RESUMEN
BACKGROUND: Müllerian duct anomalies (MDAs) are congenital developmental disorders that present as a series of abnormalities within the reproductive tracts of females. Genetic factors are linked to MDAs and recent advancements in whole-exome sequencing (WES) provide innovative perspectives in this field. However, relevant mechanism has only been investigated in a restricted manner without clear elucidation of respective observations. METHODS: Our previous study reported that 2 of 12 patients with MDAs harbored the CHD1L variant c.348-1G>C. Subsequently, an additional 85 MDAs patients were recruited. Variants in CHD1L were screened through the in-house database of WES performed in the cohort and two cases were identified. One presented with partial septate uterus with left renal agenesis and the other with complete septate uterus, duplicated cervices and longitudinal vaginal septum. The pathogenicity of the discovered variants was further assessed by molecular dynamics simulation and various functional assays. RESULTS: Ultimately, two novel heterozygous CHD1L variants, including a missense variant c.956G>A (p.R319Q) and a nonsense variant c.1831C>T (p.R611*) were observed. The variants were absent in 100 controls. Altogether, the contribution yield of CHD1L to MDAs was calculated as 4.12% (4/97). All three variants were assessed as pathogenic through various functional analysis. The splice-site variant c.348-1G>C resulted in a 11 bp sequence skipping in exon 4 of CHD1L and led to nonsense mediated decay of its transcripts. Unlike WT CHD1L, the truncated R611* protein mislocalized to the cytoplasm, abolish the ability of CHD1L to promote cell migration and failed to interact with PARP1 owing to the loss of macro domain. The R319Q variant exhibited conformational disparities and showed abnormal protein recruitment behavior through laser microirradiation comparing with the WT CHD1L. All these variants impaired the CHD1L function in DNA damage repair, thus participating in MDAs. CONCLUSIONS: The current study not only expands the mutational spectrum of CHD1L in MDAs but determines three variants as pathogenic according to ACMG guidelines with reliable functional evidence. Additionally, the impairment in DNA damage repair is an underlying mechanism involved in MDAs.
Asunto(s)
ADN Helicasas , Proteínas de Unión al ADN , Conductos Paramesonéfricos , Femenino , Humanos , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Secuenciación del Exoma , Conductos Paramesonéfricos/anomalías , Mutación , Mutación MissenseRESUMEN
Weaning results in intestinal dysfunction, mucosal atrophy, transient anorexia, and intestinal barrier defects. In this study, the effect of prodigiosin (PG) on the intestinal inflammation of weaned rats was investigated by using 1H-NMR spectroscopy and biochemistry indexes to regulate the intestinal metabolism. After administration for 14 days, the body mass of the PG group was increased by 1.29- and 1.26-fold compared with those of the control and alcohol groups, respectively, using a dose of 200 µg PG·kg-1 body weight per day. PG increased organic acid content and decreased moisture, pH values, and free ammonia in feces. In addition, PG alleviated the intestinal inflammation of weaned rats. The analysis of 1H-NMR signal peak attribution and the model validation of metabolic data of feces contents showed that PG significantly affected the metabolism of small molecular compounds in the intestinal tract of weaned rats. This study presents the promising alternative of using PG to alleviate intestinal inflammation effectively in the intestinal tract of weaned rats.
Asunto(s)
Animales , Masculino , Ratas , Prodigiosina/efectos adversos , Destete , Bioquímica/clasificación , Espectroscopía de Protones por Resonancia Magnética/métodos , Inflamación/clasificación , Anorexia , Dosificación/efectos adversos , Concentración de Iones de Hidrógeno , Metabolismo/efectos de los fármacosRESUMEN
BACKGROUND: Timely access to emergency cardiac care and survival is partly dependent on early recognition of heart attack symptoms and immediate action by calling emergency services. We assessed public recognition of major heart attack symptoms and knowledge to call 9-1-1 for an acute event. METHODS: Data are from the 2001 Behavioral Risk Factor Surveillance System, a state-based telephone survey. Participants (n = 61,018) in 17 states and the U.S. Virgin Islands indicated whether the following were heart attack symptoms: pain or discomfort in the jaw, neck, back; feeling weak, lightheaded, faint; chest pain or discomfort; sudden trouble seeing in 1 or both eyes (false symptom); pain or discomfort in the arms or shoulder; shortness of breath. Participants also indicated their first action if someone was having a heart attack. RESULTS: Most persons (95%) recognized chest pain as a heart attack symptom. However, only 11% correctly classified all symptoms and knew to call 9-1-1 when someone was having a heart attack. Symptom recognition and the need to call 9-1-1 was lower among men than women, persons of various ethnic groups than whites, younger and older persons than middle-aged persons, and persons with less education. Persons with high blood pressure, high cholesterol, diabetes mellitus, or prior heart attack or stroke were not appreciably more likely to recognize heart attack symptoms than were persons without these conditions. CONCLUSIONS: Public health efforts are needed to increase recognition of the major heart attack symptoms in both the general public and groups at high risk for an acute event.