Anchoring Single-Atomic Metal Sites in Metalloporphyrin-Based Covalent Organic Frameworks for Enhanced Photocatalytic Hydrogen Evolution.

A photoactive covalent organic framework (COF) was built from metalloporphyrin and bipyridine monomers and single-atomic Pt sites were subsequently installed. Integrating photosensitizing metalloporphyrin and substrate-activating Pt(bpy) moieties in a single solid facilitates multielectron transfer and accelerates photocatalytic hydrogen evolution with a maximum production rate of 80.4 mmol h-1 gPt-1 and turnover frequency (TOF) of 15.7 h-1 observed. This work demonstrates that incorporation of single-atomic metal sites with photoactive COFs greatly enhances photocatalytic activity and provides an effective strategy for the design and construction of novel photocatalysts.

Photoredox Synthesis of Silicon-Containing Isoindolin-1-ones and Deuterated Analogues Through Hydrosilylation and Deuterium-silylation.

An efficient, practical, and metal-free protocol for the synthesis of silicon-containing isoindolin-1-ones and deuterated analogues via the synergistic combination of an organic photoredox and hydrogen atom transfer process is described. This strategy features mild reaction conditions, high atom economy, and excellent functional group compatibility, delivering a myriad of structurally diverse and valuable products with good to excellent yields.

Revealing prognostic insights of programmed cell death (PCD)-associated genes in advanced non-small cell lung cancer.

The management of patients with advanced non-small cell lung cancer (NSCLC) presents significant challenges due to cancer cells' intricate and heterogeneous nature. Programmed cell death (PCD) pathways are crucial in diverse biological processes. Nevertheless, the prognostic significance of cell death in NSCLC remains incompletely understood. Our study aims to investigate the prognostic importance of PCD genes and their ability to precisely stratify and evaluate the survival outcomes of patients with advanced NSCLC. We employed Weighted Gene Co-expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), univariate and multivariate Cox regression analyses for prognostic gene screening. Ultimately, we identified seven PCD-related genes to establish the PCD-related risk score for the advanced NSCLC model (PRAN), effectively stratifying overall survival (OS) in patients with advanced NSCLC. Multivariate Cox regression analysis revealed that the PRAN was the independent prognostic factor than clinical baseline factors. It was positively related to specific metabolic pathways, including hexosamine biosynthesis pathways, which play crucial roles in reprogramming cancer cell metabolism. Furthermore, drug prediction for different PRAN risk groups identified several sensitive drugs explicitly targeting the cell death pathway. Molecular docking analysis suggested the potential therapeutic efficacy of navitoclax in NSCLC, as it demonstrated strong binding with the amino acid residues of C-C motif chemokine ligand 14 (CCL14), carboxypeptidase A3 (CPA3), and C-X3-C motif chemokine receptor 1 (CX3CR1) proteins. The PRAN provides a robust personalized treatment and survival assessment tool in advanced NSCLC patients. Furthermore, identifying sensitive drugs for distinct PRAN risk groups holds promise for advancing targeted therapies in NSCLC.

The relationship between mean corpuscular hemoglobin concentration and mortality in hypertensive individuals: A population-based cohort study.

INTRODUCTION: Hematology is an essential field for investigating the prognostic outcomes of cardiovascular diseases (CVDs). Recent research has suggested that mean corpuscular hemoglobin concentration (MCHC) is associated with a poor prognosis in several CVDs. There is no evidence of a correlation between MCHC and hypertension. Therefore, our study aimed to analyze the association of MCHC with all-cause and cardiovascular mortality in hypertensive patients. METHODS: We used cohort data from U.S. adults who participated in the National Health and Nutrition Examination Survey from 1999-2014. COX regression was applied to analyze the relationship between MCHC and all-cause and cardiovascular mortality. In addition, three models were adjusted to reduce confounding factors. We reanalyzed the data after propensity score matching (PSM) to inspect the stability of the results. Stratified analysis was additionally adopted to investigate the results of each subgroup. RESULTS: Our research included 15,154 individuals. During a mean follow-up period of 129 months, 30.6% of the hypertensive population succumbed to mortality. Based on previous studies, we categorized patients with MCHC ≤33mg/dl as the hypochromia group and those with >33mg/dl as the non-hypochromia group. After PSM, the hypochromia group had higher all-cause mortality (adjusted hazard ratio [HR]:1.26, 95% confidence interval [95%CI]:1.11-1.43) and cardiovascular mortality (adjusted HR:1.42, 95%CI:1.12-1.80) than the non-hypochromia group. The results of the COX regression remain stable after matching. Stratified analyses before PSM revealed an interaction of anemia in the relationship between MCHC and mortality, whereas there was no significant interaction after matching. CONCLUSION: In hypertensive individuals, low MCHC was correlated with a poor prognosis. Further studies on MCHC are necessary to analyze the potential mechanisms of its poor prognosis in hypertensive populations.

The substitution effect of financial and non-financial incentives at different income levels in physician recruitment: evidence from medical students in China.

BACKGROUND: Understanding how medical students respond to financial and non-financial incentives is crucial for recruiting health workers and attracting health talents in medical education. However, both incentives are integrated in working practice, and existing theoretical studies have suggested that various income levels may influence the substitution effect of both incentives, while the empirical evidence is lacking. Furthermore, little attention has been paid to the intrinsic motivation. This study aimed to explore the substitution effect of extrinsic incentives at different income levels, also taking intrinsic altruism into account. METHODS: We used the behavioral data from Zhang et al.'s experiments, which involved discrete choice experiments (DCEs) to assess the job preferences of medical students from six teaching hospitals in Beijing, China. The incentive factors included monthly income, work location, work environment, training and career development opportunities, work load, and professional recognition. Additionally, a lab-like experiment in the medical decision-making context was conducted to quantify altruism based on utility function. Furthermore, we separated the choice sets based on the actual income and distinguished the medical students on altruism. The willingness to pay (WTP) was used to estimate the substitution effect of incentives through conditional logit model. RESULTS: There was a significant substitution effect between non-financial and financial incentives. As income increased, non-financial incentives such as an excellent work environment, and sufficient career development became relatively more important. The impact of the increase in income on the substitution effect was more pronounced among individuals with higher altruism. Concerning the non-financial incentive work environment, in contrast to the growth of 546 CNY (84 USD) observed in the low-altruism group, the high-altruism group experienced a growth of 1040 CNY (160 USD) in the substitution effect. CONCLUSIONS: The increase in the income level exerted an influence on the substitution effect of non-financial incentives and financial incentives, especially in high-altruism medical students. Policymakers should attach importance to a favorable environment and promising career prospects on the basis of ensuring a higher income level. Medical school administrations should focus on promoting altruistic values in medical education, enhancing talent incentives and teaching strategies to encourage medical students to devote themselves to the medical professions.

Complete Laparoscopic Type C2 Radical Surgery for Cervical Stump Cancer: No-Look and No-Touch Techniques.

BACKGROUND: Due to previous surgical history and subsequent adhesions between pelvic organs, surgery for cervical stump cancer (CSC) is technically more challenging than surgery for cervical cancer with an intact uterus.1 We aimed to illustrate the related anatomy, surgical steps and techniques of complete laparoscopic type C2 radical surgery (CLRS) for early-stage CSC. METHODS: CLRS for six patients with CSC was performed from January 2021 to January 2022. We demonstrated the detailed skills of parametrial management during CLRS for CSC in case 5 by means of a video. A 58-year-old woman diagnosed with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIA1 CSC received CLRS through five operative ports (Fig. 1). RESULTS: The magnetic resonance imaging (MRI) scans and gross appearance of the specimen are shown in Fig. 2. The median age and body mass index (BMI) of the six patients were 53 years and 23.8, respectively. The median blood loss was 275 mL; the median time of operation was 218 min; the median length of hospitalization was 15 days; and the median time to recover urinary function was 12 days. One patient underwent postoperative radiation for pathologically proven adenocarcinoma with deep stromal invasion,2 while the other five did not. After a median follow-up of 24 months, no patients experienced complications, recurrence, or death (Table 1). CONCLUSIONS: This study details the skills of CLRS for CSC, especially space development and the 'no-look, no-touch' tumor-free principle. It is helpful for clinicians to perform safe and standardized surgery on patients with early-stage CSC. Fig. 1 Trocar placement of complete laparoscopic type C2 radical surgery for early-stage CSC. CSC cervical stump cancer, S superior, I inferior, R right, L left, U umbilicus Fig. 2 MRI scans and gross appearance of the specimen for case 5 with CSC at FIGO 2018 stage IIA1. The tumor lesion on the cervical stump is indicated by yellow arrows. a Axial T2-weighted image; b DKI image; c ADC map; d sagittal T2-weighted image; e sagittal T1-weighted image; f gross appearance of the surgical specimen. MRI magnetic resonance imaging, CSC cervical stump cancer, FIGO International Federation of Gynecology and Obstetrics, DKI diffusional kurtosis imaging, ADC apparent diffusion coefficient Table 1 Clinicopathological characteristics, operative details, and outcomes of patients with cervical stump cancer Patient no. Age at diagnosis (years) BMI Reasons for subtotal hysterectomy FIGO 2018 stage Histology Operation Operation time (mins) Blood loss (mL) Urinary catheter (days) Hospital stay (days) Complications Depth of invasion LVSI LNs dissected TNM stage Tumor size (mm) Postoperative radiotherapy Follow-up (months) Recurrence Death 1 50 25.9 Uterine myoma IIA1 ASC CLRS+PLND 221 360 10 12 No Middle one-third N 13 T2a1N0M0 16 No 30 No No 2 55 17.3 Uterine myoma IB1 AC CLRS+PLND 191 270 20 12 No Deep one-third N 24 T1b1N0M0 10 Yes 20 No No 3 50 24.8 Uterine myoma IB1 SC CLRS+PLND 295 310 13 15 No Superficial one-third N 21 T1b1N0M0 15 No 25 No No 4 63 30.1 Uterine myoma IB1 SC CLRS+PLND 213 180 6 16 No Superficial one-third N 25 T1b1N0M0 15 No 19 No No 5 58 20.2 Postpartum hemorrhage IIA1 SC CLRS+PLND 220 100 11 14 No Middle one-third N 21 T2a1N0M0 15 No 24 No No 6 46 22.7 Uterine myoma IB1 SC CLRS+PLND 215 120 14 17 No Superficial one-third N 26 T1b1N0M0 12 No 23 No No BMI body mass index, FIGO International Federation of Gynecology and Obstetrics, ASC cervical adenosquamous carcinoma, AC cervical adenocarcinoma, SC cervical squamous carcinoma, CLRS+PLND complete laparoscopic radical surgery and pelvic node dissections, LVSI lymphovascular space invasion, N negative, LNs lymph nodes, TNM tumor node metastasis.

Atorvastatin combined with imipenem alleviates lung injury in sepsis by inhibiting neutrophil extracellular trap formation via the ERK/NOX2 signaling pathway.

Sepsis is a systemic inflammatory response syndrome caused by the invasion of pathogenic microorganisms. Despite major advances in diagnosis and technology, morbidity and mortality remain high. The level of neutrophil extracellular traps (NETs) is closely associated with the progression and prognosis of sepsis, suggesting the regulation of NET formation as a new strategy in sepsis treatment. Owing to its pleiotropic effects, atorvastatin, a clinical lipid-lowering drug, affects various aspects of sepsis-related inflammation and immune responses. To align closely with clinical practice, we combined it with imipenem for the treatment of sepsis. In this study, we used a cecum ligation and puncture-induced lung injury mouse model and employed techniques including western blot, immunofluorescence, and enzyme-linked immunosorbent assay to measure the levels of NETs and other sepsis-related lung injury indicators. Our findings indicate that atorvastatin effectively inhibited the formation of NETs. When combined with imipenem, it significantly alleviated lung injury, reduced systemic inflammation, and improved the 7-day survival rate of septic mice. Additionally, we explored the inhibitory mechanism of atorvastatin on NET formation in vitro, revealing its potential action through the ERK/NOX2 pathway. Therefore, atorvastatin is a potential immunomodulatory agent that may offer new treatment strategies for patients with sepsis in clinical settings.

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

In situ mass spectrometry imaging reveals pesticide residues and key metabolic pathways throughout the entire cowpea growth process.

Cowpea plants, renowned for their high edibility, pose a significant risk of pesticide residue contamination. Elucidating the behavior of pesticide residues and their key metabolic pathways is critical for ensuring cowpea safety and human health. This study investigated the migration of pesticide residues and their key metabolic pathways in pods throughout the growth process of cowpea plants via in situ mass spectrometry. To this end, four pesticides--including systemic (thiram), and nonsystemic (fluopyram, pyriproxyfen, and cyromazine) pesticides--were selected. The results indicate the direct upward and downward transmission of pesticides in cowpea stems and pods. Systemic pesticides gradually migrate to the core of cowpea plants, whereas nonsystemic pesticides remain on the surface of cowpea peels. The migration rate is influenced by the cowpea maturity, logarithmic octanol-water partition coefficient (log Kow) value, and molecular weight of the pesticide. Further, 20 types of key metabolites related to glycolysis, tricarboxylic acid cycle, and flavonoid synthesis were found in cowpea pods after pesticide treatment. These findings afford insights into improving cowpea quality and ensuring the safe use of pesticides.

A prospective cohort-based artificial intelligence evaluation system for the protective efficacy and immune response of SARS-CoV-2 inactivated vaccines.

BACKGROUND: Novel coronaviruses constitute a significant health threat, prompting the adoption of vaccination as the primary preventive measure. However, current evaluations of immune response and vaccine efficacy are deemed inadequate. OBJECTIVES: The study sought to explore the evolving dynamics of immune response at various vaccination time points and during breakthrough infections. It aimed to elucidate the synergistic effects of epidemiological factors, humoral immunity, and cellular immunity. Additionally, regression curves were used to determine the correlation between the protective efficacy of the vaccine and the stimulated immune response. METHODS: Employing LASSO for high-dimensional data analysis, the study utilised four machine learning algorithms-logistical regression, random forest, LGBM classifier, and AdaBoost classifier-to comprehensively assess the immune response following booster vaccination. RESULTS: Neutralising antibody levels exhibited a rapid surge post-booster, escalating to 102.38 AU/mL at one week and peaking at 298.02 AU/mL at two weeks. Influential factors such as sex, age, disease history, and smoking status significantly impacted post-booster antibody levels. The study further constructed regression curves for neutralising antibodies, non-switched memory B cells, CD4+T cells, and CD8+T cells using LASSO combined with the random forest algorithm. CONCLUSION: The establishment of an artificial intelligence evaluation system emerges as pivotal for predicting breakthrough infection prognosis after the COVID-19 booster vaccination. This research underscores the intricate interplay between various components of immunity and external factors, elucidating key insights to enhance vaccine effectiveness. 3D modelling discerned distinctive interactions between humoral and cellular immunity within prognostic groups (Class 0-2). This underscores the critical role of the synergistic effect of humoral immunity, cellular immunity, and epidemiological factors in determining the protective efficacy of COVID-19 vaccines post-booster administration.

Epstein-Barr Virus Infection-Associated Facial Swelling: A Case Report.

Maxillofacial soft tissue swelling is a common clinical symptom with various etiologies. While odontogenic space infection is the most common cause, it is crucial not to overlook maxillofacial swellings caused by specific pathogenic infections and other local factors. This paper reports the case of an adult patient with right-sided swelling of his face, persistent oral mucosal ulcers, and recurrent hyperthermia for 30 days. He had received various antibiotics for the initial diagnosis of "right buccal space infection," but the antibiotics did not have any effect on his symptoms. None of the blood tests, histological examinations, bone marrow biopsies, and immune-related tests produced diagnostic findings. A diagnosis of Epstein-Barr virus (EBV) infection was finally confirmed by biopsy tissue genomics sequencing and quantitative analysis of EBV nucleic acid. In this report, we describe the diagnosis and treatment process for this patient and suggest that facial swelling could be an important clinical symptom of EBV infection.

Insight into N2O emission and denitrifier communities under different aeration intensities in composting of cattle manure from perspective of multi-factor interaction analysis.

Nitrous oxide (N2O) emission from composting is a significant contributor to greenhouse effect and ozone depletion, which poses a threat to environment. To address the challenge of mitigating N2O emission during composting, this study investigated the response of N2O emission and denitrifier communities (detected by metagenome sequencing) to aeration intensities of 6 L/min (C6), 12 L/min (C12), and 18 L/min (C18) in cattle manure composting using multi-factor interaction analysis. Results showed that N2O emission occurred mainly at mesophilic phase. Cumulative N2O emission (QN2O, 9.79 mg·kg-1 DW) and total nitrogen loss (TN loss, 16.40 %) in C12 composting treatment were significantly lower than those in the other two treatments. The lower activity of denitrifying enzymes and the more complex and balanced network of denitrifiers and environmental factors might be responsible for the lower N2O emission. Denitrification was confirmed to be the major pathway for N2O production. Moisture content (MC) and Luteimonas were the key factors affecting N2O emission, and nosZ-carrying denitrifier played a significant role in reducing N2O emission. Although relative abundance of nirS was lower than that of nirK significantly (P < 0.05), nirS was the key gene influencing N2O emission. Community composition of denitrifier varied significantly with different aeration treatments (R2 = 0.931, P = 0.001), and Achromobacter was unique to C12 at mesophilic phase. Physicochemical factors had higher effect on QN2O, whereas denitrifying genes, enzymes and NOX- had lower effect on QN2O in C12. The complex relationship between N2O emission and the related factors could be explained by multi-factor interaction analysis more comprehensively. This study provided a novel understanding of mechanism of N2O emission regulated by aeration intensity in composting.

TRPV1 signaling of perirenal adipose tissue promotes DOCA-Salt-induced hypertension and kidney injury.

BACKGROUND: Denervation of renal or perirenal adipose tissue (PRAT) can reduce arterial blood pressure in various hypertensive experimental models. Trpv1 (transient receptor potential vanillin 1) channel is highly expressed in the renal sensory nerves and the dorsal root ganglias (DRGs) projected by PRAT. However, it is currently unclear whether Trpv1 in DRGs projected from PRAT can regulate renal hypertension. METHODS: We used resintoxin (RTX) to block the afferent sensory nerves of rat PRAT. We also constructed Trpv1-/- mice and Trpv1+/- mice or used the injection of AAV2-retro-shTrpv1 to detect the effects of Trpv1 knockout or knockdown of PRAT-projected DRGs on deoxycorticosterone acetate (DOCA)-Salt-induced hypertension and kidney injury. RESULTS: Blocking the afferent sensory nerves of PRAT with RTX can alleviate DOCA-Salt-induced hypertension and renal injury in rats. And this blockade reduces the expression of Trpv1 in the DRGs projected by PRAT. Injecting AAV2-retro-shTrpv1 into the PRAT of DOCA-Salt mice also achieved the same therapeutic effect. However, DOCA-Salt-induced hypertension and renal injury can be treated in Trpv1+/- mice but not alleviated or even worsened in Trpv1-/- mice, possibly because of compensatory increase of Trpv5 in DRG of Trpv1-/- mice. CONCLUSION: Reducing, rather than eliminating, Trpv1 in DRG from PRAT-projection can reduce blood pressure and kidney damage in DOCA-Salt in rats or mice. Trpv1 in PRAT-DRGs may serve as a therapeutic target for salt-sensitive hypertension and its renal complications.

Migrating foreign bodies of penis: a case report and literature review.

BACKGROUND: Only a few cases have been reported about active foreign body implantation in the cavernous body of the penis. CASE PRESENTATION: A 47-year-old man inserted two needles from the glans penis into the bilateral penile sponge body. Subsequently, two needles migrated through the penile cavernous body into the pelvic cavity. Attempts to remove the needles through the penis were unsuccessful. Eventually, after a duration exceeding one month, the displaced needles were removed in stages from the buttocks. CONCLUSION: A few cases of intracavernosal-injection-therapy-associated needle breakage and retention have been reported globally. And this is the first case in China documenting the migration of foreign bodies within the penile region. In this condition, it is of utmost importance to engage the expertise of experienced andrologists to minimize the risk of excessive manipulation, thereby ensuring that inadvertent deep penetration of the needle into the penile tissue is prevented. In case the foreign body has migrated deeper into the tissues and the patient does not exhibit any specific symptoms or risks of macrovascular injury-related bleeding, close surveillance of its movement can be implemented. Surgical intervention can be initiated once the foreign body has reached a suitable position. Moreover, a psychiatric evaluation should be recommended for patient to discover any underlying mental health disorders.

RéSUMé: CONTEXTE: Seuls quelques cas ont été rapportés concernant l'implantation active d'un corps étranger dans le corps caverneux du pénis. PRéSENTATION DU CAS: Un homme de 47 ans a inséré deux aiguilles, par le gland du pénis, dans les corps spongieux du pénis. Par la suite, les deux aiguilles ont migré à travers le corps caverneux du pénis jusque dans la cavité pelvienne. Les tentatives pour retirer les aiguilles à travers le pénis ont été infructueuses. Finalement, après une durée de plus d'un mois, les aiguilles déplacées ont été retirées, par étapes, au niveau des fesses. CONCLUSION: Quelques cas de rupture et de rétention d'aiguille associés au traitement par injection intracaverneuse ont été signalés dans le monde. Il s'agit ici du premier cas en Chine qui documente la migration de corps étrangers dans la région du pénis. Dans cette situation, il est de la plus haute importance de faire appel à l'expertise d'andrologues expérimentés pour minimiser le risque de manipulation excessive, garantissant ainsi que la pénétration profonde par inadvertance de l'aiguille dans le tissu pénien est prévenue. Dans le cas où le corps étranger a migré plus profondément dans les tissus et que le patient ne présente pas de symptômes spécifiques ou de risques de saignements liés à une lésion macrovasculaire, une surveillance étroite du mouvement du corps étranger peut être mise en œuvre. L'intervention chirurgicale peut être initiée une fois que le corps étranger a atteint une position appropriée. Enfin, une évaluation psychiatrique devrait être recommandée à la recherche de tout trouble sous-jacent de santé mentale.

Application of Developmental Regulators for Enhancing Plant Regeneration and Genetic Transformation.

Establishing plant regeneration systems and efficient genetic transformation techniques plays a crucial role in plant functional genomics research and the development of new crop varieties. The inefficient methods of transformation and regeneration of recalcitrant species and the genetic dependence of the transformation process remain major obstacles. With the advancement of plant meristematic tissues and somatic embryogenesis research, several key regulatory genes, collectively known as developmental regulators, have been identified. In the field of plant genetic transformation, the application of developmental regulators has recently garnered significant interest. These regulators play important roles in plant growth and development, and when applied in plant genetic transformation, they can effectively enhance the induction and regeneration capabilities of plant meristematic tissues, thus providing important opportunities for improving genetic transformation efficiency. This review focuses on the introduction of several commonly used developmental regulators. By gaining an in-depth understanding of and applying these developmental regulators, it is possible to further enhance the efficiency and success rate of plant genetic transformation, providing strong support for plant breeding and genetic engineering research.

Single-cell transcriptome reveals highly complement activated microglia cells in association with pediatric tuberculous meningitis.

Background: Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) causing high mortality and disability. TBM arises due to immune dysregulation, but the underlying immune mechanisms are unclear. Methods: We performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells isolated from children (n=6) with TBM using 10 xGenomics platform. We used unsupervised clustering of cells and cluster visualization based on the gene expression profiles, and validated the protein and cytokines by ELISA analysis. Results: We revealed for the first time 33 monocyte populations across the CSF cells and PBMCs of children with TBM. Within these populations, we saw that CD4_C04 cells with Th17 and Th1 phenotypes and Macro_C01 cells with a microglia phenotype, were enriched in the CSF. Lineage tracking analysis of monocyte populations revealed myeloid cell populations, as well as subsets of CD4 and CD8 T-cell populations with distinct effector functions. Importantly, we discovered that complement-activated microglial Macro_C01 cells are associated with a neuroinflammatory response that leads to persistent meningitis. Consistently, we saw an increase in complement protein (C1Q), inflammatory markers (CRP) and inflammatory factor (TNF-α and IL-6) in CSF cells but not blood. Finally, we inferred that Macro_C01 cells recruit CD4_C04 cells through CXCL16/CXCR6. Discussion: We proposed that the microglial Macro_C01 subset activates complement and interacts with the CD4_C04 cell subset to amplify inflammatory signals, which could potentially contribute to augment inflammatory signals, resulting in hyperinflammation and an immune response elicited by Mtb-infected tissues.

Advances and challenges in thermal runaway modeling of lithium-ion batteries.

The broader application of lithium-ion batteries (LIBs) is constrained by safety concerns arising from thermal runaway (TR). Accurate prediction of TR is essential to comprehend its underlying mechanisms, expedite battery design, and enhance safety protocols, thereby significantly promoting the safer use of LIBs. The complex, nonlinear nature of LIB systems presents substantial challenges in TR modeling, stemming from the need to address multiscale simulations, multiphysics coupling, and computing efficiency issues. This paper provides an extensive review and outlook on TR modeling technologies, focusing on recent advances, current challenges, and potential future directions. We begin with an overview of the evolutionary processes and underlying mechanisms of TR from multiscale perspectives, laying the foundation for TR modeling. Following a comprehensive understanding of TR phenomena and mechanisms, we introduce a multiphysics coupling model framework to encapsulate these aspects. Within this framework, we detail four fundamental physics modeling approaches: thermal, electrical, mechanical, and fluid dynamic models, highlighting the primary challenges in developing and integrating these models. To address the intrinsic trade-off between computational accuracy and efficiency, we discuss several promising modeling strategies to accelerate TR simulations and explore the role of AI in advancing next-generation TR models. Last, we discuss challenges related to data availability, model scalability, and safety standards and regulations.

miR-4645-3p attenuates podocyte injury and mitochondrial dysfunction in diabetic kidney disease by targeting Cdk5.

Podocyte injury plays a critical role in the progression of diabetic kidney disease (DKD), but the underlying cellular and molecular mechanisms remain poorly understanding. MicroRNAs (miRNAs) can disrupt gene expression by inducing translation inhibition and mRNA degradation, and recent evidence has shown that miRNAs may play a key role in many kidney diseases. In this study, we identified miR-4645-3p by global transcriptome expression profiling as one of the major downregulated miRNAs in high glucose-cultured podocytes. Moreover, whether DKD patients or STZ-induced diabetic mice, expression of miR-4645-3p was also significantly decreased in kidney. In the podocytes cultured by normal glucose, inhibition of miR-4645-3p expression promoted mitochondrial damage and podocyte apoptosis. In the podocytes cultured by high glucose (30 mM glucose), overexpression of miR-4645-3p significantly attenuated mitochondrial dysfunction and podocyte apoptosis induced by high glucose. Furthermore, we found that miR-4645-3p exerted protective roles by targeting Cdk5 inhibition. In vitro, miR-4645-3p obviously antagonized podocyte injury by inhibiting overexpression of Cdk5. In vivo of diabetic mice, podocyte injury, proteinuria, and impaired renal function were all effectively ameliorated by treatment with exogenous miR-4645-3p. Collectively, these findings demonstrate that miR-4645-3p can attenuate podocyte injury and mitochondrial dysfunction in DKD by targeting Cdk5. Sustaining the expression of miR-4645-3p in podocytes may be a novel strategy to treat DKD.

Molecular characteristics of early-onset compared with late-onset colorectal cancer: A case controlled study.

BACKGROUND: Early-Onset Colorectal Cancer (EOCRC) is associated with a poorer prognosis relative to Late-Onset Colorectal Cancer (LOCRC), and its incidence has witnessed a gradual escalation in recent years. This necessitates a comprehensive examination of the underlying pathogenesis and the identification of therapeutic targets specific to EOCRC patients. The present study aimed to delineate the distinct molecular landscape of EOCRC by juxtaposing it with that of LOCRC. METHODS: A total of 11,344 colorectal cancer patients, diagnosed between 2003 and 2022, were enrolled in this study, comprising 578 EOCRC cases and 10,766 LOCRC cases. Next-generation sequencing technology was employed to assess the tumor-related mutation and tumor mutation burden (TMB) in these patients. PD-L1 expression was quantified using immunohistochemistry. Microsatellite instability (MSI) was determined via capillary electrophoresis (2B3D NCI Panel). RESULTS: Upon comparing LOCRC with EOCRC patients, the latter group demonstrated a tendency towards advanced TNM stage, lower tumor differentiation, and less favorable histological types. Among LOCRC patients, those with MSI-H status were found to have an earlier TNM stage compared to those with MSI-L/MSS status. Significantly, the incidence of MSI-H was notably higher in EOCRC (10.2%) compared to LOCRC (2.2%). Mutations in the 7-gene panel (ARID1A, FANCI, CASP8, DGFRA, DPYD, TSHR, and PRKCI) were more prevalent in LOCRC. Within the EOCRC cohort, patients with the MSI-H subtype displayed an earlier TNM stage but concurrently exhibited poorer tissue differentiation and a higher frequency of mucinous adenocarcinoma. Among EOCRC patients, FBXW7, FAT1, ATM, ARID1A, and KMT2B mutations were significantly enriched in the MSI-H subgroup. A comparative analysis of MSI-H patients revealed heightened mutation frequencies of FGFBR2, PBRM1, RNF43, LRP1B, FBXW7, ATM, and ARID1A in the EOCRC group. Furthermore, EOCRC patients demonstrated a higher overall TMB, particularly in the MSI-H subtype. PD-L1 expression was elevated in EOCRC and positively associated with MSI status. CONCLUSIONS: This study revealed a significantly higher MSI-H distribution rate in early-onset colorectal cancer, and EOCRC exhibits a distinct mutational signature coupled with higher PD-L1 expression. These findings hold promise in guiding personalized therapeutic strategies for improved disease management in EOCRC patients.

Effect of a fall within three months of admission on delirium in critically Ill elderly patients: a population-based cohort study.

BACKGROUND: Delirium is common among elderly patients in the intensive care unit (ICU) and is associated with prolonged hospitalization, increased healthcare costs, and increased risk of death. Understanding the potential risk factors and early prevention of delirium is critical to facilitate timely intervention that may reverse or mitigate the harmful consequences of delirium. AIM: To clarify the effects of pre-admission falls on ICU outcomes, primarily delirium, and secondarily pressure injuries and urinary tract infections. METHODS: The study relied on data sourced from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Statistical tests (Wilcoxon rank-sum or chi-squared) compared cohort characteristics. Logistic regression was employed to investigate the association between a history of falls and delirium, as well as secondary outcomes, while Kaplan-Meier survival curves were used to assess short-term survival in delirium and non-delirium patients. RESULTS: Study encompassed 22,547 participants. Delirium incidence was 40%, significantly higher in patients with a history of falls (54.4% vs. 34.5%, p < 0.001). Logistic regression, controlling for confounders, not only confirmed that a history of falls elevates the odds of delirium (OR: 2.11; 95% CI: 1.97-2.26; p < 0.001) but also showed it increases the incidence of urinary tract infections (OR:1.50; 95% CI:1.40-1.62; p < 0.001) and pressure injuries (OR:1.36; 95% CI:1.26-1.47; p < 0.001). Elderly delirium patients exhibited lower 30-, 180-, and 360-day survival rates than non-delirium counterparts (all p < 0.001). CONCLUSIONS: The study reveals that history of falls significantly heighten the risk of delirium and other adverse outcomes in elderly ICU patients, leading to decreased short-term survival rates. This emphasizes the critical need for early interventions and could inform future strategies to manage and prevent these conditions in ICU settings.