CSF neurofilament light chain profiling and quantitation in neurological diseases.

Neurofilament light chain is an established marker of neuroaxonal injury that is elevated in CSF and blood across various neurological diseases. It is increasingly used in clinical practice to aid diagnosis and monitor progression and as an outcome measure to assess safety and efficacy of disease-modifying therapies across the clinical translational neuroscience field. Quantitative methods for neurofilament light chain in human biofluids have relied on immunoassays, which have limited capacity to describe the structure of the protein in CSF and how this might vary in different neurodegenerative diseases. In this study, we characterized and quantified neurofilament light chain species in CSF across neurodegenerative and neuroinflammatory diseases and healthy controls using targeted mass spectrometry. We show that the quantitative immunoprecipitation-tandem mass spectrometry method developed in this study strongly correlates to single-molecule array measurements in CSF across the broad spectrum of neurodegenerative diseases and was replicable across mass spectrometry methods and centres. In summary, we have created an accurate and cost-effective assay for measuring a key biomarker in translational neuroscience research and clinical practice, which can be easily multiplexed and translated into clinical laboratories for the screening and monitoring of neurodegenerative disease or acute brain injury.

Evaluation of Exploratory Fluid Biomarker Results from a Phase 1 Senolytic Trial in Mild Alzheimer's Disease.

Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome measures. Our team recently published data from the first open-label trial to evaluate senolytics (dasatinib plus quercetin) in AD. After 12-weeks of intermittent treatment, we reported brain exposure to dasatinib, favorable safety and tolerability, and modest post-treatment changes in cerebrospinal fluid (CSF) inflammatory and AD biomarkers using commercially available assays. Herein, we present more comprehensive exploratory analyses of senolytic associated changes in AD relevant proteins, metabolites, lipids, and transcripts measured across blood, CSF, and urine. These analyses included mass spectrometry for precise quantification of amyloid beta (Aß) and tau in CSF; immunoassays to assess senescence associated secretory factors in plasma, CSF, and urine; mass spectrometry analysis of urinary metabolites and lipids in blood and CSF; and transcriptomic analyses relevant to chronic stress measured in peripheral blood cells. Levels of Aß and tau species remained stable. Targeted cytokine and chemokine analyses revealed treatment-associated increases in inflammatory plasma fractalkine and MMP-7 and CSF IL-6. Urinary metabolites remained unchanged. Modest treatment-associated lipid profile changes suggestive of decreased inflammation were observed both peripherally and centrally. Blood transcriptomic analysis indicated downregulation of inflammatory genes including FOS, FOSB, IL1ß, IL8, JUN, JUNB, PTGS2. These data provide a foundation for developing standardized outcome measures across senolytic studies and indicate distinct biofluid-specific signatures that will require validation in future studies. ClinicalTrials.gov: NCT04063124.

Global, regional, and national time trends in incidence for tuberculosis, 1990-2019: An age-period-cohort analysis for the Global Burden of Disease 2019 study.

BACKGROUND: Tuberculosis (TB) represents a significant global health concern, being the leading cause of mortality from a single infectious agent worldwide. The investigation of TB incidence and epidemiological trends is critical for evaluating the effectiveness of control strategies and identifying ongoing challenges. OBJECTIVES: This study presents the trend in TB incidence across 204 countries and regions over a 30-year period. METHODS: The study utilises data sourced from the Global Burden of Disease (GBD) database. The age cohort model and gender subgroup analysis were employed to estimate the net drift (overall annual percentage change), local drift (age annual percentage change), longitudinal age curve (expected age ratio), and cycle and cohort effect (relative risk of cycle and birth cohort) of TB incidence from 1990 to 2019. This approach facilitates the examination and differentiation of age, period, and cohort effects in TB incidence trends, potentially identifying disparities in TB prevention across different countries. RESULTS: Over the past three decades, a general downward trend in TB incidence has been observed in most countries. However, in 15 of the 204 countries, the overall incidence rate is still on the rise (net drift ≥0.0 %) or stagnant decline (≥-0.5 %). From 1990 to 2019, the net drift of tuberculosis mortality ranged from -2.2 % [95 % confidence interval (CI): -2.33, -2.05] in high Socio-demographic Index (SDI) countries to -1.7 % [95 % CI: -1.81, -1.62] in low SDI countries. In some below-average SDI countries,men in the birth cohort are at a disadvantage and at risk of deterioration, necessitating comprehensive TB prevention and treatment. CONCLUSIONS: While the global incidence of TB has declined, adverse period and cohort effects have been identified in numerous countries, raising questions about the adequacy of TB healthcare provision across all age groups. Furthermore, this study reveals gender disparities in TB incidence.

Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests.

With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-ß (Aß) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aß42/40 and p-tau181/Aß42. The primary and secondary outcomes were detection of brain Aß or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aß PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89-90% for Aß PET and 87-88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments.

Identifying the Interaction Between Tuberculosis and SARS-CoV-2 Infections via Bioinformatics Analysis and Machine Learning.

The number of patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 is still increasing. In the case of COVID-19 and tuberculosis (TB), the presence of one disease affects the infectious status of the other. Meanwhile, coinfection may result in complications that make treatment more difficult. However, the molecular mechanisms underpinning the interaction between TB and COVID-19 are unclear. Accordingly, transcriptome analysis was used to detect the shared pathways and molecular biomarkers in TB and COVID-19, allowing us to determine the complex relationship between COVID-19 and TB. Two RNA-seq datasets (GSE114192 and GSE163151) from the Gene Expression Omnibus were used to find concerted differentially expressed genes (DEGs) between TB and COVID-19 to identify the common pathogenic mechanisms. A total of 124 common DEGs were detected and used to find shared pathways and drug targets. Several enterprising bioinformatics tools were applied to perform pathway analysis, enrichment analysis and networks analysis. Protein-protein interaction analysis and machine learning was used to identify hub genes (GAS6, OAS3 and PDCD1LG2) and datasets GSE171110, GSE54992 and GSE79362 were used for verification. The mechanism of protein-drug interactions may have reference value in the treatment of coinfection of COVID-19 and TB.

Genetic variation and recombination analysis of the GP5 (GP5a) gene of PRRSV-2 strains in China from 1996 to 2022.

Porcine reproductive and respiratory syndrome virus (PRRSV) has been prevalent in China for more than 25 years and remains one of the most significant pathogens threatening the pig industry. The high rate of mutation and frequent recombination of PRRSV have exacerbated its prevalence, particularly with the emergence of highly pathogenic PRRSV (HP-PRRSV) has significantly increased the pathogenicity of PRRSV, posing a serious threat to the development of Chinese pig farming. To monitor the genetic variation of PRRSV-2 in China, the GP5 sequences of 517 PRRSV-2 strains from 1996 to 2022 were analyzed and phylogenetic trees were constructed. Furthermore, a total of 60 PRRSV strains, originating from various lineages, were carefully chosen for nucleotide and amino acid homologies analysis. The results showed that the nucleotide homologies of the PRRSV GP5 gene ranged from 81.4 to 100.0%, and the amino acid homologies ranged from 78.1 to 100.0%. Similarly, the PRRSV GP5a gene showed 78.0 ~ 100.0% nucleotide homologies and 70.2 ~ 100.0% amino acid homologies. Amino acid sequence comparisons of GP5 and GP5a showed that some mutations, such as substitutions, deletions, and insertions, were found in several amino acid sites in GP5, these mutations were primarily found in the signal peptide region, two highly variable regions (HVRs), and near two T-cell antigenic sites, while the mutation sites of GP5a were mainly concentrated in the transmembrane and intramembrane regions. Phylogenetic analysis showed that the prevalent PRRSV-2 strains in China were divided into lineages 1, 3, 5, and 8. Among these, strains from lineage 8 and lineage 1 are currently the main prevalent strains, lineage 5 and lineage 8 have a closer genetic distance. Recombination analysis revealed that one recombination event occurred in 517 PRRSV-2 strains, this event involved recombination between lineage 8 and lineage 1. In conclusion, this analysis enhances our understanding of the prevalence and genetic variation of PRRSV-2 in China. These findings provide significant insights for the development of effective prevention and control strategies for PRRS and serve as a foundation for future research in this field.

Research Progress on the Development of Porcine Reproductive and Respiratory Syndrome Vaccines.

Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious disease in the pig industry, but its pathogenesis is not yet fully understood. The disease is caused by the PRRS virus (PRRSV), which primarily infects porcine alveolar macrophages and disrupts the immune system. Unfortunately, there is no specific drug to cure PRRS, so vaccination is crucial for controlling the disease. There are various types of single and combined vaccines available, including live, inactivated, subunit, DNA, and vector vaccines. Among them, live vaccines provide better protection, but cross-protection is weak. Inactivated vaccines are safe but have poor immune efficacy. Subunit vaccines can be used in the third trimester of pregnancy, and DNA vaccines can enhance the protective effect of live vaccines. However, vector vaccines only confer partial protection and have not been widely used in practice. A PRRS vaccine that meets new-generation international standards is still needed. This manuscript provides a comprehensive review of the advantages, disadvantages, and applicability of live-attenuated, inactivated, subunit, live vector, DNA, gene-deletion, synthetic peptide, virus-like particle, and other types of vaccines for the prevention and control of PRRS. The aim is to provide a theoretical basis for vaccine research and development.

SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy.

OBJECTIVES: The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown. METHODS: We applied empagliflozin treatment to lupus-prone MRL/lpr mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. RESULTS: In MRL/lpr mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/lpr mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors. CONCLUSION: This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.

Research Progress on NSP11 of Porcine Reproductive and Respiratory Syndrome Virus.

Porcine reproductive and respiratory syndrome (PRRS) is a virulent infectious disease caused by the PRRS virus (PRRSV). The non-structural protein 11 (NSP11) of PRRSV is a nidovirus-specific endonuclease (NendoU), which displays uridine specificity and catalytic functions conserved throughout the entire NendoU family and exerts a wide range of biological effects. This review discusses the genetic evolution of NSP11, its effects on PRRSV replication and virulence, its interaction with other PRRSV and host proteins, its regulation of host immunity, the conserved characteristics of its enzyme activity (NendoU), and its diagnosis, providing an essential theoretical basis for in-depth studies of PRRSV pathogenesis and vaccine design.

CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer's disease.

Aggregated insoluble tau is one of two defining features of Alzheimer's disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates ('T').

Epstein-Barr Virus Envelope Glycoprotein gp110 Inhibits IKKi-Mediated Activation of NF-κB and Promotes the Degradation of ß-Catenin.

Epstein-Barr virus (EBV) infects host cells and establishes a latent infection that requires evasion of host innate immunity. A variety of EBV-encoded proteins that manipulate the innate immune system have been reported, but whether other EBV proteins participate in this process is unclear. EBV-encoded envelope glycoprotein gp110 is a late protein involved in virus entry into target cells and enhancement of infectivity. Here, we reported that gp110 inhibits RIG-I-like receptor pathway-mediated promoter activity of interferon-ß (IFN-ß) as well as the transcription of downstream antiviral genes to promote viral proliferation. Mechanistically, gp110 interacts with the inhibitor of NF-κB kinase (IKKi) and restrains its K63-linked polyubiquitination, leading to attenuation of IKKi-mediated activation of NF-κB and repression of the phosphorylation and nuclear translocation of p65. Additionally, gp110 interacts with an important regulator of the Wnt signaling pathway, ß-catenin, and induces its K48-linked polyubiquitination degradation via the proteasome system, resulting in the suppression of ß-catenin-mediated IFN-ß production. Taken together, these results suggest that gp110 is a negative regulator of antiviral immunity, revealing a novel mechanism of EBV immune evasion during lytic infection. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects almost all human beings, and the persistence of EBV in the host is largely due to immune escape mediated by its encoded products. Thus, elucidation of EBV's immune escape mechanisms will provide a new direction for the design of novel antiviral strategies and vaccine development. Here, we report that EBV-encoded gp110 serves as a novel viral immune evasion factor, which inhibits RIG-I-like receptor pathway-mediated interferon-ß (IFN-ß) production. Furthermore, we found that gp110 targeted two key proteins, inhibitor of NF-κB kinase (IKKi) and ß-catenin, which mediate antiviral activity and the production of IFN-ß. gp110 inhibited K63-linked polyubiquitination of IKKi and induced ß-catenin degradation via the proteasome, resulting in decreased IFN-ß production. In summary, our data provide new insights into the EBV-mediated immune evasion surveillance strategy.

CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer's disease.

Cerebrospinal fluid (CSF) amyloid-ß peptide (Aß)42/Aß40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer's disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aß42/Aß40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman's ρ = 0.69) than Aß42/Aß40 (ρ = -0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.

Mitigating the Associations of Kidney Dysfunction With Blood Biomarkers of Alzheimer Disease by Using Phosphorylated Tau to Total Tau Ratios.

Importance: Chronic kidney disease (CKD) has been associated with increased plasma concentrations of phosphorylated tau (p-tau) 217 and p-tau181, which potentially decreases their usefulness in the diagnostic workup of Alzheimer disease (AD). Objective: To investigate associations of CKD with plasma ratios of p-tau217 and p-tau181 to the corresponding unphosphorylated peptides in AD. Design, Setting, and Participants: This cross-sectional study included patients with mild cognitive impairment (cohort 1; enrollment in 2000-2005) and replication in cohort 2 from the Swedish BioFINDER-2 study, including both cognitively unimpaired individuals and those with cognitive impairment (enrollment in 2017-2022). All participants were from 2 memory clinics in Sweden and had plasma tau assessments and CKD status established within 6 months of plasma collection. Exposures: P-tau217 and p-tau181, unphosphorylated peptides (Tau212-221 and Tau181-190), and the ratios (pT217/T217 and pT181/T181) as well as estimated glomerular filtration rate (eGFR) as an indicator of CKD. Main Outcomes and Measures: Associations between plasma-soluble p-tau and CKD. Results: A total of 141 participants from cohort 1 (mean [SD] age, 72.2 [7.7] years; 82 [58.2%] women) and 332 participants from cohort 2 (172 with cognitive impairment and 160 cognitively unimpaired individuals; mean [SD] age, 69.8 [9.4] years; 169 [50.9%] women) were included. Higher eGFR was associated with increased levels of plasma p-tau217, p-tau181, Tau212-221, and Tau181-190 in individuals with cognitive impairment (cohort 1: R range, -0.24 to -0.59; P < .004; cohort 2: R range, -0.18 to -0.53; P < .02) and cognitively unimpaired individuals (cohort 2: R range, -0.44 to -0.50; P < .001). However, eGFR did not correlate with the pT217/T217 ratio in patients with cognitive impairment (cohort 1: R, -0.11; P = .19; cohort 2: R, -0.02; P = .78), and the correlations with pT217/T217 ratio were significantly attenuated in cognitively unimpaired individuals (difference: R, -0.14 [95% CI, -0.22 to -0.007]; P = .001). For p-tau217 and pT217/T217, the mean fold increases in amyloid-ß positive (Aß+) compared with Aß- groups ranged from 2.31 (95% CI, 1.86-2.77) to 4.61 (95% CI, 3.39-5.83) in participants with cognitive impairment and from 1.26 (95% CI, 0.98-1.55) to 1.27 (95% CI, 0.94-1.59) in cognitively unimpaired individuals and were clearly higher than the mean fold increases in those with CKD compared with those without CKD, ranging from 0.05 (95% CI, -0.28 to 0.38) to 0.72 (95% CI, 0.25-1.19) in participants with cognitive impairment and from 0.09 (95% CI, -0.08 to 0.26) to 0.36 (95% CI, 0.19-0.52) in cognitively unimpaired individuals. Conclusions and Relevance: In this study, CKD was associated with increased plasma levels of soluble tau, but for p-tau217 the associations were considerably lower than the association with Aß positivity. Importantly, the ratios, and especially pT217/T217, were less associated with CKD than p-tau forms alone and therefore are likely to more accurately reflect AD-related pathological changes.

Acute sleep loss decreases CSF-to-blood clearance of Alzheimer's disease biomarkers.

INTRODUCTION: Sleep deprivation increases cerebrospinal fluid (CSF) amyloid beta (Aß) and tau levels; however, sleep's effect on Aß and tau in plasma is unknown. METHODS: In a cross-over design, CSF Aß and tau concentrations were measured in five cognitively normal individuals who had blood and CSF collected every 2 hours for 36 hours during sleep-deprived and normal sleep control conditions. RESULTS: Aß40, Aß42, unphosphorylated tau threonine181 (T181), unphosphorylated tau threonine-217 (T217), and phosphorylated T181 (pT181) concentrations increased ∼35% to 55% in CSF and decreased ∼5% to 15% in plasma during sleep deprivation. CSF/plasma ratios of all Alzheimer's disease (AD) biomarkers increased during sleep deprivation while the CSF/plasma albumin ratio, a measure of blood-CSF barrier permeability, decreased. CSF and plasma Aß42/40, pT181/T181, and pT181/Aß42 ratios were stable longitudinally in both groups. DISCUSSION: These findings show that sleep loss alters some plasma AD biomarkers by lowering brain clearance mechanisms and needs to be taken into account when interpreting individual plasma AD biomarkers but not ratios.

Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease.

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-ß (Aß) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aß-status (i.e. abnormal CSF Aß42/40) at baseline; and 45 of these Aß-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aß status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835-0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642-0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320-0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aß or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aß-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.

CSF tau microtubule-binding region identifies pathological changes in primary tauopathies.

Despite recent advances in fluid biomarker research in Alzheimer's disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau275 and MTBR-tau282) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-MAPT and AD compared to control and other FTLD-tau (for example, Pick's disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau275 and MTBR-tau282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs.

Anti-diabetic effects of Inonotus obliquus extract in high fat diet combined streptozotocin-induced type 2 diabetic mice / Efectos antidiabéticos del extracto de Inonotus obliquus en ratones diabéticos tipo 2 inducidos por estreptozotocina combinada con una dieta rica en grasas

Introduction: type 2 diabetes (T2DM) is a complex disease affected by lifestyle and genetic factors. Although the drugs currently used to treat T2DM have certain curative effects, they still have some adverse side effects. Therefore, it is urgent to find new effective drugs with few side effects to cure T2DM. Objective: to study the role of Inonotus obliquus (IO) in diabetic model mice. Methods: we used high-fat diet (HFD) combined with streptozocin (STZ) to establish a diabetic mouse model. Mice were divided into non-high-fat diet group (ND), diabetes model group (HFD + STZ) and IO-treated diabetes model group (IO). The mice in the IO group were orally treated with IO (150 mg/kg) at 10 ml/kg for five weeks. Body weight, glucose level, food intake and water consumption, glucose tolerance and insulin tolerance were evaluated in all mice. The pathological sections of liver, kidney and pancreas were observed by hematoxylin-eosin staining. Results: after IO administration, the blood glucose level, water consumption, low-density lipoprotein (LDL) and triacylglycerol (TG) levels of mice decreased. Compared with the HFD + STZ group, the number of normal islet iiiiiiii cells increased and focal necrosis of the liver was significantly reduced in the IO administration group. Conclusions: IO reduced the levels of blood glucose, restored body weight, and enhanced insulin sensitivity along with insulin tolerance and glucose tolerance in diabetic mice. Additionally, IO also reversed HFD and STZ-induced organ injury. (AU)

Introducción: la diabetes mellitus tipo 2 (T2DM) es una enfermedad compleja influenciada por el estilo de vida y los factores genéticos. En la actualidad, aunque los medicamentos para la diabetes tipo 2 tienen cierto efecto curativo, todavía tienen algunos efectos secundarios. Por lo tanto, es urgente encontrar nuevos medicamentos para la diabetes tipo 2 que tengan un buen efecto curativo y menos efectos secundarios. Objetivo: estudiar el papel del Inonotus obliquus (IO) en ratones diabéticos. Métodos: se estableció un modelo de ratón diabético con dieta de alto contenido en grasas (HFD) y estreptozocina (STZ). Los ratones se dividieron en el grupo de dieta no alta en grasas (ND), el grupo modelo de diabetes mellitus (HFD + STZ) y el grupo modelo de diabetes mellitus tratado con IO. Los ratones del grupo IO recibieron 10 ml/kg de IO (150 mg/kg) durante cinco semanas. Se observaron el peso corporal, el nivel de azúcar en sangre, la ingesta de alimentos, la ingesta de agua potable, la tolerancia a la glucosa y la tolerancia a la insulina de los ratones de cada grupo, y se estudiaron muestras de biopsias hepáticas, renales y pancreáticas mediante tinción de hematoxilina eosina. Resultados: los niveles de glucosa en sangre, el consumo de agua, la lipoproteína de baja densidad (LDL) y los triglicéridos (TG) disminuyeron después de la administración de IO. En comparación con el grupo HFD+STZ, el número de células β pancreáticas normales y la necrosis focal hepática disminuyeron significativamente en el grupo IO. Conclusiones: el IO redujo el nivel de glucosa en sangre, ayudó a recuperar el peso corporal y mejorar la sensibilidad a la insulina, la tolerancia a la insulina y la tolerancia a la glucosa en ratones diabéticos. Además, el IO revirtió el daño orgánico inducido por HFD y STZ. (AU)

Anti-diabetic effects of Inonotus obliquus extract in high fat diet combined streptozotocin-induced type 2 diabetic mice.

Introduction: Introduction: type 2 diabetes (T2DM) is a complex disease affected by lifestyle and genetic factors. Although the drugs currently used to treat T2DM have certain curative effects, they still have some adverse side effects. Therefore, it is urgent to find new effective drugs with few side effects to cure T2DM. Objective: to study the role of Inonotus obliquus (IO) in diabetic model mice. Methods: we used high-fat diet (HFD) combined with streptozocin (STZ) to establish a diabetic mouse model. Mice were divided into non-high-fat diet group (ND), diabetes model group (HFD + STZ) and IO-treated diabetes model group (IO). The mice in the IO group were orally treated with IO (150 mg/kg) at 10 ml/kg for five weeks. Body weight, glucose level, food intake and water consumption, glucose tolerance and insulin tolerance were evaluated in all mice. The pathological sections of liver, kidney and pancreas were observed by hematoxylin-eosin staining. Results: after IO administration, the blood glucose level, water consumption, low-density lipoprotein (LDL) and triacylglycerol (TG) levels of mice decreased. Compared with the HFD + STZ group, the number of normal islet ß cells increased and focal necrosis of the liver was significantly reduced in the IO administration group. Conclusions: IO reduced the levels of blood glucose, restored body weight, and enhanced insulin sensitivity along with insulin tolerance and glucose tolerance in diabetic mice. Additionally, IO also reversed HFD and STZ-induced organ injury.

Introducción: Introducción: la diabetes mellitus tipo 2 (T2DM) es una enfermedad compleja influenciada por el estilo de vida y los factores genéticos. En la actualidad, aunque los medicamentos para la diabetes tipo 2 tienen cierto efecto curativo, todavía tienen algunos efectos secundarios. Por lo tanto, es urgente encontrar nuevos medicamentos para la diabetes tipo 2 que tengan un buen efecto curativo y menos efectos secundarios. Objetivo: estudiar el papel del Inonotus obliquus (IO) en ratones diabéticos. Métodos: se estableció un modelo de ratón diabético con dieta de alto contenido en grasas (HFD) y estreptozocina (STZ). Los ratones se dividieron en el grupo de dieta no alta en grasas (ND), el grupo modelo de diabetes mellitus (HFD + STZ) y el grupo modelo de diabetes mellitus tratado con IO. Los ratones del grupo IO recibieron 10 ml/kg de IO (150 mg/kg) durante cinco semanas. Se observaron el peso corporal, el nivel de azúcar en sangre, la ingesta de alimentos, la ingesta de agua potable, la tolerancia a la glucosa y la tolerancia a la insulina de los ratones de cada grupo, y se estudiaron muestras de biopsias hepáticas, renales y pancreáticas mediante tinción de hematoxilina eosina. Resultados: los niveles de glucosa en sangre, el consumo de agua, la lipoproteína de baja densidad (LDL) y los triglicéridos (TG) disminuyeron después de la administración de IO. En comparación con el grupo HFD+STZ, el número de células ß pancreáticas normales y la necrosis focal hepática disminuyeron significativamente en el grupo IO. Conclusiones: el IO redujo el nivel de glucosa en sangre, ayudó a recuperar el peso corporal y mejorar la sensibilidad a la insulina, la tolerancia a la insulina y la tolerancia a la glucosa en ratones diabéticos. Además, el IO revirtió el daño orgánico inducido por HFD y STZ.

CD36 aggravates podocyte injury by activating NLRP3 inflammasome and inhibiting autophagy in lupus nephritis.

A major cause of proteinuria in lupus nephritis (LN) is podocyte injury, and determining potential therapeutic targets to prevent podocyte injury is important from a clinical perspective in the treatment of LN. CD36 is involved in podocyte injury in several glomerulopathies and was reported to be a vital candidate gene in LN. Here, we determined the role of CD36 in the podocyte injury of LN and the underlying mechanisms. We observed that CD36 and NLRP3 (NLR family pyrin domain containing 3) were upregulated in the podocytes of lupus nephritis patients and MRL/lpr mice with renal impairment. In vitro, CD36, NLRP3 inflammasome, and autophagy were elevated accompanied with increased podocyte injury stimulated by IgG extracted from lupus nephritis patients compared that from healthy donors. Knocking out CD36 with the CRISPR/cas9 system decreased the NLRP3 inflammasome levels, increased the autophagy levels and alleviated podocyte injury. By enhancing autophagy, NLRP3 inflammasome was decreased and podocyte injury was alleviated. These results demonstrated that, in lupus nephritis, CD36 promoted podocyte injury by activating NLRP3 inflammasome and inhibiting autophagy by enhancing which could decrease NLRP3 inflammasome and alleviate podocyte injury.

Glucose-6-phosphate dehydrogenase deficiency and intracranial atherosclerotic stenosis in stroke patients.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic stenosis (ICAS) is a major cause of stroke in Asian countries. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a hereditary enzyme defect prevalent in Asian countries, has been associated with atherosclerotic cardiovascular disease and worse poststroke outcomes. However, the impact of G6PD deficiency on ICAS remains unclear. We aimed to compare the risk of ICAS in stroke patients with and without G6PD deficiency in a Chinese cohort. METHODS: We prospectively and consecutively recruited stroke patients from four centers in China. All patients received intracranial artery assessment by magnetic resonance/computed tomography angiography or digital subtraction angiography, as well as G6PD enzyme evaluation. The prevalence, burden, and characteristics of ICAS were compared between patients with and without G6PD deficiency using multivariate regression analysis. RESULTS: Among 1593 patients, 116 (63.7%) of 182 patients with G6PD deficiency and 714 (50.6%) of 1411 patients with normal G6PD levels were identified as ICAS. Age, hypertension, diabetes, and G6PD deficiency were independent predictors of ICAS. Among patients with ICAS, G6PD-deficient individuals were more likely to have multiple (≥2 segments) intracranial stenosis (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.25-2.81, p = 0.002). G6PD deficiency increased the risk of ICAS in patients who were male (OR = 1.82, 95% CI = 1.24-2.66, p = 0.002), aged ≥70 years (OR = 2.40, 95% CI = 1.33-4.31, p = 0.004), or hypertensive (OR = 1.88, 95% CI = 1.28-2.77, p = 0.001). CONCLUSIONS: Stroke patients with G6PD deficiency have a higher prevalence and ICAS burden than those with normal G6PD, particularly those who are male, older, and hypertensive.