RESUMO
Our understanding of the normal variation in the upper respiratory tract (URT) microbiota across the human lifespan and how these relate to host, environment, and health is limited. We studied the microbiota of 3,104 saliva (<10 year-olds)/oropharynx (≥10 year-olds) and 2,485 nasopharynx samples of 3,160 Dutch individuals 0-87 years of age, participating in a cross-sectional population-wide study (PIENTER-3) using 16S-rRNA sequencing. The microbiota composition was strongly related to age, especially in the nasopharynx, with maturation occurring throughout childhood and adolescence. Clear niche- and age-specific associations were found between the microbiota composition and host/environmental factors and health outcomes. Among others, social interaction, sex, and season were associated with the nasopharyngeal microbial community. By contrast, the oral microbiota was more related to antibiotics, tobacco, and alcohol use. We present an atlas of the URT microbiota across the lifespan in association with environment and health, establishing a baseline for future research.
Assuntos
Microbiota , Humanos , Idoso , Pré-Escolar , Adulto , Criança , Pessoa de Meia-Idade , Adolescente , Idoso de 80 Anos ou mais , Masculino , Feminino , Lactente , Adulto Jovem , RNA Ribossômico 16S/genética , Estudos Transversais , Recém-Nascido , Sistema Respiratório/microbiologia , Longevidade , Nasofaringe/microbiologia , Saliva/microbiologia , Meio AmbienteRESUMO
The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
Assuntos
Microbioma Gastrointestinal/genética , Regulação da Expressão Gênica/genética , Síndrome do Intestino Irritável/metabolismo , Metaboloma , Purinas/metabolismo , Transcriptoma/genética , Animais , Ácidos e Sais Biliares/metabolismo , Biópsia , Butiratos/metabolismo , Cromatografia Líquida , Estudos Transversais , Epigenômica , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Regulação da Expressão Gênica/fisiologia , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Hipoxantina/metabolismo , Síndrome do Intestino Irritável/genética , Síndrome do Intestino Irritável/microbiologia , Estudos Longitudinais , Masculino , Metaboloma/fisiologia , Camundongos , Estudos Observacionais como Assunto , Estudos Prospectivos , Software , Espectrometria de Massas em Tandem , Transcriptoma/fisiologiaRESUMO
To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Perfilação da Expressão Gênica , Membrana Sinovial/metabolismo , Transcriptoma , Artrite Reumatoide/patologia , Autoimunidade/genética , Biomarcadores , Biologia Computacional/métodos , Estudos Transversais , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fluxo de TrabalhoRESUMO
Population studies provide insights into the interplay between the gut microbiome and geographical, lifestyle, genetic and environmental factors. However, low- and middle-income countries, in which approximately 84% of the world's population lives1, are not equitably represented in large-scale gut microbiome research2-4. Here we present the AWI-Gen 2 Microbiome Project, a cross-sectional gut microbiome study sampling 1,801 women from Burkina Faso, Ghana, Kenya and South Africa. By engaging with communities that range from rural and horticultural to post-industrial and urban informal settlements, we capture a far greater breadth of the world's population diversity. Using shotgun metagenomic sequencing, we identify taxa with geographic and lifestyle associations, including Treponema and Cryptobacteroides species loss and Bifidobacterium species gain in urban populations. We uncover 1,005 bacterial metagenome-assembled genomes, and we identify antibiotic susceptibility as a factor that might drive Treponema succinifaciens absence in urban populations. Finally, we find an HIV infection signature defined by several taxa not previously associated with HIV, including Dysosmobacter welbionis and Enterocloster sp. This study represents the largest population-representative survey of gut metagenomes of African individuals so far, and paired with extensive clinical biomarkers and demographic data, provides extensive opportunity for microbiome-related discovery.
Assuntos
Microbioma Gastrointestinal , Metagenoma , Humanos , Microbioma Gastrointestinal/genética , Feminino , Estudos Transversais , Infecções por HIV/microbiologia , Infecções por HIV/epidemiologia , Adulto , Treponema/isolamento & purificação , Treponema/genética , Treponema/classificação , África , População Urbana/estatística & dados numéricos , Estilo de Vida , Metagenômica , África do Sul/epidemiologia , População Rural/estatística & dados numéricos , Atlas como Assunto , GanaRESUMO
Brain-wide association studies (BWAS) are a fundamental tool in discovering brain-behaviour associations1,2. Several recent studies have shown that thousands of study participants are required for good replicability of BWAS1-3. Here we performed analyses and meta-analyses of a robust effect size index using 63 longitudinal and cross-sectional MRI studies from the Lifespan Brain Chart Consortium4 (77,695 total scans) to demonstrate that optimizing study design is critical for increasing standardized effect sizes and replicability in BWAS. A meta-analysis of brain volume associations with age indicates that BWAS with larger variability of the covariate and longitudinal studies have larger reported standardized effect size. Analysing age effects on global and regional brain measures from the UK Biobank and the Alzheimer's Disease Neuroimaging Initiative, we showed that modifying study design through sampling schemes improves standardized effect sizes and replicability. To ensure that our results are generalizable, we further evaluated the longitudinal sampling schemes on cognitive, psychopathology and demographic associations with structural and functional brain outcome measures in the Adolescent Brain and Cognitive Development dataset. We demonstrated that commonly used longitudinal models, which assume equal between-subject and within-subject changes can, counterintuitively, reduce standardized effect sizes and replicability. Explicitly modelling the between-subject and within-subject effects avoids conflating them and enables optimizing the standardized effect sizes for each separately. Together, these results provide guidance for study designs that improve the replicability of BWAS.
Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Projetos de Pesquisa , Humanos , Encéfalo/diagnóstico por imagem , Reprodutibilidade dos Testes , Idoso , Estudos Longitudinais , Masculino , Feminino , Adolescente , Pessoa de Meia-Idade , Estudos Transversais , Doença de Alzheimer/diagnóstico por imagem , Cognição/fisiologia , Tamanho do Órgão , Estudo de Associação Genômica Ampla , Adulto , Neuroimagem , Idoso de 80 Anos ou mais , Fatores EtáriosRESUMO
The record of past human adaptations provides crucial lessons for guiding responses to crises in the future1-3. To date, there have been no systematic global comparisons of humans' ability to absorb and recover from disturbances through time4,5. Here we synthesized resilience across a broad sample of prehistoric population time-frequency data, spanning 30,000 years of human history. Cross-sectional and longitudinal analyses of population decline show that frequent disturbances enhance a population's capacity to resist and recover from later downturns. Land-use patterns are important mediators of the strength of this positive association: farming and herding societies are more vulnerable but also more resilient overall. The results show that important trade-offs exist when adopting new or alternative land-use strategies.
Assuntos
Agricultura , Dinâmica Populacional , Mudança Social , Agricultura/história , Agricultura/estatística & dados numéricos , Estudos Transversais , História Antiga , Estudos Longitudinais , Dinâmica Populacional/história , Dinâmica Populacional/estatística & dados numéricos , Resiliência Psicológica , Mudança Social/história , HumanosRESUMO
Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
Assuntos
Anticorpos Antivirais , Herpesvirus Humano 4 , Hidrocortisona , Linfócitos , Células Mieloides , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , Humanos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Biomarcadores/sangue , Estudos Transversais , Herpesvirus Humano 4/imunologia , Hidrocortisona/sangue , Imunofenotipagem , Linfócitos/imunologia , Aprendizado de Máquina , Células Mieloides/imunologia , Síndrome de COVID-19 Pós-Aguda/diagnóstico , Síndrome de COVID-19 Pós-Aguda/imunologia , Síndrome de COVID-19 Pós-Aguda/fisiopatologia , Síndrome de COVID-19 Pós-Aguda/virologia , SARS-CoV-2/imunologiaRESUMO
Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards)1,2. Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering-a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries (n = 32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children's linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age.
Assuntos
Países em Desenvolvimento , Transtornos do Crescimento , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Ásia Meridional/epidemiologia , Cognição , Estudos Transversais , Países em Desenvolvimento/estatística & dados numéricos , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/prevenção & controle , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/mortalidade , Transtornos do Crescimento/prevenção & controle , Estudos Longitudinais , MãesRESUMO
Sustainable Development Goal 2.2-to end malnutrition by 2030-includes the elimination of child wasting, defined as a weight-for-length z-score that is more than two standard deviations below the median of the World Health Organization standards for child growth1. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence-key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z-score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z-score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z-scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6-59 months.
Assuntos
Caquexia , Países em Desenvolvimento , Transtornos do Crescimento , Desnutrição , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Caquexia/epidemiologia , Caquexia/mortalidade , Caquexia/prevenção & controle , Estudos Transversais , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/mortalidade , Transtornos do Crescimento/prevenção & controle , Incidência , Estudos Longitudinais , Desnutrição/epidemiologia , Desnutrição/mortalidade , Desnutrição/prevenção & controle , Chuva , Estações do AnoRESUMO
The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in terms of morphology, behaviour, risk of age-related disease and life expectancy. Given that dogs share the human environment and have a sophisticated healthcare system but are much shorter-lived than people, they offer a unique opportunity to identify the genetic, environmental and lifestyle factors associated with healthy lifespan. To take advantage of this opportunity, the Dog Aging Project will collect extensive survey data, environmental information, electronic veterinary medical records, genome-wide sequence information, clinicopathology and molecular phenotypes derived from blood cells, plasma and faecal samples. Here, we describe the specific goals and design of the Dog Aging Project and discuss the potential for this open-data, community science study to greatly enhance understanding of ageing in a genetically variable, socially relevant species living in a complex environment.
Assuntos
Envelhecimento/fisiologia , Cães/fisiologia , Disseminação de Informação , Animais de Estimação/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Biomarcadores , Ambiente Construído , Ensaios Clínicos Veterinários como Assunto , Estudos Transversais , Coleta de Dados , Cães/genética , Feminino , Fragilidade/veterinária , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Objetivos , Envelhecimento Saudável/efeitos dos fármacos , Humanos , Inflamação/veterinária , Consentimento Livre e Esclarecido , Estilo de Vida , Longevidade/efeitos dos fármacos , Longevidade/genética , Longevidade/fisiologia , Estudos Longitudinais , Masculino , Modelos Animais , Multimorbidade , Animais de Estimação/genética , Privacidade , Sirolimo/farmacologiaRESUMO
Uncovering rates at which susceptible individuals become infected with a pathogen, i.e., the force of infection (FOI), is essential for assessing transmission risk and reconstructing distribution of immunity in a population. For dengue, reconstructing exposure and susceptibility statuses from the measured FOI is of particular significance as prior exposure is a strong risk factor for severe disease. FOI can be measured via many study designs. Longitudinal serology is considered gold standard measurements, as they directly track the transition of seronegative individuals to seropositive due to incident infections (seroincidence). Cross-sectional serology can provide estimates of FOI by contrasting seroprevalence across ages. Age of reported cases can also be used to infer FOI. Agreement of these measurements, however, has not been assessed. Using 26 y of data from cohort studies and hospital-attended cases from Kamphaeng Phet province, Thailand, we found FOI estimates from the three sources to be highly inconsistent. Annual FOI estimates from seroincidence were 1.75 to 4.05 times higher than case-derived FOI. Seroprevalence-derived was moderately correlated with case-derived FOI (correlation coefficient = 0.47) with slightly lower estimates. Through extensive simulations and theoretical analysis, we show that incongruences between methods can result from failing to account for dengue antibody kinetics, assay noise, and heterogeneity in FOI across ages. Extending standard inference models to include these processes reconciled the FOI and susceptibility estimates. Our results highlight the importance of comparing inferences across multiple data types to uncover additional insights not attainable through a single data type/analysis.
Assuntos
Vírus da Dengue , Dengue , Humanos , Dengue/epidemiologia , Dengue/imunologia , Dengue/sangue , Estudos Soroepidemiológicos , Vírus da Dengue/imunologia , Tailândia/epidemiologia , Adulto , Fatores de Risco , Criança , Estudos Transversais , Adolescente , Masculino , Feminino , Pré-Escolar , Projetos de PesquisaRESUMO
Brain age (BA), distinct from chronological age (CA), can be estimated from MRIs to evaluate neuroanatomic aging in cognitively normal (CN) individuals. BA, however, is a cross-sectional measure that summarizes cumulative neuroanatomic aging since birth. Thus, it conveys poorly recent or contemporaneous aging trends, which can be better quantified by the (temporal) pace P of brain aging. Many approaches to map P, however, rely on quantifying DNA methylation in whole-blood cells, which the blood-brain barrier separates from neural brain cells. We introduce a three-dimensional convolutional neural network (3D-CNN) to estimate P noninvasively from longitudinal MRI. Our longitudinal model (LM) is trained on MRIs from 2,055 CN adults, validated in 1,304 CN adults, and further applied to an independent cohort of 104 CN adults and 140 patients with Alzheimer's disease (AD). In its test set, the LM computes P with a mean absolute error (MAE) of 0.16 y (7% mean error). This significantly outperforms the most accurate cross-sectional model, whose MAE of 1.85 y has 83% error. By synergizing the LM with an interpretable CNN saliency approach, we map anatomic variations in regional brain aging rates that differ according to sex, decade of life, and neurocognitive status. LM estimates of P are significantly associated with changes in cognitive functioning across domains. This underscores the LM's ability to estimate P in a way that captures the relationship between neuroanatomic and neurocognitive aging. This research complements existing strategies for AD risk assessment that estimate individuals' rates of adverse cognitive change with age.
Assuntos
Envelhecimento , Encéfalo , Aprendizado Profundo , Imageamento por Ressonância Magnética , Humanos , Encéfalo/diagnóstico por imagem , Feminino , Masculino , Envelhecimento/fisiologia , Idoso , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Cognição/fisiologia , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Idoso de 80 Anos ou mais , Estudos Transversais , Estudos LongitudinaisRESUMO
We conducted an international cross-sectional survey of biomedical researchers' perspectives on the reproducibility of research. This study builds on a widely cited 2016 survey on reproducibility and provides a biomedical-specific and contemporary perspective on reproducibility. To sample the community, we randomly selected 400 journals indexed in MEDLINE, from which we extracted the author names and emails from all articles published between October 1, 2020 and October 1, 2021. We invited participants to complete an anonymous online survey which collected basic demographic information, perceptions about a reproducibility crisis, perceived causes of irreproducibility of research results, experience conducting reproducibility studies, and knowledge of funding and training for research on reproducibility. A total of 1,924 participants accessed our survey, of which 1,630 provided useable responses (response rate 7% of 23,234). Key findings include that 72% of participants agreed there was a reproducibility crisis in biomedicine, with 27% of participants indicating the crisis was "significant." The leading perceived cause of irreproducibility was a "pressure to publish" with 62% of participants indicating it "always" or "very often" contributes. About half of the participants (54%) had run a replication of their own previously published study while slightly more (57%) had run a replication of another researcher's study. Just 16% of participants indicated their institution had established procedures to enhance the reproducibility of biomedical research and 67% felt their institution valued new research over replication studies. Participants also reported few opportunities to obtain funding to attempt to reproduce a study and 83% perceived it would be harder to do so than to get funding to do a novel study. Our results may be used to guide training and interventions to improve research reproducibility and to monitor rates of reproducibility over time. The findings are also relevant to policy makers and academic leadership looking to create incentives and research cultures that support reproducibility and value research quality.
Assuntos
Pesquisa Biomédica , Pesquisadores , Reprodutibilidade dos Testes , Humanos , Pesquisa Biomédica/normas , Estudos Transversais , Masculino , Inquéritos e Questionários , Feminino , Adulto , Pessoa de Meia-IdadeRESUMO
Postingestive nutrient stimulation conditions food preferences through striatal dopamine and may be associated with blunted brain responses in obesity. In a cross-sectional study, we tested flavor-nutrient conditioning (FNC) with maltodextrin-enriched yogurt, with maltodextrin previously optimized for concentration and dextrose equivalents (n = 57), and to mask texture cues (n = 102). After conditioning, healthy volunteers (n = 52) increased preference for maltodextrin-paired (+102 kcal, CS+), relative to control (+1.8 kcal, CS-) flavors, as assessed according to intake, but not pleasantness. In a clinical study (n = 61), behavioral conditioning without effects on pleasantness was confirmed across pre-bariatric candidates with obesity, weight-stable post-surgery patients, and healthy controls, without significant differences between groups. Striatal dopamine D2-like receptor (DD2lR) availability, assessed with [123I]IBZM SPECT, was reduced in the obesity group and strongly correlated with conditioning strength and a measure of restrained eating in patients with gastric bypass. These results show that postingestive nutrient stimulation influences human food choices through behavioral reinforcement, and is conserved in obesity and after bariatric surgery. Trial Registration: ISRCTN17965026: Dopaminergic neurotransmission in dietary learning and obesity.
Assuntos
Cirurgia Bariátrica , Preferências Alimentares , Obesidade , Recompensa , Humanos , Masculino , Feminino , Adulto , Obesidade/cirurgia , Obesidade/metabolismo , Obesidade/fisiopatologia , Cirurgia Bariátrica/métodos , Preferências Alimentares/fisiologia , Estudos Transversais , Receptores de Dopamina D2/metabolismo , Pessoa de Meia-Idade , Reforço Psicológico , Polissacarídeos/metabolismo , Adulto Jovem , Dopamina/metabolismo , Comportamento Alimentar/fisiologia , Corpo Estriado/metabolismoRESUMO
Cigarette smoking constitutes a leading global cause of morbidity and preventable death1, and most active smokers report a desire or recent attempt to quit2. Smoking-cessation-induced weight gain (SCWG; 4.5 kg reported to be gained on average per 6-12 months, >10 kg year-1 in 13% of those who stopped smoking3) constitutes a major obstacle to smoking abstinence4, even under stable5,6 or restricted7 caloric intake. Here we use a mouse model to demonstrate that smoking and cessation induce a dysbiotic state that is driven by an intestinal influx of cigarette-smoke-related metabolites. Microbiome depletion induced by treatment with antibiotics prevents SCWG. Conversely, fecal microbiome transplantation from mice previously exposed to cigarette smoke into germ-free mice naive to smoke exposure induces excessive weight gain across diets and mouse strains. Metabolically, microbiome-induced SCWG involves a concerted host and microbiome shunting of dietary choline to dimethylglycine driving increased gut energy harvest, coupled with the depletion of a cross-regulated weight-lowering metabolite, N-acetylglycine, and possibly by the effects of other differentially abundant cigarette-smoke-related metabolites. Dimethylglycine and N-acetylglycine may also modulate weight and associated adipose-tissue immunity under non-smoking conditions. Preliminary observations in a small cross-sectional human cohort support these findings, which calls for larger human trials to establish the relevance of this mechanism in active smokers. Collectively, we uncover a microbiome-dependent orchestration of SCWG that may be exploitable to improve smoking-cessation success and to correct metabolic perturbations even in non-smoking settings.
Assuntos
Microbioma Gastrointestinal , Abandono do Hábito de Fumar , Aumento de Peso , Animais , Estudos Transversais , Disbiose/etiologia , Disbiose/metabolismo , Disbiose/patologia , Camundongos , Modelos Animais , Fumar/metabolismo , Fumar/patologiaRESUMO
In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in China and has since caused a pandemic of coronavirus disease 2019 (COVID-19). The first case of COVID-19 in New York City was officially confirmed on 1 March 2020 followed by a severe local epidemic1. Here, to understand seroprevalence dynamics, we conduct a retrospective, repeated cross-sectional analysis of anti-SARS-CoV-2 spike antibodies in weekly intervals from the beginning of February to July 2020 using more than 10,000 plasma samples from patients at Mount Sinai Hospital in New York City. We describe the dynamics of seroprevalence in an 'urgent care' group, which is enriched in cases of COVID-19 during the epidemic, and a 'routine care' group, which more closely represents the general population. Seroprevalence increased at different rates in both groups; seropositive samples were found as early as mid-February, and levelled out at slightly above 20% in both groups after the epidemic wave subsided by the end of May. From May to July, seroprevalence remained stable, suggesting lasting antibody levels in the population. Our data suggest that SARS-CoV-2 was introduced in New York City earlier than previously documented and describe the dynamics of seroconversion over the full course of the first wave of the pandemic in a major metropolitan area.
Assuntos
Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Teste Sorológico para COVID-19/estatística & dados numéricos , COVID-19/epidemiologia , COVID-19/imunologia , Monitoramento Epidemiológico , SARS-CoV-2/imunologia , Adolescente , Adulto , Assistência Ambulatorial/estatística & dados numéricos , COVID-19/diagnóstico , COVID-19/virologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo , População Urbana/estatística & dados numéricos , Adulto JovemRESUMO
The attempted assassination of Donald Trump led to widespread concern that the event would escalate political violence between U.S. partisans. While some politicians pleaded for Americans to unite against political violence and "turn down the temperature" on partisan hostility, others continued to engage in inflammatory rhetoric and blame. Using a national survey in the field at the time of the assassination attempt, we take the temperature of America's partisans before and after the event. We exploit the natural variation induced by the assassination attempt and large daily survey coverage (preattempt: 3,572; postattempt: 703; and 690 in a panel) in the days before and after the attempt to estimate the causal effects of extreme partisan violence on measures of partisan animosity and identity. Using panel and cross-sectional interrupted time series analysis, we find no evidence that the event increased tensions or support for retaliatory violence in the immediate aftermath. On the contrary, Republicans, including MAGA Republicans, became significantly less supportive of partisan violence against Democrats. Republicans also did not become more hostile toward Democrats; instead, their attachment to their own party significantly increased. Democrats experienced no change in attitudes. While nearly a third of Americans have no positive feelings toward the other party, and a supermajority have negative feelings, this animosity was not exacerbated by an extreme but salient instance of partisan violence. Despite the ills of modern political conflict, extreme partisan violence did not cause an immediate upsurge in support for violence.
Assuntos
Política , Violência , Humanos , Estados Unidos , Violência/psicologia , Hostilidade , Estudos TransversaisRESUMO
Nuclear family structures are often thought to be essential for the well-being of children. Divorce, the loss of either biological parent, the presence of step-parents, and the practice of polygynous marriage have all been claimed to negatively impact child well-being. However, empirical research on these topics has been limited by the routine use of cross-regional and cross-sectional databases. Cross-regional data render research vulnerable to the ecological inference fallacy, and cross-sectional data prevent assessment of age-specific impacts of time-varying family-structure variables. When longitudinal data are available, they tend to be drawn from Western/urban contexts. Detailed data on family structure and children's well-being are rarely collected in more marginalized communities. In many rural and traditional communities, nonnuclear family structures are indeed prevalent and viewed as socially permissible-and, as such, may have different impacts on children's well-being than in Western contexts. Here, we draw on a detailed, longitudinal dataset from a 20-y prospective study in rural Tanzania, where polygyny and serial monogamy are common. We analyze survival outcomes for 3,693 children born between 1931 and 2014, growth outcomes for 881 children born between 1976 and 2014, and educational outcomes for 1,370 children born between 1976 and 2014. Our analyses indicate that monogamous marriage is not consistently associated with better outcomes for children-contrary to some popular and public health perspectives on human family structure.
Assuntos
Casamento , Humanos , Tanzânia , Masculino , Criança , Feminino , Características da Família , Pré-Escolar , Adolescente , Estudos Transversais , População Rural , Estudos Longitudinais , Proteção da Criança , Estudos Prospectivos , Adulto , Divórcio/psicologia , Lactente , Estrutura FamiliarRESUMO
Alzheimer's disease (AD) is the most common form of dementia with continuum of disease progression of increasing severity from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and lastly to AD. The transition from MCI to AD has been linked to brain hypersynchronization, but the underlying mechanisms leading to this are unknown. Here, we hypothesized that excessive excitation in AD disease progression would shift brain dynamics toward supercriticality across an extended regime of critical-like dynamics. In this framework, healthy brain activity during aging preserves operation at near the critical phase transition at balanced excitation-inhibition (E/I). To test this hypothesis, we used source-reconstructed resting-state MEG data from a cross-sectional cohort (N = 343) of individuals with SCD, MCI, and healthy controls (HC) as well as from a longitudinal cohort (N = 45) of MCI patients. We then assessed brain criticality by quantifying long-range temporal correlations (LRTCs) and functional EI (fE/I) of neuronal oscillations. LRTCs were attenuated in SCD in spectrally and anatomically constrained regions while this breakdown was progressively more widespread in MC. In parallel, fE/I was increased in the MCI but not in the SC cohort. Both observations also predicted the disease progression in the longitudinal cohort. Finally, using machine learning trained on functional (LRTCs, fE/I) and structural (MTL volumes) features, we show that LRTCs and f/EI are the most informative features for accurate classification of individuals with SCD while structural changes accurate classify the individuals with MCI. These findings establish that a shift toward supercritical brain dynamics reflects early AD disease progression.
Assuntos
Doença de Alzheimer , Encéfalo , Disfunção Cognitiva , Progressão da Doença , Humanos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/diagnóstico por imagem , Feminino , Masculino , Idoso , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Pessoa de Meia-Idade , Estudos Transversais , Magnetoencefalografia/métodos , Idoso de 80 Anos ou mais , Estudos LongitudinaisRESUMO
BACKGROUND: Genetic abnormalities like Y chromosome microdeletions are implicated in male infertility. This study investigated the association of azoospermia factor (AZF) region microdeletions with unsuccessful assisted reproductive techniques (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). METHODS: This cross-sectional analysis study examined 80 Iranian oligospermic men (mean age 34 years) with prior failed ICSI and IVF cycles (IR.IAU.TNB.REC.1401.041). Semen analysis evaluated quantity/quality parameters based on World Health Organization guidelines. Participants were stratified by sperm DNA fragmentation (SDF) levels into: control (SDF < 15%, n = 20), mild elevation (15% ≤ SDF ≤ 30%, n = 60), and high (SDF > 30%, n = 20). Multiplex PCR mapped AZF microdeletions in the high SDF group. The AZF-associated genes were selected by RNA Seq analysis, and the candidate genes were checked for expression level by real-time PCR. RESULTS: High SDF individuals exhibited poorer semen metrics, including 69% lower sperm concentration (P = 0.04) than those without SDF. Of this subset, 45% (9/20 men) harboured predominately AZF microdeletions. Men with AZF microdeletions showed higher SDF (32% vs 21%, P = 0.02) and altered AZF-associated genes expression. As USP9Y 3-fold, UTY 1.3-fold, and BPY2 1-fold revealed up-regulation, while IQCF1 8-fold, CDY 6.5-fold, DAZ 6-fold, and DDX3Y 1-fold underwent down-regulation. The PAWP gene was also down-regulated (5.7-fold, P = 0.029) in the IVF/ICSI failure group. CONCLUSION: AZF microdeletions significantly impact male infertility and ART outcomes. High SDF individuals exhibited poorer semen metrics, with 45% AZF microdeletions. These microdeletions altered AZF-associated genes expression, affecting fertility mediator PAWP independently. Dual AZF and SDF screening enables personalized management in severe male infertility, potentially explaining IVF/ICSI failures.