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In Situ Labeling of Pathogenic Tau Using Photo-Affinity Chemical Probes

ACS CHEMICAL BIOLOGY 2025年第3期20卷 581-591页

作者： Nie, Pengju Wu, You Robinson, John Mekala, Shekar Lee, Virginia M. Y. Li, Yue-Ming Mem Sloan Kettering Canc Ctr Chem Biol Program New York NY 10065 USA Mem Sloan Kettering Canc Ctr Triinst PhD Program Chem Biol New York NY 10065 USA Univ Penn Inst Aging Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Ctr Neurodegenerat Dis Res Perelman Sch Med Philadelphia PA 19104 USA

Tau aggregation plays a crucial role in the development of Alzheimer's disease (AD). Developing specific techniques that can isolate pathogenic tau from brain tissue is important for understanding tauopathies and advancing targeted therapies. Here, we develop photoaffinity small molecular probes and a novel method for in situ tissue labeling and investigate their activity in interacting with tau in cells and AD patient brains. Based on the reported chemical structures of tau PET tracers, we designed and synthesized two tau-specific probes, namely, Tau-2 and Tau-4. After validation in cell, mouse model, and patient brain samples, our photolabeling results suggested that Tau-2 effectively labels soluble tau in cell and mouse models, while Tau-4 selectively binds high-molecular-weight tau aggregates in late-stage AD patient brain tissues. Proteomic analysis verified the specific isolation of pathogenic tau from AD brain samples. Collectively, these findings underscore the potential of our photoaffinity probes as powerful tools for investigating tau proteins and neurofibrillary tangles in neurodegenerative diseases.

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Rationale and design of a randomized controlled trial evaluating the effects of blueberry consumption versus placebo on brain health in older adults

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CONTEMPORARY CLINICAL TRIALS 2025年 154卷 107926-107926页

作者： Uttke, Zachary Gabriel, Olivia Smith, Ceilidh Guardino, Eric T. Mukamal, Kenneth Djousse, Luc Greater Boston Med Student Aging Res Boston MA USA Brown Univ MD PhD Program Providence RI USA Univ Texas Hlth San Antonio STX MSTP San Antonio TX USA Brigham & Womens Hosp Boston MA USA Beth Israel Deaconess Med Ctr Boston MA USA Harvard Med Sch Boston MA USA Harvard TH Chan Sch Publ Hlth Boston MA USA

Background: Age-related cognitive decline results in significant clinical and public health costs. Cognitive decline predisposes individuals to dementia and leads to difficulties with activities of daily living and increased hospitalizations. While a few dietary interventions have shown considerable promise at delaying cognitive decline, studies of the effects of long-term blueberry consumption on brain health among older adults have been limited and equivocal. Objective: To test the hypothesis that a 24-week intervention with blueberry powder versus placebo will improve (i) plasma biomarkers of brain health and (ii) cognitive performance in older adults. Methods: This randomized, double-blind, placebo-controlled trial will be conducted in older Americans aged 65-99 years old. Sixty-seven participants will be randomly assigned to receive either blueberry powder (20 g/d-equivalent of one (1) cup of fresh blueberries) or a placebo powder (20 g/d) for 24 weeks. Participants will undergo four clinic visits (baseline and 8 weeks, 16 weeks, and 24 weeks after randomization) for cognitive assessments, blood pressure measurements, and blood sample collections. Primary outcomes will be plasma levels of neurofilament light chain (NFL) and phosphorylated tau protein (pTau-181). Secondary outcomes will be plasma levels of glial fibrillary acidic protein (GFAP) and non-esterified fatty acids (NEFA);blood pressure during visits;and cognitive function. Conclusion: Findings from this trial will answer the question whether a long-term intervention with blueberry powder can improve (i) plasma biomarkers of brain health and (ii) cognitive function in older adults.

关键词： Blueberries Biomarkers Cognitive function Older adults Clinical trial

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Excitatory-inhibitory synaptic imbalance induced by acute intra-hippocampus injections of amyloid-β oligomers

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2025年 742卷 151133页

作者： Arriagada, Jorge Merceron, Daymara Ardiles, Alvaro Munoz, Pablo Paula-Lima, Andrea Univ Chile PhD Program Biomed Sci Santiago Chile Univ Valparaiso Ctr Translat Res Neuropharmacol CITNE Valparaiso Chile Univ Valparaiso Fac Med Med Sch Dept Pathol & Physiol Valparaiso Chile Univ Valparaiso Interuniv Ctr Hlth Aging CIES Valparaiso Chile Univ Chile Inst Res Dent Sci Fac Dent Santiago Chile Univ Chile Biomed Neurosci Inst BNI Fac Med Santiago Chile Univ Chile Fac Med Dept Neurosci Santiago Chile

Alzheimer's disease (AD) is characterized by the accumulation of soluble amyloid-beta oligomers (A beta Os) in the brain, which disrupt synaptic function and promote cognitive decline. Here, we investigated the effects of A beta Os on excitatory and inhibitory synaptic transmission and plasticity by performing stereotaxic injections of A beta Os directly into the hippocampal CA1 region, followed by hippocampal slice isolation for electrophysiological measurements. A beta Os injections altered basal excitatory synaptic transmission, reducing field excitatory postsynaptic potentials (fEPSPs) and impairing excitatory long-term potentiation (LTP). Additionally, A beta Os injections significantly increased basal inhibitory synaptic transmission, as evidenced by the increased amplitude of field inhibitory postsynaptic potentials (fIPSPs), but impaired the induction and maintenance of inhibitory long-term potentiation (iLTP). Accordingly, we propose that A beta Os injections induce the saturation of the GABAergic system and thus disrupt the hippocampal excitatory-inhibitory balance. These findings highlight the dual impact of A beta Os on both excitatory and inhibitory synapses, generating synaptic dysregulation and possibly worsening cognitive decline in AD. Understanding these mechanisms could provide new insights for developing therapies to restore synaptic balance and hippocampal function in AD.

关键词： Alzheimer's disease Rat hippocampal slices Electrophysiology Synaptic transmission Immunofluorescence

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Geographic variations in distributions of carbapenemase-encoding genes, susceptibilities, and minimum inhibitory concentrations of inpatient meropenem-resistant Enterobacterales to ceftazidime-avibactam, meropenem-vaborbactam, and aztreonam-avibactam across four global regions: 2020-2022 data from the Antimicrobial Testing Leadership and Surveillance

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INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS 2025年第1期66卷 107500-107500页

作者： Jean, Shio-Shin Lai, Chih-Cheng Ho, Sung-Jung Liu, I-Min Hsieh, Po-Chuen Hsueh, Po-Ren Tajen Univ Dept Pharm Coll Pharm & Hlth Care Pingtung 90741 Taiwan Min Sheng Gen Hosp Dept Internal Med & Crit Care Med Taoyuan Taiwan Chi Mei Med Ctr Div Hosp Med Dept Internal Med Tainan Taiwan Natl Sun Yat Sen Univ Coll Med Sch Med Kaohsiung Taiwan Min Sheng Gen Hosp Dept Internal Med Div Pulm Med Taoyuan Taiwan China Med Univ Hosp China Med Univ Dept Lab Med & Internal Med Taichung Taiwan China Med Univ Sch Med PhD Program Aging Taichung Taiwan China Med Univ Sch Med Dept Lab Med Taichung Taiwan

Purpose: To evaluate the susceptibility profiles of regional inpatient meropenem-resistant (MEM-R) carbapenemase-producing Enterobacterales (CPE) isolates and their MIC values to ceftazidime-avibactam (CZA), meropenem-vaborbactam (MVB), and aztreonam-avibactam (ATM-AVI) Methods: The 2020-2022 Antimicrobial Testing Leadership and Surveillance database were analyzed. Carbapenemase-encoding genes in CPE isolates were identified using multiplex PCR and Sanger sequencing. Susceptibility breakpoints for CZA and MVB recommended by CLSI 2024 and EUCAST 2025 against Enterobacterales were applied. Results: A total of 2,318 CPE isolates (78.2% were Klebsiella pneumoniae ) were tested globally. Notable diversity in carbapenemase-encoding gene distributions was observed among CPE isolates from Africa/the Middle East (10 countries;n = 361), Asia (7 countries, excluding India and Pakistan;n = 182), Europe (17 countries;n = 1,002), and Latin America (10 countries;n = 773). Metallo- beta-lactamase-encoding genes, predominantly blaNDM-1 , were more frequently detected in CPE isolates from Africa/the Middle East (75.3%, except blaNDM-5 in Kuwait) and Asia (67%, except blaIMP-8 in Taiwan) compared to other regions. Among KPC variants, the KPC-2 enzyme was the predominant one in CPE isolates in Europe (43.4%, except for KPC-3 prevalent specifically in Italy) and in Latin America (62.1%). The susceptibility rates of all analyzed CPE isolates harboring only a single blaKPC gene to CZA and MVB were 99.4% and 93.5%, respectively, based on the CLSI 2024 susceptibility breakpoints. The MIC50/90 values of CPE isolates to ATM-AVI were 0.12/0.25 mg/L and 0.5/1 mg/L, respectively, regardless of collection region, dual carbapenemase production, or infection source. Conclusions: The trends in resistance to novel antibiotics among contemporary CPE isolates need close monitoring. (c) 2025 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights are reserved, including those fo

关键词： Carbapenemase-producing Enterobacterales Ceftazidime-avibactam Meropenem-vaborbactam Aztreonam-avibactam Susceptibility rates Surveillance Antimicrobial Testing Leadership and

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Exposure to autoimmune disorders is associated with increased Alzheimer's disease risk in a multi-site electronic health record analysis

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CELL REPORTS MEDICINE 2025年第3期6卷 101980-101980页

作者： Ramey, Grace D. Tang, Alice Phongpreecha, Thanaphong Yang, Monica M. Woldemariam, Sarah R. Oskotsky, Tomiko T. Montine, Thomas J. Allen, Isabel Miller, Zachary A. Aghaeepour, Nima Capra, John A. Sirota, Marina UCSF Biol & Med Informat PhD Program San Francisco CA USA UCSF Bakar Computat Hlth Sci Inst San Francisco CA 94143 USA UCSF Sch Med San Francisco CA USA Stanford Univ Dept Pathol Palo Alto CA USA Stanford Univ Dept Anesthesiol Perioperat & Pain Med Palo Alto CA USA Stanford Univ Dept Biomed Data Sci Palo Alto CA USA UCSF Dept Med Div Rheumatol San Francisco CA USA UCSF Dept Pediat San Francisco CA 94143 USA UCSF Dept Epidemiol & Biostat San Francisco CA 94143 USA UCSF Memory & Aging Ctr San Francisco CA USA Stanford Univ Dept Pediat Palo Alto CA USA

Autoimmunity has been proposed to increase Alzheimer's disease (AD) risk, but evaluating the clinical connection between autoimmune disorders and AD has been difficult in diverse populations. We investigate risk relationships between 26 autoimmune disorders and AD using retrospective observational case-control and cohort study designs based on electronic health records for >300,000 individuals at the University of California, San Francisco (UCSF) and Stanford University. We discover that autoimmune disorders are associated with increased AD risk (odds ratios [ORs] 1.4-1.7) across study designs, primarily driven by endocrine, gastrointestinal, dermatologic, and musculoskeletal disorders. We also find that autoimmune disorders associate with increased AD risk in both sexes, but the AD sex disparity remains in those with autoimmune disorders: women exhibit higher AD prevalence than men. This study identifies consistent associations between autoimmune disorders and AD across study designs and two real-world clinical databases, establishing a foundation for exploring how autoimmunity may contribute to AD risk.

关键词： autoimmunity Alzheimer’s bioinformatics case-control cohort electronic health records risk analysis sex differences statistical epidemiology

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Social and health disparities associated with healthy brain ageing in Brazil and in other Latin American countries

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LANCET GLOBAL HEALTH 2025年第2期13卷 e277-e284页

作者： Da Ros, Lucas U. Borelli, Wyllians Vendramini Aguzzoli, Cristiano Schaffer De Bastiani, Marco Antonio Schilling, Lucas Porcello Santamaria-Garcia, Hernando Pascoal, Tharick A. Rosa-Neto, Pedro Souza, Diogo O. da Costa, Jaderson Costa Ibanez, Agustin Suemoto, Claudia Kimie Zimmer, Eduardo R. Univ Fed Rio Grande do Sul Grad Program Biol Sci Biochem Porto Alegre Brazil Univ Fed Rio Grande do Sul Grad Program Biol Sci Biochem Porto Alegre Brazil Univ Fed Rio Grande do Sul Dept Pharmacol BR-90035003 Porto Alegre Brazil Hosp Moinhos Vento Memory Ctr Porto Alegre RS Brazil Pontifical Univ Rio Grande do Sul Brain Inst Rio Grande do Sul Porto Alegre Brazil Pontifical Univ Rio Grande do Sul Sch Med Dept Pediat Tokat Brazil Pontifical Univ Rio Grande do Sul Grad Program Biomed Gerontol Porto Alegre Brazil Univ Calif San Francisco Hosp Univ San Ignacio Ctr Brain & Cognit Intellectus PhD Program NeurosciPontificia Univ Javeriana San Francisco CA USA Univ Calif San Francisco Gobal Brain Hlth Inst Memory & Aging Ctr Francisco CA USA Univ Pittsburgh Dept Psychiat & Neurol Pittsburgh PA USA McGill Ctr Studies Aging Montreal PQ Canada McGill Univ Montreal Neurol Inst Dept Neurol & Neurosurg Montreal PQ Canada Douglas Hosp Res Ctr Montreal PQ Canada Univ Sao Paulo Med Sch Dept Internal Med Div Geriatr Sao Paulo Brazil Univ Adolfo Ibanez Latin Amer Brain Hlth Inst BrainLat Santiago Chile Trinity Coll Dublin Global Brain Hlth Inst Dublin Ireland Univ San Andres Cognit Neurosience Ctr Buenos Aires Argentina

Background Latin American countries present major health-related inequities due to historical, cultural, and social aspects. Recent evidence highlights that factors related to social and health disparities outweigh classic demographic factors in determining healthy brain aging in these populations. However, these analyses have not been conducted with the Brazilian population, the largest and most ethnically diverse population in Latin America. Methods Here, we evaluated demographic, social, and health factors for healthy brain ageing using a machine learning model in a Brazilian population-based cohort (n=9412) and in additional cohorts from other Latin American countries, including Colombia (n=23 694), Chile (n=1301), Ecuador (n=5235), and Uruguay (n=1450). Findings In the Brazilian population and other Latin American countries, social and health disparities were more influential than demographic factors for cognition and functional ability. Uniquely in Brazil, education emerged as the primary risk factor impacting cognitive outcomes, diverging from other Latin American countries where mental health symptoms played more prominent roles. In terms of functional ability, Brazil displayed a distinct pattern, with mental health symptoms identified as the primary contributing factor. Interpretation Our findings indicate that Brazil converges with other Latin American countries to show that heterogeneous factors impacted more than demographic factors, but also showed a unique set of health factors when compared with other Latin American countries. Therefore, our study emphasises that social and health disparity factors are relevant predictors of healthy brain ageing in Latin America, but population-specific analyses are necessary to identify the specific risk profiles of each country.

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High diversity of strain clonality and metallo-β-lactamases genes among carbapenem-resistant Enterobacterales in Taiwan

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EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES 2025年第2期44卷 251-262页

作者： Lee, Jia-Arng Kuo, Yao-Wen Du, Shin-Hei Lee, Tai-fen Liao, Chun-Hsing Huang, Yu-Tsung Hsueh, Po-Ren Natl Taiwan Univ Coll Med Dept Lab Med Natl Taiwan Univ Hosp Taipei Taiwan Natl Taiwan Univ Grad Inst Clin Lab Sci & Med Biotechnol Taipei Taiwan Natl Taiwan Univ Coll Med Natl Taiwan Univ Hosp Dept Integrated Diagnost & Therapeut Taipei Taiwan Far Eastern Mem Hosp Dept Internal Med New Taipei City Taiwan Natl Yang Ming Univ Coll Med Taipei Taiwan Natl Taiwan Univ Coll Med Dept Internal Med Natl Taiwan Univ Hosp Taipei Taiwan China Med Univ Coll Med PhD Program Aging Taichung Taiwan China Med Univ China Med Univ Hosp Dept Lab Med Taichung Taiwan China Med Univ China Med Univ Hosp Dept Internal Med Taichung Taiwan

PurposeThis study aimed to investigate the genetic and clinical characteristics of carbapenem-resistant Enterobacterales (CRE) isolates carrying metallo-beta-lactamases (MBLs) *** total of 146 non-duplicated isolates of CRE were collected in 2022. Their ceftazidime/avibactam (CZA) susceptibilities were determined using the E test. The phenotypic identification of carbapenemases was conducted using the modified carbapenem inactivation method, followed by sequencing of the five common carbapenemase genes (blaKPC, blaNDM, blaVIM, blaIMP, and blaOXA-48). Multilocus sequence typing of selected Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae complex isolates were *** the 146 CRE isolates, 52 (35.6%) were resistant to CZA. MBL-encoding genes were detected in 46 (31.5%) of all tested CRE isolates, with 82.6% (n = 38) of them exhibiting resistance to CZA. Fourteen isolates were resistant to CZA without any detected MBL genes. The most commonly identified MBL genes were blaIMP (n = 20), followed by blaNDM (n = 19), and blaVIM (n = 5). In CZA-R, the most common definite antibiotic before the CZA E test was CZA (n = 18), followed by tigecycline (n = 13), and fluroquinolone (n = 10). The 14-day and 30-day mortality rates were 9.0% (n = 13) and 22.8% (n = 34), and were associated with intensive care unit admission at onset (P = 0.029 and P = 0.001, respectively). The sequence types of CRE isolates carrying MBLs were diverse without major *** continuous emergence of MBL gene-encoding CRE with multiple clones has led to reduced CZA susceptibilities and worse outcomes.

关键词： Enterobacterales Klebsiella oxytoca Enterobacter cloacae complex Carbapenem-resistant Metallo-beta-lactamases

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A Bite of B Cells: The Potential Role of Bispecific T Cell Engager Therapy (BiTE) in Autoimmune Diseases

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INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES 2025年第5期28卷 e70252页

作者： Zheng, Jie-Fu Lee, Yung-Heng Kao, Shih-Wen Wei, James Cheng-Chung Tainan Municipal Hosp Dept Internal Med Div Rheumatol & Immunol Tainan Taiwan Minist Hlth & Welf Feng Yuan Hosp Dept Orthoped Kaohsiung Taiwan Natl Sun Yat Sen Univ Inst Med Sci & Technol Kaohsiung Taiwan Minghsin Univ Sci & Technol Dept Sr Serv Ind Management Hsinchu Taiwan Shu Te Univ Dept Recreat & Sport Management Kaohsiung Taiwan Chung Shan Med Univ Hosp Dept Orthopaed Surg Taichung Taiwan Chung Shan Med Univ Sch Med Taichung Taiwan China Med Univ Coll Med PhD Program Aging Taichung Taiwan Chung Shan Med Univ Hosp Dept Allergy Immunol & Rheumatol Taichung Taiwan Chung Shan Med Univ Inst Med Taichung Taiwan Chung Shan Med Univ Dept Nursing Taichung Taiwan China Med Univ Grad Inst Integrated Med Taichung Taiwan

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Impact of extreme weather events on food security among older people: a systematic review

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aging CLINICAL AND EXPERIMENTAL RESEARCH 2025年第1期37卷 1-15页

作者： Nucci, Daniele Pennisi, Flavia Pinto, Antonio De Ponti, Emanuele Ricciardi, Giovanni Emanuele Signorelli, Carlo Veronese, Nicola Castagna, Alberto Maggi, Stefania Cadeddu, Chiara Gianfredi, Vincenza Agenzia Tutela Salute ATS Brescia Dipartimento Igiene & Prevenz Sanit Struttura Semplice Dipartimentale Igiene Alimenti Via Duca Abruzzi 15 I-25124 Brescia Italy Univ Pavia Dept Publ Hlth Expt & Forens Med PhD Natl Program Hlth Approaches Infect Dis & Life I-27100 Pavia Italy Univ Vita Salute San Raffaele Fac Med I-20132 Milan Italy St Camillus Int Univ Hlth Sci Fac Med Rome Italy Azienda Sanit Provinciale Hlth Dist Soverato Dept Primary Care Catanzaro Italy Natl Res Council CNR Aging Sect Padua Italy Erasmus Univ Erasmus Sch Hlth Policy & Management Rotterdam Netherlands Univ Milan Dept Biomed Sci Hlth Via Pascal 36 I-20133 Milan Italy

BackgroundClimate change has intensified the frequency and severity of extreme weather events, disproportionately affecting vulnerable populations, including older people for which the literature is still limited. This systematic review investigated the impact of extreme weather events on malnutrition and food security among individuals aged 60 and *** systematic search of PubMed/MEDLINE, Scopus, and Web of Science was conducted without restrictions (October 2024), and following PRISMA guidelines. Observational studies examining older adults exposed to extreme weather events (e.g., droughts, floods, heatwaves, hurricanes) and their effects on malnutrition or food security were included. The Newcastle-Ottawa Scale assessed study quality. Protocol was registered in PROSPERO (ID: CRD42024596910).ResultsFrom 1,709 articles, six observational studies involving 265,000 participants (aged 60 years and over) were included. These studies spanned multiple geographies, with a concentration in the United States. Findings revealed a dual impact: while some studies reported protective factors, such as social support and economic stability, others highlighted increased malnutrition risk due to disrupted food supply, economic hardship, and inadequate adaptive responses. Heterogeneity in study designs, exposure definitions, and outcome measures limited *** weather events significantly impact malnutrition and food security among older adults, with outcomes influenced by socio-economic and geographical factors. Further longitudinal studies are needed to clarify causal pathways and inform targeted public health interventions to enhance resilience in aging populations.

关键词： Climate change Food insecurity Malnutrition Elderly populations Extreme weather events Public health

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SYSTEMIC CRISIS AND THE NONPROFIT SECTOR - TOWARD A POLITICAL-ECONOMY OF THE NONPROFIT HEALTH AND SOCIAL-SERVICES SECTOR

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THEORY AND SOCIETY 1990年第2期19卷 173-198页

作者： ESTES, CL ALFORD, RR UNIV CALIF SAN FRANCISCO INST HLTH & AGINGSAN FRANCISCOCA 94143 CUNY PHD PROGRAM SOCIOLNEW YORKNY 10021

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