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.
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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 JovenRESUMEN
The newly revised 2021 ISSCR Guidelines for Stem Cell Research and Clinical Translation includes scientific and ethical guidance for the transfer of human pluripotent stem cells and their direct derivatives into animal models. In this white paper, the ISSCR subcommittee that drafted these guidelines for research involving the use of nonhuman embryos and postnatal animals explains and summarizes their recommendations.
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Quimera , Investigaciones con Embriones/ética , Células Madre Pluripotentes , Guías de Práctica Clínica como Asunto , Sociedades Científicas/normas , Investigación con Células Madre/ética , Trasplante de Células Madre/normas , Animales , Humanos , Sociedades Científicas/ética , Trasplante de Células Madre/éticaRESUMEN
The International Society for Stem Cell Research has updated its Guidelines for Stem Cell Research and Clinical Translation in order to address advances in stem cell science and other relevant fields, together with the associated ethical, social, and policy issues that have arisen since the last update in 2016. While growing to encompass the evolving science, clinical applications of stem cells, and the increasingly complex implications of stem cell research for society, the basic principles underlying the Guidelines remain unchanged, and they will continue to serve as the standard for the field and as a resource for scientists, regulators, funders, physicians, and members of the public, including patients. A summary of the key updates and issues is presented here.
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Discusiones Bioéticas/normas , Políticas , Guías de Práctica Clínica como Asunto , Sociedades Científicas/normas , Investigación con Células Madre/ética , Células Madre , Humanos , Sociedades Científicas/éticaRESUMEN
Multiple summer events, including large indoor gatherings, in Provincetown, Massachusetts (MA), in July 2021 contributed to an outbreak of over one thousand COVID-19 cases among residents and visitors. Most cases were fully vaccinated, many of whom were also symptomatic, prompting a comprehensive public health response, motivating changes to national masking recommendations, and raising questions about infection and transmission among vaccinated individuals. To characterize the outbreak and the viral population underlying it, we combined genomic and epidemiological data from 467 individuals, including 40% of known outbreak-associated cases. The Delta variant accounted for 99% of sequenced outbreak-associated cases. Phylogenetic analysis suggests over 40 sources of Delta in the dataset, with one responsible for a single cluster containing 83% of outbreak-associated genomes. This cluster was likely not the result of extensive spread at a single site, but rather transmission from a common source across multiple settings over a short time. Genomic and epidemiological data combined provide strong support for 25 transmission events from, including many between, fully vaccinated individuals; genomic data alone provides evidence for an additional 64. Together, genomic epidemiology provides a high-resolution picture of the Provincetown outbreak, revealing multiple cases of transmission of Delta from fully vaccinated individuals. However, despite its magnitude, the outbreak was restricted in its onward impact in MA and the US, likely due to high vaccination rates and a robust public health response.
RESUMEN
Haematopoietic stem cells (HSCs) sustain blood production throughout life. HSCs are capable of extensive proliferative expansion, as a single HSC may reconstitute lethally irradiated hosts. In steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhaustion during adult life. Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified, transcription factors restricting their cycling have remained elusive. Here we report that the zinc-finger repressor Gfi-1 (growth factor independent 1), a cooperating oncogene in lymphoid cells, unexpectedly restricts proliferation of HSCs. After loss of Gfi-1, HSCs display elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell-cycle analysis. Gfi-1-/- HSCs are functionally compromised in competitive repopulation and serial transplantation assays, and are rapidly out-competed in the bone marrow of mouse chimaeras generated with Gfi-1-/- embryonic stem cells. Thus, Gfi-1 is essential to restrict HSC proliferation and to preserve HSC functional integrity.
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Proteínas de Unión al ADN/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Factores de Transcripción/metabolismo , Animales , Trasplante de Médula Ósea , Bromodesoxiuridina , Ciclo Celular , División Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Eliminación de Gen , Hematopoyesis , Inmunofenotipificación , Antígenos Comunes de Leucocito/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción/deficiencia , Factores de Transcripción/genéticaRESUMEN
The contribution of erythropoietin to the differentiation of the red blood cell lineage remains elusive, and the demonstration of a molecular link between erythropoietin and the transcription of genes associated with erythroid differentiation is lacking. In erythroid cells, expression of the tissue inhibitor of matrix metalloproteinase (TIMP-1) is strictly dependent on erythropoietin. We report here that erythropoietin regulates the transcription of the TIMP-1 gene upon binding to its receptor in erythroid cells by triggering the activation of phosphatidylinositol 3-kinase (PI3K)/Akt. We found that Akt directly phosphorylates the transcription factor GATA-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the TIMP-1 promoter. This chain of events can be recapitulated in nonerythroid cells by transfection of the implicated molecular partners, resulting in the expression of the normally silent endogenous TIMP-1 gene. Conversely, TIMP-1 secretion is profoundly decreased in erythroid cells from fetal livers of transgenic knock-in mice homozygous for a GATA(S310A) gene, which encodes a GATA-1 mutant that cannot be phosphorylated at Ser(310). Furthermore, retrovirus-mediated expression of GATA(S310A) into GATA-1(null)-derived embryonic stem cells decreases the rate of hemoglobinization by more than 50% compared to expressed wild-type GATA-1. These findings provide the first example of a chain of coupling mechanisms between the binding of erythropoietin to its receptor and GATA-1-dependent gene expression.
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Proteínas de Unión al ADN/metabolismo , Células Eritroides/metabolismo , Eritropoyetina/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión , Diferenciación Celular , Células Cultivadas , Chlorocebus aethiops , Proteínas de Unión al ADN/química , Células Eritroides/citología , Factores de Unión al ADN Específico de las Células Eritroides , Factor de Transcripción GATA1 , Humanos , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Fosfoserina/metabolismo , Proteínas Proto-Oncogénicas c-akt , Receptores de Eritropoyetina/metabolismo , Transducción de Señal , Inhibidor Tisular de Metaloproteinasa-1/deficiencia , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factores de Transcripción/química , Transcripción Genética/genéticaRESUMEN
The International Society for Stem Cell Research (ISSCR) presents its 2016 Guidelines for Stem Cell Research and Clinical Translation (ISSCR, 2016). The 2016 guidelines reflect the revision and extension of two past sets of guidelines (ISSCR, 2006; ISSCR, 2008) to address new and emerging areas of stem cell discovery and application and evolving ethical, social, and policy challenges. These guidelines provide an integrated set of principles and best practices to drive progress in basic, translational, and clinical research. The guidelines demand rigor, oversight, and transparency in all aspects of practice, providing confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests. Here, we highlight key elements and recommendations in the guidelines and summarize the recommendations and deliberations behind them.
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Investigación con Células Madre/legislación & jurisprudencia , Células Madre/fisiología , Investigación Biomédica Traslacional/legislación & jurisprudencia , Ensayos Clínicos como Asunto , Humanos , Consentimiento Informado , Sociedades Científicas/ética , Sociedades Científicas/legislación & jurisprudencia , Investigación con Células Madre/ética , Células Madre/citología , Investigación Biomédica Traslacional/ética , Investigación Biomédica Traslacional/métodosRESUMEN
Data sharing is an essential element of research; however, recent scientific and social developments have challenged conventional methods for protecting privacy. Here we provide guidance for determining data sharing thresholds for human pluripotent stem cell research aimed at a wide range of stakeholders, including research consortia, biorepositories, policy-makers, and funders.
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Células Madre Pluripotentes/citología , Privacidad , Investigación con Células Madre/ética , Humanos , Investigación con Células Madre/legislación & jurisprudenciaRESUMEN
Rapid advances in stem cell research have led to the derivation of hundreds of human embryonic stem (hES) cell lines in centers throughout the world, as well as the development of new technologies for producing pluripotent stem cells. These cell lines have unique characteristics and were derived using a variety of ethical guidelines. Stem cell registries have been developed in order to collect, organize, and disseminate cell line-specific information. In this review, we describe the current state of the field by providing an overview of the unique qualities and mandates of the three major stem cell registries: the European hES Cell Registry, the Registry of hES Cell Line Provenance developed by the International Society for Stem Cell Research, and the International Stem Cell Registry of hES and induced pluripotent stem cell lines established at the University of Massachusetts Medical School. While each registry has its own unique mandate and features, there is some overlap in the goals and information provided. This review discusses the challenges and prospects for an integrated approach in which all three registries effectively collaborate to minimize duplication and facilitate information exchange within the stem cell community.
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Células Madre Embrionarias/citología , Cooperación Internacional , Sistema de Registros , Animales , Línea Celular , Humanos , Facultades de MedicinaRESUMEN
A report by the International Society for Stem Cell Research (ISSCR)'s Task Force on Unproven Stem Cell Treatments outlines development of resources for patients, their families, and physicians seeking information on stem cell treatments.
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Investigaciones con Embriones/ética , Investigaciones con Embriones/legislación & jurisprudencia , Internet , Células Madre , Guías como Asunto , Humanos , Sociedades MédicasRESUMEN
The International Society for Stem Cell Research (ISSCR) task force that developed new Guidelines for the Clinical Translation of Stem Cells discusses core principles that should guide the responsible transition of basic stem cell research into appropriate clinical applications.
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Tecnología Biomédica/normas , Tratamiento Basado en Trasplante de Células y Tejidos/normas , Ensayos Clínicos como Asunto/normas , Guías de Práctica Clínica como Asunto/normas , Trasplante de Células Madre/normas , Animales , Tecnología Biomédica/ética , Tratamiento Basado en Trasplante de Células y Tejidos/ética , Comités de Monitoreo de Datos de Ensayos Clínicos/normas , Ensayos Clínicos como Asunto/ética , Humanos , Consentimiento Informado/normas , Monitoreo Fisiológico/normas , Revisión por Pares/normas , Trasplante de Células Madre/éticaRESUMEN
Gfi-1 and Gfi-1b are homologous transcriptional repressors involved in diverse developmental contexts, including hematopoiesis and oncogenesis. Transcriptional repression by Gfi proteins requires the conserved SNAG domain. To elucidate the function of Gfi proteins, we purified Gfi-1b complexes and identified interacting proteins. Prominent among these is the corepressor CoREST, the histone demethylase LSD1, and HDACs 1 and 2. CoREST and LSD1 associate with Gfi-1/1b via the SNAG repression domain. Gfi-1b further recruits these cofactors to the majority of target gene promoters in vivo. Inhibition of CoREST and LSD1 perturbs differentiation of erythroid, megakaryocytic, and granulocytic cells as well as primary erythroid progenitors. LSD1 depletion derepresses Gfi targets in lineage-specific patterns, accompanied by enhanced histone 3 lysine 4 methylation at the respective promoters. Overall, we show that chromatin regulatory proteins CoREST and LSD1 mediate transcriptional repression by Gfi proteins. Lineage-restricted deployment of these cofactors through interaction with Gfi proteins controls hematopoietic differentiation.
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Diferenciación Celular/genética , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Hematopoyesis/genética , Proteínas del Tejido Nervioso/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Linaje de la Célula , Proteínas Co-Represoras , Metilación de ADN , Proteínas de Unión al ADN/química , Células Eritroides/citología , Histona Desacetilasas/metabolismo , Histona Demetilasas , Histonas/metabolismo , Ratones , Modelos Genéticos , Datos de Secuencia Molecular , Complejos Multiproteicos/metabolismo , Oxidorreductasas N-Desmetilantes/deficiencia , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/química , Interferencia de ARN , Proteínas Represoras/química , Factores de Transcripción/químicaRESUMEN
The International Society for Stem Cell Research (ISSCR) is an independent, nonprofit organization founded in 2002 to foster professional and public communication and education regarding stem cell research. Under the leadership of prominent stem cell scientists from around the world, the ISSCR membership has grown exponentially, creating a diverse, international community of researchers who have expertise in many facets of stem cell biology. The ISSCR is dedicated to promoting the exchange of ideas and has developed two major forums for dissemination of stem cell research and related issues, an annual meeting and an information-rich website. With the field of stem cell research and technologies rapidly advancing, discourse is more critical than ever to maintain high standards across the full spectrum of research.
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Investigación Biomédica/historia , Cooperación Internacional , Sociedades Científicas/organización & administración , Células Madre , Predicción , Historia del Siglo XXI , Humanos , Sociedades Científicas/historia , Células Madre/citología , Células Madre/fisiologíaRESUMEN
Phosphorylation of transcription factors is important in posttranslational control of protein function. The indispensable zinc-finger transcription factor, Gata1, is phosphorylated constitutively at 6 serine residues (26, 49, 72, 142, 178, 187), and at a seventh (310) following induction of erythroid differentiation. However, the biologic consequences of phosphorylation with respect to function are unclear. To address this issue, we generated mice with serine-to-alanine mutations at the inducibly phosphorylated serine 310 alone or at conserved serine residues 72, 142, and 310 together. The peripheral blood parameters of the mice were normal, as was their response to acute erythropoietic stress. Analysis of hematopoietic progenitor populations during ontogeny and into adulthood showed a moderate decrease in erythroid burst-forming unit (BFU-E) and erythroid colony-forming unit (CFU-E) numbers only in the adult bone marrow of the triple mutant. Yet, later stage erythropoiesis was not perturbed. This suggests that any molecular consequences associated with loss of phosphorylation at residues 72, 142, and 310 can be compensated for in the in vivo environment.
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Factor de Transcripción GATA1/química , Factor de Transcripción GATA1/metabolismo , Hematopoyesis/fisiología , Sustitución de Aminoácidos , Animales , Ensayo de Unidades Formadoras de Colonias , Eritropoyesis/fisiología , Factor de Transcripción GATA1/genética , Ratones , Ratones Mutantes , Mutagénesis Sitio-Dirigida , Fosforilación , Serina/químicaRESUMEN
We report essential roles of zinc finger transcription factor Gfi-1 in myeloid development. Gene-targeted Gfi-1(-/-) mice lack normal neutrophils and are highly susceptible to abscess formation by gram-positive bacteria. Arrested, morphologically atypical, Gr1(+)Mac1(+) myeloid cells expand with age in the bone marrow. RNAs encoding primary but not secondary or tertiary neutrophil (granulocyte) granule proteins are expressed. The atypical Gr1(+)Mac1(+) cell population shares characteristics of both the neutrophil and macrophage lineages and exhibits phagocytosis and respiratory burst activity. Reexpression of Gfi-1 in sorted Gfi-1(-/-) progenitors ex vivo rescues neutrophil differentiation in response to G-CSF. Thus, Gfi-1 not only promotes differentiation of neutrophils but also antagonizes traits of the alternate monocyte/macrophage program.