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Previous studies have found the potential role of gout or hyperuricemia in subsequent development of Alzheimer's disease (AD) but reported inconsistent results. We conducted the current meta-analysis to evaluate whether an association exists between gout/ hyperuricemia and AD. We systematically searched PubMed and EMBASE for the published cohort studies that measured the risk of AD in subject with gout/ hyperuricemia up to May 20, 2023. Data extraction was employed by two authors independently. Rev Man 5.3 and Stata 15.0 software were used to calculate the relative ratio (RR) or hazard ratio (HR) for including studies. Subgroup analysis was performed to assess the sources of heterogeneity. A random-effects model was adopted when heterogeneity was present. The funnel plot, Begg's test, and and Egger's test were used to assess publication bias. After rigorous screening, seven eligible studies were included in the final analyses. Pooled results indicated that gout or hyperuricemia decreases the risk of AD (RR: 0.69, 95% CI: 0.64∼0.72), with a high heterogeneity of 93%. Subgroup analyses showed that regional distribution was the source of heterogeneity. Egger's and Begg's tests as well as visual inspection of funnel plot suggested no publication bias in the studies. The findings suggested that gout or hyperuricemia might have a protective effect against AD. This negative correlation should be verified by more cohort studies due to the existence of substantial heterogeneity.

Purpose: To analysis the basic characteristics, comorbidities and prognosis of elderly patients with Late‐Onset Epilepsy (LOE) in the Eastern Region of Hefei, Anhui. Methods: This study finally selected 304 participants who were enrolled at the Second People's Hospital of Hefei between January 2018 and December 2023. The analysis included baseline characteristics, etiology, seizure types, findings from electroencephalography (EEG) and cranial magnetic resonance imaging, comorbidities, anti‐seizure medication (ASM) regimens, and follow‐up of seizure control outcomes within one year. Continuous variables were presented as mean ± standard deviation (SD) or median (IQR) based on normality. Categorical variables were compared using the chi‐square test with Bonferroni correction for multiple comparisons. Results: According to our study, ischemic cerebral infarction (41.12%) was the main factor for LOE in elderly patients among structural factors. Focal seizure (92.76%) was the main seizure type. The most common comorbidity was ischemic cerebral infarction (88.16%), followed by cerebral hemorrhage (22.37%). During the one year follow‐up, the overall effectiveness of seizure control was 73.03%, and 49.34% patients were seizure‐free. The one‐year treatment efficacy of patients with comorbid psychiatric disorders, cognitive impairment or dementia were significantly lower than that of patients without these comorbidities. In terms of medications, sodium valproate accounted for the most at 86.84%. Conclusion: Structural factors are the main etiology for LOE in elderly patients, with ischemic cerebral infarction accounting for the highest proportion. Focal seizure was the main seizure type. Patients with comorbid psychiatric disorders, cognitive impairment or dementia may have poor one‐year treatment efficacy.    

Secretory-pathway Ca 2+ -ATPases (SPCAs) play critical roles in maintaining Ca 2+ homeostasis, but the exact mechanism of SPCAs-mediated Ca 2+ transport remains unclear. Here, we determined six cryo-electron microscopy (cryo-EM) structures of human SPCA1 (hSPCA1) in a series of intermediate states, revealing a near-complete conformational cycle. With the aid of molecular dynamics simulations, these structures offer a clear structural basis for Ca 2+ entry and release in hSPCA1. We found that hSPCA1 undergoes unique conformational changes during ATP binding and phosphorylation compared to other well-studied P-type II ATPases. In addition, we observed a conformational distortion of the Ca 2+ -binding site induced by the separation of transmembrane helices 4L and 6, unveiling a distinct Ca 2+ release mechanism. Particularly, we determined a structure of the long-sought CaE2P state of P-type IIA ATPases, providing valuable insights into the Ca 2+ transport cycle. Together, these findings enhance our understanding of Ca 2+ transport by hSPCA1 and broaden our knowledge of P-type ATPases.

Cryo-electron microscopy (cryo-EM) visualizes the atomic structure of macromolecules that are embedded in vitrified thin ice at their close-to-native state. However, the homogeneity of ice thickness, a key factor to ensure high image quality, is poorly controlled during specimen preparation and has become one of the main challenges for high-resolution cryo-EM. Here we found that the uniformity of thin ice relies on the surface flatness of the supporting film, and developed a method to use ultraflat graphene (UFG) as the support for cryo-EM specimen preparation to achieve better control of vitreous ice thickness. We show that the uniform thin ice on UFG improves the image quality of vitrified specimens. Using such a method we successfully determined the three-dimensional structures of hemoglobin (64 kDa), α-fetoprotein (67 kDa) with no symmetry, and streptavidin (52 kDa) at a resolution of 3.5 Å, 2.6 Å and 2.2 Å, respectively. Furthermore, our results demonstrate the potential of UFG for the fields of cryo-electron tomography and structure-based drug discovery. This paper shows that the uniformity of vitreous ice thickness relies on the surface flatness of the supporting film, and presents a method to use ultraflat graphene as the support for cryo-EM specimen preparation.

Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters. Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. Here, the authors present cryo-EM structures of hMRP5 in different states, showing that hMRP5 can be autoinhibited by a short peptide from its N-terminal tail, which prevents the entry of substrates into hMRP5’s transport pathway.

Objective To investigate the effects of brain‐derived neurotrophic factor (BDNF) overexpression in the ventrolateral periaqueductal gray (vlPAG) on behavioral changes in epilepsy–migraine comorbid rats. Method We used an adeno‐associated virus (AAV)‐mediated vector to supplement BDNF in the vlPAG area prior to the establishment of a pilocarpine‐nitroglycerin (Pilo‐NTG) combination‐induced comorbid model of epilepsy and migraine. Seizure‐ and migraine‐related behaviors were analyzed. Cell loss and apoptosis in vlPAG were detected through hematoxylin‐eosin (HE) and TUNEL staining. Immunofluorescence staining analyses were employed to detect expressions of BDNF and its receptor, tyrosine kinase B (TrkB), in vlPAG. Immunohistochemical staining was conducted to detect expressions of c‐Fos and calcitonin gene‐related peptide (CGRP) in the trigeminal nucleus caudalis (TNC) and trigeminal ganglion (TG). Results Comparing to control group, AAV–BDNF injected comorbid group showed lower pain sensitivity, scratching head, and spontaneous seizures accompanied by the downregulation of c‐Fos labeling neurons and CGRP immunoreactivity in the TNC and TG. However, these changes were still significantly higher in the comorbid group than those in both epilepsy and migraine groups under the same intervention. Conclusion These data demonstrated that supplying BDNF to vlPAG may protect structural and functional abnormalities in vlPAG and provide an antiepileptic and analgesic therapy. The important finding is that BDNF overexpression in the vlPAG region highly significantly decreases the frequency and duration of spontaneous seizures as well as pain sensitivity in the epilepsy–migraine comorbid rat. This suggested that protective intervention for vlPAG may help to reduce the risk of nociceptive behavior caused by epileptic seizures, and we believe the underlying mechanism is significant.

Serine/threonine-protein phosphatases with EF-hands (PPEFs) are a family of highly conserved proteins implicated in cancer and neuronal degeneration. The initially characterized member, Drosophila melanogaster retinal degeneration C (RDGC) contains a calmodulin (CaM)-interacting extended-IQ motif and a Ca 2+ -binding EF-like/EF-hand tandem. However, the molecular regulation of PPEF is poorly understood. In this study, we use cryogenic-electron microscopy to delineate the structures of the RDGC/CaM holoenzyme. In the absence of Ca 2+ , CaM and the EF-like/EF-hand tandem allow the extended-IQ motif to block substrate access to the catalytic sites, constituting an auto-inhibitory mechanism. Upon Ca 2+ binding, CaM and the EF-like/EF-hand tandem drive drastic conformational changes in the extended-IQ motif to unlock the catalytic sites. This dual Ca 2+ -sensor-mediated activation is evolutionarily conserved in mammals. This study provides mechanistic insight into the molecular activation of PPEFs, paving the way for the development of therapeutic strategies for PPEF-related human diseases. PPEFs are highly conserved phosphatases. Here, authors use cryo-EM to solve the holoenzyme structures of the initially characterized PPEF family member, Drosophila RDGC, with/without Ca 2+ , uncovering a dual Ca 2+ -sensor-mediated activation mechanism.

This study assessed the influence of glymphatic system (GS) dysfunction on cognitive decline in patients with late-onset epilepsy (LOE) and comorbid chronic insomnia utilizing diffusion tensor imaging along the perivascular space (DTI-ALPS). Clinical data were collected from 42 elderly LOE patients, 17 with and 25 without chronic insomnia, as well as from 22 healthy controls (HCs) matched for age and sex. Simoa assays were performed to quantify Aβ42 and Aβ40 as plasma biomarkers of age-related neuropathology, and associations between the DTI-ALPS index and age, seizure frequency and duration, Sleep Quality Index (PSQI), Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAMA), Mini-Mental State Examination (MMSE), and Aβ42:Aβ40 ratio (Aβ42/40) were assessed using Spearman correlation tests and multivariate logistic regression models. Both DTI-ALPS index and Aβ42/40 were significantly lower among LOE patients compared to HCs, and post-hoc analysis revealed even lower Aβ42/40 and DTI-ALPS index values among LOE patients with comorbid chronic insomnia compared to HCs and LOE patients without chronic insomnia. The DTI-ALPS index was negatively correlated with age, disease duration, PSQI score, and HAMA score, and positively correlated with Aβ42/40 and MMSE score among LOE patients according to Spearman's tests. Multivariate linear regression revealed independent associations of the DTI-ALPS index with age, MMSE score, Aβ42/40, and PSQI after adjusting for vascular risk factors, sex, and education. These results suggest that the GS is dysfunctional in LOE and may exacerbate sleep disruption and cognitive impairments.

Megabase-sized DNA is crucial to modern genomics research of all organisms. Among the preparation methods developed, the nuclei method is the simplest and most widely used for preparing high-quality megabase-sized DNA from divergent organisms. In this method, nuclei are first isolated by physically grinding the source tissues. The nontarget cytoplast organellar genomes and metabolites are removed by centrifugation and washing, thus maximizing the utility of the method and substantially improving the digestibility and clonability of the resultant DNA. The nuclei are then embedded in an agarose matrix containing numerous pores, allowing the access of restriction enzymes while preventing the DNA from physical shearing. DNA is extracted from the nuclei, purified and subsequently manipulated in the agarose matrix. Here we describe the nuclei method that we have successfully used to prepare high-quality megabase-sized DNA from hundreds of plant, animal, fish, insect, algal and microbial species. The entire protocol takes ∼3 d.

Objective To investigate the association of sex and neutrophil-to-lymphocyte ratio (NLR) differences with short-term adverse outcomes in patients with non-valvular atrial fibrillation (NVAF)-related cardioembolic stroke (CES). Methods Patients hospitalized in the Department of Neurology at Hefei Hospital Affiliated to Anhui Medical University between January 2023 and August 2024 with NVAF-related CES were retrospectively enrolled. Outcomes were assessed at the time of discharge or on the 14th day after onset of CES based on the modified Rankin Scale (mRS), with a score ≤ 2 defined as a good outcome and a score > 2 defined as an adverse outcome. NLR was calculated based on laboratory tests performed within 24 h of admission. Multivariable logistic regression analysis was used to identify independent risk factors. Additive interaction models (Relative Excess Risk due to Interaction [RERI], Attributable Proportion [AP], Synergy Index [SI]) and multiplicative interaction models were employed to quantify interaction effects. Bootstrap analysis was used to assess the combined effect risk. Results A total of 196 patients were enrolled, including 109 females (55.61%). Females were older (82.00 (75.00, 85.00) vs 79.00 (72.00, 83.00) years, P = 0.047) and had lower NLR (5.16 ± 2.93 vs 6.36 ± 5.17, P = 0.057),but a higher risk of adverse outcomes compared to males (55.96% vs 42.53%, P = 0.062). Multivariable logistic regression analysis showed that higher baseline NIHSS score [ OR (95%CI) 1.088 (1.023 ~ 1.157)], high NLR[ OR (95%CI) 1.279 (1.111 ~ 1.472)], and female[ OR (95%CI) 2.288 (1.017 ~ 5.149)] as independent risk factors for short-term adverse outcomes. Additive interaction analysis (Model3: RERI = 0.892, AP = 0.276, SI = 1.665) and multiplicative interaction analysis using continuous NLR [ OR (95%CI) 1.688 (1.206 ~ 2.363)] indicated a positive synergistic effect between sex and NLR. Joint effect analysis showed that female patients with higher NLR had a 15.2-fold increased risk of adverse outcomes compared to male patients with lower NLR [ OR (95%CI) 15.158 (5.303 ~ 92.832)]. Conclusions Baseline NIHSS score, NLR, and female sex are independent predictors for short-term adverse outcomes in NVAF-related CES. Our findings suggest a potential synergistic interaction between sex and NLR, particularly on the multiplicative scale, indicating that the risk of adverse outcomes may be disproportionately higher in female patients with elevated NLR. Further clinical research should focus on monitoring inflammatory status in female patients and exploring personalized interventions.