RESUMEN
Endonuclease VIII-like protein 1 (NEIL1) is a DNA glycosylase involved in initiating the base excision repair pathway, the major cellular mechanism for repairing DNA base damage. Here, we have purified the major E3 ubiquitin ligases from human cells responsible for regulation of NEIL1 by ubiquitylation. Interestingly, we have identified two enzymes that catalyse NEIL1 polyubiquitylation, Mcl-1 ubiquitin ligase E3 (Mule) and tripartite motif 26 (TRIM26). We demonstrate that these enzymes are capable of polyubiquitylating NEIL1 in vitro, and that both catalyse ubiquitylation of NEIL1 within the same C-terminal lysine residues. An siRNA-mediated knockdown of Mule or TRIM26 leads to stabilisation of NEIL1, demonstrating that these enzymes are important in regulating cellular NEIL1 steady state protein levels. Similarly, a mutant NEIL1 protein lacking residues for ubiquitylation is more stable than the wild type protein in vivo We also demonstrate that cellular NEIL1 protein is induced in response to ionising radiation (IR), although this occurs specifically in a Mule-dependent manner. Finally we show that stabilisation of NEIL1, particularly following TRIM26 siRNA, contributes to cellular resistance to IR. This highlights the importance of Mule and TRIM26 in maintaining steady state levels of NEIL1, but also those required for the cellular DNA damage response.
Asunto(s)
Daño del ADN , ADN Glicosilasas/metabolismo , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , ADN Glicosilasas/genética , Regulación de la Expresión Génica , Células HeLa , Humanos , Unión Proteica , Tolerancia a Radiación/genética , Radiación Ionizante , Proteínas Recombinantes de Fusión , Proteínas de Motivos Tripartitos , Proteínas Supresoras de Tumor , Ubiquitina-Proteína Ligasas/aislamiento & purificación , UbiquitinaciónAsunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/fisiopatología , Encéfalo/patología , Encéfalo/fisiopatología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Autopsia , Encéfalo/metabolismo , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Progresión de la Enfermedad , Diagnóstico Precoz , Predisposición Genética a la Enfermedad/genética , Humanos , Imagen por Resonancia Magnética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Placa Amiloide/diagnóstico , Placa Amiloide/genética , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Proteínas tau/análisis , Proteínas tau/metabolismoRESUMEN
White-nose syndrome (WNS) is an infectious disease that disrupts hibernation in bats, leading to premature exhaustion of fat stores. Though we know WNS does impact reproduction in hibernating female bats, we are unsure how these impacts are exacerbated by local climate factors. We compiled data from four southeastern U.S. states and used generalized linear mixed effects models to compare effects of WNS, pre-hibernation climate variables, and winter duration on the number of reproductive females in species across the range of WNS susceptibility. We predicted we would see a decline in the number of reproductive females in WNS-susceptible species, with the effect exaggerated by longer winter durations and pre-hibernation climate variables that lead to reductions in foraging. We found that the number of reproductive females in WNS-susceptible species was positively correlated with pre-hibernation local climate conditions conducive to foraging; however, WNS-susceptible species experienced an overall decline with the presence of WNS and as winter duration increased. Our long-term dataset provides evidence that pre-hibernation climate, specifically favorable summer weather conditions for foraging, greatly influences the reproduction, regardless of WNS status.
Asunto(s)
Quirópteros , Clima , Hibernación , Reproducción , Estaciones del Año , Animales , Femenino , Quirópteros/fisiología , Hibernación/fisiología , Micosis/veterinaria , Micosis/epidemiología , Reproducción/fisiologíaRESUMEN
BACKGROUND: This study analyzed the overall incidence of delirium, comorbid conditions, injury patterns, and pharmacological risk factors for the development of delirium in an alert, geriatric trauma population. METHODS: IRB-approved, prospective, consecutive cohort series at two Southeastern Level 1 trauma centers from June 11 to August 15, 2023. Delirium was assessed using the Confusion Assessment Method (CAM) score. Comorbidities and medications were detailed from electronic medical records. Inclusion criteria: age ≥55, GCS ≥14, and ICU admission for trauma. Patients on a ventilator were excluded. Data was analyzed using SPSS version 28 (Armonk, NY: IBM Corp). RESULTS: In total, 196 patients met inclusion criteria. Incidences of delirium for Hospital 1 (n = 103) and Hospital 2 (n = 93) were 15.5% and 12.9%, respectively, with an overall incidence of 14.3% and with no statistical differences between hospitals (P = .599). CAD, CKD, dementia, stroke history, and depression were statistically significant risk factors for developing delirium during ICU admission. Inpatient SSRI/SNRIs, epinephrine/norepinephrine, and lorazepam were significant risk factors. Injury patterns, operative intervention, and use of lidocaine infusions and gabapentin were not statistically significant in delirium development. Using binary linear regression (BLR) analysis, independent risk factors for delirium were dementia, any stage CKD, home SSRI/SRNI prescription, any spine injury and cerebrovascular disease, or injury. DISCUSSION: Comorbidities of CAD, CHF, CKD, and depression, and these medications: home lorazepam and ICU epinephrine/norepinephrine statistically are more common in patients developing delirium. Dementia, CKD, home SSRI/SRNI and stroke/cerebrovascular disease/injury, and spine injuries are independent predictors by BLR.