Citations

Acute myocardial infarction (AMI) is a significant factor leading to the death of patients with coronary heart disease. Both AMI and reperfusion therapy after AMI cause myocardial cell death, which plays a significant role in heart failure. Following the restoration of blood flow during reperfusion, myocardial cells generate a large amount of oxygen free radicals, causing various forms of myocardial ischemia–reperfusion (IR) injury (IRI), ultimately leading to multiple types of myocardial cell death, among which apoptosis and necroptosis are the two major types. Given the extremely limited regenerative capacity of myocardium, inhibiting myocardial cell apoptosis and necroptosis is a key strategy for reducing mortality in patients with AMI. Both apoptosis and necroptosis are regulated by the BCL2 family of proteins, which were modulated by multiple signaling pathways, converging at BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP), as well as mitochondrial inner membrane permeabilization (MIMP). BAK/BAX double knock out (DKO) mice showed reduced cell apoptosis, necroptosis, and infarct size in AMI animal models compared to wild type. This review describes the role of BCL2 family proteins in regulating apoptotic and necroptotic myocardial cell death during AMI and IR, explores the upstream pathways modulating apoptosis and necroptosis, and summarizes the recent advances in targeting BAK and/or BAX for cardiac protection. In addition, targeted delivery of BAK/BAX inhibitors to cardiomyocytes during AMI or myocardial IR has the potential to reduce myocardial cell death and therefore lower the mortality and enhance long-term prognosis for myocardial infarction patients.

Abstract Background Gastrointestinal (GI) cancer remains a major global health challenge. This study provides updated 2022 estimates of GI cancer incidence and mortality worldwide, along with projections of incident cases and deaths through 2050 to inform cancer control strategies. Methods In this population‐based study, data from the GLOBOCAN 2022 database were used to examine incidence and deaths associated with GI cancer. By using global demographic projections, this study estimated the projected number of incident cases and deaths until the year 2050. Results By 2050, the global burden of GI cancer is projected to reach 9.06 million incident cases (+85%) and 6.42 million deaths (+93%) from 2022. Increases in incidence are projected for both females (+87%) and males (+83%), as are increases in mortality for both females (+97%) and males (+91%). Whereas the Western Pacific region will have the highest absolute burden, with 3.88 million new cases and 2.79 million deaths, the greatest relative increase is expected in Africa, with incidence and deaths rising by 157% and 160%, respectively. As measured by the Human Development Index (HDI), the steepest increases are projected in low (+151% incidence; +152% deaths) and medium (+112% incidence; +114% deaths) HDI countries. Overall, all GI cancer types are projected to increase, led by pancreatic cancer in incidence (+95%) and colorectal cancer in deaths (+103%). Conclusions GI cancer incidence and deaths are expected to nearly double by 2050, with increases across sexes, cancer types, and regions, especially in lower HDI countries.

Parkinson’s Disease (PD) is a neurodegenerative disorder in which gait abnormalities serve as key indicators of motor impairment and disease progression. Although wearable sensor-based gait analysis has advanced, existing methods still face challenges in modeling multi-sensor spatial relationships, extracting adaptive multi-scale temporal features, and effectively integrating time–frequency information. To address these issues, this paper proposes a multi-sensor gait neural network that integrates biomechanical priors with time–frequency collaborative learning for the automatic assessment of PD gait severity. The framework consists of three core modules: (1) BGS-GAT (Biomechanics-Guided Graph Attention Network), which constructs a sensor graph based on plantar anatomy and explicitly models inter-regional force dependencies via graph attention; (2) AMS-Inception1D (Adaptive Multi-Scale Inception-1D), which employs dilated convolutions and channel attention to extract multi-scale temporal features adaptively; and (3) TF-Branch (Time–Frequency Branch), which applies Real-valued Fast Fourier Transform (RFFT) and frequency-domain convolution to capture rhythmic and high-frequency components, enabling complementary time–frequency representation. Experiments on the PhysioNet multi-channel foot pressure dataset demonstrate that the proposed model achieves 0.930 in accuracy and 0.925 in F1-score for four-class severity classification, outperforming state-of-the-art deep learning models.

Abstract Coarsening Visium HD resolution from 8 to 64 µ m can flip cell-type co-localization from negative to positive ( r = −0.12 → +0.80 ), yet many widely used compositional deconvolution workflows require coarsening or subsampling at million-bin scale. Here we introduce FlashDeconv, which combines leverage-score importance sampling with sparse spatial regularization to achieve competitive benchmark accuracy while processing 1.6 million bins in 153 seconds on commodity hardware. Systematic multi-resolution analysis of Visium HD mouse intestine reveals a tissue-specific resolution horizon (8–16 µ m)—the scale at which this sign inversion occurs—validated by Xenium ground truth. Below this horizon, FlashDeconv provides, to our knowledge, the first sequencing-based quantification of Tuft cell chemosensory niches (15.3-fold stem cell enrichment). In a 1.6-million-bin human colorectal cancer cohort, FlashDeconv uncovers neutrophil inflammatory microdomains co-localized with immunoregulatory dendritic cells (mRegDC) at the tumor–stroma interface—spatial niches largely missed by discrete-label summaries, with RCTD doublet mode labeling only 2.3% of hotspot bins as neutrophil singlets.

Abstract Background Brain cells secrete extracellular vesicles (EVs) containing signaling and pathological proteins related to Alzheimer's disease (AD) and related disorders. Recent studies demonstrate brain‐derived EVs (BDEVs) contain misfolded tau and are transmissible of tau pathology in the brain. However, the underlying mechanism regarding EV‐mediated tau pathology is still largely uncharacterized. Method We conducted the immuno‐affinity purification of tau in human brain‐derived EVs (BDEVs) isolated from age and sex‐matched 14 AD and 14 CTRL cases and performed tandem mass‐tag mass spectrometry to profile unbiased tau interactome in BDEVs. We used Nanotemper Monolith to validate the interaction of EV‐tau interactors with tau, and super‐resolution microscopy (Nanoimager) to detect their colocalization in a single‐EV level. We next designed siRNAs to silence EV‐tau interactors in SH‐SY5Y cells overexpressing human P301L tau (SH‐SY5Y‐P301Ltau) and assessed tau loading to EVs by Flow Nanoanalyzer. These EVs were tested for their uptake and tau seeding by human iPSC‐derived neurons (iNeurons). We finally tested the inhibitors of identified molecules on BDEV‐mediated tau propagation in vivo . Result A total of 764 proteins were identified in BDEV‐associated tau interactome from CTRL and AD patients. Sixty‐five proteins were significantly downregulated in AD BDEVs; whereas 5 proteins were significantly upregulated in AD BDEVs compared to CTRL BDEVs. The most enriched tau‐interacting proteins were significantly positively correlated with Braak stage. We confirmed the direct binding of candidate proteins to tau with micromolar binding affinities by Monolith, and their colocalization with tau in human BDEVs using Nanoimager. Silencing of candidate molecules in human SH‐SY5Y‐P301Ltau cells showed reduced loading of tau in EVs, their reduced uptake by iNeurons, and tau seeding activities. Finally, intracerebroventricular injection of neutralizing antibody against the most promising target results in reduction of tau pathology in PS19 mice expressing P301S human tau mutant. Conclusion Our study identified tau‐interacting molecules highly enriched in AD BDEVs compared to CTRL BDVs. Silencing of candidate molecule reduced tau loading to the EVs and their uptake by iNeurons and neutralizing antibody suppressed tau dissemination, highlighting them as promising therapeutic targets to halt tau pathology in AD and related tauopathy.

Abstract Background Extracellular vesicles (EVs) are key mediators in transferring pathological proteins associated with Alzheimer's disease (AD). The apolipoprotein E (APOE) gene, particularly the ε4 allele, is a major genetic risk factor for late‐onset AD. However, the influence of APOE genotype on the biological characteristics and cargo composition of brain‐derived extracellular vesicles (BDEVs) in AD remains poorly understood. Method In this study, BDEVs were isolated from human AD temporal cortex with APOE3/3 and APOE4/4 genotypes ( N = 20 / group). Nanoflow cytometry and super‐resolution microscopy were used to evaluate the tau load within these BDEVs. EV‐mediated tau transmission was assessed in aged human Tau KI and APP NL‐G‐F : Tau KI mice in vivo . BDEV uptake and tau seeding were evaluated in iPSC‐derived neurons through live imaging. Additionally, shotgun lipidomics and data independent acquisition proteomics were analyzed lipidome and proteome of BDEVs, respectively. Key molecules linked to APOE genotype were identified through integrated weighted gene co‐expression network and trait correlation analysis. Result APOE4/4 BDEVs exhibited a higher proportion of phosphorylated tau (pS396) at single EV levels. Upon injection of 300pg tau of BDEVs into aged Tau KI and APP NL‐G‐F : Tau KI mice, APOE4/4 BDEVs significantly increased AT8 + phosphorylated tau levels, and induced neuroinflammation in vivo . Moreover, APOE4/4 BDEVs demonstrated stronger neuronal uptake and tau transfer compared to APOE3/3 BDEVs, impairing the neuronal activity of iPSC‐derived neurons. Lipidomic revealed that APOE4/4 BDEVs were significantly more enriched in pro‐inflammatory long‐chain polyunsaturated fatty acids (PUFA) compared to APOE3/3 with Braak stage association. Furthermore, gene ontology pathway analysis using differentially expressed proteins in APOE4/4 BDEVs showed increased activity in oxidative phosphorylation and sterol‐binding. Multi‐omics integrated data revealed that upregulation of PUFA was significantly associated with elevated cell adhesion molecules and ATPase transporter activity with neural cell adhesion molecule as one of key molecule. Notably, neutralizing antibody against the molecule effectively reduced APOE4/4 BDEV internalization and mitigated EV‐mediated tau pathology in recipient cells. Conclusion Our comprehensive analysis suggested that AD APOE4/4 BDEV may enhance transmissibility of tau pathology and neuroinflammation via enriched pro‐inflammatory PUFA and cell adhesion molecules. Targeting these pathways presents a promising therapeutic strategy to mitigate disease progression, particularly in APOE4 individuals.

Abstract Background We previously identified a novel mechanism describing how pathological tau transfers via extracellular vesicles (EVs) in Alzheimer's disease (AD). Targeting EV secretion to mitigate tau transfer is, therefore, a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP‐gated cationic channel predominantly expressed in microglia, regulates the secretion and biogenesis of EVs. Here we investigated the effect of P2rx7 deficiency in PS19 tauopathy mouse model and by proteomic profiling of brain EVs. Method PS19: P2rx7 –/– mice at 9‐10 months of age were tested for fear conditioning and their brain sections were assessed for brain atrophy. Tau pathology was evaluated using ELISA and immunofluorescence against phosphorylated (AT8) and misfolded (Alz50) tau. Brain tissues were further assessed by bulk and single cell RNA‐seq (scRNA‐seq) and brain‐EVs were subjected to proteomic profiling by mass‐spectrometry. P2rx7 –/– mice were intracranially injected with viral vectors expressing P301L tau in neurons and mEmerald‐CD9 in microglia to visualize the secretion of microglial EVs in vivo . Mice conditional knockout (cKO) for P2rx7 in microglia, neurons and astrocytes were injected with a viral vector expressing P301L tau in entorhinal cortex for tau propagation assessment. Result PS19: P2rx7 –/– mice showed significant improvement in contextual and cued memory compared to age‐matched PS19 mice, which was accompanied by preserved cortical and hippocampal volume, and significant reduction of hippocampal synapse loss and tau pathology. By weighted gene co‐expression network analysis (WGCNA) we identified a microglial and EV‐related module strongly correlated with tau pathology which was remarkably downregulated in PS19: P2rx7 –/– mice hippocampus. PS19 mice showed increased secretion of EVs containing tau and mitochondrial proteins in the mouse brain parenchyma, which was significantly downregulated in PS19: P2rx7 –/– mice. scRNA‐seq analysis showed that P2rx7 is required for microglia conversion to inflammatory phenotype with increased expression of EV genes in PS19 mice. P2rx7 deficiency reduced microglial mEmerald‐CD9 + ‐EV secretion in mice expressing P301L tau. Moreover, microglia and neuron‐specific deletion of P2rx7 inhibit tau propagation from the entorhinal cortex to the mouse hippocampus. Conclusion Our study demonstrated a microglial P2RX7‐EV axis with potential implications on neuroinflammation and neurodegeneration associated with tau pathology, further indicating the therapeutic potential of targeting P2rx7 to ameliorate AD progression.

Abstract Background Our group recently performed the largest‐to‐date X‐chromosome wide association study (XWAS) of Alzheimer's disease (AD). Here, we expand on this with additional samples, novel sex‐ and APOE *4‐stratified analyses, and evaluate escape from random X chromosome inactivation (eXCI) to better capture female‐biased risk genes. We then integrate these results with XWASs of various AD‐relevant traits to elucidate shared genetic signals and ultimately uncover novel AD risk genes and mechanisms. Method The AD XWAS design is shown in Figure 1A and includes random X chromosome inactivation (rXCI) and eXCI models. We further assessed suggestive AD signals ( p <1x10 ‐3 ) for pleiotropy using genetic colocalization with 2852 AD‐relevant traits (Figure 2A). Loci exhibiting X chromosome‐wide significance ( p <1x10 ‐5 ) or apparent trait colocalization underwent quantitative trait locus (QTL) colocalization analyses across 62 tissues and cell types to functionally prioritize AD risk genes. Result Full sample analyses reproduced Belloy et al. 2024 findings and identified 3 additional loci, including a male‐specific signal near GLUD2 that impacts glutamate/glutamine metabolism (Figure 1B). APOE *4‐stratified analyses revealed 9 additional loci, including 3 eXCI hits in APOE *4 carriers (Figure 1C‐D). Pleiotropy colocalization identified 38 loci, most being novel and many driven by eXCI and/or female‐specific AD XWAS, including MOSPD2, PNMA3 and GABRE loci that showed extensive colocalization with brain imaging traits (Figure 2B). The most significant XWAS locus, SLC9A7 , colocalized with total testosterone, HDL‐C, and various brain imaging traits. Only the NLGN4X locus colocalized with amyloid positivity, linking its proposed role in synaptic dysfunction to amyloid pathology. The locus at KDM6A , previously implicated as an AD resilience gene, colocalized with a functional MRI (fMRI) phenotype. QTL colocalization analyses confirmed gene prioritizations in Belloy et al. 2024, and additionally provided support for PNMA3 , an antigen highly expressed in the brain, and 3 APOE ‐stratified loci, including ACLS4 , which impacts lipid metabolism. Conclusion This study provides novel insights into biological mechanisms that contribute to X‐linked genetic risk for AD in an APOE *4 and sex‐specific manner, identifying various novel risk loci. Notably, 29 female‐biased risk loci were uncovered, which may shed light on sex disparities in AD. Overall, our findings will aid in elucidating AD pathways and drug targets relevant to personalized medicine.

ABSTRACT Background Pulsed‐field ablation (PFA) offers myocardial selectivity with minimal thermal injury, but depth for ventricular lesions may be insufficient or heterogeneous at clinically tolerable field strengths. Calcium electroporation—local calcium chloride (CaCl₂) infusion after PFA—may amplify electroporation‐mediated cell death while maintaining low energy settings. Objective To determine whether immediate post‐PFA CaCl₂ infusion enhances acute and chronic ventricular lesion formation in vivo. Methods Nine swine underwent focal ventricular PFA (750–1000 V, biphasic, 20 μs × 50 pulses, 200 ms interpulse) via an irrigated focal catheter and benchtop electroporator. Immediately post‐PFA, lesions were randomized to saline, 0.2 g Ca, or 0.4 g Ca infused locally through the catheter tip. Acute hearts were explanted for TTC analysis; surviving animals were studied at 7 days for chronic lesion geometry. Results Among 41 acute lesions (17 control, 12 Ca 0.2 g, 12 Ca 0.4 g), Ca 0.4 g increased dark‐zone depth (3.5 ± 1.4 vs. 2.3 ± 0.8 mm; p = 0.038) and pale‐zone depth (2.6 ± 1.3 vs. 1.3 ± 0.8 mm; p = 0.011) versus control. At 7 days ( n = 33 lesions), Ca 0.4 g produced larger scars than control (width 11.6 ± 2.1 vs. 10.0 ± 1.9 mm; p = 0.027; depth 4.2 ± 1 vs. 3.0 ± 0.8 mm; p < 0.001; volume 193.6.4 ± 82.3 vs. 109.4 ± 48.2 mm³; p = 0.001). Conclusions Local CaCl₂ infusion after ventricular PFA significantly augments acute electroporation effect and chronic lesion size at low output, supporting facilitated PFA as a strategy for deeper, more durable ventricular ablation.