Subtype-Specific Association of Mitochondrial DNA Copy Number With Poststroke/TIA Outcomes in 10†241 Patients in China.

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) is associated with the severity and mortality in patients with stroke, but the associations in different stroke subtypes remain unexplored. METHODS: We conducted an observational prospective cohort analysis on patients with ischemic stroke or transient ischemic attack enrolled in the Third China National Stroke Registry. We applied logistic models to assess the association of mtDNA-CN with functional outcome (modified Rankin Scale score, 3-6 versus 0-2) and Cox proportional hazard models to assess the association with stroke recurrence (treating mortality as a competing risk) and mortality during a 12-month follow-up, adjusting for sex, age, physical activity, National Institutes of Health Stroke Scale at admission, history of stroke and peripheral artery disease, small artery occlusion, and interleukin-6. Subgroup analyses stratified by age and stroke subtypes were conducted. RESULTS: The Third China National Stroke Registry enrolled 15 166 patients, of which 10 241 with whole-genome sequencing data were retained (mean age, 62.2 [SD, 11.2] years; 68.8% men). The associations between mtDNA-CN and poststroke/transient ischemic attack outcomes were specific to patients aged ≤65 years, with lower mtDNA-CN significantly associated with stroke recurrence in 12 months (subdistribution hazard ratio, 1.15 per SD lower mtDNA-CN [95% CI, 1.04-1.27]; P=5.2×10-3) and higher all-cause mortality in 3 months (hazard ratio, 2.19 [95% CI, 1.41-3.39]; P=5.0×10-4). Across subtypes, the associations of mtDNA-CN with stroke recurrence were specific to stroke of undetermined cause (subdistribution hazard ratio, 1.28 [95% CI, 1.11-1.48]; P=6.6×10-4). In particular, lower mtDNA-CN was associated with poorer functional outcomes in stroke of undetermined cause patients diagnosed with embolic stroke of undetermined source (odds ratio, 1.53 [95% CI, 1.20-1.94]; P=5.4×10-4), which remained significant after excluding patients with recurrent stroke (odds ratio, 1.49 [95% CI, 1.14-1.94]; P=3.0×10-3). CONCLUSIONS: Lower mtDNA-CN is associated with higher stroke recurrence rate and all-cause mortality, as well as poorer functional outcome at follow-up, among stroke of undetermined cause, embolic stroke of undetermined source, and younger patients.

Controllable Silver Release for Efficient Treatment of Drug-Resistant Bacterial-Infected Wounds.

The use of traditional Ag-based antibacterial agents is usually accompanied by uncontrollable silver release, which makes it difficult to find a balance between antibacterial performance and biosafety. Herein, we prepared a core-shell system of ZIF-8-derived amorphous carbon-coated Ag nanoparticles (Ag@C) as an ideal research model to reveal the synergistic effect and structure-activity relationship of the structural transformation of carbon shell and Ag core on the regulation of silver release behavior. It is found that Ag@C prepared at 600 °C (AC6) exhibits the best ion release kinetics due to the combination of relatively simple shell structure and lower crystallinity of the Ag core, thereby exerting stronger antibacterial properties (>99.999 %) at trace doses (20 µg mL-1) compared with most other Ag-based materials. Meanwhile, the carbon shell prevents the metal Ag from being directly exposed to the organism and thus endows AC6 with excellent biocompatibility. In animal experiments, AC6 can effectively promote wound healing by inactivating drug-resistant bacteria while regulating the expression of TNF-α and CD31. This work provides theoretical support for the scientific design and clinical application of controllable ion-releasing antibacterial agents.

Non-O blood types are associated with a greater risk of large artery atherosclerosis stroke and dysregulation of cholesterol metabolism: an observational study.

BACKGROUND: Previous research on ABO blood types and stroke has been controversial, predominantly suggesting heightened risk of stroke in non-O blood types. Nonetheless, investigations into the correlation and underlying mechanisms between ABO blood groups and stroke subtypes, especially within Chinese cohorts, remain limited. METHODS: The ABO blood types of 9,542 ischaemic stroke (IS) patients were inferred using two ABO gene loci (c.261G > del; c.802G > A). The healthy population was derived from the 1000 Genomes Project. Patients were classified by the causative classification system (CCS). Volcano plot and gene ontology (GO) analysis were employed to explore protein differential expression among blood types. Additionally, HT29 and SW480 cell lines with downregulated ABO expression were generated to evaluate its impact on cholesterol uptake and efflux. RESULTS: A greater proportion of stroke patients had non-O blood types (70.46%) than did healthy individuals (61.54%). Notable differences in blood type distributions were observed among stroke subtypes, with non-O blood type patients mainly classified as having large artery atherosclerosis (LAA). Clinical baseline characteristics, such as the low-density lipoprotein cholesterol level, activated partial thromboplastin time and thrombin time, varied significantly among blood types. A volcano plot revealed 17 upregulated and 42 downregulated proteins in the O blood type. GO term analysis indicated that downregulated proteins were primarily associated with lipid metabolism pathways. In vitro experiments revealed that reducing ABO gene expression decreased cholesterol uptake and increased cholesterol efflux. CONCLUSIONS: This study revealed that the non-O blood type increased the risk of LAA stroke through cholesterol metabolism.

A pipeline for sample tagging of whole genome bisulfite sequencing data using genotypes of whole genome sequencing.

BACKGROUND: In large-scale high-throughput sequencing projects and biobank construction, sample tagging is essential to prevent sample mix-ups. Despite the availability of fingerprint panels for DNA data, little research has been conducted on sample tagging of whole genome bisulfite sequencing (WGBS) data. This study aims to construct a pipeline and identify applicable fingerprint panels to address this problem. RESULTS: Using autosome-wide A/T polymorphic single nucleotide variants (SNVs) obtained from whole genome sequencing (WGS) and WGBS of individuals from the Third China National Stroke Registry, we designed a fingerprint panel and constructed an optimized pipeline for tagging WGBS data. This pipeline used Bis-SNP to call genotypes from the WGBS data, and optimized genotype comparison by eliminating wildtype homozygous and missing genotypes, and retaining variants with identical genomic coordinates and reference/alternative alleles. WGS-based and WGBS-based genotypes called from identical or different samples were extensively compared using hap.py. In the first batch of 94 samples, the genotype consistency rates were between 71.01%-84.23% and 51.43%-60.50% for the matched and mismatched WGS and WGBS data using the autosome-wide A/T polymorphic SNV panel. This capability to tag WGBS data was validated among the second batch of 240 samples, with genotype consistency rates ranging from 70.61%-84.65% to 49.58%-61.42% for the matched and mismatched data, respectively. We also determined that the number of genetic variants required to correctly tag WGBS data was on the order of thousands through testing six fingerprint panels with different orders for the number of variants. Additionally, we affirmed this result with two self-designed panels of 1351 and 1278 SNVs, respectively. Furthermore, this study confirmed that using the number of genetic variants with identical coordinates and ref/alt alleles, or identical genotypes could not correctly tag WGBS data. CONCLUSION: This study proposed an optimized pipeline, applicable fingerprint panels, and a lower boundary for the number of fingerprint genetic variants needed for correct sample tagging of WGBS data, which are valuable for tagging WGBS data and integrating multi-omics data for biobanks.

A novel highly specific colorimetric fluorescent probe for the detection of nitrite in aqueous solution.

Developing an effective method for the detection of nitrite (NO2 - ) ions in the natural environment especially in environmental waters and soils is very necessary, since they will cause serious damage to human health once excess NO2 - ions enters the human body. Therefore, a new colorimetric fluorescent probe NB-NO2 - for determining NO2 - ions was designed, which possesses good water-solubility and satisfactory selectivity over other common ions for NO2 - ions. The addition of NO2 - ions changed the color of solution from blue to colorless seen by the naked-eye. Furthermore, through test and calculation, the detection limit of the probe NB-NO2 - is 129 nM. Based on the earlier excellent characteristics, the probe NB-NO2 - was successfully used for monitoring NO2 - ions in environmental waters and soils.

DNA methylation: A critical epigenetic mechanism underlying the detrimental effects of airborne particulate matter.

Exposure to airborne particulate matter (PM) does great harm to the health of human beings. To date, PM exposure has been closely associated with respiratory and cardiovascular diseases, as well as some types of cancer. As the associations of PM with the adverse health effects are well documented in literatures, the underlying mechanisms have not been completely clarified. With the field of epigenetics rising in recent years, PM-associated epigenetic alterations have gradually turned into the hot research topic. DNA methylation is one of the earliest-discovered and best-studied epigenetic mechanisms, of which the alteration can influence the transcription initiation of genes. A number of studies have been published to demonstrate that PM exposure is linked with DNA methylation patterns in the human genome. DNA methylation is the potential regulator of the biological effects of PM exposure. In the present review, DNA methylation related to PM exposure was elaborated on genome-wide and gene-specific methylation. In particular, genome-wide DNA methylation was composed of the alterations in global methylation content and genome-wide methylation profile; gene-specific methylation included the methylation changes in mechanism-related and disease-specific genes. Representative epidemiological and experimental studies were cited to elucidate the viewpoints, focusing on both PM-related methylation changes and the mediating effects of DNA methylation between PM and the health impacts. This review will provide advantageous clues for subsequent studies on the DNA methylation in relation to PM exposure.

Cytotoxicity induced by fine particulate matter (PM2.5) via mitochondria-mediated apoptosis pathway in human cardiomyocytes.

Although the strongly causal associations were between fine particulate matter (PM2.5) and cardiovascular disease, the toxic effect and potential mechanism of PM2.5 on heart was poorly understood. Thus, the aim of this study was to evaluate the cardiac toxicity of PM2.5 exposure on human cardiomyocytes (AC16). The cell viability was decreased while the LDH release was increased in a dose-dependent way after AC16 exposed to PM2.5. The reactive oxygen species (ROS) generation and production of malondialdehyde (MDA) were increased followed by the decreasing in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). The damage of mitochondria was observed by ultra-structural analysis and MMP measurement. The apoptotic rate of AC16 were markedly elevated which was triggered by PM2.5. In addition, the proteins involved in mitochondria- mediated apoptosis pathway were measured. The protein levels of Caspase-3, Caspase-9 and Bax were up-regulated while the anti-apoptotic protein, Bcl-2 was down-regulated after AC16 exposed to PM2.5. In summary, our results demonstrated that mitochondria-mediated apoptosis pathway played a critical role in PM2.5-induced myocardial cytotoxicity in AC16, which suggested that PM2.5 may contribute to cardiac dysfunction.

Pregnancy-related adverse events associated with statins: a real-world pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Statins, previously rated as pregnancy category X agents, were contraindicated during pregnancy due to the teratogenic effects observed in animal studies. However, it is still controversial whether statins have detrimental impact on pregnant women or not, and some studies even suggest a potential benefit of statin use against pregnancy complications. The aim of this study was to explore whether maternal exposure to statins is associated with increased rates of pregnancy-related adverse events (AEs), including abortion, abortion spontaneous, preterm birth, low birth weight, stillbirth/fetal death, and fetal complications. RESEARCH DESIGN AND METHODS: Data from 1 January 2004 to 30 June 2022 were extracted through the U.S. FDA Adverse Event Reporting System (FAERS) database, to conduct disproportionality analysis and Bayesian analysis by reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) algorithms. To identify the potential risks of pregnancy-related AEs, each statin was compared to all the other drugs, all the other statins, and the reference drugs (fenofibrate and evolocumab). RESULTS: A total of 477 cases involving pregnancy-related AEs associated with stains were submitted to the FAERS database by healthcare professionals. No obvious disproportionate association of abortion, abortion spontaneous, or stillbirth/fetal death was identified for all statins during gestation. In comparison with all the other drugs, lovastatin showed an increased risk of fetal complications (ROR = 2.45, 95% CI, 1.22-4.95; IC025 = 0.63), and pravastatin demonstrated increased risks of preterm birth (ROR = 4.89, 95% CI, 3.65-6.54; IC025 = 1.69) and low birth weight (ROR = 9.60, 95% CI, 5.56-16.56; IC025 = 1.88). Similar results were found when compared lovastatin or pravastatin with fenofibrate. Furthermore, statins were associated with higher proportion of fetal complications and preterm birth when comparing with evolocumab. CONCLUSIONS: Statins did not increase the risk of pregnancy-related AEs, including abortion, abortion spontaneous, or stillbirth/fetal death. However, we did find significant disproportionality signals for preterm birth and low birth weight associated with pravastatin, and lovastatin was related to a higher proportion of fetal complications. The results in this study may provide evidence on the safety of statins during pregnancy, which need to be verified in further investigations.

A pharmacovigilance study of adverse events associated with polymyxins based on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.

BACKGROUND: Polymyxins have been regarded as last-line treatment for multidrug-resistant gram-negative bacterial infections. Nonetheless, concerns regarding toxicity persist. This study aimed to explore and compare potential adverse events (AEs) between colistin and polymyxin B (PMB). METHODS: Polymyxins-related AEs were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System between 2004 and 2022. Potential signals were estimated by the reporting odds ratio (ROR), and subgroup analyses were preformed to adjust for potential factors in AEs with significant disproportionality. RESULTS: Analysis of 3,915 records involving 718 patients revealed a higher disproportionality of renal and urinary disorders (ROR 1.62, 95% CI 1.01-2.59) and acute kidney injury (ROR 1.75, 95% CI 1.07-2.87) with colistin treatment. Conversely, colistin exhibited a lower risk for neurotoxicity (ROR 0.47, 95% CI 0.30-0.73). Seven cases of skin hyperpigmentation were reported with PMB, whereas none were reported with colistin. Over 80% of cases involving polymyxin-related AEs occurred during the first two weeks of therapies, with a median onset time of 4.5 days. CONCLUSIONS: Patients received colistin displayed a higher potential risk of nephrotoxicity but a lower risk of neurotoxicity. Clinicians should be vigilant in monitoring the AEs of hyperpigmentation disorders induced by PMB.

MoOxNWs with mechanical damage - oriented synergistic photothermal / photodynamic therapy for highly effective treating wound infections.

Reactive oxygen species (ROS)-based therapy has emerged as a promising antibacterial strategy. However, it faces the limitations of uncontrollable space-time release and excessive lipid peroxidation, which may lead to a series of metabolic disorders and decreased immune function. In this study, mechanical damage by molybdenum oxide nanowires (MoOxNWs) is introduced as a synergistic factor to enhance the photothermal and photodynamic effects for controllable and efficient antibacterial therapy. Through their sharp ends, the nanowires can effectively pierce and damage the bacterial cells, thus facilitating the entry of externally generated ROS into the cells. The ROS are generated via photodynamic effect of the nanowires under a mere 5 min of near-infrared light irradiation. This approach enhances the photothermal (by 27.3 %) and photodynamic properties of ROS generation. MoOxNWs (100 µg·mL-1) achieve sterilisation rates of 97.67 % for extended-spectrum ß-lactamase-producing E. coli and 96.34 % for methicillin-resistant Staphylococcus aureus, which are comparable or even exceeding the efficacy of most MoOx-based antibacterial agents. Moreover, they exhibit good biocompatibility and low in vivo toxicity.

Defect-Engineering-Mediated Long-Lived Charge-Transfer Excited-State in Fe-Gallate Complex Improves Iron Cycle and Enables Sustainable Fenton-Like Reaction.

Fenton reactions are inefficient because the Fe(II) catalyst cannot be recycled in time due to the lack of a rapid electron transport pathway. This results in huge H2 O2 wastage in industrial applications. Here, it is shown that a sustainable heterogeneous Fenton system is attainable by enhancing the ligand-to-metal charge-transfer (LMCT) excited-state lifetime in Fe-gallate complex. By engineering oxygen defects in the complex, the lifetime is improved from 10-90 ps. The lengthened lifetime ensures sufficient concentrations of excited-states for an efficient Fe cycle, realizing previously unattainable H2 O2 activation kinetics and hydroxyl radical (• OH) productivity. Spectroscopic and electrochemical studies show the cyclic reaction mechanism involves in situ Fe(II) regeneration and synchronous supply of oxygen atoms from water to recover dissociated Fe─O bonds. Trace amounts of this catalyst effectively destroy two drug-resistant bacteria even after eight reaction cycles. This work reveals the link among LMCT excited-state lifetime, Fe cycle, and catalytic activity and stability, with implications for de novo design of efficient and sustainable Fenton-like processes.

Integration of STING activation and COX-2 inhibition via steric-hindrance effect tuned nanoreactors for cancer chemoimmunotherapy.

Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn2+) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn2+ can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting "cold" tumors into "hot" tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.

Redox-neutral electrochemical decontamination of hypersaline wastewater with high technology readiness level.

Industrial hypersaline wastewaters contain diverse pollutants that harm the environment. Recovering clean water, alkali and acid from these wastewaters can promote circular economy and environmental protection. However, current electrochemical and advanced oxidation processes, which rely on hydroxyl radicals to degrade organic compounds, are inefficient and energy intensive. Here we report a flow-through redox-neutral electrochemical reactor (FRER) that effectively removes organic contaminants from hypersaline wastewaters via the chlorination-dehalogenation-hydroxylation route involving radical-radical cross-coupling. Bench-scale experiments demonstrate that the FRER achieves over 75% removal of total organic carbon across various compounds, and it maintains decontamination performance for over 360 h and continuously treats real hypersaline wastewaters for two months without corrosion. Integrating the FRER with electrodialysis reduces operating costs by 63.3% and CO2 emissions by 82.6% when compared with traditional multi-effect evaporation-crystallization techniques, placing our system at technology readiness levels of 7-8. The desalinated water, high-purity NaOH (>95%) and acid produced offset industrial production activities and thus support global sustainable development objectives.

Primary Amine Functionalized Carbon Dots for Dead and Alive Bacterial Imaging.

Small molecular dyes are commonly used for bacterial imaging, but they still meet a bottleneck of biological toxicity and fluorescence photobleaching. Carbon dots have shown high potential for bio-imaging due to their low cost and negligible toxicity and anti-photobleaching. However, there is still large space to enhance the quantum yield of the carbon quantum dots and to clarify their mechanisms of bacterial imaging. Using carbon dots for dyeing alive bacteria is difficult because of the thick density and complicated structure of bacterial cell walls. In this work, both dead or alive bacterial cell imaging can be achieved using the primary amine functionalized carbon dots based on their small size, excellent quantum yield and primary amine functional groups. Four types of carbon quantum dots were prepared and estimated for the bacterial imaging. It was found that the spermine as one of precursors can obviously enhance the quantum yield of carbon dots, which showed a high quantum yield of 66.46% and high fluorescence bleaching-resistance (70% can be maintained upon 3-h-irradiation). Furthermore, a mild modifying method was employed to bound ethylenediamine on the surface of the spermine-carbon dots, which is favorable for staining not only the dead bacterial cells but also the alive ones. Investigations of physical structure and chemical groups indicated the existence of primary amine groups on the surface of spermine-carbon quantum dots (which own a much higher quantum yield) which can stain alive bacterial cells visibly. The imaging mechanism was studied in detail, which provides a preliminary reference for exploring efficient and environment-friendly carbon dots for bacterial imaging.

Electrogenerated copper selenide with positive charge to efficiently capture and combat drug-resistant bacteria for wound healing.

Limited by the effective radius of metal ion release, higher concentrations of antibacterial agents are usually required to achieve satisfactory efficacy. Unfortunately, the potential cytotoxicity of metal ions limits the administered dose, which greatly hinders the widespread use of metal antibacterial agents. In this work, we used a convenient electrochemical method to prepare electropositive copper selenide (CuSe) nanosheets gathered from the cathode. Under physiological conditions, trace amounts of electrolytic CuSe (E-CuSe, 1 µg mL-1) could electrostatically bind to bacterial membranes and almost completely kill three resistant bacteria models (106 colony forming unit (CFU) mL-1). The extremely low effective dose of E-CuSe reaches a new benchmark in comparison with copper-based nanomaterials in other related studies. In addition, due to the reasonable coupling of selenium and copper, the as-prepared E-CuSe nanosheets exhibit lower cytotoxicity compared to copper oxide. As expected, the E-CuSe performed well in resistant bacteria-infected wound healing in rats, rapidly promoting wound tissue with a diameter of about 1 cm recovery within 7 days. Transcriptome analysis revealed the E-CuSe mainly acted on the membrane transport and DNA synthesis systems of bacterial cells. This work presents an efficient and in-depth paradigm for the scientific design and inactivation mechanism of metal antibacterial agents.

Highly selective fluorescent probe for detecting mercury ions in water.

Mercury ion (Hg2+) is a well-known toxic heavy metal. It has become one of the most significant environmental pollutants in the world because of its serious physiological toxicity, persistence, easy migration, and high bioconcentration. Thus, the development of methods for monitoring Hg2+ is indispensable. Herein, we have designed and synthesized a new fluorescent probe, TPH, for the detection of Hg2+ in the water environment. The TPH probe could quantitatively detect Hg2+ between 0 and 5 µM (LOD = 16 nM), with a linear range of 0-2.5 µM. In addition, the TPH probe was used to monitor Hg2+ in water samples successfully. Thus, this probe is suitable for monitoring Hg2+ in the actual water environment.

Array Study of VLF Thin-Film Magnetoelectric Antenna with a Microbridge Structure.

Recently, magnetoelectric (ME) antennas have become a hot topic in the field of antenna miniaturization in the very-low-frequency (VLF) band because their size can be reduced to one-ten-thousandth of the size of conventional electric antennas. However, they still suffer from narrow transmission/reception bandwidth and weak radiation intensity. To address these issues, VLF thin-film ME antennas with a microbridge structure are designed, and the method of array connection is used. Test results show that the detection limit of the ME antenna unit is 636 pT/√Hz at 23 kHz and the radiant magnetic field intensity at 0.12 m is 0.87 nT (input power of 10 mW). By series-connecting three ME antenna units with the same resonance frequency, the output response has been increased to 1.72 times and the EM wave radiation intensity is increased to 1.9 times compared to a single unit. By parallel-connecting two ME antenna units with different resonance frequencies, the output response bandwidth has been expanded to 1.56 times compared to a single unit, and the signal radiation bandwidth has been expanded to 1.47 times. This work provides a valuable reference for the future larger-scale arraying of ME antennas.

Insights into the antibacterial mechanism of iron doped carbon dots.

Antibacterial nanomaterials provide promising alternative strategies to combat the bacterial infection due to deteriorating resistance. However, few have been practically applied due to the lack of clear antibacterial mechanisms. In this work, we selected good-biocompatibility iron-doped CDs (Fe-CDs) with antibacterial activity as a comprehensive research model to systematically reveal the intrinsic antibacterial mechanism. Through energy dispersive spectroscopy (EDS) mapping of in situ ultrathin sections of bacteria, we found that a large amount of iron was accumulated inside the bacteria treated with Fe-CDs. Then, combining the data of cell level and transcriptomics, it can be elucidated that Fe-CDs could interact with cell membranes, enter bacterial cells through iron transport and infiltration, increase intracellular iron levels, trigger increased reactive oxygen species (ROS), and lead to disruption of Glutathione (GSH)-dependent antioxidant mechanisms. Excessive ROS further leads to lipid peroxidation and DNA damage in cells, lipid peroxidation destroys the integrity of the cell membrane, and finally leads to the leakage of intracellular substances resulting in bacterial growth inhibition and death. This result provides important insights into the antibacterial mechanism of Fe-CDs and further provides a basis for the deep application of nanomaterials in biomedicine.

A Nano-Autophagy Inhibitor Triggering Reciprocal Feedback Control of Cholesterol Depletion for Solid Tumor Therapy.

Solid tumors are characterized by enhanced metabolism of lipid, particularly cholesterol, inspiring the exploration of metabolic therapy through cholesterol oxidase (COD)-mediated cholesterol deprivation. However, the therapeutic efficacy of COD is limited due to the hypoxic tumor microenvironment and the protective autophagy triggered by cholesterol deprivation. Herein, a combination therapy for metabolically treating solid tumors through COD in conjunction with molybdenum oxide nanodots (MONDs), which serve as both potent oxygen generators and autophagy inhibitors, is reported. MONDs convert H2 O2 (arising from COD-mediated cholesterol oxidation) into O2 , which is then recycled by COD to form reciprocal feedback for cholesterol depletion. Concurrently, MONDs can overcome autophagy-induced therapeutic resistance frequently occurring in conventional nutrient deprivation therapy by activating AKT/mTOR pathway phosphorylation. Combination therapy in the xenograft model results in an ≈5-fold increase in therapeutic efficiency as compared with COD treatment alone. This functionally cooperative metabolic coupling strategy holds great promise as a novel polytherapy approach that will benefit patients with solid tumors.

The STROMICS genome study: deep whole-genome sequencing and analysis of 10K Chinese patients with ischemic stroke reveal complex genetic and phenotypic interplay.

Ischemic stroke is a leading cause of global mortality and long-term disability. However, there is a paucity of whole-genome sequencing studies on ischemic stroke, resulting in limited knowledge of the interplay between genomic and phenotypic variations among affected patients. Here, we outline the STROMICS design and present the first whole-genome analysis on ischemic stroke by deeply sequencing and analyzing 10,241 stroke patients from China. We identified 135.59 million variants, > 42% of which were novel. Notable disparities in allele frequency were observed between Chinese and other populations for 89 variants associated with stroke risk and 10 variants linked to response to stroke medications. We investigated the population structure of the participants, generating a map of genetic selection consisting of 31 adaptive signals. The adaption of the MTHFR rs1801133-G allele, which links to genetically evaluated VB9 (folate acid) in southern Chinese patients, suggests a gene-specific folate supplement strategy. Through genome-wide association analysis of 18 stroke-related traits, we discovered 10 novel genetic-phenotypic associations and extensive cross-trait pleiotropy at 6 lipid-trait loci of therapeutic relevance. Additionally, we found that the set of loss-of-function and cysteine-altering variants present in the causal gene NOTCH3 for the autosomal dominant stroke disorder CADASIL displayed a broad neuro-imaging spectrum. These findings deepen our understanding of the relationship between the population and individual genetic layout and clinical phenotype among stroke patients, and provide a foundation for future efforts to utilize human genetic knowledge to investigate mechanisms underlying ischemic stroke outcomes, discover novel therapeutic targets, and advance precision medicine.