Association of chrononutrition patterns with biological aging: evidence from a nationally representative cross-sectional study.

Previous studies mostly focused on the benefits of caloric restriction and fasting on longevity. However, whether the timing and frequency of eating affect aging remains unclear. Here, we investigated the associations between chrononutrition patterns and biological aging, and explored whether and to what extent dietary inflammation mediated this association. 16 531 adults aged 20 to 84 years from the National Health and Nutrition Examination Survey were collected. Chrononutrition patterns were determined with two 24-hour dietary recalls. Phenotypic age was calculated to reflect the biological aging status. The dietary inflammatory index (DII) was used to assess the dietary inflammation. After adjustment of the survey weight and multiple covariates including total energy intake, participants in the third tertile of the time of the first meal (mean 10 : 26) exhibited more advanced biological age (ß 0.64; 95% CI, 0.26-1.00) and a higher incidence of accelerated aging (odds ratio (OR) 1.25; 95% CI, 1.06-1.47) compared to those of the first tertile (mean 6 : 14). Higher eating frequency was associated with delayed biological aging in both multivariable linear (ß -0.31; 95% CI, -0.44 to -0.19) and logistic regression model (OR 0.90; 95% CI, 0.85-0.95). Furthermore, we found that DII rather than metabolic factors mediated the inverse association between eating frequency and biological aging (mediation proportion 24.67%; 95% CI, 19.83%-32.00%). Our findings demonstrated the association between chrononutrition patterns and biological aging among the US general population and the potential role of dietary inflammation in this association, suggesting that modifying chrononutrition patterns may be a practical and cost-effective strategy for combating aging.

Effect of ozone treatment on phenylpropanoid metabolism in harvested cantaloupes.

Phenylpropanoid metabolism plays an important role in cantaloupe ripening and senescence, but the mechanism of ozone regulation on phenylpropanoid metabolism remains unclear. This study investigated how ozone treatment modulates the levels of secondary metabolites associated with phenylpropanoid metabolism, the related enzyme activities, and gene expression in cantaloupe. Treating cantaloupes with 15 mg/m3 of ozone after precooling can help maintain postharvest hardness. This treatment also enhances the production and accumulation of secondary metabolites, such as total phenols, flavonoids, and lignin. These metabolites are essential components of the phenylpropanoid metabolic pathway, activating enzymes like phenylalanine ammonia-lyase, cinnamate 4-hydroxylase, 4CL, chalcone synthase, and chalcone isomerase. The results of the transcriptional expression patterns showed that differential gene expression related to phenylpropanoid metabolism in the peel of ozone-treated cantaloupes was primarily observed during the middle and late storage stages. In contrast, the pulp exhibited significant differential gene expression mainly during the early storage stage. Furthermore, it was observed that the level of gene expression in the peel was generally higher than that in the pulp. The correlation between the relative amount of gene changes in cantaloupe, activity of selected enzymes, and concentration of secondary metabolites could be accompanied by positive regulation of the phenylpropanoid metabolic pathway. Therefore, ozone stress induction positively enhances the biosynthesis of flavonoids in cantaloupes, leading to an increased accumulation of secondary metabolites. Additionally, it also improves the postharvest storage quality of cantaloupes.

Intraoperative hypotension is associated with decreased long-term survival in older patients after major noncardiac surgery: Secondary analysis of three randomized trials.

STUDY OBJECTIVE: To assess the association of intraoperative hypotension with long-term survivals in older patients after major noncardiac surgery mainly for cancer. DESIGN: A secondary analysis of databases from three randomized trials with long-term follow-up. SETTING: The underlying trials were conducted in 17 tertiary hospitals in China. PATIENTS: Patients aged 60 to 90 years who underwent major noncardiac thoracic or abdominal surgeries (≥ 2 h) in a single center were included in this analysis. EXPOSURES: Restricted cubic spline models were employed to determine the lowest mean arterial pressure (MAP) threshold that was potentially harmful for long-term survivals. Patients were arbitrarily divided into three groups according to the cumulative duration or area under the MAP threshold. The association between intraoperative hypotension exposure and long-term survivals were analyzed with the Cox proportional hazard regression models. MEASUREMENTS: Our primary endpoint was overall survival. Secondary endpoints included recurrence-free and event-free survivals. MAIN RESULTS: A total of 2664 patients (mean age 69.0 years, 34.9% female sex, 92.5% cancer surgery) were included in the final analysis. MAP < 60 mmHg was adopted as the threshold of intraoperative hypotension. Patients were divided into three groups according to duration under MAP < 60 mmHg (<1 min, 1-10 min, and > 10 min) or area under MAP <60 mmHg (< 1 mmHg⋅min, 1-30 mmHg⋅min, and > 30 mmHg⋅min). After adjusting confounders, duration under MAP < 60 mmHg for > 10 min was associated with a shortened overall survival when compared with the < 1 min patients (adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.57, P = 0.004); area under MAP < 60 mmHg for > 30 mmHg⋅min was associated with a shortened overall survival when compared with the < 1 mmHg⋅min patients (adjusted HR 1.40, 95% CI 1.16 to 1.68, P < 0.001). Similar associations exist between duration under MAP < 60 mmHg for > 10 min or area under MAP < 60 mmHg for > 30 mmHg⋅min and recurrence-free or event-free survivals. CONCLUSIONS: In older patients who underwent major noncardiac surgery mainly for cancer, intraoperative hypotension was associated with worse overall, recurrence-free, and event-free survivals.

A multi-bin rarefying method for evaluating alpha diversities in TCR sequencing data.

MOTIVATION: T cell receptors (TCRs) constitute a major component of our adaptive immune system, governing the recognition and response to internal and external antigens. Studying the TCR diversity via sequencing technology is critical for a deeper understanding of immune dynamics. However, library sizes differ substantially across samples, hindering the accurate estimation/comparisons of alpha diversities. To address this, researchers frequently use an overall rarefying approach in which all samples are sub-sampled to an even depth. Despite its pervasive application, its efficacy has never been rigorously assessed. RESULTS: In this paper, we develop an innovative "multi-bin" rarefying approach that partitions samples into multiple bins according to their library sizes, conducts rarefying within each bin for alpha diversity calculations, and performs meta-analysis across bins. Extensive simulations using real-world data highlight the inadequacy of the overall rarefying approach in controlling the confounding effect of library size. Our method proves robust in addressing library size confounding, outperforming competing normalization strategies by achieving better-controlled type-I error rates and enhanced statistical power in association tests. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/mli171/MultibinAlpha. The datasets are freely available at https://doi.org/10.21417/B7001Z and https://doi.org/10.21417/AR2019NC. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Self-crosslinking hyaluronic acid hydrogel as an enteroprotective agent for the treatment of inflammatory bowel disease.

The pathological changes in inflammatory bowel disease (IBD) include the disruption of intestinal barrier function and the infiltration of pathogenic microbes. The application of an artificial protective barrier at the site of inflammation can prevent bacterial infiltration, promote epithelial cell migration, and accelerate wound healing. In this study, dopamine-modified hyaluronic acid (HA-DA) was developed as a bioadhesive self-cross-linkable hydrogel, which acted as an enteroprotective agent to promote the healing of inflamed intestinal tissue. The adhesion strength HA-DA to mouse colon was 3.81-fold higher than HA. Moreover, HA-DA promoted Caco-2 cell proliferation and migration as well as had a strong physical barrier effect after gelation. After oral administration, the HA-DA reduced weight loss and attenuated impaired goblet cell function in mice with dextran sodium sulfate-induced IBD. In addition, HA-DA promoted restoration of the epithelial barrier by the upregulation of tight junction proteins. The results reported herein substantiated that self-cross-linkable hydrogel-based enteroprotective agents are a promising approach for the treatment of IBD.

Postbiotics Prepared Using Lactobacillus reuteri Ameliorates Ethanol-Induced Liver Injury by Regulating the FXR/SHP/SREBP-1c Axis.

SCOPE: While probiotics-based therapies have exhibited potential in alleviating alcohol-associated liver disease (ALD), the specific role of postbiotics derived from Lactobacillus reuteri (L. reuteri) in ALD remains elusive. This study aims to investigate the impact of postbiotics on ameliorating alcohol-induced hepatic steatosis and the underlying mechanisms. METHODS AND RESULTS: Using network pharmacology, the study elucidates the targets and pathways impacted by postbiotics from L. reuteri, identifying the farnesoid X receptor (FXR) as a promising target for postbiotics against ALD, and lipid metabolism and alcoholism act as crucial pathways associated with postbiotics-targeting ALD. Furthermore, the study conducts histological and biochemical analyses coupled with LC/MS to evaluate the protective effects and mechanisms of postbiotics against ALD. Postbiotics may modulate bile acid metabolism in vivo by regulating FXR signaling, activating the FXR/FGF15 pathway, and influencing the enterohepatic circulation of bile acids (BAs). Subsequently, postbiotics regulate hepatic FXR activated by BAs and modulate the expression of FXR-mediated protein, including short regulatory partner (SHP) and sterol regulatory element binding protein-1c (SREBP-1c), thereby ameliorating hepatic steatosis in mice with ALD. CONCLUSION: Postbiotics effectively alleviate ethanol-induced hepatic steatosis by regulating the FXR/SHP/SREBP-1c axis, as rigorously validated in both in vivo and in vitro.

GaN Nano Air Channel Diodes: Enabling High Rectification Ratio and Neutron Robust Radiation Operation.

Nano air channel transistors (NACTs) provide numerous advantages over traditional silicon devices, including faster switching speeds, higher operating frequencies, and enhanced radiation hardness attributable to the ballistic transport of electrons. In the development of field-emission-based integrated circuits, low-power consumption rectifying nano air channel diodes (NACDs) play a crucial role. However, achieving rectification characteristics in NACDs is challenging due to their structural and material symmetry. This paper proposes a vertical GaN NACD with a consistent nano air channel fabricated using IC-compatible processes. The GaN NACD exhibits an exceptionally low turn-on voltage of 0.3 V while delivering a high output current of 5.02 mA at 3 V. Notably, it demonstrates a high rectification ratio of up to 2.2 × 105, attributing to significant work function disparities within the GaN-Au structure, coupled with the reduction of Au surface roughness to minimize reverse current. Furthermore, the junction-free structure and superior material properties of GaN enable the NACD to be suitable for use in radiation-rich environments. With its potential as a fundamental component of ultrafast and ultrahigh-frequency integrated circuits, this intriguing and cost-effective rectifying diode is anticipated to garner widespread interest within the electronics community.

Teleost-specific TLR23 in Takifugu rubripes recruits MyD88 to trigger ERK pathway and promotes antibacterial defense.

Takifugu rubripes is a highly valued cultured fish in Asia, while pathogen infections can result in severe diseases and lead to substantial economic losses. Toll-like receptors (TLRs), as pattern recognition receptors, play a crucial role on recognition pathogens and initiation innate immune response. However, the immunological properties of teleost-specific TLR23 remain largely unknown. In this study, we investigated the biological functions of TLR23 (TrTLR23) from T. rubripes, found that TrTLR23 existed in various organs. Following bacterial pathogen challenge, the expression levels of TrTLR23 were significantly increased in immune related organs. TrTLR23 located on the cellular membrane and specifically recognized pathogenic microorganism. Co-immunoprecipitation and antibody blocking analysis revealed that TrTLR23 recruited myeloid differentiation primary response protein (MyD88), thereby mediating the activation of the ERK signaling pathway. Furthermore, in vivo showed that, when TrTLR23 is overexpressed in T. rubripes, bacterial replication in fish tissues is significantly inhibited. Consistently, when TrTLR23 expression in T. rubripes is knocked down, bacterial replication is significantly enhanced. In conclusion, these findings suggested that TrTLR23 played a critical role on mediation TLR23-MyD88-ERK axis against bacterial infection. This study revealed that TLR23 involved in the innate immune mechanism, and provided the foundation for development disease control strategies in teleost.

A critical review of biochar as an environmental functional material in soil ecosystems for migration and transformation mechanisms and ecological risk assessment.

At present, biochar has a large application potential in soil amelioration, pollution remediation, carbon sequestration and emission reduction, and research on the effect of biochar on soil ecology and environment has made positive progress. However, under natural and anthropogenic perturbations, biochar may undergo a series of environmental behaviors such as migratory transformation, mineralization and decomposition, and synergistic transport, thus posing certain potential risks. This paper outlines the multi-interfacial migration pathway of biochar in "air-soil-plant-animal-water", and analyzes the migration process and mechanism at different interfaces during the preparation, transportation and application of biochar. The two stages of the biochar mineralization process (mineralization of easily degradable aliphatic carbon components in the early stage and mineralization of relatively stable aromatic carbon components in the later stage) were described, the self-influencing factors and external environmental factors of biochar mineralization were analyzed, and the mineral stabilization mechanism and positive/negative excitation effects of biochar into the soil were elucidated. The proximity between field natural and artificially simulated aging of biochar were analyzed, and the change of its properties showed a trend of biological aging > chemical aging > physical aging > natural aging, and in order to improve the simulation and prediction, the artificially simulated aging party needs to be changed from a qualitative method to a quantitative method. The technical advantages, application scope and potential drawbacks of different biochar modification methods were compared, and biological modification can create new materials with enhanced environmental application. The stability performance of modified biochar was compared, indicating that raw materials, pyrolysis temperature and modification method were the key factors affecting the stability of biochar. The potential risks to the soil environment from different pollutants carried by biochar were summarized, the levels of pollutants released from biochar in the soil environment were highlighted, and a comprehensive selection of ecological risk assessment methods was suggested in terms of evaluation requirements, data acquisition and operation difficulty. Dynamic tracing of migration decomposition behavior, long-term assessment of pollution remediation effects, and directional design of modified composite biochar materials were proposed as scientific issues worthy of focused attention. The results can provide a certain reference basis for the theoretical research and technological development of biochar.

Effects of zein extractions on the structural properties of SPI-zein composite gels: Implications for gluten-free plant-based products.

The growing global interest in physical and environmental health has led to the development of plant-based products. Although soy protein and wheat gluten are commonly utilized, concerns regarding gluten-related health issues have driven exploration into alternative proteins. Zein has emerged as a promising option. This research investigated the impact of extraction methods on zein characteristics and the structures of SPI-zein composite gels. Different extraction methods yielded zein with protein contents ranging from 48.12 % to 64.34 %. Ethanol-extracted Z1 and Z3, obtained at different pH conditions, exhibited zeta potential of -3.25 and 5.43 mV, respectively. They displayed similar characteristics to commercial zein and interacted comparably in composite gels. Conversely, alkaline-extracted Z2 had a zeta potential of -2.37 mV and formed distinct gels when combined with SPI. These results indicated that extraction methods influence zein behaviour in composite gels, offering possibilities for tailored formulations and expanding zein's applications, particularly in gluten-free plant-based products.

circZNF532 promotes endothelial-to-mesenchymal transition in diabetic retinopathy by recruiting TAF15 to stabilize PIK3CD.

Endothelial-to-mesenchymal transition (EndMT) is a pivotal event in diabetic retinopathy (DR). This study explored the role of circRNA zinc finger protein 532 (circZNF532) in regulating EndMT in DR progression. Human retinal microvascular endothelial cells (HRMECs) were exposed to high glucose (HG) to induce the DR cell model. Actinomycin D-treated HRMECs were used to confirm the mRNA stability of phosphoinositide-3 kinase catalytic subunit δ (PIK3CD). The interaction between TATA-box-binding protein-associated factor 15 (TAF15) and circZNF532/PIK3CD was subsequently analyzed using RNA immunoprecipitation (RIP), RNA pull-down. It was found that HG treatment accelerated EndMT process, facilitated cell migration and angiogenesis, and enhanced PIK3CD and p-AKT levels in HRMECs, whereas si-circZNF532 transfection neutralized these effects. Further data showed that circZNF532 recruited TAF15 to stabilize PIK3CD, thus elevating PIK3CD expression. Following rescue experiments suggested that PIK3CD overexpression partially negated the inhibitory effect of circZNF532 silencing on EndMT, migration, and angiogenesis of HG-treated HRMECs. In conclusion, our results suggest that circZNF532 recruits TAF15 to stabilize PIK3CD, thereby facilitating EndMT in DR.

Treatment of Syringomyelia Characterized by Focal Dilatation of the Central Canal Using Mesenchymal Stem Cells and Neural Stem Cells.

BACKGROUND: Syringomyelia is a progressive chronic disease that leads to nerve pain, sensory dissociation, and dyskinesia. Symptoms often do not improve after surgery. Stem cells have been widely explored for the treatment of nervous system diseases due to their immunoregulatory and neural replacement abilities. METHODS: In this study, we used a rat model of syringomyelia characterized by focal dilatation of the central canal to explore an effective transplantation scheme and evaluate the effect of mesenchymal stem cells and induced neural stem cells for the treatment of syringomyelia. RESULTS: The results showed that cell transplantation could not only promote syrinx shrinkage but also stimulate the proliferation of ependymal cells, and the effect of this result was related to the transplantation location. These reactions appeared only when the cells were transplanted into the cavity. Additionally, we discovered that cell transplantation transformed activated microglia into the M2 phenotype. IGF1-expressing M2 microglia may play a significant role in the repair of nerve pain. CONCLUSION: Cell transplantation can promote cavity shrinkage and regulate the local inflammatory environment. Moreover, the proliferation of ependymal cells may indicate the activation of endogenous stem cells, which is important for the regeneration and repair of spinal cord injury.

The change of intimate relationship between people with Alzheimer's disease and their adult child caregivers: An interpretative phenomenological analysis.

This study aims to explore the change of intimate relationship between people with Alzheimer's disease and their adult child caregivers as the disease progresses. Twelve adult child caregivers were recruited through purposive sampling. Explanatory phenomenological analysis was conducted to analyse data collected by semi-structured in-depth interviews. This study found a dynamically changing relationship between adult child caregivers and their parents with Alzheimer's disease during care giving that evolved with the progress of the disease. The relationship was the most intimate in the middle stage of the disease for most caregivers and a new reciprocal relationship developed due to caregiving. Caregivers experienced different degrees of self-growth when providing care, though caregiver burdens were common. The positive experience and perception of caregivers were important for improving the quality of life for adult child caregivers of people with Alzheimer's disease.

Ordered mesoporous hairbrush-like nanocarbon assembled microfibers for solid-phase microextraction of benzene series in oilfield sewage.

The development of advanced functional nanomaterials for solid-phase microextraction (SPME) remains an imperative aspect of sample pretreatment. Herein, we introduce a novel SPME fiber consisting of graphene fibers modified with ordered mesoporous carbon nanotubes arrays (CNTAs) tailored for the determination of benzene series in oilfield wastewater, which is synthesized by an ionic liquid-assisted wet spinning process of graphene nanosheets, followed by a precisely controlled growth of metal-organic framework and subsequent pyrolysis treatment. The resulting robust microfiber structure resembles a "hairbrush" configuration, with a crumpled graphene fiber "stem" and high-order mesoporous CNTAs "hairs". This unique architecture significantly enhances the SPME capacity, as validated by gas chromatography-mass spectrometry. The hairbrush-like nanocarbon assembled microfibers possess structural characteristics, a high specific surface area, and numerous binding sites, offering efficient enrichment of benzene series compounds in oilfield wastewater, including benzene, ethylbenzene, m-xylene, p-xylene, and toluene. Our analysis demonstrates that these microfibers exhibit broad linear ranges (0.2-600 µg L-1), low detection limits (0.005-0.03 mg L-1), and excellent repeatability (3.2-5.5% for one fiber, 2.1-6.7% for fiber-to-fiber) for detection. When compared to commercial alternatives, these hairbrush-like nanocarbon-assembled microfibers exhibit significantly enhanced extraction efficiency for benzene series compounds.

PARP inhibitors suppress tumours via centrosome error-induced senescence independent of DNA damage response.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as promising chemotherapeutic drugs primarily against BRCA1/2-associated tumours, known as synthetic lethality. However, recent clinical trials reported patients' survival benefits from PARP inhibitor treatments, irrelevant to homologous recombination deficiency. Therefore, revealing the therapeutic mechanism of PARP inhibitors beyond DNA damage repair is urgently needed, which can facilitate precision medicine. METHODS: A CRISPR-based knock-in technology was used to establish stable BRCA1 mutant cancer cells. The effects of PARP inhibitors on BRCA1 mutant cancer cells were evaluated by biochemical and cell biological experiments. Finally, we validated its in vivo effects in xenograft and patient-derived xenograft (PDX) tumour mice. FINDINGS: In this study, we uncovered that the majority of clinical BRCA1 mutations in breast cancers were in and near the middle of the gene, rather than in essential regions for DNA damage repair. Representative mutations such as R1085I and E1222Q caused transient extra spindle poles during mitosis in cancer cells. PAR, which is synthesized by PARP2 but not PARP1 at mitotic centrosomes, clustered these transient extra poles, independent of DNA damage response. Common PARP inhibitors could effectively suppress PARP2-synthesized PAR and induce cell senescence by abrogating the correction of mitotic extra-pole error. INTERPRETATION: Our findings uncover an alternative mechanism by which PARP inhibitors efficiently suppress tumours, thereby pointing to a potential new therapeutic strategy for centrosome error-related tumours. FUNDING: Funded by National Natural Science Foundation of China (NSFC) (T2225006, 82272948, 82103106), Beijing Municipal Natural Science Foundation (Key program Z220011), and the National Clinical Key Specialty Construction Program, P. R. China (2023).

Clinical factors and major pathological response after neoadjuvant chemoimmunotherapy in potentially resectable lung squamous cell carcinoma.

Objective: Major pathological response (MPR) helps evaluate the prognosis of patients with lung squamous cell carcinoma (LUSC). However, the clinical factors that affect the achievement of MPR after neoadjuvant chemoimmunotherapy (NCIO) in patients with LUSC remain unclear. This study aimed to explore the clinical factors affecting the MPR after NCIO in patients with potentially resectable LUSC. Methods: This retrospective study included patients with stage IIB-IIIC LUSC who underwent surgical resection after receiving NCIO at a center between March 2020 and November 2022. In addition to the postoperative pathological remission rate, sex, age, body mass index (BMI), smoking history, TNM stage, hematological and imaging test results, and other indicators were examined before NCIO. According to the pathological response rate of the surgically removed tumor tissue, the patients were split into MPR and non-MPR groups. Results: In total, 91 LUSC patients who met the study's eligibility criteria were enrolled: 32 (35%) patients in the non-MPR group and 59 (65%) in the MPR group, which included 43 cases of pathological complete remission (pCR). Pre-treatment lymphocyte level (LY) (odds ratio [OR] =5.997), tumor burden (OR=0.958), N classification (OR=15.915), radiographic response (OR=11.590), pulmonary atelectasis (OR=5.413), and PD-L1 expression (OR=1.028) were independently associated with MPR (all P < 0.05). Based on these six independent predictors, we developed a nomogram model of prediction having an area under the curve (AUC) of 0.914 that is simple to apply clinically to predict the MPR. The MPR group showed greater disease-free survival (DFS) than the non-MPR group, according to the survival analysis (P < 0.001). Conclusion: The MPR rate of NCIO for potentially resectable LUSC was 65%. LY, tumor burden, N classification, radiographic response, pulmonary atelectasis, and PD-L1 expression in patients with LUSC before NCIO were the independent and ideal predictors of MPR. The developed nomogram demonstrated a good degree of accuracy and resilience in predicting the MPR following NCIO, indicating that it is a useful tool for assuring customized therapy for patients with possibly resectable LUSC.

IPEV: identification of prokaryotic and eukaryotic virus-derived sequences in virome using deep learning.

BACKGROUND: The virome obtained through virus-like particle enrichment contains a mixture of prokaryotic and eukaryotic virus-derived fragments. Accurate identification and classification of these elements are crucial to understanding their roles and functions in microbial communities. However, the rapid mutation rates of viral genomes pose challenges in developing high-performance tools for classification, potentially limiting downstream analyses. FINDINGS: We present IPEV, a novel method to distinguish prokaryotic and eukaryotic viruses in viromes, with a 2-dimensional convolutional neural network combining trinucleotide pair relative distance and frequency. Cross-validation assessments of IPEV demonstrate its state-of-the-art precision, significantly improving the F1-score by approximately 22% on an independent test set compared to existing methods when query viruses share less than 30% sequence similarity with known viruses. Furthermore, IPEV outperforms other methods in accuracy on marine and gut virome samples based on annotations by sequence alignments. IPEV reduces runtime by at most 1,225 times compared to existing methods under the same computing configuration. We also utilized IPEV to analyze longitudinal samples and found that the gut virome exhibits a higher degree of temporal stability than previously observed in persistent personal viromes, providing novel insights into the resilience of the gut virome in individuals. CONCLUSIONS: IPEV is a high-performance, user-friendly tool that assists biologists in identifying and classifying prokaryotic and eukaryotic viruses within viromes. The tool is available at https://github.com/basehc/IPEV.

Modulation of the microhomology-mediated end joining pathway suppresses large deletions and enhances homology-directed repair following CRISPR-Cas9-induced DNA breaks.

BACKGROUND: CRISPR-Cas9 genome editing often induces unintended, large genomic rearrangements, posing potential safety risks. However, there are no methods for mitigating these risks. RESULTS: Using long-read individual-molecule sequencing (IDMseq), we found the microhomology-mediated end joining (MMEJ) DNA repair pathway plays a predominant role in Cas9-induced large deletions (LDs). We targeted MMEJ-associated genes genetically and/or pharmacologically and analyzed Cas9-induced LDs at multiple gene loci using flow cytometry and long-read sequencing. Reducing POLQ levels or activity significantly decreases LDs, while depleting or overexpressing RPA increases or reduces LD frequency, respectively. Interestingly, small-molecule inhibition of POLQ and delivery of recombinant RPA proteins also dramatically promote homology-directed repair (HDR) at multiple disease-relevant gene loci in human pluripotent stem cells and hematopoietic progenitor cells. CONCLUSIONS: Our findings reveal the contrasting roles of RPA and POLQ in Cas9-induced LD and HDR, suggesting new strategies for safer and more precise genome editing.

Causes and global, regional, and national burdens of traumatic brain injury from 1990 to 2019.

PURPOSE: Traumatic brain injury (TBI), currently a major global public health problem, imposes a significant economic burden on society and families. We aimed to quantify and predict the incidence and severity of TBI by analyzing its incidence, prevalence, and years lived with disability (YLDs). The epidemiological changes in TBI from 1990 to 2019 were described and updated to provide a reference for developing prevention, treatment, and incidence-reducing measures for TBI. METHODS: A secondary analysis was performed on the incidence, prevalence, and YLDs of TBI by sex, age group, and region (n = 21,204 countries and territories) between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Proportions in the age-standardized incidence rate due to underlying causes of TBI and proportions of minor and moderate or severe TBI were also reported. RESULTS: In 2019, there were 27.16 million (95% uncertainty intervals (UI): 23.36 - 31.42) new cases of TBI worldwide, with age-standardized incidence and prevalence rates of 346 per 100,000 population (95% UI: 298-401) and 599 per 100,000 population (95% UI: 573-627), respectively. From 1990 to 2019, there were no significant trends in global age-standardized incidence (estimated annual percentage changes: -0.11%, 95% UI: -0.18% - -0.04%) or prevalence (estimated annual percentage changes: 0.01%, 95% UI: -0.04% - 0.06%). TBI caused 7.08 million (95% UI: 5.00 - 9.59) YLDs in 2019, with age-standardized rates of 86.5 per 100,000 population (95% UI: 61.1 - 117.2). In 2019, the countries with higher incidence rates were mainly distributed in Central Europe, Eastern Europe, and Australia. The 2019 global age-standardized incidence rate was higher in males than in females. The 2019 global incidence of moderate and severe TBI was 182.7 per 100,000 population, accounting for 52.8% of all TBI, with falls and road traffic injuries being the main causes in most regions. CONCLUSIONS: The incidence of moderate and severe TBI was slightly higher in 2019, and TBI still accounts for a significant portion of the global injury burden. The likelihood of moderate to severe TBI and the trend of major injury under each injury cause from 1990 to 2019 and the characteristics of injury mechanisms in each age group are presented, providing a basis for further research on injury causes in each age group and the future establishment of corresponding policies and protective measures.

[Effects of Platelet-Rich Plasma-Derived Exosomes on Proliferation and Migration of Tendon Stem/Progenitor Cell].

Objective To investigate the effects of platelet-rich plasma-derived exosomes (PRP-Exos) on the proliferation and migration of tendon stem/progenitor cell (TSPC).Methods PRP-Exos were extracted through the combination of polymer-based precipitation and ultracentrifugation.The morphology,concentration,and particle size of PRP-Exos were identified by transmission electron microscopy and nanoparticle tracking analysis.The expression levels of surface marker proteins on PRP-Exos and platelet membrane glycoproteins were determined by Western blot analysis.Rat TSPC was extracted and cultured,and the expression of surface marker molecules on TSPC was detected using flow cytometry and immunofluorescence staining.The proliferation of TSPC influenced by PRP-Exos was evaluated using CCK-8 assay and EdU assay.The effect of PRP-Exos on the migration of TSPC was evaluated by cell scratch assay and Transwell assay.Results The extracted PRP-Exos exhibit typical saucer-like structures,with a concentration of 4.9×1011 particles/mL,an average particle size of (132.2±56.8) nm,and surface expression of CD9,CD63 and CD41.The extracted TSPC expressed the CD44 protein.PRP-Exos can be taken up by TSPC,and after co-cultured for 48 h,concentrations of 50 and 100 µg/mL of PRP-Exos significantly promoted the proliferation of TSPC (both P<0.001),with no statistical difference between the two concentrations (P=0.283).Additionally,after co-cultured for 24 h,50 µg/mL of PRP-Exos significantly promoted the migration of TSPC (P<0.001).Conclusion Under in vitro culture conditions,PRP-Exos significantly promote the proliferation and migration of rat TSPC.