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1.
Annu Rev Immunol ; 41: 1-15, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37126416

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 Biomédica
2.
Annu Rev Immunol ; 41: 127-151, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-36630598

RESUMO

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 , Decídua
3.
Annu Rev Immunol ; 40: 499-523, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35471839

RESUMO

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/microbiologia
4.
Annu Rev Immunol ; 40: 75-94, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-34985929

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 Sexuais
5.
Cell ; 187(4): 802-804, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38364784

RESUMO

Akorfa Dagadu is a winner of the fourth 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, 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
Distinções e Prêmios , Polímeros , Humanos , Feminino , População Negra
6.
Cell ; 187(6): 1335-1342, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490175

RESUMO

Gender inequality in STEM fields remains pervasive and undermines the ability for talented individuals to excel. Despite advances, women still encounter obstacles in pursuing academic careers and reaching leadership positions. This commentary discusses the "scissor-shaped curve" and examines effective strategies to fix it, including data-driven initiatives that we have implemented at our university.


Assuntos
Academia , Equidade de Gênero , Humanos , Feminino , Liderança , Universidades
7.
Cell ; 187(6): 1347-1349, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490177

RESUMO

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 , Sexo
8.
Cell ; 187(6): 1354-1357, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490178

RESUMO

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 Sexuais
9.
Cell ; 187(6): 1350-1353, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38417438

RESUMO

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 , Pesquisa
10.
Cell ; 187(6): 1327-1334, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490174

RESUMO

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.


Assuntos
Minorias Sexuais e de Gênero , Pessoas Transgênero , Masculino , Feminino , Humanos , Identidade de Gênero
11.
Cell ; 187(5): 1109-1126.e21, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38382525

RESUMO

Oocytes are among the longest-lived cells in the body and need to preserve their cytoplasm to support proper embryonic development. Protein aggregation is a major threat for intracellular homeostasis in long-lived cells. How oocytes cope with protein aggregation during their extended life is unknown. Here, we find that mouse oocytes accumulate protein aggregates in specialized compartments that we named endolysosomal vesicular assemblies (ELVAs). Combining live-cell imaging, electron microscopy, and proteomics, we found that ELVAs are non-membrane-bound compartments composed of endolysosomes, autophagosomes, and proteasomes held together by a protein matrix formed by RUFY1. Functional assays revealed that in immature oocytes, ELVAs sequester aggregated proteins, including TDP-43, and degrade them upon oocyte maturation. Inhibiting degradative activity in ELVAs leads to the accumulation of protein aggregates in the embryo and is detrimental for embryo survival. Thus, ELVAs represent a strategy to safeguard protein homeostasis in long-lived cells.


Assuntos
Vesículas Citoplasmáticas , Oócitos , Agregados Proteicos , Animais , Feminino , Camundongos , Autofagossomos , Vesículas Citoplasmáticas/metabolismo , Lisossomos/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Complexo de Endopeptidases do Proteassoma , Proteólise
12.
Cell ; 187(1): 110-129.e31, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38181737

RESUMO

X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X chromosome in cis to mediate gene silencing chromosome-wide. In female naive human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration, and XCI does not occur, raising questions about XIST's function. We found that XIST spreads across the X chromosome and induces dampening of X-linked gene expression in naive hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences in autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting.


Assuntos
Genes Ligados ao Cromossomo X , RNA Longo não Codificante , Cromossomo X , Animais , Feminino , Humanos , Masculino , Camundongos , Inativação Gênica , RNA Longo não Codificante/genética , Cromossomo X/genética , Células-Tronco Pluripotentes/metabolismo
13.
Cell ; 187(3): 764-781.e14, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38306985

RESUMO

Pregnancy induces dramatic metabolic changes in females; yet, the intricacies of this metabolic reprogramming remain poorly understood, especially in primates. Using cynomolgus monkeys, we constructed a comprehensive multi-tissue metabolome atlas, analyzing 273 samples from 23 maternal tissues during pregnancy. We discovered a decline in metabolic coupling between tissues as pregnancy progressed. Core metabolic pathways that were rewired during primate pregnancy included steroidogenesis, fatty acid metabolism, and arachidonic acid metabolism. Our atlas revealed 91 pregnancy-adaptive metabolites changing consistently across 23 tissues, whose roles we verified in human cell models and patient samples. Corticosterone and palmitoyl-carnitine regulated placental maturation and maternal tissue progenitors, respectively, with implications for maternal preeclampsia, diabetes, cardiac hypertrophy, and muscle and liver regeneration. Moreover, we found that corticosterone deficiency induced preeclampsia-like inflammation, indicating the atlas's potential clinical value. Overall, our multi-tissue metabolome atlas serves as a framework for elucidating the role of metabolic regulation in female health during pregnancy.


Assuntos
Metabolômica , Gravidez , Animais , Feminino , Humanos , Gravidez/metabolismo , Corticosterona/metabolismo , Metaboloma/fisiologia , Placenta/metabolismo , Pré-Eclâmpsia , Primatas/metabolismo
14.
Cell ; 187(14): 3541-3562.e51, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38996487

RESUMO

Analyses of ancient DNA typically involve sequencing the surviving short oligonucleotides and aligning to genome assemblies from related, modern species. Here, we report that skin from a female woolly mammoth (†Mammuthus primigenius) that died 52,000 years ago retained its ancient genome architecture. We use PaleoHi-C to map chromatin contacts and assemble its genome, yielding 28 chromosome-length scaffolds. Chromosome territories, compartments, loops, Barr bodies, and inactive X chromosome (Xi) superdomains persist. The active and inactive genome compartments in mammoth skin more closely resemble Asian elephant skin than other elephant tissues. Our analyses uncover new biology. Differences in compartmentalization reveal genes whose transcription was potentially altered in mammoths vs. elephants. Mammoth Xi has a tetradic architecture, not bipartite like human and mouse. We hypothesize that, shortly after this mammoth's death, the sample spontaneously freeze-dried in the Siberian cold, leading to a glass transition that preserved subfossils of ancient chromosomes at nanometer scale.


Assuntos
Genoma , Mamutes , Pele , Animais , Mamutes/genética , Genoma/genética , Feminino , Elefantes/genética , Cromatina/genética , Fósseis , DNA Antigo/análise , Camundongos , Humanos , Cromossomo X/genética
15.
Cell ; 187(6): 1402-1421.e21, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38428422

RESUMO

Neonates are highly susceptible to inflammation and infection. Here, we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPCs) respond to inflammation, testing the hypothesis that deficits in the engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical adult-like EM transcriptional program. Moreover, we find that fetal HSPCs can respond to EM-inducing inflammatory stimuli in vitro but are restricted by maternal anti-inflammatory factors, primarily interleukin-10 (IL-10), from activating EM pathways in utero. Accordingly, we demonstrate that the loss of maternal IL-10 restores EM activation in fetal HSPCs but at the cost of fetal demise. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus unresponsive to EM activation signals and susceptible to infection.


Assuntos
Inflamação , Interleucina-10 , Mielopoese , Animais , Camundongos , Gravidez/imunologia , Feto , Hematopoese , Células-Tronco Hematopoéticas/citologia , Inflamação/imunologia , Interleucina-10/imunologia , Animais Recém-Nascidos , Feminino
16.
Cell ; 187(1): 204-215.e14, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38070508

RESUMO

Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.


Assuntos
Diabetes Mellitus , Diabetes Gestacional , Feto , Animais , Feminino , Camundongos , Gravidez , Diabetes Mellitus/metabolismo , Feto/metabolismo , Glucose/metabolismo , Placenta/metabolismo , Diabetes Gestacional/metabolismo
17.
Cell ; 187(4): 981-998.e25, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38325365

RESUMO

The female reproductive tract (FRT) undergoes extensive remodeling during reproductive cycling. This recurrent remodeling and how it shapes organ-specific aging remains poorly explored. Using single-cell and spatial transcriptomics, we systematically characterized morphological and gene expression changes occurring in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrous cycle, during decidualization, and into aging. These analyses reveal that fibroblasts play central-and highly organ-specific-roles in FRT remodeling by orchestrating extracellular matrix (ECM) reorganization and inflammation. Our results suggest a model wherein recurrent FRT remodeling over reproductive lifespan drives the gradual, age-related development of fibrosis and chronic inflammation. This hypothesis was directly tested using chemical ablation of cycling, which reduced fibrotic accumulation during aging. Our atlas provides extensive detail into how estrus, pregnancy, and aging shape the organs of the female reproductive tract and reveals the unexpected cost of the recurrent remodeling required for reproduction.


Assuntos
Envelhecimento , Genitália Feminina , Animais , Feminino , Camundongos , Gravidez , Genitália Feminina/citologia , Genitália Feminina/metabolismo , Inflamação/metabolismo , Útero/citologia , Vagina/citologia , Análise de Célula Única
18.
Cell ; 187(3): 750-763.e20, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38242132

RESUMO

Breastfeeding offers demonstrable benefits to newborns and infants by providing nourishment and immune protection and by shaping the gut commensal microbiota. Although it has been appreciated for decades that breast milk contains complement components, the physiological relevance of complement in breast milk remains undefined. Here, we demonstrate that weanling mice fostered by complement-deficient dams rapidly succumb when exposed to murine pathogen Citrobacter rodentium (CR), whereas pups fostered on complement-containing milk from wild-type dams can tolerate CR challenge. The complement components in breast milk were shown to directly lyse specific members of gram-positive gut commensal microbiota via a C1-dependent, antibody-independent mechanism, resulting in the deposition of the membrane attack complex and subsequent bacterial lysis. By selectively eliminating members of the commensal gut community, complement components from breast milk shape neonate and infant gut microbial composition to be protective against environmental pathogens such as CR.


Assuntos
Proteínas do Sistema Complemento , Microbioma Gastrointestinal , Leite , Animais , Feminino , Humanos , Lactente , Camundongos , Bactérias , Aleitamento Materno , Citrobacter rodentium , Proteínas do Sistema Complemento/análise , Fatores Imunológicos , Saúde do Lactente , Leite Humano , Leite/química , Infecções por Enterobacteriaceae/imunologia
19.
Cell ; 187(9): 2129-2142.e17, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38670071

RESUMO

Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis.


Assuntos
Prosencéfalo , Animais , Prosencéfalo/metabolismo , Prosencéfalo/embriologia , Camundongos , Ratos , Blastocisto/metabolismo , Feminino , Sistemas CRISPR-Cas/genética , Transcriptoma , Organogênese , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Masculino , Camundongos Endogâmicos C57BL
20.
Cell ; 187(13): 3338-3356.e30, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38810644

RESUMO

Suspended animation states allow organisms to survive extreme environments. The African turquoise killifish has evolved diapause as a form of suspended development to survive a complete drought. However, the mechanisms underlying the evolution of extreme survival states are unknown. To understand diapause evolution, we performed integrative multi-omics (gene expression, chromatin accessibility, and lipidomics) in the embryos of multiple killifish species. We find that diapause evolved by a recent remodeling of regulatory elements at very ancient gene duplicates (paralogs) present in all vertebrates. CRISPR-Cas9-based perturbations identify the transcription factors REST/NRSF and FOXOs as critical for the diapause gene expression program, including genes involved in lipid metabolism. Indeed, diapause shows a distinct lipid profile, with an increase in triglycerides with very-long-chain fatty acids. Our work suggests a mechanism for the evolution of complex adaptations and offers strategies to promote long-term survival by activating suspended animation programs in other species.


Assuntos
Diapausa , Animais , Evolução Biológica , Diapausa/genética , Embrião não Mamífero/metabolismo , Fundulidae/genética , Fundulidae/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Peixes Listrados/genética , Peixes Listrados/metabolismo , Metabolismo dos Lipídeos/genética , Proteínas de Peixes/genética , Masculino , Feminino
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