ABSTRACT
A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.
ABSTRACT
Background: Numerous studies demonstrated the risk factors for urological complications in patients with diabetes before sodium-glucose co-transporter 2 inhibitor (SGLT2i) became commercially available. This study aimed to comprehensively investigate urological characteristics in patients with type 2 diabetes (T2DM) after SGLT2i became commercially available. Methods: We examined 63 outpatients with T2DM suspected of bacteriuria based on urinary sediment examinations. Urine cultures were performed, and lower urinary tract symptoms (LUTS) were assessed via questionnaires. Patients with bacteriuria were assessed using ultrasonography to measure post-void residual volume (PVR). Utilizing demographic and laboratory data, a random forest algorithm predicted LUTS, bacteriuria, and symptomatic bacteriuria (SB). Results: Thirty-two patients had LUTS and 31 had bacteriuria. High-density lipoprotein cholesterol level was crucial in predicting LUTS, while age was crucial in predicting bacteriuria. In predicting SB among patients with bacteriuria, creatinine level and estimated glomerular filtration rate were crucial. Our models had high predictive accuracy for LUTS (area under the curve [AUC] = 0.846), followed by bacteriuria (AUC = 0.770) and SB (AUC = 0.938) in receiver operating characteristic curve analysis. These predictors were previously reported as risk factors for urological complications. Although SGLT2i use was not an important predictor in our study, all SGLT2i users with bacteriuria had SB and exhibited higher PVR compared to non-SGLT2i users with bacteriuria. Conclusion: This study's random forest model highlighted distinct essential predictors for each urological condition. The predictors were consistent before and after SGLT2i became commercially available. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00687-1.
ABSTRACT
H3.1 histone is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, as a new component of duplicating nucleosomes. Here, we found that p53 is necessary to secure the normal behavior and modification of H3.1 in the nucleus during the G1/S phase, in which p53 increases C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) levels and decreases enhancer of zeste homolog 2 (EZH2) levels in the H3.1 interactome. In the absence of p53, H3.1 molecules tended to be tethered at or near the nuclear envelope (NE), where they were predominantly trimethylated at lysine 27 (H3K27me3) by EZH2, without forming nucleosomes. This accumulation was likely caused by the high affinity of H3.1 toward phosphatidic acid (PA). p53 reduced nuclear PA levels by increasing levels of CTDNEP1, which activates lipin to convert PA into diacylglycerol. We moreover found that the cytosolic H3 chaperone HSC70 attenuates the H3.1-PA interaction, and our molecular imaging analyses suggested that H3.1 may be anchored around the NE after their nuclear entry. Our results expand our knowledge of p53 function in regulation of the nuclear behavior of H3.1 during the G1/S phase, in which p53 may primarily target nuclear PA and EZH2.