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N-bridged [3.2.1]octanes (tropanes) and their related bridged bicyclic systems constitute highly sought-after scaffolds in drug discovery and development. Notably, the enantioselective synthesis of chiral 3-aryltropanes which are compounds widely distributed across bioactive pharmaceutical agents remains underdeveloped. Tropinone is a readily available and cost-effective starting material. By initiating the synthesis from tropinone, it is possible to substantially lower the synthesis costs. Here...

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease that develops in response to chronic epithelial injury. Unlike injury-induced homeostatic lung repair during which fibroblasts undergo apoptosis and clearance, the lungs of IPF patients continue to accumulate apoptosis-resistant, pro-fibrotic, extracellular matrix-producing fibroblasts. Here, we show that prevention of PDGFRα^(+) fibroblast apoptosis by conditional BCL-2 expression leads to the emergence and persistence of...

Intestinal aging characterized by imbalance between cell senescence and mucosal self-renewal, increases susceptibility to the elderly-onset ulcerative colitis (UC), while the underlying mechanisms remain elusive. Here, we identify mRNA N4-acetylcytidine (ac⁴C) modification and its specific writer, N-acetyltransferase 10 (NAT10), as critical regulators of human colonic epithelial cell senescence. Knockdown of NAT10 significantly alleviates human colonic epithelial cell senescence in vitro and...

The rising global burden of pathological aging engenders an urgent need for accessible tools enabling early detection of physical decline, which significantly impacts quality of life and healthcare systems. We hypothesized that speech analysis could capture phenotype-specific signatures of physical deterioration through shared neuromuscular pathways, offering a novel approach to physical assessment. In this study, we employed machine learning to analyze multimodal speech features (acoustic,...

α-Synuclein conformational strains provide a potential explanation for the clinical and pathological differences among synucleinopathies such as Parkinson's disease and multiple system atrophy. However, how distinct α-synuclein strains arise remains unknown. Here, we observed conformational heterogeneity between individual preparations of α-synuclein pre-formed fibrils (PFFs) generated by polymerizing wild-type or A53T-mutant human α-synuclein under identical conditions. Moreover, we found that...

CONCLUSIONS: From 1990 to 2021, there was an overall upward trend in the global burden of ADOD among postmenopausal women. Driven by demographic shifts (population growth and aging) and metabolic risks (particularly high fasting plasma glucose), the burden of postmenopausal women with ADOD is expected to increase substantially. Postmenopausal women in higher SDI countries bore a disproportionately higher ADOD burden, and the SDI-related inequalities among countries widened during the study...

CONCLUSIONS: From 1990 to 2021, there was an overall upward trend in the global burden of ADOD among postmenopausal women. Driven by demographic shifts (population growth and aging) and metabolic risks (particularly high fasting plasma glucose), the burden of postmenopausal women with ADOD is expected to increase substantially. Postmenopausal women in higher SDI countries bore a disproportionately higher ADOD burden, and the SDI-related inequalities among countries widened during the study...

BACKGROUND: Total hip replacement is a successful operation that aims to restore function and quality of life to millions of people globally. Knowing how long a total hip replacement might last is important for patients, surgeons, and health-care institutions for planning and resource allocation. Over the past 20 years, the use of contemporary bearing surfaces for total hip replacement has substantially altered implant wear and, possibly, longevity. To date, there has been no large-scale study...

Congressional impasse has halted billions in research funding for innovative technologies

CONCLUSION: This multimodal analysis links PD-related ALFF and ReHo alterations to distinct yet converging transcriptomic, cellular, and neurochemical substrates. The findings suggest that PD-related functional alterations spatially align with glial-neurovascular transcriptional gradients and serotonergic receptor distribution, providing convergent but indirect evidence for their involvement in PD-related network reorganization.

Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6 + 4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer's disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, dementia, and ultimately death. Recent anatomical and functional discoveries of neuroimmune interactions during the development and progression of AD are beginning to shed light on disease mechanisms and potential precision immunotherapies. Here, we review the current understanding of the contribution of innate and adaptive immunity to AD pathogenesis and progression. We discuss how microglia...

Parkinson's disease (PD) is a complex neurodegenerative disorder with both genetic and environmental contributions. Over the past two and a half decades, advances in genetics, genomics and molecular biology have uncovered several monogenic forms of PD, linked to mutations in a number PD genes (collectively called PARK genes) such as SNCA, LRRK2, PRKN, PINK1, and DJ-1. To date there are 26 PARK genes reported with more than 100 genetic variants that increase the risk of PD. These genetic...

Alzheimer's disease (AD), the leading cause of dementia, is predominantly sporadic and influenced by non-genetic factors, including the gut microbiota. Cohabitation studies have shown microbial transmission between AD transgenic (Tg) and wild-type (WT) mice, leading to cognitive impairment; however, the mechanisms during early-life co-housing exposure remain largely undetermined. Here, one-month-old WT mice were housed with age-matched AD Tg (5XFAD) mice for 3 months. Gut microbiota composition...

Alzheimer's disease (AD) involves proteostasis dysregulation causing protein misfolding, but whether these structural changes manifest as plasma conformational biomarkers remains unclear. We profiled plasma protein structures from 520 participants including individuals with AD, individuals with mild cognitive impairment (MCI) and healthy controls. Using mass spectrometry and machine learning, we systematically characterized the structural proteome changes associated with ApoE variations and...

Age-related macular degeneration (AMD) represents one of the therapeutic challenges of aging eye diseases. Our investigation reveals the stimulator of interferon genes (STING) pathway as an orchestrator of immune-mediated retinal degeneration, exhibiting biphasic, stage-dependent functionality-providing cytoprotection in healthy tissue but driving pathogenic inflammation during early AMD progression. Through immunohistochemical analysis of human eyes, we demonstrate stage-dependent cytoplasmic...

Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, suggesting the existence of specialized mechanisms that maintain LC mitochondrial homeostasis under such constrains. Here we identify a mitochondrial transfer network between LCs and different testicular macrophage (tMac) subpopulations. Leydig cells release extracellular vesicles...

CONCLUSIONS: Despite gradual increases in the prevalence of impaired physical function during ageing, regular physical activity may help to preserve physical function in older adults.

No abstract

Walking is fundamental to human mobility, and slowing gait speed is a widely recognized indicator of aging-related mobility decline. Although mobility decline in older adults has been associated with aging-related neural and morphological changes in muscle, the specific neural and morphological correlates of gait speed remain incompletely characterized. Thus, our primary aim was to quantify how peripheral nerve function, muscle cross-sectional area (MCSA) and intramuscular fat (IMAT) are related...