in western China, as would be expected if this ancestry was associated with the spread of proto-Tocharian Indo-European languages. Two later gene flows affected western Mongolia: migrants after around 2000 BC with Yamnaya and European farmer ancestry, and episodic influences of later groups with ancestry from Turan.
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Genoma Humano/genética , Genómica , Migración Humana/historia , China , Producción de Cultivos/historia , Femenino , Haplotipos/genética , Historia Antigua , Humanos , Japón , Lenguaje/historia , Masculino , Mongolia , Nepal , Oryza , Polimorfismo de Nucleótido Simple/genética , Siberia , TaiwánRESUMEN
Accurate prediction of the efficacy of immunotherapy for cancer patients through the characterization of both genetic and phenotypic heterogeneity in individual patient cells holds great promise in informing targeted treatments, and ultimately in improving care pathways and clinical outcomes. Here, we describe the nanoplatform for interrogating living cell host-gene and (micro-)environment (NICHE) relationships, that integrates micro- and nanofluidics to enable highly efficient capture of circulating tumor cells (CTCs) from blood samples. The platform uses a unique nanopore-enhanced electrodelivery system that efficiently and rapidly integrates stable multichannel fluorescence probes into living CTCs for in situ quantification of target gene expression, while on-chip coculturing of CTCs with immune cells allows for the real-time correlative quantification of their phenotypic heterogeneities in response to immune checkpoint inhibitors (ICI). The NICHE microfluidic device provides a unique ability to perform both gene expression and phenotypic analysis on the same single cells in situ, allowing us to generate a predictive index for screening patients who could benefit from ICI. This index, which simultaneously integrates the heterogeneity of single cellular responses for both gene expression and phenotype, was validated by clinically tracing 80 non-small cell lung cancer patients, demonstrating significantly higher AUC (area under the curve) (0.906) than current clinical reference for immunotherapy prediction.
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Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Microfluídica/métodos , Análisis de la Célula Individual/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Fenotipo , Línea Celular Tumoral , Inmunoterapia/métodos , Perfilación de la Expresión Génica/métodos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/sangre , Técnicas Analíticas Microfluídicas/métodos , Técnicas Analíticas Microfluídicas/instrumentaciónRESUMEN
Modern humans have experienced explosive population growth in the past thousand years. We hypothesized that recent human populations have inhabited environments with relaxation of selective constraints, possibly due to the more abundant food supply after the Last Glacial Maximum. The ratio of nonsynonymous to synonymous mutations (N/S ratio) is a useful and common statistic for measuring selective constraints. In this study, we reconstructed a high-resolution phylogenetic tree using a total of 26,419 East Eurasian mtDNA genomes, which were further classified into expansion and non-expansion groups on the basis of the frequencies of their founder lineages. We observed a much higher N/S ratio in the expansion group, especially for nonsynonymous mutations with moderately deleterious effects, indicating a weaker effect of purifying selection in the expanded clades. However, this observation on N/S ratio was unlikely in computer simulations where all individuals were under the same selective constraints. Thus, we argue that the expanded populations were subjected to weaker selective constraints than the non-expanded populations were. The mildly deleterious mutations were retained during population expansion, which could have a profound impact on present-day disease patterns.
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Mitochondrial and synaptic dysfunction are pathological features of brain aging and cognitive decline. Synaptic mitochondria are vital for meeting the high energy demands of synaptic transmission. However, little is known about the link between age-related metabolic changes and the integrity of synaptic mitochondria. To this end, we investigate the mechanisms of advanced glycation endproducts (AGEs)-mediated mitochondrial and synaptic stress and evaluate the strategies to eliminate these toxic metabolites. Using aged brain and novel transgenic mice overexpressing neuronal glyoxalase 1 (GLO1), we comprehensively analyzed alterations in accumulation/buildup of AGEs and related metabolites in synaptic mitochondria and the association of AGE levels with mitochondrial function. We demonstrate for the first time that synaptic mitochondria are an early and major target of AGEs and the related toxic metabolite methylglyoxal (MG), a precursor of AGEs. MG/AGEs-insulted synaptic mitochondria exhibit deterioration of mitochondrial and synaptic function. Such accumulation of MG/AGEs positively correlated with mitochondrial perturbation and oxidative stress in aging brain. Importantly, clearance of AGEs-related metabolites by enhancing neuronal GLO1, a key enzyme for detoxification/of AGEs, reduces synaptic mitochondrial AGEs accumulation and improves mitochondrial and cognitive function in aging and AGE-challenged mice. Furthermore, we evaluated the direct effect of AGEs on synaptic function in hippocampal neurons in live brain slices as an ex-vivo model and in vitro cultured hippocampal neurons by recording long-term potentiation (LTP) and measuring spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs). Neuronal GLO1 rescues deficits in AGEs-induced synaptic plasticity and transmission by fully recovery of decline in LTP or frequency of mEPSC. These studies explore crosstalk between synaptic mitochondrial dysfunction and age-related metabolic changes relevant to brain aging and cognitive decline. Synaptic mitochondria are particularly susceptible to AGEs-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction in synaptic degeneration in age-related cognitive decline. Thus, augmenting GLO1 function to scavenge toxic metabolites represents a therapeutic approach to reduce age-related AGEs accumulation and to improve mitochondrial function and learning and memory.
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Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer's disease. However, there is currently no effective CypD inhibitor for Alzheimer's disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of â¼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer's disease mitochondrial and glycolytic bioenergetics in Alzheimer's disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer's disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer's disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer's disease- and amyloid-ß-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer's disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer's disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.
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Enfermedad de Alzheimer , Isoindoles , Mitocondrias , Compuestos de Organoselenio , Peptidil-Prolil Isomerasa F , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Peptidil-Prolil Isomerasa F/metabolismo , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones , Humanos , Cognición/efectos de los fármacos , Azoles/farmacología , Azoles/uso terapéutico , Ciclofilinas/metabolismo , Ciclofilinas/antagonistas & inhibidores , Ratones Transgénicos , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
The study of language origin and divergence is important for understanding the history of human populations and their cultures. The Sino-Tibetan language family is the second largest in the world after Indo-European, and there is a long-running debate about its phylogeny and the time depth of its original divergence1. Here we perform a Bayesian phylogenetic analysis to examine two competing hypotheses of the origin of the Sino-Tibetan language family: the 'northern-origin hypothesis' and the 'southwestern-origin hypothesis'. The northern-origin hypothesis states that the initial expansion of Sino-Tibetan languages occurred approximately 4,000-6,000 years before present (BP; taken as AD 1950) in the Yellow River basin of northern China2-4, and that this expansion is associated with the development of the Yangshao and/or Majiayao Neolithic cultures. The southwestern-origin hypothesis states that an early expansion of Sino-Tibetan languages occurred before 9,000 years BP from a region in southwest Sichuan province in China5 or in northeast India6, where a high diversity of Tibeto-Burman languages exists today. Consistent with the northern-origin hypothesis, our Bayesian phylogenetic analysis of 109 languages with 949 lexical root-meanings produced an estimated time depth for the divergence of Sino-Tibetan languages of approximately 4,200-7,800 years BP, with an average value of approximately 5,900 years BP. In addition, the phylogeny supported a dichotomy between Sinitic and Tibeto-Burman languages. Our results are compatible with the archaeological records, and with the farming and language dispersal hypothesis7 of agricultural expansion in China. Our findings provide a linguistic foothold for further interdisciplinary studies of prehistoric human activity in East Asia.
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Teorema de Bayes , Lenguaje/historia , Modelos Teóricos , Filogenia , Arqueología , China , Evolución Cultural/historia , Historia Antigua , Humanos , TibetRESUMEN
Caenorhabditis elegans is a frequently employed genetic model organism and has been the object of a wide range of developmental, genetic, proteomic, and glycomic studies. Here, using an off-line MALDI-TOF-MS approach, we have analyzed the N-glycans of mixed embryos and liquid- or plate-grown L4 larvae. Of the over 200 different annotatable N-glycan structures, variations between the stages as well as the mode of cultivation were observed. While the embryonal N-glycome appears less complicated overall, the liquid- and plate-grown larvae differ especially in terms of methylation of bisecting fucose, α-galactosylation of mannose, and di-ß-galactosylation of core α1,6-fucose. Furthermore, we analyzed the O-glycans by LC-electrospray ionization-MS following ß-elimination; especially the embryonal O-glycomes included a set of phosphorylcholine-modified structures, previously not shown to exist in nematodes. However, the set of glycan structures cannot be clearly correlated with levels of glycosyltransferase transcripts in developmental RNA-Seq datasets, but there is an indication for coordinated expression of clusters of potential glycosylation-relevant genes. Thus, there are still questions to be answered in terms of how and why a simple nematode synthesizes such a diverse glycome.
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Caenorhabditis , Animales , Caenorhabditis/metabolismo , Fucosa/metabolismo , Proteómica , Cromatografía Líquida de Alta Presión , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Caenorhabditis elegans/metabolismo , Polisacáridos/metabolismo , GlicómicaRESUMEN
BACKGROUND: Analysis of time-resolved postprandial metabolomics data can improve the understanding of metabolic mechanisms, potentially revealing biomarkers for early diagnosis of metabolic diseases and advancing precision nutrition and medicine. Postprandial metabolomics measurements at several time points from multiple subjects can be arranged as a subjects by metabolites by time points array. Traditional analysis methods are limited in terms of revealing subject groups, related metabolites, and temporal patterns simultaneously from such three-way data. RESULTS: We introduce an unsupervised multiway analysis approach based on the CANDECOMP/PARAFAC (CP) model for improved analysis of postprandial metabolomics data guided by a simulation study. Because of the lack of ground truth in real data, we generate simulated data using a comprehensive human metabolic model. This allows us to assess the performance of CP models in terms of revealing subject groups and underlying metabolic processes. We study three analysis approaches: analysis of fasting-state data using principal component analysis, T0-corrected data (i.e., data corrected by subtracting fasting-state data) using a CP model and full-dynamic (i.e., full postprandial) data using CP. Through extensive simulations, we demonstrate that CP models capture meaningful and stable patterns from simulated meal challenge data, revealing underlying mechanisms and differences between diseased versus healthy groups. CONCLUSIONS: Our experiments show that it is crucial to analyze both fasting-state and T0-corrected data for understanding metabolic differences among subject groups. Depending on the nature of the subject group structure, the best group separation may be achieved by CP models of T0-corrected or full-dynamic data. This study introduces an improved analysis approach for postprandial metabolomics data while also shedding light on the debate about correcting baseline values in longitudinal data analysis.
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Medicina , Metabolómica , Humanos , Simulación por Computador , Análisis de Datos , Estado de SaludRESUMEN
Simple organisms are often considered to have simple glycomes, but plentiful paucimannosidic and oligomannosidic glycans overshadow the less abundant N-glycans with highly variable core and antennal modifications; Caenorhabditis elegans is no exception. By use of optimized fractionation and assessing wildtype in comparison to mutant strains lacking either the HEX-4 or HEX-5 ß-N-acetylgalactosaminidases, we conclude that the model nematode has a total N-glycomic potential of 300 verified isomers. Three pools of glycans were analyzed for each strain: either PNGase F released and eluted from a reversed-phase C18 resin with either water or 15% methanol or PNGase Ar released. While the water-eluted fractions were dominated by typical paucimannosidic and oligomannosidic glycans and the PNGase Ar-released pools by glycans with various core modifications, the methanol-eluted fractions contained a huge range of phosphorylcholine-modified structures with up to three antennae, sometimes with four N-acetylhexosamine residues in series. There were no major differences between the C. elegans wildtype and hex-5 mutant strains, but the hex-4 mutant strains displayed altered sets of methanol-eluted and PNGase Ar-released pools. In keeping with the specificity of HEX-4, there were more glycans capped with N-acetylgalactosamine in the hex-4 mutants, as compared with isomeric chito-oligomer motifs in the wildtype. Considering that fluorescence microscopy showed that a HEX-4::enhanced GFP fusion protein colocalizes with a Golgi tracker, we conclude that HEX-4 plays a significant role in late-stage Golgi processing of N-glycans in C. elegans. Furthermore, finding more "parasite-like" structures in the model worm may facilitate discovery of glycan-processing enzymes occurring in other nematodes.
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Caenorhabditis elegans , beta-N-Acetilhexosaminidasas , Animales , Acetilgalactosamina/metabolismo , beta-N-Acetilhexosaminidasas/metabolismo , Caenorhabditis elegans/metabolismo , Glicosilación , Hexosaminidasas/metabolismo , Metanol , Polisacáridos/metabolismoRESUMEN
INTRODUCTION: Longitudinal metabolomics data from a meal challenge test contains both fasting and dynamic signals, that may be related to metabolic health and diseases. Recent work has explored the multiway structure of time-resolved metabolomics data by arranging it as a three-way array with modes: subjects, metabolites, and time. The analysis of such dynamic data (where the fasting data is subtracted from postprandial states) reveals dynamic markers of various phenotypes, and differences between fasting and dynamic states. However, there is still limited success in terms of extracting static and dynamic biomarkers for the same subject stratifications. OBJECTIVES: Through joint analysis of fasting and dynamic metabolomics data, our goal is to capture static and dynamic biomarkers of a phenotype for the same subject stratifications providing a complete picture, that will be more effective for precision health. METHODS: We jointly analyze fasting and dynamic metabolomics data collected during a meal challenge test from the COPSAC 2000 cohort using coupled matrix and tensor factorizations (CMTF), where the dynamic data (subjects by metabolites by time) is coupled with the fasting data (subjects by metabolites) in the subjects mode. RESULTS: The proposed data fusion approach extracts shared subject stratifications in terms of BMI (body mass index) from fasting and dynamic signals as well as the static and dynamic metabolic biomarker patterns corresponding to those stratifications. Specifically, we observe a subject stratification showing the positive association with all fasting VLDLs and higher BMI. For the same subject stratification, a subset of dynamic VLDLs (mainly the smaller sizes) correlates negatively with higher BMI. Higher correlations of the subject quantifications with the phenotype of interest are observed using such a data fusion approach compared to individual analyses of the fasting and postprandial state. CONCLUSION: The CMTF-based approach provides a complete picture of static and dynamic biomarkers for the same subject stratifications-when markers are present in both fasting and dynamic states.
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Biomarcadores , Ayuno , Metabolómica , Periodo Posprandial , Humanos , Biomarcadores/sangre , Biomarcadores/metabolismo , Metabolómica/métodos , Ayuno/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana EdadRESUMEN
INTRODUCTION: Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time. OBJECTIVES: Our goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles. METHODS: We analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC2000 cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences. RESULTS: Our analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state. CONCLUSION: The CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.
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Metabolómica , Periodo Posprandial , Humanos , Periodo Posprandial/fisiología , Masculino , Femenino , Metabolómica/métodos , Adulto , Ayuno/metabolismo , Análisis de Componente Principal , Espectroscopía de Resonancia Magnética/métodos , Persona de Mediana Edad , Análisis de Datos , Metaboloma/fisiologíaRESUMEN
AIM: Primary mucinous adenocarcinoma of the urethra represents an extremely rare entity. We sought to characterise further these tumours' clinicopathological, immunohistochemical and molecular features. METHODS AND RESULTS: Thirty-five cases were identified, occurring in 18 males and 17 females. The mean age at diagnosis was 65 years (28-89 years). The main presentation symptoms were haematuria and urinary outlet obstruction. Microscopic analysis revealed that all 35 tumours have stromal dissection by mucin. Ten tumours showed villoglandular dysplasia, nine showed mucinous metaplasia, two showed adenocarcinoma in situ and four showed signet ring cell features. All tumours were immunopositive for CEA, while immunonegative for nuclear ß-catenin; 19 of 23 (83%) expressed high molecular weight cytokeratin; 19 of 33 (58%) CK7; 28 of 34 (82%) CK20; 32 of 35 (91%) CDX2; 22 of 27 (81%) cadherin-17 (CDH-17); 26 of 29 (90%) SATB2; and one of 31 (3%) GATA3. Mismatch repair gene products, including MLH1, PMS2, MSH2 and MSH6, were immunopositive, suggesting the MSI-low genotype of mucinous adenocarcinoma of the urethra. BRAF V600E and ALK rearrangements were not detected. During the mean follow-up of 20 months, nine patients either developed distant metastasis or succumbed to the illness. CONCLUSION: Our study, encompassing the most extensive series of 35 cases of primary mucinous adenocarcinoma of the urethra, provides crucial insights into its precise diagnosis, management and potential targeted treatments. We found a greater CDX2, SATB2 and CDH17 sensitivity in these urethral tumours for the first time, to our knowledge. We identified characteristics such as an MSI-low profile, non-V600E BRAF mutations and an absence of ALK rearrangements.
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Adenocarcinoma Mucinoso , Proteínas Proto-Oncogénicas B-raf , Masculino , Femenino , Humanos , Anciano , Proteínas Proto-Oncogénicas B-raf/genética , Uretra/química , Uretra/patología , Biomarcadores de Tumor/análisis , Adenocarcinoma Mucinoso/patología , Factores de Transcripción , Proteínas Tirosina Quinasas ReceptorasRESUMEN
BACKGROUND: Lung adenocarcinoma (LUAD) patients have a dismal survival rate because of cancer metastasis and drug resistance. The study aims to identify the genes that concurrently modulate EMT, metastasis and EGFR-TKI resistance, and to investigate the underlying regulatory mechanisms. METHODS: Cox regression and Kaplan-Meier analyses were applied to identify prognostic oncogenes in LUAD. Gene set enrichment analysis (GSEA) was used to indicate the biological functions of the gene. Wound-healing and Transwell assays were used to detect migratory and invasive ability. EGFR-TKI sensitivity was evaluated by assessing the proliferation, clonogenic survival and metastatic capability of cancer cells with treatment with gefitinib. Methylated RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) analyses established the level of m6A modification present on the target gene and the protein's capability to interact with RNA, respectively. Single-sample gene set enrichment (ssGSEA) algorithm used to investigate levels of immune cell infiltration. RESULTS: Our study identified dual-specificity phosphatase 5 (DUSP5) as a novel and powerful predictor of adverse outcomes for LUAD by using public datasets. Functional enrichment analysis found that DUSP5 was positively enriched in EMT and transforming growth factor-beta (TGF-ß) signaling pathway, a prevailing pathway involved in the induction of EMT. As expected, DUSP5 knockdown suppressed EMT via inhibiting the canonical TGF-ß/Smad signaling pathway in in vitro experiments. Consistently, knockdown of DUSP5 was first found to inhibit migratory ability and invasiveness of LUAD cells in in vitro and prevent lung metastasis in in vivo. DUSP5 knockdown re-sensitized gefitinib-resistant LUAD cells to gefitinib, accompanying reversion of EMT progress. In LUAD tissue samples, we found 14 cytosine-phosphate-guanine (CpG) sites of DUSP5 that were negatively associated with DUSP5 gene expression. Importantly, 5'Azacytidine (AZA), an FDA-approved DNA methyltransferase inhibitor, restored DUSP5 expression. Moreover, RIP experiments confirmed that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a m6A reader protein, could bind DUSP5 mRNA. YTHDF1 promoted DUSP5 expression and the malignant phenotype of LUAD cells. In addition, the DUSP5-derived genomic model revealed the two clusters with distinguishable immune features and tumor mutational burden (TMB). CONCLUSIONS: Briefly, our study discovered DUSP5 which was regulated by epigenetic modification, might be a potential therapeutic target, especially in LUAD patients with acquired EGFR-TKI resistance.
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Volatile sulfur compounds, such as dimethyl sulfide (DMS), carbonyl sulfide (OCS), and carbon disulfide (CS2), have significant implications for both atmospheric chemistry and climate change. Despite the crucial role of oceans in regulating their atmospheric budgets, our comprehension of their cycles in seawater remains insufficient. To address this gap, a field investigation was conducted in the western North Pacific to clarify the sources, sinks, and biogeochemical controls of these gases in two different marine environments, including relatively eutrophic Kuroshio-Oyashio extension (KOE) and oligotrophic North Pacific subtropical gyre. Our findings revealed higher concentrations of these gases in both seawater and the atmosphere in the KOE compared to the subtropical gyre. In the KOE, nutrient-rich upwelling stimulated rapid DMS biological production, while reduced seawater temperatures hindered the removal of OCS and CS2, leading to their accumulation. Furthermore, we have quantitatively evaluated the relative contribution of each pathway to the source and sink of DMS, OCS, and CS2 within the mixed layer and identified vertical exchange as a potential sink in most cases, transporting substantial amounts of these gases from the mixed layer to deeper waters. This research advances our understanding of sulfur gas source-sink dynamics in seawater, contributing to the assessment of their marine emissions and atmospheric budgets.
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The combustion agglomeration of nano-aluminum (nAl) powder leads to incomplete combustion, which seriously hinders its application as metal fuel. In this work, nAl@AlF3 composites were produced by coating nAl with AlF3via a facile chemical deposition method. TEM and SEM analyses indicated that the AlF3 layer was evenly coated on the surface of nAl with a thickness of 4.6-9.1 nm, thereby varying the quantity of AlF3 applied. Experimental results from combustion indicated that the prepared nAl@AlF3 composites exhibit superior combustion efficiency, a higher combustion rate, and reduced combustion agglomeration as compared to raw nAl. Contrary to the widely accepted explanation that volatilization of AlF3 hinders Al combustion agglomeration, we proved that the gas-solid reaction between nAl and AlF3 plays an important role in inhibiting the sintering of nAl particles produced. The gaseous intermediate (i.e., AlOF and HF) released from the hydrolysis of AlF3 could reduce the diffusion barrier of Al2O3 to facilitate the reaction of Al core, which enhances the combustion reaction kinetics. More importantly, these gaseous products actively participate in the reaction cycle to continuously exert their catalytic effects.
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Reasonable design and construction of functionalized materials are of great importance for the enrichment of global phosphopeptides. In this work, Ti4+ functionalized hydrophilic covalent organic frameworks by introducing glutathione (GSH) and 2,3,4-trihydroxy benzaldehyde (THBA) via click chemistry and Schiff base reaction (COF-V@GSH-THBA-Ti4+ ) was constructed and applied for selective enrichment of phosphopeptides in serum. Benefit from the high surface area, excellent hydrophilicity as well as regular mesoporous structure, COF-V@GSH-THBA-Ti4+ displayed high selectivity (molar ratio of 2000:1), low limit of detection (0.5 fmol), high load capacity (100.0 mg/g) and excellent size-exclusion effect (1:10000) for enrichment of phosphopeptides. For actual bio-sample analysis, 15 phosphopeptides assigned to 10 phosphoproteins with 16 phosphorylated sites and 33 phosphopeptides assigned to 25 phosphoproteins with 34 phosphorylated sites were detected from the serum of patients with chronic obstructive pulmonary disease (COPD), and normal controls. Biological processes and molecular functions analysis further disclosed the difference of serums with phosphoproteomics between COPD and normal controls.
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Estructuras Metalorgánicas , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Fosfopéptidos/química , Estructuras Metalorgánicas/química , Química Clic , Bases de Schiff , Fosfoproteínas , Cromatografía de Afinidad/métodos , Titanio/químicaRESUMEN
BACKGROUND: Positive psychological interventions (PPIs) are known to be effective in alleviating depression. However, the effect of PPIs on positive and negative emotions in depressed participants is not unclear. AIMS: To systematically investigate the effects of PPIs on positive and negative emotions in depressed individuals. METHODS: 6 databases were searched for randomized controlled trials of PPIs in individuals with depressive disorders or depressive symptoms. Hedges' g value was computed using a random-effects model to determine effect sizes. RESULTS: 14 trials from 13 studies were included. Our meta-analysis showed that PPIs had significant but small effects on improving positive affect (g = 0.33, p = .02), life satisfaction (g = 0.26, p = .03), happiness (g = 0.62, p = .03) and depression (g = -0.32, p = .001), and negligible effects on improving well-being (g = 0.13, p = .24) and negative affect (g = -0.15, p = .31). Subgroup analyses of depression showed that PPIs have experienced benefits in improving depression in most subgroups. In addition, none of the subgroup analyses performed for outcomes other than depression found PPIs to be more effective than controls. CONCLUSION: PPIs can improve positive affect, life satisfaction, happiness and depression in depressed individuals, but further studies are needed to validate their effects on well-being, and negative affect.
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AIM: To evaluate the mediating roles of occupational resilience and the moderationg role of perceived organizational support in the relationship between career calling and nurse burnout. BACKGROUND: Burnout is a frequent and serious problem in the field of nursing, and it poses a serious threat to both nurses' health and patient safety. Although many studies have described the links between burnout, career calling, and occupational resilience, little is known about the actual mechanisms between career calling and nurse burnout. METHODS: A cross-sectional study of 615 nurses in China was conducted using a convenience sampling method. The data were analyzed using descriptive statistics and Pearson correlation analysis. Hypotheses were tested using structural equation models and bootstrapping methods. STROBE guidelines were followed. RESULTS: Career calling was found to be negatively associated with nurse burnout, and occupational resilience mediated the relationship between career calling and burnout. Additionally, perceived organizational support was found to play a moderating role in the relationship between occupational resilience and burnout. CONCLUSION: Career calling can reduce burnout by increasing nurses' levels of occupational resilience, and perceived organizational support moderates this mechanism. Hence, policies focused on encouraging and sustaining career calling should be provided by nurse managers in order to enhance stress resistance and reduce burnout.
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Panax ginseng, known as the "king of herbs", is a highly valued medicinal plant, and its medicinal parts include roots, stems, leaves, flowers, and fruits, among which the roots are the most commonly used. The main active components of this medicinal plant include triterpenoid saponins, polysaccharides, peptides, and volatile oils. The chemical components and active metabolites endow this herb with a variety of pharmacological effects, and thus this herb is used to treat various diseases and play healthcare roles. Currently, a wide range of preparations of P. ginseng have been officially registered and marketed, including tablets, oral liquids, and injections, which demonstrate good clinical efficacy in regulating immunity, adjuvant treatment of tumors, alleviating fatigue, delaying the aging process, improving glucose and lipid metabolism, treating cardiovascular diseases, and relieving inflammation and pain. The production process and quality standards of these drugs are of great significance to ensure their efficacy. According to the theory that Ginseng Radix et Rhizoma can greatly replenish original Qi, tonify the spleen and lung, promote fluid production to quench thirst, tranquilize mind and enrich the intelligence, this paper systematically summarized the clinical application progress of P. ginseng and rela-ted preparations on the market and prospected the further development of preparations from P. ginseng, providing a reference for further exploring the medicinal value and healthcare function of this herb. The above contents, as an important basis for the in-depth development of P. ginseng and related drugs, increase the possibilities for the application of P. ginseng.
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Medicamentos Herbarios Chinos , Panax , Panax/química , Humanos , Medicamentos Herbarios Chinos/química , AnimalesRESUMEN
High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new clickable building blocks remain exceedingly challenging. Herein, we describe a double-click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO2NCO) via a modular amidation/SuFEx (sulfur-fluoride exchange) process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO2F) and N-acylsulfamides (RCONHSO2NR'R'') in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compounds exhibit high antimicrobial activities against Gram-positive bacterium S. aureus and drug-resistant MRSA (MIC up to 6.25â µg â mL-1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry.