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1.
Cell ; 185(1): 95-112.e18, 2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34995520

RESUMEN

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.


Asunto(s)
Dermatoglifia , Dedos/crecimiento & desarrollo , Organogénesis/genética , Polimorfismo de Nucleótido Simple , Dedos del Pie/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Pueblo Asiatico/genética , Tipificación del Cuerpo/genética , Niño , Estudios de Cohortes , Femenino , Miembro Anterior/crecimiento & desarrollo , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Proteína del Locus del Complejo MDS1 y EV11/genética , Masculino , Ratones , Persona de Mediana Edad , Adulto Joven
2.
Cell ; 185(3): 493-512.e25, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-35032429

RESUMEN

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.


Asunto(s)
COVID-19/inmunología , COVID-19/patología , Activación de Complemento , Proteoma , SARS-CoV-2/inmunología , Linfocitos T Citotóxicos/inmunología , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/virología , Factores Quimiotácticos/metabolismo , Citotoxicidad Inmunológica , Células Endoteliales/virología , Femenino , Humanos , Activación de Linfocitos , Masculino , Microvasos/virología , Persona de Mediana Edad , Monocitos/metabolismo , Neutrófilos/metabolismo , Receptores de IgG/metabolismo , Análisis de la Célula Individual , Adulto Joven
3.
Cell ; 185(5): 881-895.e20, 2022 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-35216672

RESUMEN

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.


Asunto(s)
COVID-19/complicaciones , COVID-19/diagnóstico , Convalecencia , Inmunidad Adaptativa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Progresión de la Enfermedad , Femenino , Humanos , Inmunidad Innata/genética , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , SARS-CoV-2/aislamiento & purificación , Transcriptoma , Adulto Joven , Síndrome Post Agudo de COVID-19
4.
Cell ; 185(3): 485-492.e10, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-35051367

RESUMEN

An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021-the first large outbreak mostly in vaccinated individuals in the US-prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.


Asunto(s)
COVID-19/epidemiología , COVID-19/inmunología , COVID-19/transmisión , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/virología , Niño , Preescolar , Trazado de Contacto/métodos , Brotes de Enfermedades , Femenino , Genoma Viral , Humanos , Lactante , Recién Nacido , Masculino , Massachusetts/epidemiología , Persona de Mediana Edad , Epidemiología Molecular , Filogenia , SARS-CoV-2/clasificación , Vacunación , Secuenciación Completa del Genoma , Adulto Joven
5.
Nat Immunol ; 25(7): 1218-1230, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38914866

RESUMEN

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.


Asunto(s)
Enfermedad Celíaca , Dieta Sin Gluten , Proteínas de Unión al GTP , Perfilación de la Expresión Génica , Glútenes , Mucosa Intestinal , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas , Enfermedad Celíaca/inmunología , Humanos , Glútenes/inmunología , Transglutaminasas/metabolismo , Transglutaminasas/antagonistas & inhibidores , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/antagonistas & inhibidores , Proteínas de Unión al GTP/genética , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/efectos de los fármacos , Femenino , Masculino , Adulto , Transcriptoma , Duodeno/patología , Duodeno/inmunología , Duodeno/metabolismo , Interferón gamma/metabolismo , Persona de Mediana Edad , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Adulto Joven , Inmunidad Adaptativa/efectos de los fármacos
6.
Cell ; 184(18): 4772-4783.e15, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34388390

RESUMEN

Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.


Asunto(s)
Crecimiento y Desarrollo , Mosaicismo , Espermatozoides/metabolismo , Adolescente , Envejecimiento/sangre , Alelos , Células Clonales , Estudios de Cohortes , Humanos , Masculino , Modelos Biológicos , Mutación/genética , Factores de Riesgo , Factores de Tiempo , Adulto Joven
7.
Cell ; 184(9): 2302-2315.e12, 2021 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-33838112

RESUMEN

By following up the gut microbiome, 51 human phenotypes and plasma levels of 1,183 metabolites in 338 individuals after 4 years, we characterize microbial stability and variation in relation to host physiology. Using these individual-specific and temporally stable microbial profiles, including bacterial SNPs and structural variations, we develop a microbial fingerprinting method that shows up to 85% accuracy in classifying metagenomic samples taken 4 years apart. Application of our fingerprinting method to the independent HMP cohort results in 95% accuracy for samples taken 1 year apart. We further observe temporal changes in the abundance of multiple bacterial species, metabolic pathways, and structural variation, as well as strain replacement. We report 190 longitudinal microbial associations with host phenotypes and 519 associations with plasma metabolites. These associations are enriched for cardiometabolic traits, vitamin B, and uremic toxins. Finally, mediation analysis suggests that the gut microbiome may influence cardiometabolic health through its metabolites.


Asunto(s)
Bacterias/genética , Proteínas Bacterianas/metabolismo , Microbioma Gastrointestinal , Metaboloma , Metagenoma , Microbiota , Adulto , Anciano , Anciano de 80 o más Años , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Proteínas Bacterianas/genética , Farmacorresistencia Microbiana , Heces/microbiología , Femenino , Inestabilidad Genómica , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Adulto Joven
8.
Cell ; 184(7): 1895-1913.e19, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33657410

RESUMEN

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.


Asunto(s)
COVID-19/inmunología , Megacariocitos/inmunología , Monocitos/inmunología , ARN Viral , SARS-CoV-2/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , China , Estudios de Cohortes , Citocinas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , ARN Viral/aislamiento & purificación , Análisis de la Célula Individual , Transcriptoma/inmunología , Adulto Joven
9.
Cell ; 184(23): 5699-5714.e11, 2021 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-34735795

RESUMEN

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.


Asunto(s)
Vacunas contra la COVID-19/inmunología , Vacunas Sintéticas/inmunología , Adulto , Anciano , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacuna BNT162 , COVID-19/sangre , COVID-19/inmunología , COVID-19/virología , Reactividad Cruzada/inmunología , Relación Dosis-Respuesta Inmunológica , Etnicidad , Femenino , Humanos , Inmunidad , Inmunoglobulina G/inmunología , Modelos Lineales , Masculino , Persona de Mediana Edad , Estándares de Referencia , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Resultado del Tratamiento , Adulto Joven , Vacunas de ARNm
10.
Cell ; 184(7): 1836-1857.e22, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33713619

RESUMEN

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.


Asunto(s)
COVID-19/inmunología , Citocinas/metabolismo , Células Dendríticas/metabolismo , Expresión Génica/inmunología , Células Asesinas Naturales/metabolismo , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , COVID-19/mortalidad , Estudios de Casos y Controles , Células Dendríticas/citología , Femenino , Humanos , Células Asesinas Naturales/citología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Transcriptoma/inmunología , Adulto Joven
11.
Cell ; 184(15): 3915-3935.e21, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34174187

RESUMEN

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.


Asunto(s)
Epigenómica , Inmunidad/genética , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Análisis de la Célula Individual , Transcripción Genética , Vacunación , Adolescente , Adulto , Antibacterianos/farmacología , Antígenos CD34/metabolismo , Antivirales/farmacología , Reprogramación Celular , Cromatina/metabolismo , Citocinas/biosíntesis , Combinación de Medicamentos , Femenino , Regulación de la Expresión Génica , Histonas/metabolismo , Humanos , Inmunidad Innata/genética , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Interferón Tipo I/metabolismo , Masculino , Células Mieloides/metabolismo , Polisorbatos/farmacología , Escualeno/farmacología , Receptores Toll-Like/metabolismo , Factor de Transcripción AP-1/metabolismo , Transcriptoma/genética , Adulto Joven , alfa-Tocoferol/farmacología
12.
Nat Immunol ; 24(1): 96-109, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36510022

RESUMEN

Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4+ T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4+ T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4+ T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.


Asunto(s)
Envejecimiento , Linfocitos T CD4-Positivos , Factor de Transcripción Ikaros , Anciano , Animales , Humanos , Ratones , Adulto Joven , Envejecimiento/inmunología , Envejecimiento/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Ensamble y Desensamble de Cromatina , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T , Factor de Transcripción STAT5 , Factor de Transcripción Ikaros/metabolismo
13.
Cell ; 181(7): 1464-1474, 2020 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-32589957

RESUMEN

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.


Asunto(s)
Ejercicio Físico/fisiología , Resistencia Física/fisiología , Adolescente , Adulto , Animales , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Proyectos de Investigación , Adulto Joven
14.
Cell ; 183(1): 228-243.e21, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32946810

RESUMEN

Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations. Moreover, during resting behavior, coactivation of hippocampal cells in sharp-wave/ripples represent inferred relationships that include reward, thereby "joining-the-dots" between events that have not been observed together but lead to profitable outcomes. Computing mnemonic links in this manner may provide an important mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.


Asunto(s)
Toma de Decisiones/fisiología , Red Nerviosa/fisiología , Pensamiento/fisiología , Animales , Encéfalo/fisiología , Femenino , Hipocampo/metabolismo , Hipocampo/fisiología , Humanos , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Neuronas/metabolismo , Neuronas/fisiología , Estudios Prospectivos , Adulto Joven
15.
Cell ; 181(6): 1246-1262.e22, 2020 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-32442405

RESUMEN

There is considerable inter-individual variability in susceptibility to weight gain despite an equally obesogenic environment in large parts of the world. Whereas many studies have focused on identifying the genetic susceptibility to obesity, we performed a GWAS on metabolically healthy thin individuals (lowest 6th percentile of the population-wide BMI spectrum) in a uniquely phenotyped Estonian cohort. We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene. In Drosophila, RNAi mediated knockdown of Alk led to decreased triglyceride levels. In mice, genetic deletion of Alk resulted in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Delgadez/genética , Tejido Adiposo/metabolismo , Adulto , Animales , Línea Celular , Estudios de Cohortes , Drosophila/genética , Estonia , Femenino , Humanos , Leptina/genética , Lipólisis/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/genética , Interferencia de ARN/fisiología , Adulto Joven
16.
Cell ; 183(5): 1264-1281.e20, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-33091337

RESUMEN

The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS.


Asunto(s)
Subtipos Serológicos HLA-DR/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Alelos , Antígenos/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Reacciones Cruzadas/inmunología , Femenino , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Péptidos/inmunología , Proteoma/metabolismo , Adulto Joven
17.
Cell ; 183(6): 1714-1731.e10, 2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-33275901

RESUMEN

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.


Asunto(s)
Proteínas Quinasas/metabolismo , Proteolisis , Proteoma/metabolismo , Adulto , Línea Celular , Bases de Datos de Proteínas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Quinasas/genética , Proteómica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Adulto Joven
18.
Cell ; 180(3): 454-470.e18, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32004459

RESUMEN

Metagenomic inferences of bacterial strain diversity and infectious disease transmission studies largely assume a dominant, within-individual haplotype. We hypothesize that within-individual bacterial population diversity is critical for homeostasis of a healthy microbiome and infection risk. We characterized the evolutionary trajectory and functional distribution of Staphylococcus epidermidis-a keystone skin microbe and opportunistic pathogen. Analyzing 1,482 S. epidermidis genomes from 5 healthy individuals, we found that skin S. epidermidis isolates coalesce into multiple founder lineages rather than a single colonizer. Transmission events, natural selection, and pervasive horizontal gene transfer result in population admixture within skin sites and dissemination of antibiotic resistance genes within-individual. We provide experimental evidence for how admixture can modulate virulence and metabolism. Leveraging data on the contextual microbiome, we assess how interspecies interactions can shape genetic diversity and mobile gene elements. Our study provides insights into how within-individual evolution of human skin microbes shapes their functional diversification.


Asunto(s)
Evolución Molecular , Transferencia de Gen Horizontal , Interacciones Microbiota-Huesped/genética , Microbiota/genética , Polimorfismo de Nucleótido Simple , Piel/microbiología , Staphylococcus epidermidis/genética , Adulto , ADN Bacteriano/genética , Farmacorresistencia Bacteriana/genética , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Staphylococcus epidermidis/aislamiento & purificación , Staphylococcus epidermidis/patogenicidad , Virulencia/genética , Adulto Joven
19.
Cell ; 182(2): 317-328.e10, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32526205

RESUMEN

Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87-0.96] at baseline and 0.98 [95% CI 0.97-1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.


Asunto(s)
Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Virosis/patología , Adulto , Anciano , Área Bajo la Curva , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Curva ROC , Factores de Riesgo , Virosis/complicaciones , Adulto Joven , alfa-Fetoproteínas/análisis
20.
Cell ; 181(6): 1263-1275.e16, 2020 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-32437658

RESUMEN

Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.


Asunto(s)
Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Intestinos/inmunología , Intestinos/microbiología , Células Th17/inmunología , Células Th17/fisiología , Adolescente , Adulto , Animales , Dieta Alta en Grasa/métodos , Dieta Cetogénica/métodos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota/inmunología , Microbiota/fisiología , Persona de Mediana Edad , Células Th17/microbiología , Adulto Joven
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