RESUMO
I have been a scientific grasshopper throughout my career, moving from question to question within the domain of lupus. This has proven to be immensely gratifying. Scientific exploration is endlessly fascinating, and succeeding in studies you care about with colleagues and trainees leads to strong and lasting bonds. Science isn't easy; being a woman in science presents challenges, but the drive to understand a disease remains strong.
Assuntos
Escolha da Profissão , Lúpus Eritematoso Sistêmico , Feminino , Humanos , Pesquisa BiomédicaRESUMO
The presence of granulated lymphocytes in the human uterine mucosa, known as decidua during pregnancy, or endometrium otherwise, was first noted in the nineteenth century, but it was not until 1990 that these cells were identified as a type of natural killer (NK) cell. From the outset, uterine NK (uNK) cells were found to be less cytotoxic than their circulating counterparts, peripheral NK (pNK) cells. Recently, unbiased approaches have defined three subpopulations of uNK cells, all of which cluster separately from pNK cells. Here, we review the history of research into uNK cells, including their ability to interact with placental extravillous trophoblast cells and their potential role in regulating placental implantation. We go on to review more recent advances that focus on uNK cell development and heterogeneity and their potential to defend against infection and to mediate memory effects. Finally, we consider how a better understanding of these cells could be leveraged in the future to improve outcomes of pregnancy for mothers and babies.
Assuntos
Placenta , Útero , Humanos , Gravidez , Feminino , Animais , Células Matadoras Naturais/metabolismo , Mucosa , DecíduaRESUMO
The bladder is a major component of the urinary tract, an organ system that expels metabolic waste and excess water, which necessitates proximity to the external environment and its pathogens. It also houses a commensal microbiome. Therefore, its tissue immunity must resist pathogen invasion while maintaining tolerance to commensals. Bacterial infection of the bladder is common, with half of women globally experiencing one or more episodes of cystitis in their lifetime. Despite this, our knowledge of bladder immunity, particularly in humans, is incomplete. Here we consider the current view of tissue immunity in the bladder, with a focus on defense against infection. The urothelium has robust immune functionality, and its defensive capabilities are supported by resident immune cells, including macrophages, dendritic cells, natural killer cells, and γδ T cells. We discuss each in turn and consider why adaptive immune responses are often ineffective in preventing recurrent infection, as well as areas of priority for future research.
Assuntos
Infecções Bacterianas , Bexiga Urinária , Animais , Feminino , Humanos , Tolerância Imunológica , Imunidade Inata , Macrófagos , Bexiga Urinária/microbiologiaRESUMO
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.
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COVID-19 , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Caracteres Sexuais , Fatores SexuaisRESUMO
Kenna Gloria Agbugba is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the physical, data, earth, and environmental sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, the experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.
Assuntos
Ciência , Nigéria , Humanos , Estados Unidos , Negro ou Afro-Americano , Distinções e Prêmios , História do Século XXI , Feminino , BrancosRESUMO
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
Jheannelle Johnson is a winner of the fifth annual Rising Black Scientists Awards for a scholar in the life and health sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.
Assuntos
Música , Humanos , Música/psicologia , Negro ou Afro-Americano , Distinções e Prêmios , Memória/fisiologia , Feminino , Racismo , BrancosRESUMO
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.
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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
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.
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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
Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.
Assuntos
Epigênese Genética , Fibroblastos , Histonas , Histona Desmetilases com o Domínio Jumonji , Parto , Útero , Animais , Feminino , Gravidez , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Fibroblastos/metabolismo , Parto/metabolismo , Útero/metabolismo , Histonas/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.
Assuntos
Quinase do Linfoma Anaplásico , Neoplasias Pulmonares , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Humanos , Fosforilação , Quinase do Linfoma Anaplásico/metabolismo , Quinase do Linfoma Anaplásico/genética , Animais , Camundongos , Linhagem Celular Tumoral , Guanosina Trifosfato/metabolismo , Feminino , Transdução de Sinais , Proliferação de CélulasRESUMO
Despite recent advances in imaging- and antibody-based methods, achieving in-depth, high-resolution protein mapping across entire tissues remains a significant challenge in spatial proteomics. Here, we present parallel-flow projection and transfer learning across omics data (PLATO), an integrated framework combining microfluidics with deep learning to enable high-resolution mapping of thousands of proteins in whole tissue sections. We validated the PLATO framework by profiling the spatial proteome of the mouse cerebellum, identifying 2,564 protein groups in a single run. We then applied PLATO to rat villus and human breast cancer samples, achieving a spatial resolution of 25 µm and uncovering proteomic dynamics associated with disease states. This approach revealed spatially distinct tumor subtypes, identified key dysregulated proteins, and provided novel insights into the complexity of the tumor microenvironment. We believe that PLATO represents a transformative platform for exploring spatial proteomic regulation and its interplay with genetic and environmental factors.
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Neoplasias da Mama , Microfluídica , Proteômica , Microambiente Tumoral , Animais , Proteômica/métodos , Humanos , Camundongos , Ratos , Microfluídica/métodos , Feminino , Neoplasias da Mama/metabolismo , Proteoma/metabolismo , Proteoma/análise , Cerebelo/metabolismo , Aprendizado ProfundoRESUMO
This study investigated the cervicovaginal microbiome's (CVM's) impact on Chlamydia trachomatis (CT) infection among Black and Hispanic adolescent and young adult women. A total of 187 women with incident CT were matched to 373 controls, and the CVM was characterized before, during, and after CT infection. The findings highlight that a specific subtype of bacterial vaginosis (BV), identified from 16S rRNA gene reads using the molBV algorithm and community state type (CST) clustering, is a significant risk factor for CT acquisition. A microbial risk score (MRS) further identified a network of bacterial genera associated with increased CT risk. Post treatment, the CVM associated with CT acquisition re-emerged in a different subset of cases leading to reinfection. Additionally, the analysis showed a connection between post-treatment CVM and the development of pelvic inflammatory disease (PID) and miscarriage, further underscoring the CVM's contributing role to incident CT natural history and highlighting its consideration as a therapeutic target.
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Colo do Útero , Infecções por Chlamydia , Chlamydia trachomatis , Microbiota , RNA Ribossômico 16S , Vagina , Humanos , Feminino , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , Adolescente , Infecções por Chlamydia/microbiologia , Vagina/microbiologia , Adulto Jovem , RNA Ribossômico 16S/genética , Colo do Útero/microbiologia , Adulto , Vaginose Bacteriana/microbiologia , Fatores de Risco , Doença Inflamatória Pélvica/microbiologia , Estudos de Casos e Controles , Hispânico ou Latino/genética , BrancosRESUMO
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
Transcriptional activation of the embryonic genome (EGA) is a major developmental landmark enabling the embryo to become independent from maternal control. The magnitude and control of transcriptional reprogramming during this event across mammals remains poorly understood. Here, we developed Smart-seq+5' for high sensitivity, full-length transcript coverage and simultaneous capture of 5' transcript information from single cells and single embryos. Using Smart-seq+5', we profiled 34 developmental stages in 5 mammalian species and provide an extensive characterization of the transcriptional repertoire of early development before, during, and after EGA. We demonstrate widespread transposable element (TE)-driven transcription across species, including, remarkably, of DNA transposons. We identify 19,657 TE-driven genic transcripts, suggesting extensive TE co-option in early development over evolutionary timescales. TEs display similar expression dynamics across species and species-specific patterns, suggesting shared and divergent regulation. Our work provides a powerful resource for understanding transcriptional regulation of mammalian development.
Assuntos
Elementos de DNA Transponíveis , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Animais , Elementos de DNA Transponíveis/genética , Camundongos , Desenvolvimento Embrionário/genética , Humanos , Mamíferos/genética , Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Iniciação da Transcrição Genética , Genoma , Transcrição Gênica , FemininoRESUMO
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
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.