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Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and Aβ generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.

Alzheimer’s disease (AD) poses a growing global health challenge as populations age. Recent research highlights the crucial role of peripheral immunity in AD pathogenesis. This review explores how blood-brain barrier disruption allows peripheral immune cells to infiltrate the central nervous system (CNS), worsening neuroinflammation and disease progression. We examine recent findings on interactions between peripheral immune cells and CNS-resident microglia, forming a self-perpetuating inflammatory cycle leading to neuronal dysfunction. Moreover, this review emphasizes recent developments in the dysregulation of immune factors from both the periphery and CNS, and their impact on AD progression. With ongoing research and development of new therapeutic strategies, this review underscores the importance of modulating interactions between the peripheral immune system and CNS in AD therapy.

BACKGROUND: Praziquantel (PZQ) is an effective pesticide against monogeneans. Its pharmacokinetics in fish may be affected by water environment and temperature. The present study was designed to compare the pharmacokinetics, tissue distribution, and elimination of PZQ in freshwater-acclimated grass carp and brackish water cultured grass carp. Plasma and tissue PZQ concentrations were determined after a single 10 mg/kg oral PZQ dose. RESULTS: The datas of plasma and tissues drug concentration was calculated by the software SPSS 13.0. According to the One-Way ANOVA, the results showed that the salinity had a significant effect on the drug concentration of plasma (p < 0.01), muscle (p < 0.01), liver (p < 0.01) and kidney (p < 0.01) in the all sampling time points between the brackish water grass carps and the freshwater grass carps, wherein, PZQ plasma and tissue concentrations in the brackish water group were constantly lower than that in the freshwater group. The peak PZQ levels of plasma, muscle, liver, and kidneys in the brackish water group were 0.76 μg/ml, 0.51 μg/g, 2.7 μg/g, and 2.99 μg/g, respectively; and that in the freshwater group were 0.91 μg/ml, 0.62 μg/g, 3.87 μg/g, and 3.39 μg/g, respectively. The elimination half-lives (t₁/₂ᵦ) in plasma and all tissues of the freshwater group were significantly longer than that in the brackish water group. The elimination half-lives (t₁/₂ᵦ) of plasma, muscle, liver and kidneys in brackish water grass carps were 56.46, 36.17, 15.31, and 132.64 h, respectively; and that in the freshwater grass carps were 71.15, 44.88, 23.86, and 150.23 h, respectively. CONCLUSION: These findings indicate that water environment affects the tissue distribution and elimination of PZQ in grass carps, the elimination in brackish water grass carps is more rapid than that in fresh water grass carps and tissue concentrations of brackish water grass carps are lower than that in freshwater grass carps after orally administrating the same dosage at the same water temperature. We speculate that the main excretion pathway of the drug is through renal elimination, and the decreased kidney function in brackish water grass carps is likely responsible for the considerable difference in pharmacokinetics between the two groups of grass carps.

Our purpose of this study was to investigate the value of ultrasound combined with disposable cervical dilating stick and lidocaine in hysteroscopic intrauterine device (IUD) removal in postmenopausal women. Ninety-six postmenopausal women who requested IUD removal in our hospital from March 2020 to March 2022 were selected and randomly divided into a control group (48 cases) and a study group (48 cases) according to random number table method, with the control group undergoing conventional hysteroscopic IUD removal and the study group undergoing hysteroscopic IUD removal with ultrasound combined with a single-use cervical dilator rod and lidocaine. The time of IUD removal, subjective comfort evaluation scale (SECS) scores, treatment compliance, quality of life scale (SF-36) scores, IUD removal results, hospital anxiety and depression scale (HAD) scores and complications were compared between the two groups. The ring removal time of the study group was shorter than that of the control group, the postoperative SECS and SF-36 scores were higher than those of the control group, the compliance rate and the excellent and good rate of ring removal efficacy were higher than those of the control group, the postoperative HAD score was lower than that of the control group, and the incidence rate of complications was lower than that of the control group (P < .05). In hysteroscopic IUD removal, ultrasound combined with single-use cervical dilation sticks and lidocaine can gently soften and dilate the cervix in a short time, shortening the procedure time and reducing pain. The procedure is simplified, rapid, safe and has a high success rate.

β2-Microglobulin (β 2 M) is an amyloidogenic protein. β 2 M coaggregates with β-amyloid (Aβ) in the brains of patients with Alzheimer’s disease and enhances Aβ deposition. β 2 M is essential for Aβ neurotoxicity in vivo, and neutralization of pathogenetic β 2 M–Aβ aggregates ameliorates the amyloid pathology and cognitive deficits associated with disease in a mouse model.

Extensive studies indicate that β-amyloid (Aβ) aggregation is pivotal for Alzheimer’s disease (AD) progression; however, cumulative evidence suggests that Aβ itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of β 2 -microglobulin (β 2 M) and Aβ that trigger neurodegeneration in AD. β 2 M, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of β 2 M aggravates amyloid pathology independent of MHC class I, and coaggregation with β 2 M is essential for Aβ neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated β 2 M depletion mitigates AD-associated neuropathology, and inhibition of β 2 M–Aβ coaggregation with a β 2 M-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify β 2 M as an essential factor for Aβ neurotoxicity and a potential target for treating AD. Zhao et al. identified β 2 -microglobulin (β 2 M) as an essential factor driving β-amyloid (Aβ) neurotoxicity and cognitive impairment in mouse models of Alzheimer’s disease (AD) and implicated targeting β 2 M–Aβ coaggregation as a strategy for AD therapeutics.

Objective The aim of this study was to evaluate the predictive value of the monocyte-to-high-density lipoprotein ratio (MHR) in Kawasaki disease (KD) complicated with coronary artery lesions (CALs) and to construct a nomogram prediction model. Methods The medical records of KD inpatients diagnosed in the Department of Pediatrics of Lanzhou University Second Hospital from May 2015 to September 2021 were retrospectively analyzed. ROC curves were applied to evaluate the predictive value of MHR in KD complicated with CALs, and logistic regression analysis was used to screen independent risk factors. We constructed a nomogram model and performed internal validation. Results A total of 568 KD patients were enrolled in the study. MHR was significantly higher in KD patients complicated with CALs and was identified as an independent risk factor for CALs (OR: 1.604, 95% CI: 1.292–1.990). The area under the ROC curve for MHR in predicting CALs was 0.661. The C-index of the nomogram model constructed by incorporating MHR was 0.725 (95% CI: 0.682–0.768), and the calibration curve revealed good agreement between the predicted and actual probabilities. Conclusions MHR may not be suitable as a single biomarker to predict the occurrence of CALs, but the nomogram model constructed in combination with other independent risk factors had acceptable predictive performance. Impact The inflammatory response plays an important role in the pathogenesis of Kawasaki disease. The monocyte-to-high-density lipoprotein ratio is a novel systemic inflammation marker. The monocyte-to-high-density lipoprotein ratio is an independent risk factor for Kawasaki disease complicated with coronary artery lesions. The nomogram established by incorporating the monocyte-to-high-density lipoprotein ratio has satisfactory predictive performance for coronary artery lesion formation.

Alzheimer's disease (AD) poses a growing global health challenge as populations age. Recent research highlights the crucial role of peripheral immunity in AD pathogenesis. This review explores how blood-brain barrier disruption allows peripheral immune cells to infiltrate the central nervous system (CNS), worsening neuroinflammation and disease progression. We examine recent findings on interactions between peripheral immune cells and CNS-resident microglia, forming a self-perpetuating inflammatory cycle leading to neuronal dysfunction. Moreover, this review emphasizes recent developments in the dysregulation of immune factors from both the periphery and CNS, and their impact on AD progression. With ongoing research and development of new therapeutic strategies, this review underscores the importance of modulating interactions between the peripheral immune system and CNS in AD therapy.

Cognition presents evolutionary research with one of its greatest challenges. Cognitive evolution has been explained at the proximate level by shifts in absolute and relative brain volume and at the ultimate level by differences in social and dietary complexity. However, no study has integrated the experimental and phylogenetic approach at the scale required to rigorously test these explanations. Instead, previous research has largely relied on various measures of brain size as proxies for cognitive abilities. We experimentally evaluated these major evolutionary explanations by quantitatively comparing the cognitive performance of 567 individuals representing 36 species on two problem-solving tasks measuring self-control. Phylogenetic analysis revealed that absolute brain volume best predicted performance across species and accounted for considerably more variance than brain volume controlling for body mass. This result corroborates recent advances in evolutionary neurobiology and illustrates the cognitive consequences of cortical reorganization through increases in brain volume. Within primates, dietary breadth but not social group size was a strong predictor of species differences in self-control. Our results implicate robust evolutionary relationships between dietary breadth, absolute brain volume, and self-control. These findings provide a significant first step toward quantifying the primate cognitive phenome and explaining the process of cognitive evolution.

Background. Although several studies have examined the association between chronic kidney disease (CKD) and hyperuricemia (HUA), the direction of the association remains unclear. We aimed to investigate whether there was a bidirectional association between them. Methods. The present study was conducted in three analyses. Analysis I included 25,433 participants free of HUA at baseline to evaluate the associations between CKD and estimated glomerular filtration rate (eGFR) with incident HUA. Analysis II had 28,422 participants free of CKD at baseline to analyze the relationships between HUA and serum uric acid (sUA) with new-onset CKD. Cox proportional hazards regression models were applied to evaluate the association involved in Analysis I and II. Analysis III included 31,028 participants with complete data and further dissected the bidirectional association between sUA and eGFR using cross-lag models. Results. New-onset HUA and CKD were observed in the first round of the follow-up study among 1597 and 1212 participants, respectively. A significantly higher risk of HUA was observed in individuals with CKD compared to individuals without CKD (HR = 1.58, 95% CI: 1.28–1.95). The adjusted HRs (95% CIs) of HUA were 3.56 (2.50–5.05) for the participants in the group of eGFR less than 60 mL·min−1·1.73 m−2, 1.61 (1.42–1.83) for those in the group of eGFR between 60 and 90 mL·min−1·1.73 m−2, and 1.74 (1.42–2.14) for those in the group of eGFR more than 120 mL·min−1·1.73 m−2, compared with the group of eGFR between 90 and 120 mL·min−1·1.73 m−2. A higher risk of CKD was also observed in individuals with HUA compared to individuals without HUA (HR = 1.28, 95% CI: 1.12–1.47). Compared with the first quintile of sUA, the adjusted HR (95% CI) of CKD was 1.24 (1.01–1.51) for the participants in the fourth quantile. There was a bidirectional relationship between sUA and eGFR, with the path coefficients (ρ1 = −0.024, p < 0.001) from baseline eGFR to follow-up sUA and the path coefficients (ρ2 = −0.015, p = 0.002) from baseline sUA to follow-up eGFR. Conclusions. The present study indicated that CKD and HUA were closely associated, and there was a bidirectional relationship between sUA and eGFR.