Downregulation of Ripk1 and Nsf mediated by CRISPR-CasRx ameliorates stroke volume and neurological deficits after ischemia stroke in mice.

Necroptosis is implicated in the pathogenesis of ischemic stroke. However, the mechanism underlying the sequential recruitment of receptor-interacting protein kinase 1 (RIPK1) and N-ethylmaleimide-sensitive fusion ATPase (NSF) in initiating necroptosis remains poorly understood, and the role of NSF in ischemic stroke is a subject of controversy. Here, we utilized a recently emerging RNA-targeting CRISPR system known as CasRx, delivered by AAVs, to knockdown Ripk1 mRNA and Nsf mRNA around the ischemic brain tissue. This approach resulted in a reduction in infarct and edema volume, as well as an improvement in neurological deficits assessed by Bederson score, RotaRod test, and Adhesive removal test, which were achieved by RIPK1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein signaling pathway involved in neuronal necroptosis. In conclusion, the downregulation of Ripk1 mRNA and Nsf mRNA mediated by CRISPR-CasRx holds promise for future therapeutic applications aimed at ameliorating cerebral lesions and neurological deficits following the ischemic stroke.

Quantitative electroencephalography (qEEG), apolipoprotein A-I (APOA-I), and apolipoprotein epsilon 4 (APOE ɛ4) alleles for the diagnosis of mild cognitive impairment and Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is the most common type of dementia. Amnestic mild cognitive impairment (aMCI), a pre-dementia stage is an important stage for early diagnosis and intervention. This study aimed to investigate the diagnostic value of qEEG, APOA-I, and APOE ɛ4 allele in aMCI and AD patients and found the correlation between qEEG (Delta + Theta)/(Alpha + Beta) ratio (DTABR) and different cognitive domains. METHODS: All participants were divided into three groups: normal controls (NCs), aMCI, and AD, and all received quantitative electroencephalography (qEEG), neuropsychological scale assessment, apolipoprotein epsilon 4 (APOE ɛ4) alleles, and various blood lipid indicators. Different statistical methods were used for different data. RESULTS: The cognitive domains except executive ability were all negatively correlated with DTABR in different brain regions while executive ability was positively correlated with DTABR in several brain regions, although without statistical significance. The consequences confirmed that the DTABR of each brain area were related to MMSE, MoCA, instantaneous memory, and the language ability (p < 0.05), and the DTABR in the occipital area was relevant to all cognitive domains (p < 0.01) except executive function (p = 0.272). Also, occipital DTABR was most correlated with language domain when tested by VFT with a moderate level (r = 0.596, p < 0.001). There were significant differences in T3, T5, and P3 DTABR between both AD and NC and aMCI and NCs. As for aMCI diagnosis, the maximum AUC was achieved when using T3 combined with APOA-I and APOE ε4 (0.855) and the maximum AUC was achieved when using T5 combined with APOA-I and APOE ε4 (0.889) for AD diagnosis. CONCLUSION: These findings highlight that APOA-I, APOE ɛ4, and qEEG play an important role in aMCI and AD diagnosis. During AD continuum, qEEG DTABR should be taken into consideration for the early detection of AD risk.

Research on digital tool in cognitive assessment: a bibliometric analysis.

Objective: The number of research into new cognitive assessment tools has increased rapidly in recent years, sparking great interest among professionals. However, there is still little literature revealing the current status and future trends of digital technology use in cognitive assessment. The aim of this study was to summarize the development of digital cognitive assessment tools through the bibliometric method. Methods: We carried out a comprehensive search in the Web of Science Core Collection to identify relevant papers published in English between January 1, 2003, and April 3, 2023. We used the subjects such as "digital," "computer," and "cognitive," and finally 13,244 related publications were collected. Then we conducted the bibliometric analysis by Bibliometrix" R-package, VOSviewer and CiteSpace software, revealing the prominent countries, authors, institutions, and journals. Results: 11,045 articles and 2,199 reviews were included in our analyzes. The number of annual publications in this field was rising rapidly. The results showed that the most productive countries, authors and institutions were primarily located in economically developed regions, especially the North American, European, and Australian countries. Research cooperation tended to occur in these areas as well. The application of digital technology in cognitive assessment appealed to growing attention during the outbreak of the COVID-19 epidemic. Conclusion: Digital technology uses have had a great impact on cognitive assessment and health care. There have been substantial papers published in these areas in recent years. The findings of the study indicate the great potential of digital technology in cognitive assessment.

Genetic Insights into Obesity and Brain: Combine Mendelian Randomization Study and Gene Expression Analysis.

As a major public-health concern, obesity is imposing an increasing social burden around the world. The link between obesity and brain-health problems has been reported, but controversy remains. To investigate the relationship among obesity, brain-structure changes and diseases, a two-stage analysis was performed. At first, we used the Mendelian-randomization (MR) approach to identify the causal relationship between obesity and cerebral structure. Obesity-related data were retrieved from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and the UK Biobank, whereas the cortical morphological data were from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. Further, we extracted region-specific expressed genes according to the Allen Human Brian Atlas (AHBA) and carried out a series of bioinformatics analyses to find the potential mechanism of obesity and diseases. In the univariable MR, a higher body mass index (BMI) or larger visceral adipose tissue (VAT) was associated with a smaller global cortical thickness (pBMI = 0.006, pVAT = 1.34 × 10-4). Regional associations were found between obesity and specific gyrus regions, mainly in the fusiform gyrus and inferior parietal gyrus. Multivariable MR results showed that a greater body fat percentage was linked to a smaller fusiform-gyrus thickness (p = 0.029) and precuneus surface area (p = 0.035). As for the gene analysis, region-related genes were enriched to several neurobiological processes, such as compound transport, neuropeptide-signaling pathway, and neuroactive ligand-receptor interaction. These genes contained a strong relationship with some neuropsychiatric diseases, such as Alzheimer's disease, epilepsy, and other disorders. Our results reveal a causal relationship between obesity and brain abnormalities and suggest a pathway from obesity to brain-structure abnormalities to neuropsychiatric diseases.

Mechanism of ERK/CREB pathway in pain and analgesia.

Research has long centered on the pathophysiology of pain. The Transient Receiver Potential (TRP) protein family is well known for its function in the pathophysiology of pain, and extensive study has been done in this area. One of the significant mechanisms of pain etiology and analgesia that lacks a systematic synthesis and review is the ERK/CREB (Extracellular Signal-Regulated Kinase/CAMP Response Element Binding Protein) pathway. The ERK/CREB pathway-targeting analgesics may also cause a variety of adverse effects that call for specialized medical care. In this review, we systematically compiled the mechanism of the ERK/CREB pathway in the process of pain and analgesia, as well as the potential adverse effects on the nervous system brought on by the inhibition of the ERK/CREB pathway in analgesic drugs, and we suggested the corresponding solutions.

Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer's disease.

Background: Several blood-based biomarkers are promising to be used in the diagnosis of Alzheimer's disease (AD) including Aß42/40, p-tau181, and neurofilament light (NfL). The kidney is associated with the clearance of proteins. It is crucial to evaluate the effect of renal function on the diagnostic performance of these biomarkers before clinical implementation, which is important for the establishment of reference ranges and the interpretation of results. Methods: This study is a cross-sectional analysis based on ADNI cohort. Renal function was determined by the estimated glomerular filtration rate (eGFR). Plasma Aß42/40 was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma p-tau181 and NfL were analyzed by Single Molecule array (Simoa) technique. [18F] florbetapir-PET (Aß-PET) was used as a reference standard to estimate the brain amyloid load. The cutoff of Aß-PET positivity was defined as ≥1.11. Linear regression models were used to investigate the associations of continuous eGFR with each plasma biomarker separately. The diagnostic accuracies of plasma biomarkers for positive brain amyloid across different renal function groups were analyzed by Receiver operating characteristic (ROC) curve. Youden-Index was used to determine the cutoff levels. Results: A total of 645 participants were included in this study. The levels and diagnostic performance of Aß42/40 were not affected by renal function. eGFR was only found negatively associated with p-tau181 levels in Aß-PET negetive sample (ß = -0.09, p = 0.039). eGFR was found negatively associated with NfL levels both in whole sample and Aß-PET stratified groups (ß = -0.27, p < 0.001 in whole sample; ß = -0.28, p = 0.004 in A-; ß = -0.27, p < 0.001 in A+). The diagnostic accuracies of p-tau181 and NfL were not affected by renal function. But the cutoff values of p-tau181 and NfL changed in participants with mild to moderate eGFR decline compared to participants with normal eGFR. Conclusion: Plasma Aß42/40 was a robust biomarker for AD which was not affected by renal function. Plasma p-tau181 and NfL levels were affected by renal function, specific reference values of them should be considered in populations with different renal function stages.

Identification of hsa-miR-365b-5p's role in Alzheimer's disease: A combined analysis of miRNA and mRNA microarrays.

BACKGROUND: Alzheimer's disease is a prevalent health problem with a heavy global burden. Definitely diagnosed by autopsy, the clear mechanism of Alzheimer's disease pathogenesis process needs to be illustrated. MicroRNAs are suggested to be involved in many diseases. We aimed to investigate the role of microRNA in Alzheimer's disease. METHODS: We attempted to discover the role of microRNA in Alzheimer's disease by microarray bioinformatics analysis using autopsy sample data from the GEO database. Temporal cortex samples were included in this study. Bioinformatics analyses and visualization were processed based on R. RESULTS: After filtering out significantly differential expressed microRNAs and genes, enrichment analyses of both microRNAs and genes were conducted, respectively. Then, we constructed a transcription factor-microRNA-mRNA network and a protein-protein interaction network. In parallel, we used the receiver operating characteristic curve to evaluate the diagnostic value of microRNA. Based on the evidence, we finally identified hsa-miR-365b-5p as a key target in Alzheimer's disease. CONCLUSIONS: Hsa-miR-365b-5p act as a key target in Alzheimer's disease. It regulates Alzheimer's disease pathogenesis process via neuroinflammation, Wnt and oxidative stress pathway which provides a potential target for Alzheimer's disease treatment.

Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: A systematic review and meta-analysis.

Objective: Detecting plasma tau biomarkers used to be impossible due to their low concentrations in blood samples. Currently, new high-sensitivity assays made it a reality. We performed a systematic review and meta-analysis in order to test the accuracy of plasma tau protein in diagnosing Alzheimer's disease (AD) or mild cognitive impairment (MCI). Methods: We searched PubMed, Cochrane, Embase and Web of Science databases, and conducted correlation subgroup analysis, sensitivity analysis and publication bias analysis using R Programming Language. Results: A total of 56 studies were included. Blood t-tau and p-tau levels increased from controls to MCI to AD patients, and showed significant changes in pairwise comparisons of AD, MCI and normal cognition. P-tau217 was more sensitive than p-tau181 and p-tau231 in different cognition periods. In addition, ultrasensitive analytical platforms, immunomagnetic reduction (IMR), increased the diagnostic value of tau proteins, especially the diagnostic value of t-tau. Conclusion: Both t-tau and p-tau are suitable AD blood biomarkers, and p-tau217 is more sensitive than other tau biomarkers to differentiate MCI and AD. Detection techniques also have an impact on biomarkers' results. New ultrasensitive analytical platforms of IMR increase the diagnostic value of both t-tau and p-tau biomarkers. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, registration number: CRD42021264701.

Identification of TLR2 as a Key Target in Neuroinflammation in Vascular Dementia.

Vascular dementia (VaD) is the second most common cause of dementia. At present, precise molecular processes of VaD are unclear. We attempted to discover the VaD relevant candidate genes, enrichment biological processes and pathways, key targets, and the underlying mechanism by microarray bioinformatic analysis. We selected GSE122063 related to the autopsy samples of VaD for analysis. We first took use of Weighted Gene Co-expression Network Analysis (WGCNA) to achieve modules related to VaD and hub genes. Second, we filtered out significant differentially expressed genes (DEGs). Third, significant DEGs then went through Geno Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Fourth, Gene Set Enrichment Analysis (GSEA) was performed. At last, we constructed the protein-protein interaction (PPI) network. The results showed that the yellow module had the strongest correlation with VaD, and we finally identified 21 hub genes. Toll-like receptor 2 (TLR2) was the top hub gene and was strongly correlated with other possible candidate genes. In total, 456 significant DEGs were filtered out and these genes were found to be enriched in the Toll receptor signaling pathway and several other immune-related pathways. In addition, Gene Set Enrichment Analysis results showed that similar pathways were significantly over-represented in TLR2-high samples. In the PPI network, TLR2 was still an important node with high weight and combined scores. We concluded that the TLR2 acts as a key target in neuroinflammation which may participate in the pathophysiological process of VaD.

Relationship of Soluble Grape-Derived Proteins to Condensed Tannin Extractability during Red Wine Fermentation.

In red winemaking, the extractability of condensed tannins (CT) can vary considerably even under identical fermentation conditions, and several explanations for this phenomenon have been proposed. Recent work has demonstrated that grape pathogenesis-related proteins (PRPs) may limit retention of CT added to finished wines, but their relevance to CT extractability has not been evaluated. In this work, Vitis vinifera and interspecific hybrids (Vitis ssp.) from both hot and cool climates were vinified under small-scale, controlled conditions. The final CT concentration in wine was well modeled from initial grape tannin and juice protein concentrations using the Freundlich equation (r2= 0.686). In follow-up experiments, separation and pretreatment of juice by bentonite, heating, freezing, or exogenous tannin addition reduced protein concentrations in juices from two grape varieties. The bentonite treatment also led to greater wine CT for one of the varieties, indicating that prefermentation removal of grape protein may be a viable approach to increasing wine CT.

Low-income parents' views on the redesign of well-child care.

OBJECTIVE: To examine the perspectives of low-income parents on redesigning well-child care (WCC) for children aged 0 to 3 years, focusing on possible changes in 3 major domains: providers, locations, and formats. METHODS: Eight focus groups (4 English and 4 Spanish) were conducted with 56 parents of children aged 6 months to 5 years, recruited through a federally qualified health center. Discussions were recorded, transcribed, and analyzed by using the constant comparative method of qualitative analysis. RESULTS: Parents were mostly mothers (91%), nonwhite (64% Latino, 16% black), and <30 years of age (66%) and had an annual household income of <$35000 (96%). Parents reported substantial problems with WCC, focusing largely on limited provider access (especially with respect to scheduling and transportation) and inadequate behavioral/developmental services. Most parents endorsed nonphysician providers and alternative locations and formats as desirable adjuncts to usual physician-provided, clinic-based WCC. Nonphysician providers were viewed as potentially more expert in behavioral/developmental issues than physicians and more attentive to parent-provider relationships. Some alternative locations for care (especially home and day care visits) were viewed as creating essential context for providers and dramatically improving family convenience. Alternative locations whose sole advantage was convenience (eg, retail-based clinics), however, were viewed more skeptically. Among alternative formats, group visits in particular were seen as empowering, turning parents into informal providers through mutual sharing of behavioral/developmental advice and experiences. CONCLUSIONS: Low-income parents of young children identified major inadequacies in their WCC experiences. To address these problems, they endorsed a number of innovative reforms that merit additional investigation for feasibility and effectiveness.

Molecular signatures of antinuclear antibodies-contributions of heavy chain CDR residues.

A database of the Ig heavy chains of 143 anti-ssDNA, 103 anti-dsDNA and 23 anti-nucleosome antinuclear antibodies (ANAs) was constructed, with no clonal overlap, gleaning from published literature. In comparison to the Kabat database of antibodies (N>3600), ANAs (total=269) demonstrated several significant changes, particularly in the incidence of charged or polar residues, in their CDR regions. In particular, anti-dsDNA ANAs differed significantly from anti-ssDNA ANAs in having (a) more 'D' residues at H31 and more 'Y' residues at H33, in CDR1, (b) significantly different distributions of charged or polar residues at H53, H55 and H56 of CDR2, and (c) more 'R' residues at H95-H100 of CDR3. Whereas, the differences in CDR1 and CDR3 are likely to characterize anti-dsDNA ANAs encoded by all VH families, the sequence differences in CDR2 are likely to be VH family specific. Finally, among anti-dsDNA ANAs, there was an enrichment of VH1/J558 germline genes (notably, VH 45.21.1), which bear germline-encoded amino acid residues in their CDR regions that may potentially facilitate nuclear antigen binding. This ANA heavy chain database thus constitutes a useful resource for analyzing the molecular requirements for nuclear antigen reactivity.