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1.
Cell ; 187(3): 750-763.e20, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38242132

RESUMEN

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.


Asunto(s)
Proteínas del Sistema Complemento , Microbioma Gastrointestinal , Leche , Animales , Femenino , Humanos , Lactante , Ratones , Bacterias , Lactancia Materna , Citrobacter rodentium , Proteínas del Sistema Complemento/análisis , Factores Inmunológicos , Salud del Lactante , Leche Humana , Leche/química , Infecciones por Enterobacteriaceae/inmunología
2.
Cell ; 185(2): 311-327.e24, 2022 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-35063073

RESUMEN

The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ∼200 genes, including regulators of cell adhesion and synapse formation. One of these genes, Igsf9b, a vision-dependent gene encoding an inhibitory synaptic cell adhesion molecule, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell-type-specific gene expression programs.


Asunto(s)
Visión Ocular , Corteza Visual/citología , Corteza Visual/embriología , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Ácido Glutámico/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , RNA-Seq , Transcriptoma/genética , Visión Binocular/genética , Ácido gamma-Aminobutírico/metabolismo
3.
Nat Immunol ; 22(3): 381-390, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33589816

RESUMEN

The integrin α4ß7 selectively regulates lymphocyte trafficking and adhesion in the gut and gut-associated lymphoid tissue (GALT). Here, we describe unexpected involvement of the tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec-2) in the regulation of α4ß7 surface expression and gut immunity. Shp1 selectively inhibited ß7 endocytosis, enhancing surface α4ß7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid-dependent manner with integrin ß7 on the cell surface to target intracellular Shp1 to ß7. Shp1 restrained plasma membrane ß7 phosphorylation and inhibited ß7 endocytosis without affecting ß1 integrin. B cells with reduced Shp1 activity, lacking CD22 or expressing CD22 with mutated Shp1-binding or carbohydrate-binding domains displayed parallel reductions in surface α4ß7 and in homing to GALT. Consistent with the specialized role of α4ß7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.


Asunto(s)
Linfocitos B/enzimología , Inmunidad Mucosa , Cadenas beta de Integrinas/metabolismo , Integrinas/metabolismo , Mucosa Intestinal/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/virología , Quimiotaxis de Leucocito , Modelos Animales de Enfermedad , Endocitosis , Femenino , Cadenas beta de Integrinas/inmunología , Integrinas/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 6/deficiencia , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Rotavirus/inmunología , Rotavirus/patogenicidad , Infecciones por Rotavirus/genética , Infecciones por Rotavirus/inmunología , Infecciones por Rotavirus/metabolismo , Lectina 2 Similar a Ig de Unión al Ácido Siálico/deficiencia , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , Transducción de Señal , Técnicas de Cultivo de Tejidos
4.
Physiol Rev ; 102(4): 1625-1667, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35378997

RESUMEN

For nearly 50 years the proximal tubule (PT) has been known to reabsorb, process, and either catabolize or transcytose albumin from the glomerular filtrate. Innovative techniques and approaches have provided insights into these processes. Several genetic diseases, nonselective PT cell defects, chronic kidney disease (CKD), and acute PT injury lead to significant albuminuria, reaching nephrotic range. Albumin is also known to stimulate PT injury cascades. Thus, the mechanisms of albumin reabsorption, catabolism, and transcytosis are being reexamined with the use of techniques that allow for novel molecular and cellular discoveries. Megalin, a scavenger receptor, cubilin, amnionless, and Dab2 form a nonselective multireceptor complex that mediates albumin binding and uptake and directs proteins for lysosomal degradation after endocytosis. Albumin transcytosis is mediated by a pH-dependent binding affinity to the neonatal Fc receptor (FcRn) in the endosomal compartments. This reclamation pathway rescues albumin from urinary losses and cellular catabolism, extending its serum half-life. Albumin that has been altered by oxidation, glycation, or carbamylation or because of other bound ligands that do not bind to FcRn traffics to the lysosome. This molecular sorting mechanism reclaims physiological albumin and eliminates potentially toxic albumin. The clinical importance of PT albumin metabolism has also increased as albumin is now being used to bind therapeutic agents to extend their half-life and minimize filtration and kidney injury. The purpose of this review is to update and integrate evolving information regarding the reabsorption and processing of albumin by proximal tubule cells including discussion of genetic disorders and therapeutic considerations.


Asunto(s)
Albúminas , Túbulos Renales Proximales , Albúminas/metabolismo , Transporte Biológico , Endocitosis/fisiología , Humanos , Túbulos Renales Proximales/metabolismo
5.
Nature ; 624(7990): 138-144, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37968391

RESUMEN

Diabetes is a leading cause of morbidity, mortality and cost of illness1,2. Health behaviours, particularly those related to nutrition and physical activity, play a key role in the development of type 2 diabetes mellitus3. Whereas behaviour change programmes (also known as lifestyle interventions or similar) have been found efficacious in controlled clinical trials4,5, there remains controversy about whether targeting health behaviours at the individual level is an effective preventive strategy for type 2 diabetes mellitus6 and doubt among clinicians that lifestyle advice and counselling provided in the routine health system can achieve improvements in health7-9. Here we show that being referred to the largest behaviour change programme for prediabetes globally (the English Diabetes Prevention Programme) is effective in improving key cardiovascular risk factors, including glycated haemoglobin (HbA1c), excess body weight and serum lipid levels. We do so by using a regression discontinuity design10, which uses the eligibility threshold in HbA1c for referral to the behaviour change programme, in electronic health data from about one-fifth of all primary care practices in England. We confirm our main finding, the improvement of HbA1c, using two other quasi-experimental approaches: difference-in-differences analysis exploiting the phased roll-out of the programme and instrumental variable estimation exploiting regional variation in programme coverage. This analysis provides causal, rather than associational, evidence that lifestyle advice and counselling implemented at scale in a national health system can achieve important health improvements.


Asunto(s)
Diabetes Mellitus Tipo 2 , Conductas Relacionadas con la Salud , Promoción de la Salud , Programas Nacionales de Salud , Estado Prediabético , Humanos , Peso Corporal , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/prevención & control , Registros Electrónicos de Salud , Inglaterra , Ejercicio Físico , Hemoglobina Glucada/análisis , Promoción de la Salud/métodos , Promoción de la Salud/normas , Estilo de Vida , Lípidos/sangre , Programas Nacionales de Salud/normas , Estado Prediabético/sangre , Estado Prediabético/prevención & control , Atención Primaria de Salud
6.
Mol Cell ; 81(1): 49-66.e8, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33242393

RESUMEN

Breathing depends on pulmonary surfactant, a mixture of phospholipids and proteins, secreted by alveolar type II cells. Surfactant requires lamellar bodies (LBs), organelles containing densely packed concentric membrane layers, for storage and secretion. LB biogenesis remains mysterious but requires surfactant protein B (SP-B), which is synthesized as a precursor (pre-proSP-B) that is cleaved during trafficking into three related proteins. Here, we elucidate the functions and cooperation of these proteins in LB formation. We show that the N-terminal domain of proSP-B is a phospholipid-binding and -transfer protein whose activities are required for proSP-B export from the endoplasmic reticulum (ER) and sorting to LBs, the conversion of proSP-B into lipoprotein particles, and neonatal viability in mice. The C-terminal domain facilitates ER export of proSP-B. The mature middle domain, generated after proteolytic cleavage of proSP-B, generates the striking membrane layers characteristic of LBs. Together, our results lead to a mechanistic model of LB biogenesis.


Asunto(s)
Retículo Endoplásmico/metabolismo , Lipoproteínas/metabolismo , Complejos Multiproteicos/metabolismo , Proteína B Asociada a Surfactante Pulmonar/metabolismo , Animales , Femenino , Células HEK293 , Humanos , Lipoproteínas/química , Ratones , Complejos Multiproteicos/química , Dominios Proteicos , Proteína B Asociada a Surfactante Pulmonar/química
7.
Physiol Rev ; 101(1): 303-318, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32969772

RESUMEN

There are many unknowns for pregnant women during the coronavirus disease 2019 (COVID-19) pandemic. Clinical experience of pregnancies complicated with infection by other coronaviruses e.g., Severe Acute Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome, has led to pregnant woman being considered potentially vulnerable to severe SARS-CoV-2 infection. Physiological changes during pregnancy have a significant impact on the immune system, respiratory system, cardiovascular function, and coagulation. These may have positive or negative effects on COVID-19 disease progression. The impact of SARS-CoV-2 in pregnancy remains to be determined, and a concerted, global effort is required to determine the effects on implantation, fetal growth and development, labor, and neonatal health. Asymptomatic infection presents a further challenge regarding service provision, prevention, and management. Besides the direct impacts of the disease, a plethora of indirect consequences of the pandemic adversely affect maternal health, including reduced access to reproductive health services, increased mental health strain, and increased socioeconomic deprivation. In this review, we explore the current knowledge of COVID-19 in pregnancy and highlight areas for further research to minimize its impact for women and their children.


Asunto(s)
COVID-19/complicaciones , Complicaciones Infecciosas del Embarazo/patología , Complicaciones Infecciosas del Embarazo/virología , SARS-CoV-2 , Femenino , Humanos , Embarazo , Resultado del Embarazo , Factores de Riesgo
8.
Nat Immunol ; 22(7): 797-798, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34035525
9.
Immunity ; 50(1): 121-136.e5, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30594464

RESUMEN

Dermal fibroblasts (dFBs) resist infection by locally differentiating into adipocytes and producing cathelicidin antimicrobial peptide in response to Staphylococcus aureus (S. aureus). Here, we show that neonatal skin was enriched with adipogenic dFBs and immature dermal fat that highly expressed cathelicidin. The pool of adipogenic and antimicrobial dFBs declined after birth, leading to an age-dependent loss of dermal fat and a decrease in adipogenesis and cathelidicin production in response to infection. Transforming growth factor beta (TGF-ß), which acted on uncommitted embryonic and adult dFBs and inhibited their adipogenic and antimicrobial function, was identified as a key upstream regulator of this process. Furthermore, inhibition of the TGF-ß receptor restored the adipogenic and antimicrobial function of dFBs in culture and increased resistance of adult mice to S. aureus infection. These results provide insight into changes that occur in the skin innate immune system between the perinatal and adult periods of life.


Asunto(s)
Envejecimiento/inmunología , Fibroblastos/fisiología , Piel/metabolismo , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/fisiología , Grasa Subcutánea/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Adipocitos/metabolismo , Adipogénesis , Animales , Antiinfecciosos/metabolismo , Péptidos Catiónicos Antimicrobianos/metabolismo , Células Cultivadas , Embrión de Mamíferos , Humanos , Inmunidad Innata , Ratones , Catelicidinas
10.
N Engl J Med ; 390(11): 1009-1021, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38477988

RESUMEN

BACKGROUND: Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed. METHODS: We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed. RESULTS: The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed. CONCLUSIONS: The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT04605159.).


Asunto(s)
Nacimiento Prematuro , Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Femenino , Humanos , Lactante , Recién Nacido , Embarazo , Nacimiento Prematuro/inducido químicamente , Nacimiento Prematuro/etiología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/administración & dosificación , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Vacunas contra Virus Sincitial Respiratorio/uso terapéutico , Enfermedades Respiratorias/prevención & control , Enfermedades Respiratorias/virología , Eficacia de las Vacunas , Resultado del Tratamiento , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Riesgo
11.
Cell ; 150(4): 816-30, 2012 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-22901811

RESUMEN

Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.


Asunto(s)
Encéfalo/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células-Madre Neurales/patología , Neurofibromatosis 1/patología , Neurofibromina 1/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cuerpo Calloso/patología , Humanos , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Neurofibromatosis 1/embriología , Neurofibromatosis 1/metabolismo , Neurofibromina 1/genética , Neuroglía/patología , Factor de Transcripción 2 de los Oligodendrocitos
12.
Nature ; 599(7886): 667-672, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34707292

RESUMEN

Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility1. The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (TH2) cells within a distinct microanatomical niche. TH2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as TH2-interacting fascial fibroblasts (TIFFs), which expand in response to TH2 cytokines to form subcutaneous fibrous bands. Activation of the TH2-TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified TH2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life.


Asunto(s)
Fibroblastos/citología , Inflamación/patología , Piel/citología , Nicho de Células Madre , Células Th2/citología , Animales , Animales Recién Nacidos , Citocinas/inmunología , Eosinofilia/patología , Fascitis/patología , Fibrosis/patología , Salud , Humanos , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Masculino , Ratones , Piel/patología , Linfocitos T Reguladores/citología , Cicatrización de Heridas
13.
Nature ; 594(7863): 408-412, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33979832

RESUMEN

The COVID-19 pandemic has seen the emergence of digital contact tracing to help to prevent the spread of the disease. A mobile phone app records proximity events between app users, and when a user tests positive for COVID-19, their recent contacts can be notified instantly. Theoretical evidence has supported this new public health intervention1-6, but its epidemiological impact has remained uncertain7. Here we investigate the impact of the National Health Service (NHS) COVID-19 app for England and Wales, from its launch on 24 September 2020 to the end of December 2020. It was used regularly by approximately 16.5 million users (28% of the total population), and sent approximately 1.7 million exposure notifications: 4.2 per index case consenting to contact tracing. We estimated that the fraction of individuals notified by the app who subsequently showed symptoms and tested positive (the secondary attack rate (SAR)) was 6%, similar to the SAR for manually traced close contacts. We estimated the number of cases averted by the app using two complementary approaches: modelling based on the notifications and SAR gave an estimate of 284,000 (central 95% range of sensitivity analyses 108,000-450,000), and statistical comparison of matched neighbouring local authorities gave an estimate of 594,000 (95% confidence interval 317,000-914,000). Approximately one case was averted for each case consenting to notification of their contacts. We estimated that for every percentage point increase in app uptake, the number of cases could be reduced by 0.8% (using modelling) or 2.3% (using statistical analysis). These findings support the continued development and deployment of such apps in populations that are awaiting full protection from vaccines.


Asunto(s)
COVID-19/epidemiología , COVID-19/prevención & control , Trazado de Contacto/instrumentación , Trazado de Contacto/métodos , Aplicaciones Móviles/estadística & datos numéricos , Número Básico de Reproducción , COVID-19/mortalidad , COVID-19/transmisión , Inglaterra/epidemiología , Humanos , Mortalidad , Programas Nacionales de Salud , Cuarentena , Gales/epidemiología
14.
Proc Natl Acad Sci U S A ; 121(27): e2314056121, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38917008

RESUMEN

In one of the first papers on the impact of early-life conditions on individuals' health in older age, Barker and Osmond [Lancet, 327, 1077-1081 (1986)] show a strong positive relationship between infant mortality rates in the 1920s and ischemic heart disease in the 1970s. We merge historical data on infant mortality rates to 370,000 individual records in the UK Biobank using information on local area and year of birth. We replicate the association between the early-life infant mortality rate and later-life ischemic heart disease in our sample. We then go "beyond Barker," by showing considerable genetic heterogeneity in this association that is robust to within-area as well as within-family analyses. We find no association between the polygenic index and heart disease in areas with the lowest infant mortality rates, but a strong positive relationship in areas characterized by high infant mortality. These findings suggest that advantageous environments can cushion one's genetic disease risk.


Asunto(s)
Predisposición Genética a la Enfermedad , Mortalidad Infantil , Isquemia Miocárdica , Humanos , Isquemia Miocárdica/genética , Isquemia Miocárdica/mortalidad , Femenino , Masculino , Lactante , Reino Unido/epidemiología , Factores de Riesgo , Persona de Mediana Edad , Recién Nacido , Anciano , Adulto
15.
Proc Natl Acad Sci U S A ; 121(15): e2320299121, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38557172

RESUMEN

Racism is associated with negative intergenerational (infant) outcomes. That is, racism, both perceived and structural, is linked to critical, immediate, and long-term health factors such as low birth weight and infant mortality. Antiracism-resistance to racism such as support for the Black Lives Matter (BLM) movement-has been linked to positive emotional, subjective, and mental health outcomes among adults and adolescents. To theoretically build on and integrate such past findings, the present research asked whether such advantageous health correlations might extend intergenerationally to infant outcomes? It examined a theoretical/correlational process model in which mental and physical health indicators might be indirectly related to associations between antiracism and infant health outcomes. Analyses assessed county-level data that measured BLM support (indexed as volume of BLM marches) and infant outcomes from 2014 to 2020. As predicted, in the tested model, BLM support was negatively correlated with 1) low birth weight (Ncounties = 1,445) and 2) mortalities (Ncounties = 409) among African American infants. Given salient, intergroup, policy debates tied to antiracism, the present research also examined associations among White Americans. In the tested model, BLM marches were not meaningfully related to rates of low birth weight among White American infants (Ncounties = 2,930). However, BLM support was negatively related to mortalities among White American infants (Ncounties = 862). Analyses controlled for structural indicators of income inequality, implicit/explicit bias, voting behavior, prior low birth weight/infant mortality rates, and demographic characteristics. Theory/applied implications of antiracism being linked to nonnegative and positive infant health associations tied to both marginalized and dominant social groups are discussed.


Asunto(s)
Antiracismo , Racismo , Humanos , Lactante , Recién Nacido , Peso al Nacer , Negro o Afroamericano , Población Negra , Mortalidad Infantil , Recién Nacido de Bajo Peso
16.
Am J Hum Genet ; 110(5): 863-879, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-37146589

RESUMEN

Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death, outcomes ameliorated by rapid diagnosis and treatment. Here, we develop a high-throughput functional assay for human OTC and individually measure the impact of 1,570 variants, 84% of all SNV-accessible missense mutations. Comparison to existing clinical significance calls, demonstrated that our assay distinguishes known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. This functional stratification allowed us to identify score ranges corresponding to clinically relevant levels of impairment of OTC activity. Examining the results of our assay in the context of protein structure further allowed us to identify a 13 amino acid domain, the SMG loop, whose function appears to be required in human cells but not in yeast. Finally, inclusion of our data as PS3 evidence under the current ACMG guidelines, in a pilot reclassification of 34 variants with complete loss of activity, would change the classification of 22 from variants of unknown significance to clinically actionable likely pathogenic variants. These results illustrate how large-scale functional assays are especially powerful when applied to rare genetic diseases.


Asunto(s)
Hiperamonemia , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa , Ornitina Carbamoiltransferasa , Humanos , Sustitución de Aminoácidos , Hiperamonemia/etiología , Hiperamonemia/genética , Mutación Missense/genética , Ornitina Carbamoiltransferasa/genética , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/genética , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/terapia
17.
N Engl J Med ; 389(19): 1753-1765, 2023 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-37937777

RESUMEN

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).


Asunto(s)
Toxinas Botulínicas Tipo A , Temblor Esencial , Fármacos Neuromusculares , Temblor , Adulto , Humanos , Toxinas Botulínicas Tipo A/administración & dosificación , Toxinas Botulínicas Tipo A/efectos adversos , Toxinas Botulínicas Tipo A/uso terapéutico , Método Doble Ciego , Temblor Esencial/tratamiento farmacológico , Cabeza , Resultado del Tratamiento , Temblor/tratamiento farmacológico , Electromiografía/métodos , Inyecciones Intramusculares/métodos , Cefalea/inducido químicamente , Dolor de Cuello/inducido químicamente , Fármacos Neuromusculares/administración & dosificación , Fármacos Neuromusculares/efectos adversos , Fármacos Neuromusculares/uso terapéutico
18.
Nat Immunol ; 15(10): 895-9, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25232810

RESUMEN

Vaccines can have nonspecific effects through their modulation of responses to infections not specifically targeted by the vaccine. However, lack of knowledge about the underlying immunological mechanisms and molecular cause-and-effect relationships prevent use of this potentially powerful early-life intervention to its greatest benefit. The World Health Organization has identified investigations into the molecular basis of nonspecific vaccine effects as a research priority.


Asunto(s)
Medicina Preventiva/métodos , Salud Pública/métodos , Vacunación/métodos , Vacunas/administración & dosificación , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Evaluación de Resultado en la Atención de Salud/tendencias , Guías de Práctica Clínica como Asunto , Medicina Preventiva/normas , Medicina Preventiva/tendencias , Salud Pública/normas , Salud Pública/tendencias , Vacunación/normas , Vacunación/tendencias , Vacunas/inmunología , Organización Mundial de la Salud
19.
Nature ; 586(7831): 757-762, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33057194

RESUMEN

De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.


Asunto(s)
Análisis Mutacional de ADN , Análisis de Datos , Bases de Datos Genéticas , Conjuntos de Datos como Asunto , Atención a la Salud/estadística & datos numéricos , Discapacidades del Desarrollo/genética , Enfermedades Genéticas Congénitas/genética , Estudios de Cohortes , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/diagnóstico , Europa (Continente) , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Mutación de Línea Germinal/genética , Haploinsuficiencia/genética , Humanos , Masculino , Mutación Missense/genética , Penetrancia , Muerte Perinatal , Tamaño de la Muestra
20.
Nature ; 583(7818): 752-759, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32728242

RESUMEN

Cytosine DNA methylation is essential for mammalian development but understanding of its spatiotemporal distribution in the developing embryo remains limited1,2. Here, as part of the mouse Encyclopedia of DNA Elements (ENCODE) project, we profiled 168 methylomes from 12 mouse tissues or organs at 9 developmental stages from embryogenesis to adulthood. We identified 1,808,810 genomic regions that showed variations in CG methylation by comparing the methylomes of different tissues or organs from different developmental stages. These DNA elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. During late stages of fetal development, non-CG methylation accumulated within the bodies of key developmental transcription factor genes, coinciding with their transcriptional repression. Integration of genome-wide DNA methylation, histone modification and chromatin accessibility data enabled us to predict 461,141 putative developmental tissue-specific enhancers, the human orthologues of which were enriched for disease-associated genetic variants. These spatiotemporal epigenome maps provide a resource for studies of gene regulation during tissue or organ progression, and a starting point for investigating regulatory elements that are involved in human developmental disorders.


Asunto(s)
Metilación de ADN , Epigenoma , Feto/embriología , Feto/metabolismo , Animales , Animales Recién Nacidos , Cromatina/genética , Cromatina/metabolismo , Enfermedad/genética , Regulación hacia Abajo , Elementos de Facilitación Genéticos/genética , Represión Epigenética , Femenino , Silenciador del Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Anotación de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Análisis Espacio-Temporal
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