RESUMO
Strong epidemiological evidence now exists that sex is an important biologic variable in immunity. Recent studies, for example, have revealed that sex differences are associated with the severity of symptoms and mortality due to coronavirus disease 2019 (COVID-19). Despite this evidence, much remains to be learned about the mechanisms underlying associations between sex differences and immune-mediated conditions. A growing body of experimental data has made significant inroads into understanding sex-influenced immune responses. As physicians seek to provide more targeted patient care, it is critical to understand how sex-defining factors (e.g., chromosomes, gonadal hormones) alter immune responses in health and disease. In this review, we highlight recent insights into sex differences in autoimmunity; virus infection, specifically severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; and cancer immunotherapy. A deeper understanding of underlying mechanisms will allow the development of a sex-based approach to disease screening and treatment.
Assuntos
COVID-19 , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Caracteres Sexuais , Fatores SexuaisRESUMO
Industrialization adversely affects the gut microbiome and predisposes individuals to chronic non-communicable diseases. We tested a microbiome restoration strategy comprising a diet that recapitulated key characteristics of non-industrialized dietary patterns (restore diet) and a bacterium rarely found in industrialized microbiomes (Limosilactobacillus reuteri) in a randomized controlled feeding trial in healthy Canadian adults. The restore diet, despite reducing gut microbiome diversity, enhanced the persistence of L. reuteri strain from rural Papua New Guinea (PB-W1) and redressed several microbiome features altered by industrialization. The diet also beneficially altered microbiota-derived plasma metabolites implicated in the etiology of chronic non-communicable diseases. Considerable cardiometabolic benefits were observed independently of L. reuteri administration, several of which could be accurately predicted by baseline and diet-responsive microbiome features. The findings suggest that a dietary intervention targeted toward restoring the gut microbiome can improve host-microbiome interactions that likely underpin chronic pathologies, which can guide dietary recommendations and the development of therapeutic and nutritional strategies.
Assuntos
Dieta , Microbioma Gastrointestinal , Humanos , Adulto , Masculino , Feminino , Limosilactobacillus reuteri/fisiologia , Pessoa de Meia-Idade , Canadá , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/prevenção & controle , Adulto JovemRESUMO
The nervous system needs to balance the stability of neural representations with plasticity. It is unclear what the representational stability of simple well-rehearsed actions is, particularly in humans, and their adaptability to new contexts. Using an electrocorticography brain-computer interface (BCI) in tetraplegic participants, we found that the low-dimensional manifold and relative representational distances for a repertoire of simple imagined movements were remarkably stable. The manifold's absolute location, however, demonstrated constrained day-to-day drift. Strikingly, neural statistics, especially variance, could be flexibly regulated to increase representational distances during BCI control without somatotopic changes. Discernability strengthened with practice and was BCI-specific, demonstrating contextual specificity. Sampling representational plasticity and drift across days subsequently uncovered a meta-representational structure with generalizable decision boundaries for the repertoire; this allowed long-term neuroprosthetic control of a robotic arm and hand for reaching and grasping. Our study offers insights into mesoscale representational statistics that also enable long-term complex neuroprosthetic control.
Assuntos
Interfaces Cérebro-Computador , Imaginação , Movimento , Plasticidade Neuronal , Humanos , Masculino , Imaginação/fisiologia , Adulto , Feminino , Eletrocorticografia , Pessoa de Meia-Idade , Quadriplegia/fisiopatologia , Robótica , Adulto JovemRESUMO
Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.
Assuntos
Cromotripsia , Evolução Clonal , Mutação , Osteossarcoma , Proteína Supressora de Tumor p53 , Osteossarcoma/genética , Osteossarcoma/patologia , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Perda de Heterozigosidade , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Criança , Adulto , Genoma Humano , Translocação Genética , Sequenciamento Completo do Genoma , Masculino , Prognóstico , FemininoRESUMO
Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.
Assuntos
Imunoterapia , Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Neoplasias/imunologia , Neoplasias/terapia , Criança , Adolescente , Pré-Escolar , Feminino , Masculino , Mutação , Linfócitos T Citotóxicos/imunologia , Lactente , Estudos de Coortes , Adulto , Inflamação/imunologiaRESUMO
Xist RNA initiates X inactivation as it spreads in cis across the chromosome. Here, we reveal a biophysical basis for its cis-limited diffusion. Xist RNA and HNRNPK together drive a liquid-liquid phase separation (LLPS) that encapsulates the chromosome. HNRNPK droplets pull on Xist and internalize the RNA. Once internalized, Xist induces a further phase transition and "softens" the HNRNPK droplet. Xist alters the condensate's deformability, adhesiveness, and wetting properties in vitro. Other Xist-interacting proteins are internalized and entrapped within the droplet, resulting in a concentration of Xist and protein partners within the condensate. We attribute LLPS to HNRNPK's RGG and Xist's repeat B (RepB) motifs. Mutating these motifs causes Xist diffusion, disrupts polycomb recruitment, and precludes the required mixing of chromosomal compartments for Xist's migration. Thus, we hypothesize that phase transitions in HNRNPK condensates allow Xist to locally concentrate silencing factors and to spread through internal channels of the HNRNPK-encapsulated chromosome.
Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo K , RNA Longo não Codificante , Inativação do Cromossomo X , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , Animais , Camundongos , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Humanos , Masculino , Difusão , Cromossomo X/metabolismo , Cromossomo X/genéticaRESUMO
During early mammalian development, the endoderm germ layer forms the foundation of the respiratory and digestive systems through complex patterning. This intricate process, guided by a series of cell fate decisions, remains only partially understood. Our study introduces innovative genetic tracing codes for 14 distinct endodermal regions using novel mouse strains. By integrating high-throughput and high-precision single-cell RNA sequencing with sophisticated imaging, we detailed the spatiotemporal and genetic lineage differentiation of the endoderm at single-cell resolution. We discovered an unexpected multipotentiality within early endodermal regions, allowing differentiation into various organ primordia. This research illuminates the complex and underestimated phenomenon where endodermal organs develop from multiple origins, prompting a reevaluation of traditional differentiation models. Our findings advance understanding in developmental biology and have significant implications for regenerative medicine and the development of advanced organoid models, providing insights into the intricate mechanisms that guide organogenesis.
Assuntos
Diferenciação Celular , Linhagem da Célula , Endoderma , Organogênese , Análise de Célula Única , Animais , Linhagem da Célula/genética , Endoderma/citologia , Endoderma/metabolismo , Endoderma/embriologia , Camundongos , Regulação da Expressão Gênica no Desenvolvimento , Feminino , Camundongos Endogâmicos C57BL , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , MasculinoRESUMO
Understanding mammalian preimplantation development, particularly in humans, at the proteomic level remains limited. Here, we applied our comprehensive solution of ultrasensitive proteomic technology to measure the proteomic profiles of oocytes and early embryos and identified nearly 8,000 proteins in humans and over 6,300 proteins in mice. We observed distinct proteomic dynamics before and around zygotic genome activation (ZGA) between the two species. Integrative analysis with translatomic data revealed extensive divergence between translation activation and protein accumulation. Multi-omic analysis indicated that ZGA transcripts often contribute to protein accumulation in blastocysts. Using mouse embryos, we identified several transcriptional regulators critical for early development, thereby linking ZGA to the first lineage specification. Furthermore, single-embryo proteomics of poor-quality embryos from over 100 patient couples provided insights into preimplantation development failure. Our study may contribute to reshaping the framework of mammalian preimplantation development and opening avenues for addressing human infertility.
Assuntos
Blastocisto , Desenvolvimento Embrionário , Proteômica , Humanos , Animais , Camundongos , Blastocisto/metabolismo , Proteômica/métodos , Feminino , Oócitos/metabolismo , Zigoto/metabolismo , Masculino , Proteoma/metabolismo , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
The cerebral cortex and hippocampus are crucial brain regions for learning and memory, which depend on activity-induced synaptic plasticity involving N-methyl-á´ -aspartate receptors (NMDARs). However, subunit assembly and molecular architecture of endogenous NMDARs (eNMDARs) in the brain remain elusive. Using conformation- and subunit-dependent antibodies, we purified eNMDARs from adult rat cerebral cortex and hippocampus. Three major subtypes of GluN1-N2A-N2B, GluN1-N2B, and GluN1-N2A eNMDARs were resolved by cryoelectron microscopy (cryo-EM) at the resolution up to 4.2 Å. The particle ratio of these three subtypes was 9:7:4, indicating that about half of GluN2A and GluN2B subunits are incorporated into the tri-heterotetramers. Structural analysis revealed the asymmetric architecture of the GluN1-N2A-N2B receptor throughout the extracellular to the transmembrane layers. Moreover, the conformational variations between GluN1-N2B and GluN1-N2A-N2B receptors revealed the distinct biophysical properties across different eNMDAR subtypes. Our findings imply the structural and functional complexity of eNMDARs and shed light on structure-based therapeutic design targeting these eNMDARs in vivo.
Assuntos
Córtex Cerebral , Microscopia Crioeletrônica , Hipocampo , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/química , Animais , Hipocampo/metabolismo , Córtex Cerebral/metabolismo , Ratos , Masculino , Subunidades Proteicas/metabolismo , Ratos Sprague-Dawley , Humanos , Células HEK293 , Plasticidade NeuronalRESUMO
Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine α1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.
Assuntos
Vírus da Doença de Newcastle , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Animais , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Vírus da Doença de Newcastle/genética , Suínos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias/terapia , Neoplasias/imunologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Neoplasias Hepáticas/terapia , Camundongos , Linhagem Celular TumoralRESUMO
Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a "compositional dysbiosis" and a concomitant species-specific "functional dysbiosis" driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.
Assuntos
Dieta , Fezes , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Metagenoma , Proteômica , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Animais , Proteômica/métodos , Fezes/microbiologia , Fezes/química , Camundongos , Disbiose/microbiologia , Expossoma , Feminino , Masculino , Camundongos Endogâmicos C57BL , Biomarcadores/metabolismoRESUMO
Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.
Assuntos
Mitocôndrias , Ubiquinona , Animais , Camundongos , Ubiquinona/metabolismo , Ubiquinona/análogos & derivados , Transporte de Elétrons , Humanos , Mitocôndrias/metabolismo , Fumaratos/metabolismo , Succinato Desidrogenase/metabolismo , Elétrons , Oxigênio/metabolismo , Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , MasculinoRESUMO
In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.
Assuntos
Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Humanos , Animais , Camundongos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Herança Multifatorial/genética , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Análise de Célula Única , População Branca/genética , Masculino , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , FemininoRESUMO
In Huntington's disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat's length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40-45 to 100-500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150-500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron's life.
Assuntos
Proteína Huntingtina , Doença de Huntington , Neurônios , Doença de Huntington/genética , Doença de Huntington/patologia , Doença de Huntington/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Animais , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Humanos , Expansão das Repetições de Trinucleotídeos/genética , Expansão das Repetições de DNA/genética , Masculino , Degeneração Neural/genética , Degeneração Neural/patologia , FemininoRESUMO
As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep. We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain. On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.
Assuntos
Sistema Glinfático , Norepinefrina , Sono , Norepinefrina/metabolismo , Sistema Glinfático/metabolismo , Animais , Sono/fisiologia , Masculino , Camundongos , Locus Cerúleo/metabolismo , Locus Cerúleo/fisiologia , Locus Cerúleo/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Zolpidem/metabolismo , Zolpidem/farmacologia , Camundongos Endogâmicos C57BL , Vigília/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , OptogenéticaRESUMO
Dr. Shirin Heidari is the lead author of the Sex and Gender Equity in Research (SAGER) guidelines. In this interview with Dr. Isabel Goldman at Cell, she discusses her research, GENDRO, the SAGER guidelines and importance of considering sex- and gender-related variables in research, and her work on sexual and reproductive health in forced displacement.
Assuntos
Identidade de Gênero , Equidade em Saúde , Feminino , Humanos , Masculino , Guias como Assunto , SexoRESUMO
Our understanding of sex and gender evolves. We asked scientists about their work and the future of sex and gender research. They discuss, among other things, interdisciplinary collaboration, moving beyond binary conceptualizations, accounting for intersecting factors, reproductive strategies, expanding research on sex-related differences, and sex's dynamic nature.
Assuntos
Pesquisa Biomédica , Identidade de Gênero , Sexo , Feminino , Humanos , Masculino , Caracteres SexuaisRESUMO
Dr. Londa Schiebinger is an international leader on the intersection of sex, gender, and science. In this interview with Cell, she discusses the Gendered Innovations project, the persistent STEM gender gap, the importance of considering sex- and gender-related variables and intersectionality in research, and the future of sex and gender research.
Assuntos
Ciência , Feminino , Humanos , Masculino , Previsões , Relações Interpessoais , PesquisaRESUMO
We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.
Assuntos
DNA Mitocondrial , Linhagem , Humanos , DNA Mitocondrial/genética , Feminino , Islândia , Masculino , Mutação , Taxa de MutaçãoRESUMO
To build a just, equitable, and diverse academy, scientists and institutions must address systemic barriers that sex and gender minorities face. This Commentary summarizes (1) critical context informing the contemporary oppression of transgender people, (2) how this shapes extant research on sex and gender, and (3) actions to build an inclusive and rigorous academy for all.