RESUMEN
BACKGROUND: White blood cell (WBC) count increases during pregnancy, necessitating reliable reference intervals for assessing infections and pregnancy-related complications. This study aimed to establish comprehensive reference intervals for WBC counts during pregnancy. METHODS: The analysis included 17,737 pregnant women, with weekly WBC count measurements from pre-pregnancy to postpartum. A threshold linear regression model determined reference intervals, while Harris and Boyd's test partitioned the intervals. RESULTS: WBC count exhibited a significant increase during pregnancy, characterized by a rapid rise before 7 weeks of gestation, followed by a plateau. Neutrophils primarily drove this increase, showing a similar pattern. The threshold regression model and Harris and Boyd's test supported partitioned reference intervals for WBC counts: 4.0-10.0 × 10^9/L for < = 2 weeks, 4.7-11.9 × 10^9/L for 3-5 weeks, and 5.7-14.4 × 10^9/L for > = 6 weeks of gestation. These reference intervals identified pregnant women with high WBC counts, who had a higher incidence of pregnancy-related complications including placenta previa, oligohydramnios, secondary uterine inertia, and intrauterine growth restriction. CONCLUSION: This study establishes comprehensive reference intervals for WBC counts during pregnancy. Monitoring WBC counts is clinically relevant, as elevated levels are associated with an increased risk of infection and pregnancy-related complications.
Asunto(s)
Neutrófilos , Oligohidramnios , Embarazo , Humanos , Femenino , Recuento de Leucocitos , Retardo del Crecimiento Fetal , Modelos LinealesRESUMEN
Despite numerous observational studies indicating an increased risk of cutaneous melanoma (CM) due to childhood sunburn, no studies have established a definitive cause-and-effect relationship. Therefore, our objective was to employ a Mendelian randomization (MR) design to explore a possible causal association between childhood sunburn and the risk of CM. To investigate the causal relationship between childhood sunburn and CM, we used large-scale genetic summary-level data from genome-wide association studies (GWAS), including childhood sunburn (n = 346,955) and CM (n = 262,288), building upon previous observational studies. In the analysis, we mainly used the inverse-variance weighted (IVW) method of the random effects model, supplemented by the weighted median method and MR-Egger method. The results of the IVW method demonstrated that genetically predicted childhood sunburn was significantly associated with higher odds of CM, with an odds ratio (OR) of 2.418 (95%CI, 1.426-4.099; p = .001). The weighted median method and MR-Egger regression also demonstrated directionally similar results (both p < .05). Furthermore, both the funnel plot and the MR-Egger intercepts showed the absence of directional pleiotropy between childhood sunburn and CM. Our study offers potential evidence linking genetically predicted childhood sunburn with CM, underscoring the need for individuals with a history of childhood sunburn to be extra vigilant regarding the occurrence of CM.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Quemadura Solar , Humanos , Melanoma/epidemiología , Melanoma/genética , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Quemadura Solar/complicaciones , Quemadura Solar/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización MendelianaRESUMEN
Background: The increasing incidence of diabetes mellitus (DM) and osteoporosis have different effects on prognosis. The two often co-occur, so we aimed to investigate whether DM and osteoporosis have an effect on all-cause death and whether DM and osteoporosis have a synergistic effect. Methods: This study analyzed 18,658 subjects from five cycles of the National Health and Nutrition Examination Survey (NHANES). The primary endpoint was all-cause death. The subjects were divided into four groups based on the presence or absence of DM and osteoporosis. Survival curves and Cox regression analysis based on NHANES recommended weights were used to assess the risk of all-cause death between the diseased and non-diseased groups and to calculate additive interactions to assess whether there was a synergistic effect between diabetes and osteoporosis. Results: The group with DM and osteoporosis had the lowest survival rate. After full adjustment for confounders, patients with DM alone had a 30% higher risk of all-cause death compared with those without DM and osteoporosis (HR: 1.30, 95%CI: 1.09-1.55). Patients with osteoporosis alone had a 67% higher risk of all-cause death (HR: 1.67, 95%CI:1.16-2.43) and patients with combined DM and osteoporosis had a 127% higher risk of all-cause death (HR:2.27, 95%CI: 1.57-3.27). There was an additive interaction between DM and osteoporosis [RERI (95%CI): 1.03(0.55-1.50)] and excess mortality risk of 38% [AP (95% CI) 0.38(0.30-0.46)]. Conclusions: There might be a synergistic effect of DM and osteoporosis on all-cause mortality, and patients with both conditions have a higher risk of death.
Asunto(s)
Diabetes Mellitus , Osteoporosis , Humanos , Estados Unidos/epidemiología , Estudios de Cohortes , Encuestas Nutricionales , Diabetes Mellitus/diagnóstico , Osteoporosis/complicaciones , Osteoporosis/epidemiología , Tasa de SupervivenciaRESUMEN
Background: Although numerous observational studies have indicated a potential association between autoimmune diseases, such as rheumatoid arthritis (RA) and alopecia areata (AA), the research reports lack a clear causal relationship. In this study, our objective is to utilize the Mendelian randomization (MR) design to examine the potential causal association between RA and AA. Methods: To investigate the causal relationship between RA and AA, we utilized large-scale gene aggregation data from genome-wide association studies (GWAS), including RA (n=58,284) and AA (n=361,822) based on previous observational studies. In our analysis, we mainly employed the inverse variance-weighted (IVW) method of the random effects model, supplemented by the weighted median (WM) method and the MR Egger method. Results: The findings from the IVW methods revealed a significant association between genetically predicted RA and an increased likelihood of AA, as evidenced by an odds ratio of 1.21 (95%CI = 1.11-1.32; P < 0.001. Both the WM method and MR-Egger regression consistently showed significant directional outcomes (Both P < 0.05), indicating a robust association between RA and AA. Additionally, both the funnel plot and the MR-Egger intercepts provided evidence of the absence of directional pleiotropy, suggesting that the observed association is not influenced by other common genetic factors. Conclusions: The results of the study suggest a possible link between genetically predicted RA and AA. This finding highlights the importance for individuals diagnosed with RA to remain vigilant and aware of the potential development of AA. Regular monitoring and early detection can be crucial in managing and addressing this potential complication.
Asunto(s)
Alopecia Areata , Artritis Reumatoide , Humanos , Alopecia Areata/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Artritis Reumatoide/genéticaRESUMEN
The transmission and maintenance of genetic information in eukaryotic cells relies on the faithful duplication of the entire genome. In each round of division, excessive replication origins are licensed, with only a fraction activated to give rise to bi-directional replication forks in the context of chromatin. However, it remains elusive how eukaryotic replication origins are selectively activated. Here we demonstrate that O-GlcNAc transferase (OGT) enhances replication initiation by catalyzing H4S47 O-GlcNAcylation. Mutation of H4S47 impairs DBF4-dependent protein kinase (DDK) recruitment on chromatin, causing reduced phosphorylation of the replicative helicase mini-chromosome maintenance (MCM) complex and compromised DNA unwinding. Our short nascent-strand sequencing results further confirm the importance of H4S47 O-GlcNAcylation in origin activation. We propose that H4S47 O-GlcNAcylation directs origin activation through facilitating MCM phosphorylation, and this may shed light on the control of replication efficiency by chromatin environment.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas de Saccharomyces cerevisiae , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Origen de Réplica , Replicación del ADN , Cromatina/metabolismo , Mamíferos/genéticaRESUMEN
AIMS: The M3 muscarinic acetylcholine receptor (M3R) is a G protein-coupled receptor that is expressed in cases of non-small cell lung cancer (NSCLC). Previous studies demonstrated that M3R antagonists reduce the proliferation of NSCLC. However, how antagonists inhibit the NSCLC proliferation and migration is still little known. This study aims to investigate the mechanism of M3R involved in the growth of NSCLC. MAIN METHODS: The CRISPR/Cas9 was used to knock out (KO) the M3R gene. A real-time cell analyzer (RTCA) was used to record the proliferation of NSCLC cells. The migration and cell cycle of NSCLC cells were evaluated with scratch test and flow cytometry (FCM), respectively. Antibody microarray analysis was performed to detect the expression of proteins after antagonizing M3R and knocking out of M3R, subsequently some of these important proteins were verified by western blot. KEY FINDINGS: The proliferation and migration of NSCLC cells were inhibited by M3R antagonist R2-8018 and knocking out of M3R. Antagonism or knocking out of M3R reduced the phosphorylation of EGFR. Moreover, c-Src and ß-arrestin-1 are involved in the mechanism of how the inhibition of M3R affects EGFR in NSCLC. Further study demonstrated that PI3K/AKT and MEK/ERK signal pathways are involved in M3R-induced EGFR transactivation in NSCLC, and the molecules involved in the cell cycle progression and migration of NSCLC cells were identified. SIGNIFICANCE: This further understanding of the relationship between M3R and NSCLC facilitates the design of therapeutic strategy with M3R antagonist as an adjuvant drug for NSCLC treatment.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Receptor Muscarínico M3/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/farmacología , Receptor Muscarínico M3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The sigma-1 receptor is a 223 amino acids molecular chaperone with a single transmembrane domain. It is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes. By chaperone-mediated interactions with ion channels, G-protein coupled receptors and cell-signaling molecules, the sigma-1 receptor performs broad physiological and pharmacological functions. Despite sigma-1 receptors have been confirmed to regulate various types of ion channels, the relationship between the sigma-1 receptor and N-type Ca2+ channel is still unclear. Considering both sigma-1 receptors and N-type Ca2+ channels are involved in intracellular calcium homeostasis and neurotransmission, we undertake studies to explore the possible interaction between these two proteins. In the experiment, we confirmed the expression of the sigma-1 receptors and the N-type calcium channels in the cholinergic interneurons (ChIs) in rat striatum by using single-cell reverse transcription-polymerase chain reaction (scRT-PCR) and immunofluorescence staining. N-type Ca2+ currents recorded from ChIs in the brain slice of rat striatum was depressed when sigma-1 receptor agonists (SKF-10047 and Pre-084) were administrated. The inhibition was completely abolished by sigma-1 receptor antagonist (BD-1063). Co-expression of the sigma-1 receptors and the N-type calcium channels in Xenopus oocytes presented a decrease of N-type Ca2+ current amplitude with an increase of sigma-1 receptor expression. SKF-10047 could further depress N-type Ca2+ currents recorded from oocytes. The fluorescence resonance energy transfer (FRET) assays and co-immunoprecipitation (Co-IP) demonstrated that sigma-1 receptors and N-type Ca2+ channels formed a protein complex when they were co-expressed in HEK-293T (Human Embryonic Kidney -293T) cells. Our results revealed that the sigma-1 receptors played a negative modulation on N-type Ca2+ channels. The mechanism for the inhibition of sigma-1 receptors on N-type Ca2+ channels probably involved a chaperone-mediated direct interaction and agonist-induced conformational changes in the receptor-channel complexes on the cell surface.
RESUMEN
The water channel aquaporin 4 (AQP4) is abundantly expressed in astrocytes and provides a mechanism by which water permeability of the plasma membrane can be regulated. Evidence suggests that AQP4 is associated with glutamate transporter-1 (GLT-1) for glutamate clearance and contributes to morphine dependence. Previous studies show that AQP4 deficiency changed the mu opioid receptor expression and opioid receptors' characteristics as well. In this study, we focused on whether AQP4 could form macromolecular complex with GLT-1 and mu opioid receptor (MOR) and participates in morphine dependence. By using immunofluorescence staining, fluorescence resonance energy transfer, and co-immunoprecipitation, we demonstrated that AQP4 forms protein complexes with GLT-1 and MOR in both brain tissue and primary cultured astrocytes. We then showed that the C-terminus of AQP4 containing the amino acid residues 252 to 323 is the site of interaction with GLT-1. Protein kinase C, activated by morphine, played an important role in regulating the expression of these proteins. These findings may help to reveal the mechanism that AQP4, GLT-1, and MOR form protein complex and participate in morphine dependence, and deeply understand the reason that AQP4 deficiency maintains extracellular glutamate homeostasis and attenuates morphine dependence, moreover emphasizes the function of astrocyte in morphine dependence.