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PINK1-dependent activation of PRKN/parkin on depolarized mitochondria causes mitophagy. The deficiency of NME3, a nucleoside diphosphate kinase/NDPK on the outer mitochondria membrane (OMM), is associated with a fatal neurodegenerative disorder. Here, we report that NME3 deficiency impairs p-S65-ubiquitin (Ub)-dependent PRKN binding on depolarized mitochondria without involving the loss of Ub phosphorylation by PINK1. Our mechanistic investigation revealed that NME3 interacts with PLD6/MitoPLD...

The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signalling (IIS) is a leading example, which can extend healthy lifespan in a range of animals, but whether benefits and costs of reduced IIS vary genetically within species is under-studied. This information is critical for...

Alzheimer's disease (AD) represents a continuously advancing neurodegenerative condition distinguished by the unremitting deterioration of cognitive abilities and memory impairment, which significantly hampers daily functioning of life. In the absence of disease modifying treatments, it continues to pose a significant global challenge. Though symptomatic treatment exists, the inherent complexity involved with AD pathogenesis related to Aβ plaques, neurofibrillary tangles, neuroinflammation,...

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How the memory engram is organized at the cell-assembly level to support not only encoding of learned information but also memory flexibility remains elusive. Here, we propose a novel engram model encoded by two orthogonal learning-recruited neuronal ensembles in the mouse dentate gyrus. Reactivation of the Fos-tagged ensemble promotes memory retrieval, whereas reactivation of the Npas4-dependent ensemble drives forgetting, with manipulation of the forgetting ensemble inversely shifting memory...

The native microbiome influences numerous host processes, including neurological function. However, its impacts on diverse brain cell types remain poorly understood. Here, we performed single-nucleus RNA sequencing on the hippocampus of wild-type, germ-free mice, revealing the microbiome-dependent transcriptional landscape across all major neural cell types. We found conserved impacts on key adaptive immune and neurodegenerative transcriptional pathways. Mono-colonization with select indigenous...

Recent advances in high-throughput technologies have led to an increased generation of biological data across genomics, transcriptomics, proteomics, epigenomics, and metabolomics. However, a major challenge remains: effectively integrating these multi-omics datasets to allow a more holistic understanding of the complex, interconnected mechanisms underlying human diseases. Neurodevelopmental, neurodegenerative, and psychiatric disorders are particularly multifactorial and heterogeneous, making...

Deep brain stimulation (DBS) is effective for treating neurological and psychiatric disorders. However, its tethered configuration, invasiveness, and limited tissue compatibility motivate wireless, minimally invasive alternatives. Here, we develop an in situ-gelled injectable conductive hydrogel (ICH), enabling wireless neuromodulation via electric-field localization under volume conduction. The ICH forms in vivo through bio-catalyzed polymerization and electrostatic self-assembly, yielding a...

Parkinson's disease (PD) is an incurable neurological disorder that often begins insidiously with sleep disturbances and somatic symptoms, progressing to whole-body motor and cognitive symptoms^(1-5). Dysfunction of the somato-cognitive action network (SCAN)-which is thought to control action execution^(6,7) by coordinating arousal, organ physiology and whole-body motor plans with behavioural motivation-is a potential contributor to the diverse clinical manifestations of PD. To investigate the...

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Biofluid-based biomarkers have transformed neurodegenerative disease research and care, providing insights into the molecular underpinnings of Alzheimer's disease (AD) and other neurodegenerative dementias. This Review provides an update on recent developments in biofluid-based biomarkers for amyloid-β (Aβ) pathology, tau pathology, neurodegeneration, glial reactivity, α-synuclein pathology, TAR DNA-binding protein 43 (TDP-43) pathology, synaptic pathophysiology and cerebrovascular...

Immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have been targeted in cancer therapy, however, the efficacy of these interventions remains limited. Beyond its immune function on T cell surfaces, CTLA-4 is also expressed in various intrinsic cancer cells, where it influences cell proliferation, metastasis, and apoptosis. The present study aimed to investigate the function of CTLA-4 in...

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Frailty, a hallmark of systemic vulnerability in aging populations, is increasingly recognized in the clinical management of chronic respiratory diseases (CRDs). Molecular mechanism underpinning the relationships remain insufficiently elucidated. This study hence aimed to investigate whether proteomic biomarkers-circulating plasma proteins reflecting systemic inflammation, metabolism, and tissue remodeling-are associated with CRDs and may serve as potential mediators of the observed links. We...

Our ability to sense the position and movement of our limbs is essential for all activities of daily living. This ability arises from the signal sent by muscle spindles to the brain. While there is clear evidence for age-related changes in the quantity of muscle spindles and in their sensitivity, behavioral assessment of age-related changes in position sense have produced mixed findings even though it is taken as textbook knowledge that proprioception declines with age. Yet, study results are...

CONCLUSION: Among community-dwelling older adults, the composite IC score demonstrated a significant independent association with an elevated risk of hip fracture. Regular monitoring of individual IC scores may serve as an early warning indicator to initiate preventive interventions.

In their recent study, Zhang et al. (Aging Clin Exp Res, 2025) report an association between a composite unhealthy lifestyle score and the risk of comorbid type 2 diabetes mellitus (T2DM) and arthritis in the CHARLS cohort. While the topic is of significant public health relevance, we have identified several substantive methodological and interpretative limitations that temper the conclusions. Chief among these are the oversimplified and unvalidated definition of lifestyle exposures,...

CONCLUSIONS: Hospitalization due to COVID-19 was associated with poorer multidimensional aging outcomes, whereas vaccination appeared protective against functional decline. These findings highlight the importance of preventive strategies and sustained vaccination coverage to preserve functionality and promote healthy aging in post-pandemic populations.

CONCLUSIONS: Specific muscle synergy patterns are associated with balance recovery and stability maintenance. Fractionation and merging of muscle synergies triggered in response to perturbations may relate to functional decline in older adults, serving as a mechanism for remodeling to adapt to changes in limb biomechanics and multiple motor task commands.

Dimensionality reduction is routinely applied to single-cell transcriptomic data to improve interpretability, remove noise and redundancy, and enable visualization. Most existing methods aim at preserving the most prominent data properties, which can lead to omission of rare but important signals. Here we propose a novel framework, SAKURA, that uses knowledge-derived genes of interest to guide dimensionality reduction, which can help cluster rare cells and separate highly similar cell...