Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.676
Filtrar
Mais filtros

Intervalo de ano de publicação
1.
Cell ; 187(12): 3056-3071.e17, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38848678

RESUMO

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.


Assuntos
Homeostase , Mucosa Intestinal , Receptores Acoplados a Proteínas G , Regeneração , Células-Tronco , Animais , Células-Tronco/metabolismo , Células-Tronco/citologia , Camundongos , Mucosa Intestinal/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Intestinos/citologia , Diferenciação Celular , Camundongos Endogâmicos C57BL , Células Epiteliais/metabolismo , Análise de Célula Única , Masculino
2.
Nat Immunol ; 25(1): 166-177, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38057617

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hybrid immunity is more protective than vaccination or previous infection alone. To investigate the kinetics of spike-reactive T (TS) cells from SARS-CoV-2 infection through messenger RNA vaccination in persons with hybrid immunity, we identified the T cell receptor (TCR) sequences of thousands of index TS cells and tracked their frequency in bulk TCRß repertoires sampled longitudinally from the peripheral blood of persons who had recovered from coronavirus disease 2019 (COVID-19). Vaccinations led to large expansions in memory TS cell clonotypes, most of which were CD8+ T cells, while also eliciting diverse TS cell clonotypes not observed before vaccination. TCR sequence similarity clustering identified public CD8+ and CD4+ TCR motifs associated with spike (S) specificity. Synthesis of longitudinal bulk ex vivo single-chain TCRß repertoires and paired-chain TCRÉ‘ß sequences from droplet sequencing of TS cells provides a roadmap for the rapid assessment of T cell responses to vaccines and emerging pathogens.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , Linfócitos T CD8-Positivos , Vacinação , RNA Mensageiro/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Anticorpos Antivirais
3.
Nat Immunol ; 25(4): 644-658, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38503922

RESUMO

The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens and found an association with beneficial response to PD-1 blockade. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcome. This hub is distinct from mature tertiary lymphoid structures and is enriched for stem-like TCF7+PD-1+CD8+ T cells, activated CCR7+LAMP3+ dendritic cells and CCL19+ fibroblasts as well as chemokines that organize these cells. Within the stem-immunity hub, we find preferential interactions between CXCL10+ macrophages and TCF7-CD8+ T cells as well as between mature regulatory dendritic cells and TCF7+CD4+ and regulatory T cells. These results provide a picture of the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.


Assuntos
Neoplasias Pulmonares , Humanos , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1 , Quimiocinas/metabolismo , Imunoterapia/métodos , Microambiente Tumoral
4.
Cell ; 181(5): 990-996.e5, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32386545

RESUMO

The novel coronavirus SARS-CoV-2 was first detected in the Pacific Northwest region of the United States in January 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the United States, we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated effects of federal travel restrictions. This study provides evidence of widespread sustained transmission of SARS-CoV-2 within the United States and highlights the critical need for local surveillance.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/transmissão , Pneumonia Viral/transmissão , Viagem , Betacoronavirus/isolamento & purificação , COVID-19 , Connecticut/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Monitoramento Epidemiológico , Humanos , Funções Verossimilhança , Pandemias , Filogenia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , SARS-CoV-2 , Viagem/legislação & jurisprudência , Estados Unidos/epidemiologia , Washington/epidemiologia
5.
Cell ; 173(5): 1165-1178.e20, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29706548

RESUMO

Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.


Assuntos
Trifosfato de Adenosina/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Genoma , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proteoglicanas de Sulfatos de Condroitina/genética , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/genética , Cromossomos/metabolismo , Proteínas de Ligação a DNA , Humanos , Camundongos , Mutagênese , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Coesinas
6.
Nat Immunol ; 21(9): 1058-1069, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719520

RESUMO

Innate T cells, including invariant natural killer T (iNKT) and mucosal-associated innate T (MAIT) cells, are a heterogeneous T lymphocyte population with effector properties preprogrammed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL-6 was transiently expressed in iNKT cells upon exit from positive selection and was required for their proper development beyond stage 0. Notably, development of MAIT cells was also impaired in the absence of Bcl6. BCL-6-deficient iNKT cells had reduced expression of genes that were associated with the innate T cell lineage, including Zbtb16, which encodes PLZF, and PLZF-targeted genes. BCL-6 contributed to a chromatin accessibility landscape that was permissive for the expression of development-related genes and inhibitory for genes associated with naive T cell programs. Our results revealed new functions for BCL-6 and illuminated how this transcription factor controls early iNKT cell development.


Assuntos
Cromatina/metabolismo , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Regulação da Expressão Gênica no Desenvolvimento , Imunidade Inata , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética
7.
Nature ; 627(8004): 546-552, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38467896

RESUMO

The generation of spectrally pure microwave signals is a critical functionality in fundamental and applied sciences, including metrology and communications. Optical frequency combs enable the powerful technique of optical frequency division (OFD) to produce microwave oscillations of the highest quality1,2. Current implementations of OFD require multiple lasers, with space- and energy-consuming optical stabilization and electronic feedback components, resulting in device footprints incompatible with integration into a compact and robust photonic platform3-5. Here we demonstrate all-optical OFD on a photonic chip by synchronizing two distinct dynamical states of Kerr microresonators pumped by a single continuous-wave laser. The inherent stability of the terahertz beat frequency between the signal and idler fields of an optical parametric oscillator is transferred to a microwave frequency of a Kerr soliton comb, and synchronization is achieved via a coupling waveguide without the need for electronic locking. OFD factors of N = 34 and 468 are achieved for 227 GHz and 16 GHz soliton combs, respectively. In particular, OFD enables a 46 dB phase-noise reduction for the 16 GHz soliton comb, resulting in the lowest microwave noise observed in an integrated photonics platform. Our work represents a simple, effective approach for performing OFD and provides a pathway towards chip-scale devices that can generate microwave frequencies comparable to the purest tones produced in metrological laboratories.

8.
Nature ; 626(7999): 535-541, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38297126

RESUMO

The brightness of an emitter is ultimately described by Fermi's golden rule, with a radiative rate proportional to its oscillator strength times the local density of photonic states. As the oscillator strength is an intrinsic material property, the quest for ever brighter emission has relied on the local density of photonic states engineering, using dielectric or plasmonic resonators1,2. By contrast, a much less explored avenue is to boost the oscillator strength, and hence the emission rate, using a collective behaviour termed superradiance. Recently, it was proposed3 that the latter can be realized using the giant oscillator-strength transitions of a weakly confined exciton in a quantum well when its coherent motion extends over many unit cells. Here we demonstrate single-photon superradiance in perovskite quantum dots with a sub-100 picosecond radiative decay time, almost as short as the reported exciton coherence time4. The characteristic dependence of radiative rates on the size, composition and temperature of the quantum dot suggests the formation of giant transition dipoles, as confirmed by effective-mass calculations. The results aid in the development of ultrabright, coherent quantum light sources and attest that quantum effects, for example, single-photon emission, persist in nanoparticles ten times larger than the exciton Bohr radius.

9.
Nature ; 632(8027): 1092-1100, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39048016

RESUMO

Placebo effects are notable demonstrations of mind-body interactions1,2. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain-a phenomenon known as placebo analgesia3-6. However, despite the strength of placebo effects and their impact on everyday human experience and the failure of clinical trials for new therapeutics7, the neural circuit basis of placebo effects has remained unclear. Here we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn)-a precerebellar nucleus with no established function in pain. We created a behavioural assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain-relief expectation, providing cellular-level evidence for a role of the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain.


Assuntos
Vias Neurais , Percepção da Dor , Dor , Efeito Placebo , Animais , Feminino , Masculino , Camundongos , Analgesia , Antecipação Psicológica/fisiologia , Sinalização do Cálcio , Cerebelo/citologia , Cerebelo/fisiologia , Cognição/fisiologia , Eletrofisiologia , Perfilação da Expressão Gênica , Giro do Cíngulo/citologia , Giro do Cíngulo/fisiologia , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Dor/fisiopatologia , Dor/prevenção & controle , Dor/psicologia , Manejo da Dor/métodos , Manejo da Dor/psicologia , Manejo da Dor/tendências , Percepção da Dor/fisiologia , Limiar da Dor/fisiologia , Limiar da Dor/psicologia , Ponte/citologia , Ponte/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Células de Purkinje/fisiologia , Receptores Opioides/metabolismo , Transmissão Sináptica
10.
Nature ; 621(7980): 746-752, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37758890

RESUMO

Organic semiconductors are carbon-based materials that combine optoelectronic properties with simple fabrication and the scope for tuning by changing their chemical structure1-3. They have been successfully used to make organic light-emitting diodes2,4,5 (OLEDs, now widely found in mobile phone displays and televisions), solar cells1, transistors6 and sensors7. However, making electrically driven organic semiconductor lasers is very challenging8,9. It is difficult because organic semiconductors typically support only low current densities, suffer substantial absorption from injected charges and triplets, and have additional losses due to contacts10,11. In short, injecting charges into the gain medium leads to intolerable losses. Here we take an alternative approach in which charge injection and lasing are spatially separated, thereby greatly reducing losses. We achieve this by developing an integrated device structure that efficiently couples an OLED, with exceptionally high internal-light generation, with a polymer distributed feedback laser. Under the electrical driving of the integrated structure, we observe a threshold in light output versus drive current, with a narrow emission spectrum and the formation of a beam above the threshold. These observations confirm lasing. Our results provide an organic electronic device that has not been previously demonstrated, and show that indirect electrical pumping by an OLED is a very effective way of realizing an electrically driven organic semiconductor laser. This provides an approach to visible lasers that could see applications in spectroscopy, metrology and sensing.

11.
Nature ; 624(7992): 621-629, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38049589

RESUMO

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet ß cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and ß cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3-5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by ß cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the ß cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by ß cells. RFX6 perturbation in primary human islet cells alters ß cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.


Assuntos
Diabetes Mellitus Tipo 2 , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Ilhotas Pancreáticas , Humanos , Estudos de Casos e Controles , Separação Celular , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Redes Reguladoras de Genes/genética , Estudo de Associação Genômica Ampla , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Reprodutibilidade dos Testes
12.
Nature ; 623(7985): 157-166, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37853118

RESUMO

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).


Assuntos
Neoplasias Encefálicas , Glioblastoma , Herpesvirus Humano 1 , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Glioblastoma/imunologia , Glioblastoma/patologia , Nestina/genética , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/fisiologia , Reprodutibilidade dos Testes , Análise de Sobrevida , Linfócitos T/citologia , Linfócitos T/imunologia , Resultado do Tratamento , Microambiente Tumoral/imunologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia
13.
Nat Immunol ; 17(10): 1187-96, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27487330

RESUMO

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.


Assuntos
Infecções por Arenaviridae/imunologia , Linfócitos B/imunologia , Infecções por Vírus Epstein-Barr/imunologia , HIV/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Centro Germinativo/patologia , Centro Germinativo/virologia , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Annu Rev Microbiol ; 77: 193-212, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37100405

RESUMO

Related groups of microbes are widely distributed across Earth's habitats, implying numerous dispersal and adaptation events over evolutionary time. However, relatively little is known about the characteristics and mechanisms of these habitat transitions, particularly for populations that reside in animal microbiomes. Here, we review the literature concerning habitat transitions among a variety of bacterial and archaeal lineages, considering the frequency of migration events, potential environmental barriers, and mechanisms of adaptation to new physicochemical conditions, including the modification of protein inventories and other genomic characteristics. Cells dependent on microbial hosts, particularly bacteria from the Candidate Phyla Radiation, have undergone repeated habitat transitions from environmental sources into animal microbiomes. We compare their trajectories to those of both free-living cells-including the Melainabacteria, Elusimicrobia, and methanogenic archaea-and cellular endosymbionts and bacteriophages, which have made similar transitions. We conclude by highlighting major related topics that may be worthy of future study.


Assuntos
Bacteriófagos , Microbiota , Animais , Archaea/genética , Bactérias/genética , Genômica
15.
Cell ; 155(7): 1507-20, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24360274

RESUMO

A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, we here combined DNaseI hypersensitivity, ChIP-seq, and ChIA-PET technologies to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. We confirm that enhancer usage varies widely across tissues. Unexpectedly, we find that this feature extends to broadly transcribed genes, including Myc and Pim1 cell-cycle regulators, which associate with an entirely different set of enhancers in ES and B cells. By means of high-resolution CpG methylomes, genome editing, and digital footprinting, we show that these enhancers recruit lineage-determining factors. Furthermore, we demonstrate that the turning on and off of enhancers during development correlates with promoter activity. We propose that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner.


Assuntos
Linfócitos B/metabolismo , Células-Tronco Embrionárias/metabolismo , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Regiões Promotoras Genéticas , Regulon , Animais , Linhagem da Célula , Células Cultivadas , Ilhas de CpG , Metilação de DNA , Técnicas Genéticas , Camundongos , Especificidade de Órgãos , RNA Longo não Codificante/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica
17.
Nature ; 612(7939): 252-258, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36385531

RESUMO

Integrated femtosecond pulse and frequency comb sources are critical components for a wide range of applications, including optical atomic clocks1, microwave photonics2, spectroscopy3, optical wave synthesis4, frequency conversion5, communications6, lidar7, optical computing8 and astronomy9. The leading approaches for on-chip pulse generation rely on mode-locking inside microresonators with either third-order nonlinearity10 or with semiconductor gain11,12. These approaches, however, are limited in noise performance, wavelength and repetition rate tunability 10,13. Alternatively, subpicosecond pulses can be synthesized without mode-locking, by modulating a continuous-wave single-frequency laser using electro-optic modulators1,14-17. Here we demonstrate a chip-scale femtosecond pulse source implemented on an integrated lithium niobate photonic platform18, using cascaded low-loss electro-optic amplitude and phase modulators and chirped Bragg grating, forming a time-lens system19. The device is driven by a continuous-wave distributed feedback laser chip and controlled by a single continuous-wave microwave source without the need for any stabilization or locking. We measure femtosecond pulse trains (520-femtosecond duration) with a 30-gigahertz repetition rate, flat-top optical spectra with a 10-decibel optical bandwidth of 12.6 nanometres, individual comb-line powers above 0.1 milliwatts, and pulse energies of 0.54 picojoules. Our results represent a tunable, robust and low-cost integrated pulsed light source with continuous-wave-to-pulse conversion efficiencies an order of magnitude higher than those achieved with previous integrated sources. Our pulse generator may find applications in fields such as ultrafast optical measurement19,20 or networks of distributed quantum computers21,22.


Assuntos
Óxidos , Semicondutores , Olho , Micro-Ondas
18.
Nature ; 604(7906): 502-508, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35396580

RESUMO

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.


Assuntos
Estudo de Associação Genômica Ampla , Esquizofrenia , Alelos , Predisposição Genética para Doença/genética , Genômica , Humanos , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética
19.
PLoS Genet ; 20(1): e1011110, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38236805

RESUMO

In the presence of recombination, the evolutionary relationships between a set of sampled genomes cannot be described by a single genealogical tree. Instead, the genomes are related by a complex, interwoven collection of genealogies formalized in a structure called an ancestral recombination graph (ARG). An ARG extensively encodes the ancestry of the genome(s) and thus is replete with valuable information for addressing diverse questions in evolutionary biology. Despite its potential utility, technological and methodological limitations, along with a lack of approachable literature, have severely restricted awareness and application of ARGs in evolution research. Excitingly, recent progress in ARG reconstruction and simulation have made ARG-based approaches feasible for many questions and systems. In this review, we provide an accessible introduction and exploration of ARGs, survey recent methodological breakthroughs, and describe the potential for ARGs to further existing goals and open avenues of inquiry that were previously inaccessible in evolutionary genomics. Through this discussion, we aim to more widely disseminate the promise of ARGs in evolutionary genomics and encourage the broader development and adoption of ARG-based inference.


Assuntos
Algoritmos , Recombinação Genética , Modelos Genéticos , Genoma/genética , Genômica , Filogenia , Evolução Molecular
20.
Proc Natl Acad Sci U S A ; 121(5): e2304020121, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38261619

RESUMO

Follicular regulatory T cells (Tfr) can play opposite roles in the regulation of germinal center (GC) responses. Depending on the studies, Tfr suppress or support GC and B cell affinity maturation. However, which factors determine positive vs. negative effects of Tfr on the GC B cell is unclear. In this study, we show that GC centrocytes that express MYC up-regulate expression of CCL3 chemokine that is needed for both the positive and negative regulation of GC B cells by Tfr. B cell-intrinsic expression of CCL3 contributes to Tfr-dependent positive selection of foreign Ag-specific GC B cells. At the same time, expression of CCL3 is critical for direct Tfr-mediated suppression of GC B cells that acquire cognate to Tfr nuclear proteins. Our study suggests that CCR5 and CCR1 receptors promote Tfr migration to CCL3 and highlights Ccr5 expression on the Tfr subset that expresses Il10. Based on our findings and previous studies, we suggest a model of chemotactically targeted checkpoint control of B cells undergoing positive selection in GCs by Tfr, where Tfr directly probe and license foreign antigen-specific B cells to complete their positive selection in GCs but, at the same time, suppress GC B cells that present self-antigens cognate to Tfr.


Assuntos
Linfócitos B , Linfócitos T Reguladores , Centro Germinativo , Autoantígenos , Quimiocina CCL3
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA