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Abstract As an ultra-early response gene, Nuclear receptor 4A1 (NR4A1) has been reported to be involved in the development of various diseases through various pathological pathways, but its specific mechanism in chronic kidney disease (CKD) is unknown currently. Our study showed that the expression of NR4A1 was reduced in unilateral ureteral obstruction (UUO) mice and it could exacerbate UUO-induced renal pathological injury when knocked down NR4A1 in UUO mice. We found that the knockdown of NR4A1 could promote angiogenesis, renal inflammation, and cell apoptosis to aggravate renal fibrosis induced by UUO. As an agonist of NR4A1, Cytosporone B (Csn-B) could inhibit the renal fibrosis by attenuating angiogenesis, renal inflammation and cell apoptosis. In addition, the PI3K/AKT pathway was activated with NR4A1 knockdown in vivo and in vitro experiments. In conclusion, our study demonstrates that NR4A1 can ameliorate renal fibrosis. Furthermore, we speculate that its underlying mechanism may be related to the activation of PI3K/AKT pathway according to our present results.

Abstract Background Mesenchymal stem cells (MSCs) are multipotent stem cells that are under investigation for use in clinical trials because they are capable of self-renewal and differentiating into different cell types under defined conditions. Nonetheless, the therapeutic effects of MSCs have been constrained by low engraftment rates, cell fusion, and cell survival. Various strategies have been explored to improve the therapeutic efficacy of MSCs, with platelet-derived growth factor (PDGF)-BB emerging as a promising candidate. To enhance our comprehension of the impact of PDGF-BB on the gene expression profile and chromosomal accessibility of MSCs, RNA-sequencing and analysis of chromatin accessibility profiles were conducted on three human primary MSCs in culture, both with and without stimulation by PDGF-BB. Results Integrative analysis of gene expression and chromatin accessibility demonstrated that PDGF-BB treatment modified the chromatin accessibility landscape, marking regions for activation or repression through the AP-1 family transcription factors TEAD, CEBP, and RUNX2. These changes in AP-1 transcription factor expression, in turn, led to cell proliferation and differentiation potential towards osteoblasts, adipocytes, or chondrocytes. The degree of MSC differentiation varies among cells isolated from different donors. The presence of an enrichment of exosome-related genes is also noted among all the differentially expressed genes. Conclusions In conclusion, the observed changes in AP-1 transcription factor expression not only induced cellular proliferation and differentiation, but also revealed variations in the degree of MSC differentiation based on donor-specific differences. Moreover, the enrichment of exosome-related genes among differentially expressed genes suggests a potential significant role for PDGF-BB in facilitating intercellular communication.

Abstract Background Compassion fatigue is common among nurses and can lead to decreased motivation, impaired physical and mental health, and turnover. Nursing interns often face environments the same as professional nurses, yet their compassion fatigue has received less attention. Therefore, this study aims to assess the prevalence and related factors of compassion fatigue among nursing interns. Methods This was a cross-sectional study involving 221 nursing interns in 2 tertiary-level hospitals in Shanghai, China. A general information questionnaire was formulated to investigate the demographic characteristics and internship-related factors of nursing interns. Compassion fatigue was assessed using the Professional Quality of Life Scale [compassion satisfaction (CS), burnout (BO), and secondary traumatic stress (STS)]. Psychological resilience, empathy, and perceived stress were evaluated by the Connor-Davidson Resilience Scale, Jefferson Scales of Empathy, and Perceived Stress Scale, respectively. Personality traits were assessed using the extroversion/introversion subscale of the Eysenck Personality Inventory. Descriptive statistics, t-test, one-way analysis of variance (ANOVA), Pearson’s correlation analysis, and multiple linear regressions were used to determine the predictors of the main research variables. Results The prevalence of mild, moderate, and severe compassion fatigue in 221 nursing interns (mean age 21 years, 202 [91.4%] females) was 10.4%, 46.6%, and 43.0%, respectively, and their mean scores for CS, BO, and STS were 29.75 ± 6.39, 28.72 ± 4.78, and 28.51 ± 7.51, respectively. Psychological resilience and empathy were the strongest protective factors for CS and BO, respectively (p

Abstract Background To investigate the association between surgical removal of tonsils and risk of COVID-19 with different severity. Methods Through a nested case–control study during January 31st to December 31st 2020, including 58,888 participants of the UK Biobank, we investigated the association of tonsillectomy with the future risk of mild and severe COVID-19, using binomial logistic regression. We further examined the associations of such surgery with blood inflammatory, lipid and metabolic biomarkers to understand potential mechanisms. Finally, we replicated the analysis of severe COVID-19 in the Swedish AMORIS Cohort (n = 451,960). Results Tonsillectomy was associated with a lower risk of mild (odds ratio [95% confidence interval]: 0.80 [0.75–0.86]) and severe (0.87 [0.77–0.98]) COVID-19 in the UK Biobank. The associations did not differ substantially by sex, age, Townsend deprivation index, or polygenic risk score for critically ill COVID-19. Levels of blood inflammatory, lipid and metabolic biomarkers did, however, not differ greatly by history of surgical removal of tonsils. An inverse association between tonsillectomy and severe COVID-19 was also observed in the AMORIS Cohort, primarily among older individuals (> 70 years) and those with ≤ 12 years of education. Conclusions Surgical removal of tonsils may be associated with a lower risk of COVID-19. This association is unlikely attributed to alterations in common blood inflammatory, lipid and metabolic biomarkers.

Abstract There is limited data on the prognostic implications of residual mild coarctation (RMC) in patients with repaired native coarctation of the aorta (CoA). To explore the association of RMC with mid‐term comorbidities in post‐interventional patients, and the predictive value of the residual pressure gradient. The authors retrospectively analyzed 79 native CoA patients who received successful intervention at our hospital between October 2010 and June 2023. The outcomes of the study were late arterial hypertension (either raised blood pressure or commencement of hypotensive medications) only in normotensive patients at early follow‐up and the composite mid‐term comorbidities including new‐onset aortic injury, re‐stenosis, and re‐intervention. At a median follow‐up of 60 months, late hypertension and mid‐term comorbidities occurred in 16 (28.1%) and nine (11.4%) patients, respectively. Multivariate Cox proportional hazard regression analysis identified invasive peak systolic CoA pressure gradient (PSPG) as the best independent predictor of both outcomes. The maximally selected rank statistics indicated 10 mm Hg as the best PSPG cut‐off value for predicting late hypertension. Compared to patients with PSPG

Abstract People’s livelihood serves as the primary impetus driving all social activities. Faced with intense regional competition and stringent assessment, regional governments often resort to manipulating GDP figures. This study investigates the repercussions of such economic distortion on residents’ welfare. Our findings reveal a significant negative relationship between regional GDP manipulation and investment in livelihood improvements. This correlation is particularly pronounced during the initial phase of officials’ tenure and diminishes when officials serve in their hometowns. Moreover, we observe that the reduction in livelihood investment is exacerbated during periods of economic downturn. These conclusions contribute to the existing literature on regional GDP manipulation and livelihood investment, shedding light on the potential implications for residents’ welfare.

Abstract Background Overactivated microglia are a key contributor to Parkinson’s disease (PD) by inducing neuroinflammation. CD200R1, a membrane glycoprotein mainly found on microglia, is crucial for maintaining quiescence with its dysregulation linked to microglia’s abnormal activation. We and other groups have reported a decline in CD200R1 levels in several neurological disorders including PD. However, the mechanism regulating CD200R1 expression and the specific reasons for its reduction in PD remain largely unexplored. Given the pivotal role of transcription factors in gene expression, this study aimed to elucidate the transcriptional regulation of CD200R1 and its implications in PD. Methods The CD200R1 promoter core region was identified via luciferase assays. Potential transcription factors were predicted using the UCSC ChIP-seq database and JASPAR. NFKB1 binding to the CD200R1 core promoter was substantiated through electrophoretic mobility shift and chromatin immunoprecipitation assays. Knocking-down or overexpressing NFKB1 validated its regulatory effect on CD200R1. Correlation between decreased CD200R1 and deficient NFKB1 was studied using Genotype-Tissue Expression database. The clinical samples of the peripheral blood mononuclear cells were acquired from 44 PD patients (mean age 64.13 ± 9.78, 43.2% male, median Hoehn-Yahr stage 1.77) and 45 controls (mean age 64.70 ± 9.41, 52.1% male). NFKB1 knockout mice were utilized to study the impact of NFKB1 on CD200R1 expression and to assess their roles in PD pathophysiology. Results The study identified the CD200R1 core promoter region, located 482 to 146 bp upstream of its translation initiation site, was directly regulated by NFKB1. Significant correlation between NFKB1 and CD200R1 expression was observed in human PMBCs. Both NFKB1 and CD200R1 were significantly decreased in PD patient samples. Furthermore, NFKB1-/- mice exhibited exacerbated microglia activation and dopaminergic neuron loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Conclusion Our study identified that NFKB1 served as a direct regulator of CD200R1. Reduced NFKB1 played a critical role in CD200R1 dysregulation and subsequent microglia overactivation in PD. These findings provide evidence that targeting the NFKB1-CD200R1 axis would be a novel therapeutic strategy for PD.

Abstract Background It remains unclear which early gestational biomarkers can be used in predicting later development of gestational diabetes mellitus (GDM). We sought to identify the optimal combination of early gestational biomarkers in predicting GDM in machine learning (ML) models. Methods This was a nested case-control study including 100 pairs of GDM and euglycemic (control) pregnancies in the Early Life Plan cohort in Shanghai, China. High sensitivity C reactive protein, sex hormone binding globulin, insulin-like growth factor I, IGF binding protein 2 (IGFBP-2), total and high molecular weight adiponectin and glycosylated fibronectin concentrations were measured in serum samples at 11–14 weeks of gestation. Routine first-trimester blood test biomarkers included fasting plasma glucose (FPG), serum lipids and thyroid hormones. Five ML models [stepwise logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, support vector machine and k-nearest neighbor] were employed to predict GDM. The study subjects were randomly split into two sets for model development (training set, n = 70 GDM/control pairs) and validation (testing set: n = 30 GDM/control pairs). Model performance was evaluated by the area under the curve (AUC) in receiver operating characteristics. Results FPG and IGFBP-2 were consistently selected as predictors of GDM in all ML models. The random forest model including FPG and IGFBP-2 performed the best (AUC 0.80, accuracy 0.72, sensitivity 0.87, specificity 0.57). Adding more predictors did not improve the discriminant power. Conclusion The combination of FPG and IGFBP-2 at early gestation (11–14 weeks) could predict later development of GDM with moderate discriminant power. Further validation studies are warranted to assess the utility of this simple combination model in other independent cohorts.

Abstract Individuals with mental illness are at higher risk of severe COVID-19 outcomes. However, previous studies on the uptake of COVID-19 vaccination in this population have reported conflicting results. Using data from seven cohort studies (N = 325,298) included in the multinational COVIDMENT consortium, and the Swedish registers (N = 8,080,234), this study investigates the association between mental illness (defined using self-report measures, clinical diagnosis and prescription data) and COVID-19 vaccination uptake. Results from the COVIDMENT cohort studies were pooled using meta-analyses, the majority of which showed no significant association between mental illness and vaccination uptake. In the Swedish register study population, we observed a very small reduction in the uptake of both the first and second dose of a COVID-19 vaccine among individuals with vs. without mental illness; the reduction was however greater among those not using psychiatric medication. Here we show that uptake of the COVID-19 vaccine is generally high among individuals both with and without mental illness, however the lower levels of vaccination uptake observed among subgroups of individuals with unmedicated mental illness warrants further attention.

ABSTRACT Importance Aicardi–Goutières syndrome (AGS) is a rare genetic disorder mainly affecting the central nervous system and autoimmunity. However, research on AGS among Chinese patients is limited. Objective To summarize the neurologic phenotypes and genetic causes in pediatric AGS patients, providing insights for early recognition and diagnosis in the Chinese population. Methods Clinical features and neuroimaging results of the patients diagnosed with AGS from Beijing Children's Hospital between January 2018 and January 2022 were collected. Whole exome sequencing was used for genetic analysis. Results A total of 15 patients was included, all presenting with various neurological symptoms, including developmental delay (100%), motor skill impairment (100%), language disability (78.6%), dystonia (93.3%), microcephaly (73.3%), sleep disorders (26.7%), regression (20.0%), vessel disease (6.7%), and epilepsy (6.7%). Neuroimaging revealed intracranial calcification (86.7%), cerebral atrophy (73.3%), and leukodystrophy (73.3%). Seven genes were identified, with TREX1 being the most common (40.0%, 6/15), followed by IFIH1 (20.0%, 3/15). Variant c.294dupA (p.C99Mfs*3) was detected in four unrelated patients, accounting for 66.7% (4/6) patients with the TREX1 variant. A literature review showed that TREX1 gene mutations in 35.6% (21/59) of AGS patients among the Chinese population. Interpretation Neurological symptoms are the most prevalent and severe presentation of AGS. Diagnosis may be considered when symptoms such as developmental delay, dystonia, microcephaly, brain calcification, and leukodystrophy emerge. TREX1 mutations are predominant in the Chinese population.

Abstract Activin A and hepatic stellate cells (HSCs) are involved in tissue repair and fibrosis in liver injury. This study investigated the impact of activin A on HSC activation and migration. A microfluidic D4-chip was used for examining the cell migration of mouse hepatic stellate cell line MHSteC. The analysis of differentially expressed genes revealed that activin βA (Inhba), activin receptor type 1A (Acvr1a) and type 2A (Acvr2a) mRNAs were more significantly expressed in human HSCs than in the hepatocytes. Moreover, activin A promoted MHSteC proliferation and induced MHSteC migration. Furthermore, the MHSteCs treated with activin A exhibited increased levels of migration-related proteins, N-cadherin, Vimentin, α-SMA, MMP2 and MMP9, but a decreased level of E-cadherin. Additionally, activin A treatment significantly increased the p-Smad3 levels and p-Smad3/Smad3 ratio in the MHSteCs, and the Smad3 inhibitor SIS3 attenuated activin A-induced MHSteC proliferation and migration. Simultaneously, activin A increased the calcium levels in the MHSteCs, and the migratory effects of activin A on MHSteCs were weakened by the intracellular calcium ion-chelating agent BAPTA-AM. These data indicate that activin A can promote MHSteC activation and migration through the canonical Smad3 signaling and calcium signaling.

Abstract Analyzing three-dimensional excitation-emission matrix (3D-EEM) spectra through machine learning models has drawn increasing attention, whereas the reliability of these machine learning models remains unclear due to their “black box” nature. In this study, the convolutional neural network (CNN) for classifying numbers of fluorescent components in 3D-EEM spectra was interpreted by gradient-weighted class activation mapping (Grad-CAM), guided Grad-CAM, and structured attention graphs (SAGs). Results showed that the original CNN classifier with high classification accuracy may make a classification based on misleading attention to the non-fluorescence area in 3D-EEM spectra. By removing Rayleigh scatterings in 3D-EEM spectra and integrating convolutional block attention module (CBAM) in CNN classifiers, the correct attention of the trained CNN classifier with CBAM greatly increased from 17.6% to 57.2%. This work formulated strategies for improving CNN classifiers associated with environmental fields and would provide great help for water determination in both natural and artificial environments.

Abstract Background Childhood maltreatment (CM) has been indicated in adverse health outcomes across the lifespan, including severe infection-related outcomes. Yet, data are scarce on the potential role of CM in severe COVID-19-related outcomes as well as on mechanisms underlying this association. Methods We included 151,427 individuals in the UK Biobank who responded to questions on the history of CM in 2016 and 2017 and were alive on January 31, 2020. Binomial logistic regression models were performed to estimate the association between a history of CM and severe COVID-19 outcomes (i.e. hospitalization or death due to COVID-19), as well as COVID-19 diagnosis and vaccination as secondary outcomes. We then explored the potential mediating roles of socio-economic status, lifestyle and pre-pandemic comorbidities, and the effect modification by polygenic risk score for severe COVID-19 outcomes. Results The mean age of the study population at the start of the pandemic was 67.7 (SD = 7.72) years, and 56.5% were female. We found the number of CM types was associated with the risk of severe COVID-19 outcomes in a graded manner (p for trend 0.05). Mediation analysis revealed that 50.9% of the association between CM and severe COVID-19 outcomes was explained by suboptimal socio-economic status, lifestyle, and pre-pandemic diagnosis of psychiatric disorders or other chronic medical conditions. In contrast, any CM exposure was only weakly associated with COVID-19 diagnosis (1.06 [1.01–1.12]) while significantly associated with not being vaccinated for COVID-19 (1.21 [1.13–1.29]). Conclusions Our results add to the growing knowledge base indicating the role of childhood maltreatment in negative health outcomes across the lifespan, including severe COVID-19-related outcomes. The identified factors underlying this association represent potential intervention targets for mitigating the harmful effects of childhood maltreatment in COVID-19 and similar future pandemics.

Abstract Background Osteosarcoma (OS) is one of the most common primary malignant tumors of bone in children, which develops from osteoblasts and typically occurs during the rapid growth phase of the bone. Recently, Super-Enhancers(SEs)have been reported to play a crucial role in osteosarcoma growth and metastasis. Therefore, there is an urgent need to identify specific targeted inhibitors of SEs to assist clinical therapy. This study aimed to elucidate the role of BRD4 inhibitor GNE-987 targeting SEs in OS and preliminarily explore its mechanism. Methods We evaluated changes in osteosarcoma cells following treatment with a BRD4 inhibitor GNE-987. We assessed the anti-tumor effect of GNE-987 in vitro and in vivo by Western blot, CCK8, flow cytometry detection, clone formation, xenograft tumor size measurements, and Ki67 immunohistochemical staining, and combined ChIP-seq with RNA-seq techniques to find its anti-tumor mechanism. Results In this study, we found that extremely low concentrations of GNE-987(2–10 nM) significantly reduced the proliferation and survival of OS cells by degrading BRD4. In addition, we found that GNE-987 markedly induced cell cycle arrest and apoptosis in OS cells. Further study indicated that VHL was critical for GNE-987 to exert its antitumor effect in OS cells. Consistent with in vitro results, GNE-987 administration significantly reduced tumor size in xenograft models with minimal toxicity, and partially degraded the BRD4 protein. KRT80 was identified through analysis of the RNA-seq and ChIP-seq data. U2OS HiC analysis suggested a higher frequency of chromatin interactions near the KRT80 binding site. The enrichment of H3K27ac modification at KRT80 was significantly reduced after GNE-987 treatment. KRT80 was identified as playing an important role in OS occurrence and development. Conclusions This research revealed that GNE-987 selectively degraded BRD4 and disrupted the transcriptional regulation of oncogenes in OS. GNE-987 has the potential to affect KRT80 against OS.

Abstract. Background:. Understanding willingness to undergo pulmonary function tests (PFTs) and the factors associated with poor uptake of PFTs is crucial for improving early detection and treatment of chronic obstructive pulmonary disease (COPD). This study aimed to understand willingness to undergo PFTs among high-risk populations and identify any barriers that may contribute to low uptake of PFTs. Methods:. We collected data from participants in the “Happy Breathing Program” in China. Participants who did not follow physicians’ recommendations to undergo PFTs were invited to complete a survey regarding their willingness to undergo PFTs and their reasons for not undergoing PFTs. We estimated the proportion of participants who were willing to undergo PFTs and examined the various reasons for participants to not undergo PFTs. We conducted univariable and multivariable logistic regressions to analyze the impact of individual-level factors on willingness to undergo PFTs. Results:. A total of 8475 participants who had completed the survey on willingness to undergo PFTs were included in this study. Out of these participants, 7660 (90.4%) were willing to undergo PFTs. Among those who were willing to undergo PFTs but actually did not, the main reasons for not doing so were geographical inaccessibility (n = 3304, 43.1%) and a lack of trust in primary healthcare institutions (n = 2809, 36.7%). Among the 815 participants who were unwilling to undergo PFTs, over half (n = 447, 54.8%) believed that they did not have health problems and would only consider PFTs when they felt unwell. In the multivariable regression, individuals who were ≤54 years old, residing in rural townships, with a secondary educational level, with medical reimbursement, still working, with occupational exposure to dust, and aware of the abbreviation “COPD” were more willing to undergo PFTs. Conclusions:. Willingness to undergo PFTs was high among high-risk populations. Policymakers may consider implementing strategies such as providing financial incentives, promoting education, and establishing community-based programs to enhance the utilization of PFTs.

Purpose: This study aimed to identify the altered pathways and genes associated with freezing damage in human sperm during cryopreservation by multiomics analysis. Materials and Methods: Fifteen fresh human semen samples were collected for transcriptomic analysis, and another 5 fresh human semen samples were obtained for metabolomic analysis. For each semen sample, 1 mL was cryopreserved, and another 1 mL was left untreated for paired design. The results were then combined with previously published proteomic results to identify key genes/pathways. Results: Cryopreservation significantly reduced sperm motility and mitochondrial structure. Transcriptomic analysis revealed altered mitochondrial function, including changes in tRNA-methyltransferase activity and adenosine tri-phosphate/adenosine di-phosphate transmembrane transporter activity. Metabolomic analysis showed that the citrate cycle in mitochondria was significantly altered. Combining transcriptomic, proteomic, and metabolomic analyses revealed 346 genes that were altered in at least two omics analyses. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that metabolic pathways were significantly altered and strongly associated with mitochondria. Five genes were altered in all three omics analyses: COL11A1, COL18A1, LPCAT3, NME1, and NNT. Conclusions: Five genes were identified by multiomics analysis in human cryopreserved sperm. These genes might have specific functions in cryopreservation. Explorations of the functions of these genes will be helpful for sperm cryopreservation and sperm motility improvement or even for reproduction in the future.

Backgrounds: The functional recovery after peripheral nerve injury remains unsatisfactory. This study aims to perform a comprehensive evaluation of the efficacy of Fasudil Hydrochloride at treating the sciatic nerve transection injury in rats and the mechanism involved. Materials and methods: In animal experiments, 75 Sprague Dawley rats that underwent transection and repair of the right sciatic nerve were divided into a control, Fasudil, and Fas + LY group, receiving daily intraperitoneal injection of saline, Fasudil Hydrochloride (10 mg/kg), and Fasudil Hydrochloride plus LY294002 (5 mg/kg), respectively. At day 3 after surgery, the expression of ROCK2, p-PI3K, and p-AKT in L4-5 DRG and the lumbosacral enlargement was determined using Western blotting. At day 7 and 14, axon density in the distal stump was evaluated with immunostaining using the anti-Neurofilament-200 antibody. At day 30, retrograde tracing by injecting Fluoro-gold in the distal stump was performed. Three months after surgery, remyelination was analyzed with immostaining using the anti-MPZ antibody and the transmission electron microscope; Moreover, Motion-Evoked Potential, and recovery of sensorimotor functions was evaluated with a neuromonitor, Footprint, Hot Plate and Von Frey Filaments, respectively. Moveover, the Gastrocnemius muscles were weighed, and then underwent H＆E staining, and staining of the neuromuscular junction using α-Bungarotoxin to evaluate the extent of atrophy and degeneration of the endplates in the Gastrocnemius. In vitro, spinal motor neurons (SMNs) and dorsal root ganglia (DRG) were cultured to examine the impact of Fasudil Hydrochloride and LY294002 on the axon outgrowth. Results: Three days after injury, the expression of ROCK2 increased significantly (P＜0.01), and Fasudil application significantly increased the expression of p-PI3K and p-AKT in L4-6 DRG and the lumbosacral enlargement (P

Objective·To establish the early symptom network of adult intensive care unit (ICU) patients after transfer (post-ICU patients), identify the core symptoms and bridge symptoms, compare the symptom networks of two subgroups, i.e. mixed ICU and coronary care unit (CCU), and analyze the occurrence of symptoms.Methods·From December 2022 to August 2023, a total of 328 adult patients transferred to wards from mixed ICU and CCU of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine were selected by convenience sampling. The general situation and clinical data questionnaire, and symptom questionnaires (including Hospital Anxiety and Depression Scale, Fatigue Severity Scale, Richards-Campbell Sleep Questionnaire, and Pain Numeric Rating Scale) were used. Based on Spearman correlation analysis and GLASSO algorithm, contemporaneous symptom network was built, and centrality indices and differences between subgroup symptom networks were computed. The edge accuracy and the stability of centrality indices of the network were tested.Results·A total of 302 valid questionnaires were collected, and the effective rate was 92.1%. The results of the centrality indices computations showed that in the early symptom network of post-ICU patients, the highest strength was “feel cheerful” (rS=1.145), the highest closeness was “enjoy something” (rC=1.851×10-3), and the highest expected influence was “（fatigue） interferes with physical function” (rE=1.143). The top three highest bridge strengths of symptoms were “worrying thoughts” (rb=10.392), “enjoy something” (rb=10.359), and pain (rb=10.221). There were no significant differences in network structure (M=0.289) and overall connection strength (GSmixed ICU=13.876, GSCCU=13.838; S=0.039) of the early symptom networks between mixed ICU and CCU patients after being transferred to wards. When comparing the centrality indices, apart from the strength and expected influence of five symptoms showing statistically significant differences (all P

Abstract Mental disorders are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders. Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and near-complete genealogies of Denmark and Sweden (n = 17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six mental disorders and 15 cardiometabolic disorders. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with cardiometabolic disorders, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with cardiometabolic disorders was mainly or fully driven by environmental factors. In this work we provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.

Abstract The energy dissipation pathways of a photosensitizer for phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), compete directly with that of its fluorescence (FL) emission. Enriching heavy atoms on the π‐conjugated systems and aggregation‐caused quenching are two effective methods to turn off the FL emission of photosensitizers, which is expected to boost the intersystem crossing (for PDT) and nonradiative transition (for PTT) of photosensitizers for maximized phototherapeutic efficacy. Following this approach, an all‐iodine‐substituted polydiacetylene aggregate poly(diiododiacetylene) (PIDA) has been developed, which shows a superior near infrared absorption (ε808nm = 26.1 g−1 cm−1 L) with completely blocked FL, as well as high efficiency of reactive oxygen species generation (nearly 45 folds of indocyanine green) and photothermal conversion (33.4%). To make the insoluble fibrillar PIDA aggregates favorable for systemic administration, they are converted into nanospheres through a pre‐polymerization morphology transformation strategy. The in vivo study on a 4T1 tumor‐bearing mouse model demonstrates that PIDA nanospheres can almost eliminate the tumor entirely in 16 days and prolong the survival time of mice to over 60 days, validating their effective phototherapeutic response through the strategy of inhibiting FL for boosted intersystem crossing and nonradiative transition.

IntroductionThe primary objective of our study was to evaluate the first use of a novel intracardiac echocardiography (ICE) catheter in human subjects. This study aimed to assess its practicality, image clarity, and guidance role during electrophysiology procedures.MethodsTwo patients underwent procedures using the novel ICE catheter. Post-procedure evaluations were conducted by four operators, who assessed the imaging quality and overall performance of the catheter. Anatomical and blood test results were also analyzed to determine the safety and impact on internal cardiac structures.ResultsBoth patients were discharged one day after the procedure without any complications. The novel ICE catheter provided comparable imaging quality to existing commercial catheters. The catheter's advanced design allowed for detailed imaging at short distances, essential for accurate diagnosis and treatment planning. Moreover, it successfully navigated complex anatomical structures like the atrial septum and left atrial appendage.DiscussionThese preliminary studies indicate that the novel ICE catheter achieves a level of safety and effectiveness comparable to previously available commercial catheters. The findings highlight its potential to meet current clinical needs, particularly in sophisticated anatomic interventions. Despite the prolonged thrombin time after anticoagulant administration, both types of ICE catheters were non-damaging to cardiac structures during routine operations. The study underscores the importance of using trans-septal large inner diameter sheaths to minimize complications when advancing the catheter into the left atrium.

Commented article: WANG, Z. Philosophical Perspective on Artistic Development and Historic Animation Thinking. Trans/Form/Ação: revista de filosofia da Unesp, v. 47, n. 5, “Eastern thought 2”, e02400159, 2024. Available at: https://revistas.marilia.unesp.br/index.php/transformacao/article/view/15071.

Summary: Background: Pulmonary embolism causes a substantial burden of morbidity and mortality. Although there are several well-established risk factors for pulmonary embolism, a substantial proportion of cases cannot be attributed to provoked or known risk factors. Accumulating evidence has suggested an association of clonal hematopoiesis of indeterminate potential (CHIP) with the risk of arterial thromboembolism. However, the association between CHIP and the risk of pulmonary embolism remains unknown. Methods: We performed a community-based cohort study (between 2006 and 2022) including 464,417 individuals with available whole exome sequencing (WES) data in the UK biobank (UKB) to examine the association between CHIP and pulmonary embolism. CHIP was ascertained by analyzing WES data. We used Cox regression models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) to assess the association between CHIP and pulmonary embolism. In addition, we performed analyses for several types of CHIP mutations, including DNMT3A, TET2, ASXL1, PPM1D, SRSF2, and JAK2. Findings: The study included 14,418 individuals with CHIP and 449,999 individuals without CHIP. The median age at cohort entry was 58 and 63 years among individuals without and with CHIP, respectively. We observed an increased risk of pulmonary embolism (HR 1.17, 95% CI, 1.05–1.31) among individuals with CHIP. The increased risk was mainly noted for CHIP with TET2 (HR 1.42, 95% CI 1.16–1.74) or JAK2 (HR 4.17, 95% CI 2.09–8.35) mutation, but not for DNMT3A mutation (HR 1.01, 95% CI 0.86–1.19), ASXL1 mutation (HR 1.15, 95% CI 0.83–1.60), PPM1D mutation (HR 1.22, 95% CI 0.66–2.27), or SRSF2 mutation (HR 0.62, 95% CI 0.20–1.93). Interpretation: Our results highlight the association of pulmonary embolism in individuals with CHIP, especially the TET2-mutant or JAK2-mutant CHIP. If further studies will identify a causal relationship between clonal hematopoiesis and pulmonary embolism, prioritizing early screening for pulmonary embolism in individuals with CHIP could be significantly beneficial. Funding: Initial Founding for High Level Talented Scholars in Nanfang Hospital, Southern Medical University (No. 2023G001) and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University (Grant No. 2023J009).

Abstract Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5′ UTR, were specifically recognized by the m6A “reader” protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

Abstract This study investigates the expression and significance of urinary protein and coagulation‐fibrinolysis indicators in preeclampsia, categorized into mild preeclampsia (109 cases) and severe preeclampsia (97 cases) based on disease severity. Additionally, 110 patients with gestational hypertension (gestational hypertension group) were included for comparative analysis. General information, laboratory indicators, urinary protein, and coagulation‐fibrinolysis indicator levels were collected for each group. Significant differences were observed in blood pressure among groups (P .05). Total cholesterol, triglycerides, and low‐density Lipoprotein levels in severe preeclampsia were higher than those in mild preeclampsia and gestational hypertension groups, whereas high‐density lipoprotein, albumin, and platelet levels were lower in severe preeclampsia. No significant differences were observed in prothrombin time or D‐dimer levels among groups (P > .05). Urinary protein, urinary protein quantification, activated partial thromboplastin time, thrombin time, and fibrinogen were identified as influencing factors for adverse maternal and infant outcomes in severe preeclampsia patients. The study concludes that urinary protein and coagulation‐fibrinolysis indicators are elevated in preeclampsia, particularly in severe preeclampsia cases, suggesting their potential use as diagnostic influencing factors for severe preeclampsia.

Abstract Reversible solid-state hydrogen storage of magnesium hydride, traditionally driven by external heating, is constrained by massive energy input and low systematic energy density. Herein, a single phase of Mg2Ni(Cu) alloy is designed via atomic reconstruction to achieve the ideal integration of photothermal and catalytic effects for stable solar-driven hydrogen storage of MgH2. With the intra/inter-band transitions of Mg2Ni(Cu) and its hydrogenated state, over 85% absorption in the entire spectrum is achieved, resulting in the temperature up to 261.8 °C under 2.6 W cm−2. Moreover, the hydrogen storage reaction of Mg2Ni(Cu) is thermodynamically and kinetically favored, and the imbalanced distribution of the light-induced hot electrons within CuNi and Mg2Ni(Cu) facilitates the weakening of Mg-H bonds of MgH2, enhancing the “hydrogen pump” effect of Mg2Ni(Cu)/Mg2Ni(Cu)H4. The reversible generation of Mg2Ni(Cu) upon repeated dehydrogenation process enables the continuous integration of photothermal and catalytic roles stably, ensuring the direct action of localized heat on the catalytic sites without any heat loss, thereby achieving a 6.1 wt.% H2 reversible capacity with 95% retention under 3.5 W cm−2.

Abstract Objective To investigate the effectiveness and tolerability of ketogenic diet therapy (KDT) in patients with developmental and epileptic encephalopathy (DEE) associated with genetic etiology which onset within the first 6 months of life, and to explore the association between response to KDT and genotype/clinical parameters. Methods We retrospectively reviewed data from patients with genetic DEE who started KDT at Beijing Children's Hospital between January 1, 2016, and December 31, 2021. Results A total of 32 patients were included, involving 14 pathogenic or likely pathogenic single genes, and 16 (50.0%) patients had sodium/potassium channel gene variants. The median age at onset of epilepsy was 1.0 (IQR: 0.1, 3.0) months. The median age at initiation of KDT was 10.0 (IQR: 5.3, 13.8) months and the median duration of maintenance was 14.0 (IQR: 7.0, 26.5) months, with a mean blood β‐hydroxybutyrate of 2.49 ± 0.62 mmol/L. During the maintenance period of KDT, 26 (81.3%) patients had a ≥50% reduction of seizure frequency, of which 12 (37.5%) patients achieved seizure freedom. Better responses were observed in patients with STXBP1 variants, with four out of five patients achieving seizure freedom. There were no statistically differences in the age of onset, duration of epilepsy before KDT, blood ketone values, or the presence of ion channel gene variants between the seizure‐free patients and the others. The most common adverse effects were gastrointestinal side effects, which occurred in 21 patients (65.6%), but all were mild and easily corrected. Only one patient discontinued KDT due to nephrolithiasis. Significance KDT is effective in treating early onset genetic DEE, and no statistically significant relationship has been found between genotype and effectiveness in this study. KDT is well tolerated in most young patients, with mild and reversible gastrointestinal side effects being the most common, but usually not the reason to discontinue KDT. Plain Language Summary This study evaluated the response and side effects of ketogenic diet therapy (KDT) in patients who had seizures within the first 6 months of life, and were diagnosed with genetic developmental and epileptic encephalopathy (DEE), a type of severe epilepsy with developmental delay caused by gene variants. Thirty‐two patients involving 14 gene variants who started KDT at Beijing Children's Hospital between were included. KDT was effective in treating early onset genetic DEE in this cohort, and patients with STXBP1 variants responded better; however, no statistically significant relationship was found between gene variant and response. Most young patients tolerated KDT well, with mild and reversible gastrointestinal side effects being the most common.

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-β1 (TGF-β1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway. Resumen: El Losartán es ampliamente utilizado en el tratamiento de la enfermedad renal crónica (CKD) y ha logrado buenos resultados clínicos, pero su mecanismo exacto aún no está claro. Utilizamos la técnica de secuenciación de alto rendimiento (HTS) para detectar posibles dianas de losartán para el tratamiento de la CKD. Según los resultados de HTS, encontramos un enriquecimiento de la vía de señalización del factor de necrosis tumoral (TNF). Así, realizamos experimentos in vivo e in vitro para verificar esto. Encontramos que, tanto en ratas con obstrucción ureteral unilateral (uuo) como en células epiteliales tubulares renales proximal humanas (HK-2) tratadas con factor de crecimiento transformador β1 (TGF-β1), se activó la vía de señalización del TNF. El losartán inhibe significativamente la expresión de las vías de señalización del TNF y genes relacionados con la fibrosis, como COL-1, α-SMA y vicentin. Estos datos sugieren que el losartán puede mejorar la fibrosis renal regulando la vía del TNF.

Abstract Background The gaps between estrogenic effect and its effect-active compounds exist frequently due to a large number of compounds that have been reported to induce this effect and the occurrence of pollutants in environments as mixtures. Therefore, identifying the estrogen-active compounds is of importance for environmental management and pollution treatment. In the current study, the effect-directed analysis (EDA) and non-targeted screening (NTS) were integrated to identify the estrogen-active compounds in soils of the rural area with different socioeconomic types (industrial, farming and plantation village) in Northeast China. Results The cytotoxicity results indicated that the industrial and farming villages showed cytotoxic effects. The detection rates of estrogenic effects for samples of winter and summer were 100% and 87%, respectively. Of which, the effects were found to be stronger in summer than in winter, with significant difference observed from the farming village (0.1–11.3 EEQ μg/kg dry weight). A total of 159 chemicals were detected by NTS. By integrating EDA, triphenyl phosphate (TPhP) and indole were successfully identified from a raw sample and its fraction, explaining up to 19.31% of the estrogen activity. Conclusions The present study demonstrates that the successful identification of seven estrogen-active compounds in rural areas of northeastern China can be achieved through the combination of effect-directed analysis (EDA) and non-targeted screening (NTS). This finding is beneficial for risk monitoring and pollution management.

Abstract As a precursor process to cloud formation, aerosol activation over the Tibetan Plateau (TP) plays a pivotal role in regional cloud-precipitation and global climate. However, its characteristics remain unclear due to the absence of targeted observations in the TP. We conducted a ground in-situ aerosol-cloud-precipitation experiment in the southern TP (GACPE-STP), thereby unveiling the aerosol activation characteristics in this crucial region. Our findings reveal a weak aerosol activation capacity with low hygroscopicity (κ) values of less than 0.1 through multi-method κ measurements, contrasting starkly with the widely recommended κ value of 0.3 for continental regions. A κ parameterization is developed for predicting aerosol activation in this region, which can significantly reduce the overestimations of cloud droplet number concentration and hence aerosol indirect effects caused by using the recommended κ of 0.3. These findings address the unclear characteristics of aerosol activation in the TP region, contributing to the enhancement of regional cloud precipitation and global climate simulations.

Introduction: Forming a bridge made of functional axons to span the lesion is essential to reconstruct the motor circuitry following spinal cord injury (SCI). Dorsal root ganglion (DRG) axons are robust in axon growth and have been proved to facilitate the growth of cortical neurons in a process of axon-facilitated axon regeneration. However, whether DRG transplantation affects the axon outgrowth of spinal motor neurons (SMNs) that play crucial roles in motor circuitry remains unclear. Methods: We investigated the axonal growth patterns of co-cultured DRGs and SMN aggregates (SMNAs) taking advantage of a well-designed 3D-printed in vitro system. Chondroitin sulphate proteoglycans (CSPG) induced inhibitory matrix was introduced to imitate the inhibitory environment following SCI. Axonal lengths of DRG, SMNA or DRG & SMNA cultured on the permissive or CSPG induced inhibitory matrix were measured and compared. Results: Our results indicated that under the guidance of full axonal connection generated from two opposing populations of DRGs, SMNA axons were growth-enhanced and elongated along the DRG axon bridge to distances that they could not otherwise reach. Quantitatively, the co-culture increased the SMNA axonal length by 32.1 %. Moreover, the CSPG matrix reduced the axonal length of DRGs and SMNAs by 46.2 % and 17.7 %, respectively. This inhibitory effect was antagonized by the co-culture of DRGs and SMNAs. Especially for SMNAs, they extended the axons across the CSPG-coating matrix, reached the lengths close to those of SMNAs cultured on the permissive matrix alone. Conclusions: This study deepens our understanding of axon-facilitated reconstruction of the motor circuitry. Moreover, the results support SCI treatment utilizing the enhanced outgrowth of axons to restore functional connectivity in SCI patients.

Abstract Background Adverse childhood experiences (ACEs), including childhood maltreatment, have been linked with increased risk of diabetes and obesity during adulthood. A comprehensive assessment on the associations between childhood maltreatment and all major endocrine diseases, as well as the relative importance of different proposed mechanistic pathways on these associations, is currently lacking. Methods Based on the UK Biobank, we constructed a cohort including 151,659 participants with self-reported data on childhood maltreatment who were 30 years of age or older on/after January 1, 1985. All participants were followed from the index date (i.e., January 1, 1985, or their 30th birthday, whichever came later) until the first diagnosis of any or specific (12 individual diagnoses and 9 subtypes) endocrine diseases, death, or the end of follow-up (December 31, 2019), whichever occurred first. We used Cox models to examine the association of childhood maltreatment, treated as continuous (i.e., the cumulative number of experienced childhood maltreatment), ordinal (i.e., 0, 1 and ≥ 2), or binary (

Abstract Background Peripheral vertigo is often comorbid with psychiatric disorders. However, no longitudinal study has quantified the association between peripheral vertigo and risk of psychiatric disorders. Furthermore, it remains unknown how the white matter integrity of frontal-limbic network relates to the putative peripheral vertigo-psychiatric disorder link. Methods We conducted a cohort study including 452,053 participants of the UK Biobank with a follow-up from 2006 through 2021. We assessed the risks of depression and anxiety disorders in relation to a hospitalization episode involving peripheral vertigo using Cox proportional hazards models. We also examined the associations of peripheral vertigo, depression, and anxiety with MRI fractional anisotropy (FA) in a subsample with brain MRI data (N = 36,087), using multivariable linear regression. Results Individuals with an inpatient diagnosis of peripheral vertigo had elevated risks of incident depression (hazard ratio (HR) 2.18; 95% confidence interval (CI) 1.79–2.67) and anxiety (HR 2.11; 95% CI 1.71–2.61), compared to others, particularly within 2 years after hospitalization (HR for depression 2.91; 95% CI 2.04–4.15; HR for anxiety 4.92; 95% CI 3.62–6.69). Depression was associated with lower FA in most studied white matter regions, whereas anxiety and peripheral vertigo did not show statistically significant associations with FA. Conclusions Individuals with an inpatient diagnosis of peripheral vertigo have increased subsequent risks of depression and anxiety disorders, especially within 2 years after hospitalization. Our findings further indicate a link between depression and lower microstructural connectivity as well as integrity beyond the frontal-limbic network.

Abstract Background Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM. Methods The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses. Results In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM. Conclusion In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

Abstract Anxiety/stress-related disorders have been associated with multiple diseases, whereas a comprehensive assessment of the structure and interplay of subsequent associated diseases and their genetic underpinnings is lacking. Here, we first identify 136, out of 454 tested, medical conditions associated with incident anxiety/stress-related disorders attended in specialized care using a population-based cohort from the nationwide Swedish Patient Register, comprising 70,026 patients with anxiety/stress-related disorders and 1:10 birth year- and sex-matched unaffected individuals. By combining findings from the comorbidity network and disease trajectory analyses, we identify five robust disease clusters to be associated with a prior diagnosis of anxiety/stress-related disorders, featured by predominance of psychiatric disorders, eye diseases, ear diseases, cardiovascular diseases, and skin and genitourinary diseases. These five clusters and their featured diseases are largely validated in the UK Biobank. GWAS analyses based on the UK Biobank identify 3, 33, 40, 4, and 16 significantly independent single nucleotide polymorphisms for the link to the five disease clusters, respectively, which are mapped to several distinct risk genes and biological pathways. These findings motivate further mechanistic explorations and aid early risk assessment for cluster-based disease prevention among patients with newly diagnosed anxiety/stress-related disorders in specialized care.

Abstract Background Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system, and childhood AML accounts for about 20% of pediatric leukemia. ANP32B, an important nuclear protein associated with proliferation, has been found to regulate hematopoiesis and CML leukemogenesis by inhibiting p53 activity. However, recent study suggests that ANP32B exerts a suppressive effect on B-cell acute lymphoblastic leukemia (ALL) in mice by activating PU.1. Nevertheless, the precise underlying mechanism of ANP32B in AML remains elusive. Results Super enhancer related gene ANP32B was significantly upregulated in AML patients. The expression of ANP32B exhibited a negative correlation with overall survival. Knocking down ANP32B suppressed the proliferation of AML cell lines MV4-11 and Kasumi-1, along with downregulation of C-MYC expression. Additionally, it led to a significant decrease in H3K27ac levels in AML cell lines. In vivo experiments further demonstrated that ANP32B knockdown effectively inhibited tumor growth. Conclusions ANP32B plays a significant role in promoting tumor proliferation in AML. The downregulation of ANP32B induces cell cycle arrest and promotes apoptosis in AML cell lines. Mechanistic analysis suggests that ANP32B may epigenetically regulate the expression of MYC through histone H3K27 acetylation. ANP32B could serve as a prognostic biomarker and potential therapeutic target for AML patients.

Epilepsy affects ∼ 65 million people worldwide. In this study, peripheral blood mononuclear cells were isolated from a young patient patient bearing a Nitrogen Perntease Regulator Like 3 Protein (NPRL3) mutation and suffering from Epilepsy verified by clinical and genetic diagnosis. Induced pluripotent stem cells (iPSCs) were established by a non-integrative method, using plasmids carrying OCT4, SOX2, KLF4, BCL-XL and C-MYC. The established iPSCs presented typical pluripotent cells morphology, normal karyotype, and potential to differentiate into three germ layers. Our approach offers a useful model to explore pathogenesis and therapy of Epilepsy.

Background Foetal growth restriction (FGR) occurs when a foetus fails to reach its growth potential. This observational study assessed the expression and significance of cell migration-including protein (CEMIP) and aldosterone synthase (CYP11B2) in the serum of pregnant women with FGR.Methods 40 singleton FGR-suffered pregnant women, as well as 40 normal singleton pregnant women, were enrolled. The expression of CEMIP and CYP11B2 in serum was detected in early pregnancy. The correlations between parameters were evaluated. The predictive variables for FGR were determined. The diagnostic value of CEMIP and CYP11B2 for FGR was analysed.Results CEMIP and CYP11B2 mRNA expression in the serum of pregnant women with FGR decreased (both P

Purpose: To elucidate the etiology of infectious uveitis through the comprehensive analysis of keratic precipitates (KPs) using in vivo confocal microscopy (IVCM). Design: Cross-sectional, observational case series. Methods: This single-center, cross-sectional study was conducted at a tertiary care eye hospital from January 2021 to October 2023. It involved a detailed ophthalmologic evaluation of all subjects and included a total of 46 eyes from 36 subjects who were diagnosed with infectious uveitis. IVCM, specifically utilizing the HRT II Rostock corneal module, was employed to study the biomicroscopic morphology of KPs. The categorization of KPs was based on cell size, morphology, and reflection. Results: Cells of KPs were assessed for size, morphology, and reflection through in vivo confocal microscopy. Patients, ranging in age from 13 to 80 years (median 51 years), exhibited diverse morphologic forms of KPs. Neutrophil-dominated KPs with uniform size were predominantly observed in bacterial and fungal endophthalmitis cases (19/19, 100 %), accompanied by small numbers of mononuclear-macrophages in three eyes (3/19, 15.8 %). Viral uveitis cases displayed a broader array of immune cell types, including characteristic striated or dendritic cells in all eyes (27/27, 100 %). Lymphocytes were commonly present (24/27, 88.9 %), forming clusters in sixteen eyes and dispersed in the corneal endothelium below the midline in eight eyes. Neutrophil infiltration was notable in three cytomegalovirus-infected eyes (3/27, 11.1 %). A marked increase in sub-basal corneal epithelial Langhans cells was associated with viral uveitis. Conclusions: Neutrophil-dominated KPs strongly indicate endogenous bacterial or fungal endophthalmitis, while the presence of dendritic cells and lymphocytes in KPs is suggestive of viral uveitis. In vivo confocal microscopy emerges as a crucial tool for differentiating the etiologic diagnosis of infectious uveitis.

Background The band and loop space maintainer is used to maintain the missing space of deciduous molars which are lost early. When the second deciduous molar is lost prematurely, the stress on the first permanent molar during different degrees of development may vary when it is the abutment. The design and use of the space maintainer may also lead to damage of the loop. The purpose of this article is to use the finite element method to study the stress on the first permanent molar and the loop with or without occlusal contact, with the first permanent molar of four different degrees of development serving as the abutment. We aimed to guide the clinical design and use of the space maintainer. Methods We developed finite element models of the mandibular first permanent molar and the band and loop space maintainer, and simulated alveolar bone, periodontal ligament (PDL), enamel and dentin. The four developmental stages were 1/2 (I), 2/3 (II), 3/4 (III) and full development (IV). Ansys Workbench was used to analyze the effects of root development and occlusal contact between the loop and the opposite jaw on abutment teeth and the loop. Abutment teeth were statically loaded vertically and obliquely with a force of 70 N. The loop was statically loaded vertically with a force of 14 N. The stress on all structures and the displacement trends of the loop were calculated. Results The stress on enamel, dentin, PDL and alveolar bone were similar, and the concentration was consistent. But if there was occlusal contact, the loop produced maximum displacement at the near middle edge of contact with the anterior teeth. When the loop was in occlusal contact with the opposing occlusal tooth, the peak value of the equivalent stress on the space maintainer under vertical load was: group I > group IV > group III > group II, and the maximum principal stress peak change was: group I > group III > group II > group IV. The change of the equivalent stress peak value of the loop under oblique load was: group I > group III > group IV > group II, and the maximum principal stress peak change was: group III > group I > group II > group IV. When the loop was not in occlusal contact with the opposing occlusal tooth, the peak value of the equivalent stress on the space maintainer under vertical load was: group IV > group I > group II > group III, and the maximum principal stress peak change was: group IV > group I > group II > group III. The change of the equivalent stress peak value of the space maintainer under oblique load was: group I > group IV > group II > group III, and the maximum principal stress peak change was: group I > group IV > group II > group III. Conclusions Our results suggested that whenever possible, choosing the teeth with nearly complete root development as the abutment of the space maintainer is advisable. The design and use of the band and loop space maintainer should avoid occlusal contact with the occlusal teeth to prevent deformation of the loop.

BackgroundThe association between fibrinogen-to-albumin ratio (FAR) and in-hospital mortality in patients with spontaneous intracerebral hemorrhage (ICH) has been established. However, the association with long-term mortality in spontaneous ICH remains unclear. This study aims to investigate the association between FAR and long-term mortality in these patients.MethodsOur retrospective study involved 3,538 patients who were diagnosed with ICH at West China Hospital, Sichuan University. All serum fibrinogen and serum albumin samples were collected within 24 h of admission and participants were divided into two groups according to the FAR. We conducted a Cox proportional hazard analysis to evaluate the association between FAR and long-term mortality.ResultsOut of a total of 3,538 patients, 364 individuals (10.3%) experienced in-hospital mortality, and 750 patients (21.2%) succumbed within one year. The adjusted hazard ratios (HR) showed significant associations with in-hospital mortality (HR 1.61, 95% CI 1.31–1.99), 1-year mortality (HR 1.45, 95% CI 1.25–1.67), and long-term mortality (HR 1.45, 95% CI 1.28–1.64). Notably, the HR for long-term mortality remained statistically significant at 1.47 (95% CI, 1.15–1.88) even after excluding patients with 1-year mortality.ConclusionA high admission FAR was significantly correlated with an elevated HR for long-term mortality in patients with ICH. The combined assessment of the ICH score and FAR at admission showed higher predictive accuracy for long-term mortality than using the ICH score in isolation.

Backgrounds: In order to detect early gastric cancer (EGC), this research sought to assess the diagnostic utility of magnifying endoscopy (ME) as well as the significance of mucin phenotype and microvessel features. Methods: 402 individuals with an EGC diagnosis underwent endoscopic submucosal dissection (ESD) at the Department of ME between 2012 and 2020. After adjusting for image distortion, high-magnification endoscopic pictures were taken and examined to find microvessels in the area of interest. The microvessel density was measured as counts per square millimeter (counts/mm2) after segmentation, and the vascular bed's size was computed as a percentage of the area of interest. To identify certain properties of the microvessels, such as end-points, crossing points, branching sites, and connection points, further processing was done using skeletonized pixels. Results: According to the research, undifferentiated tumors often lacked the MS pattern and showed an oval and tubular microsurface (MS) pattern, but differentiated EGC tumors usually lacked the MS pattern and presented a corkscrew MV pattern. Submucosal invasion was shown to be more strongly associated with the destructive MS pattern in differentiated tumors as opposed to undifferentiated tumors. While lesions with a corkscrew MV pattern and an antrum or body MS pattern revealed greater MUC5AC expression, lesions with a loop MV pattern indicated higher MUC2 expression. Furthermore, CD10 expression was higher in lesions with a papillary pattern and an antrum or body MS pattern. Conclusion: These results imply that evaluating mucin phenotype and microvessel features in conjunction with magnifying endoscopy (ME) may be a useful diagnostic strategy for early gastric cancer (EGC) detection. Nevertheless, further investigation is required to confirm these findings and identify the best course of action for EGC diagnosis.

Abstract Hydrogen storage in MgH2 is an ideal solution for realizing the safe storage of hydrogen. High operating temperature, however, is required for hydrogen storage of MgH2 induced by high thermodynamic stability and kinetic barrier. Herein, flower‐like microspheres uniformly constructed by N‐doped TiO2 nanosheets coated with TiN nanoparticles are fabricated to integrate the light absorber and thermo‐chemical catalysts at a nanometer scale for driving hydrogen storage of MgH2 using solar energy. N‐doped TiO2 is in situ transformed into TiNxOy and Ti/TiH2 uniformly distributed inside of TiN matrix during cycling, in which TiN and Ti/TiHx pairs serve as light absorbers that exhibit strong localized surface plasmon resonance effect with full‐spectrum light absorbance capability. On the other hand, it is theoretically and experimentally demonstrated that the intimate interface between TiH2 and MgH2 can not only thermodynamically and kinetically promote H2 desorption from MgH2 but also simultaneously weaken Ti─H bonds and hence in turn improve H2 desorption from the combination of weakened Ti─H and Ti─H bonds. The uniform integration of photothermal and catalytic effect leads to the direct action of localized heat generated from TiN on initiating the catalytic effect in realizing hydrogen storage of MgH2 with a capacity of 6.1 wt.% under 27 sun.

Hyperpigmentation (HP) is an unfavorable skin disease that typically caused by injury, inflammation, or photoaging and leads to numerous physical and psychological issues in patients. Recently, development and application of natural whitening substances, particularly compound curcumin (CUR), is one of the most prevalent treatments for HP. However, it is still a formidable challenge to improve the percutaneous delivery of CUR due to its inadequate solubility in water and excellent barrier function of skin. To overcome the limitations of conventional delivery and increase the percutaneous absorption of CUR, the efficient delivery of CUR is urgently required. Herein, we developed a new malic acid-sorbitol deep eutectic solvent (MS/DES) gel microneedle loaded with CUR as a transdermal delivery system for HP treatment. The MS/DES gel produces three-dimensional (3D) network structure by self-assembly of hydrogen bond interactions, which conferred the CUR-MS/DES-GMN with sufficient mechanical properties to successfully penetrate skin tissue while also helping to enhance the drug's release rate. The CUR-MS/DES-GMN exhibit high biocompatibility and mechanical property in vivo of mice. The zebrafish experiments also show that CUR-MS/DES gel has significant effect of anti-pigmentation. Therefore, the designed CUR-MS/DES-GMN system provides a novel strategy for HP treatment based on self-assembly of naturally molecules.

Abstract Background and Objective The neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) were significant and succinct indicators of systemic inflammation. We assessed the influence of stereotactic body radiotherapy (SBRT) on NLR and PLR in patients with locally advanced non‐small cell lung cancer (LA‐NSCLC). Methods We reviewed the medical data of patients with LA‐NSCLC who underwent SBRT between 1 January 2013 and 31 December 2018. NLR and PLR values recorded at pre‐ and post‐SBRT were examined. We assessed the correlation between pre/post‐SBRT NLR and PLR and survival outcomes. The decision tree evaluation was conducted using Chi‐square automatic detection. Results In total, 213 patients were included in the study with a median follow‐up duration of 40.00 (ranging from 5.28 to 100.70) months. Upon dichotomization by a median, we identified that post‐SBRT NLR > 5.5 and post‐SBRT PLR > 382.0 were negatively associated with shorter overall survival (OS). In the multivariate assessment, post‐SBRT PLR > 382.0 was the only factor. Based on post‐SBRT PLR, tumor locations, and tumor stage, we categorized patients into low, medium, or high‐risk groups. Conclusions Post‐SBRT PLR > 382.0 correlated with survival in patients undergoing SBRT. The decision tree model might play a role in future risk stratification to guide the clinical practice of individualized SBRT for LA‐NSCLC.

BackgroundSpinal cord injury (SCI) is a nervous system disease leading to motor and sensory dysfunction below the injury level, and can result in paralysis. MicroRNAs (miRNAs) play a key role in SCI treatment, and related research provides insights for SCI diagnosis and treatment. Bibliometrics is an important tool for literature statistics and evaluation, objectively summarizing multidimensional information. This study comprehensively overviews the field through bibliometric analysis of miRNA and SCI research, providing contemporary resources for future collaboration and clinical treatment.Materials and methodsIn this study, we searched the Web of Science Core Collection (WOSCC) database. After careful screening and data import, we extracted annual publications, citation counts, countries, institutions, authors, journals, highly cited articles, co-cited articles, keywords, and H-index. Bibliometrics and visualization analyses employed VOSviewer, CiteSpace, the R package “bibliometrix,” and online analytic platforms. Using Arrowsmith,1 we determined miRNA-SCI relationships and discussed potential miRNA mechanisms in SCI.ResultsFrom 2008 to 2024, the number of related papers increased annually, reaching 754. The number of yearly publications remained high and entered a period of rapid development. Researchers from 50 countries/regions, 802 institutions, 278 journals, and 3,867 authors participated in the field. Currently, China has advantages in the number of national papers, citations, institutions, and authors. However, it is necessary to strengthen cooperation among different authors, institutions, and countries to promote the production of important academic achievements. The research in the field currently focuses on nerve injury, apoptosis, and gene expression. Future research directions mainly involve molecular mechanisms, clinical trials, exosomes, and inflammatory reactions.ConclusionOverall, this study comprehensively analyzes the research status and frontier of miRNAs in SCI. A systematic summary provides a complete and intuitive understanding of the relationship between SCI and miRNAs. The presented findings establish a basis for future research and clinical application in this field.

Summary: Background: Ultra-processed foods (UPFs) are emerging as a risk factor for colorectal cancer (CRC), yet how post-diagnostic UPF intake may impact CRC prognosis remains unexplored. Methods: Data collected from food frequency questionnaires were used to estimate intakes of total UPFs and UPF subgroups (serving/d) at least 6 months but less than 4 years post-diagnosis among 2498 patients diagnosed with stages I–III CRC within the Nurses’ Health Study and Health Professionals Follow-up Study during 1980–2016. Hazard ratios (HR) and 95% confidence intervals (CIs) of all-cause, CRC- and cardiovascular disease (CVD)-specific mortality in association with UPF consumption were estimated using an inverse probability weighted multivariable Cox proportional hazards regression model, adjusted for confounders. Findings: The mean (SD) age of patients at diagnosis was 68.5 (9.4) years. A total of 1661 deaths were documented, including 321 from CRC and 335 from CVD. Compared to those in the lowest quintile (median = 3.6 servings/d), patients in the highest quintile (median = 10 servings/d) of post-diagnostic UPF intake had higher CVD mortality (HR = 1.65, 95% CI = 1.13–2.40) but not CRC or all-cause mortality. Among UPF subgroups, higher consumption of fats/condiments/sauces was associated with a higher risk of CVD-specific mortality (highest vs. lowest quintile of intake, HR = 1.96, 95% CI = 1.41–2.73), and higher intake of ice cream/sherbet was associated with an increased risk of CRC-specific mortality (highest vs. lowest quintile, HR = 1.86, 95% CI: 1.33–2.61). No statistically significant association was found between UPF subgroups and overall mortality. Interpretation: Higher post-diagnostic intake of total UPFs and fats/condiments/sauces in CRC survivors is associated with higher CVD mortality, and higher ice cream/sherbet intake is linked to higher CRC mortality. Funding: US National Institutes of Health and the American Cancer Society.

Frequency stability and security have been a vital challenge as large-scale renewable energy is integrated into power systems. In contrast, the proportion of traditional thermal power units decreases during the decarbonization transformation process, resulting in poor frequency support. This paper aims to explore the potential of frequency regulation support, dynamic assessment, and capacity promotion of thermal power plants in the transition period. Considering the dynamic characteristics of the main steam working fluid under different working conditions, a nonlinear observer is constructed by extracting the main steam pressure and valve opening degree parameters. The real-time frequency modulation capacity of thermal power units can provide a dynamic state for the power grid. A dynamic adaptive modification for primary frequency control (PFC) of power systems, including wind power and thermal power, is proposed and improved. The power dynamic allocation factor is adaptively optimized by predicting the speed droop ratio, and the frequency modulation capability of the system is improved by more than 11% under extreme conditions. Finally, through the Monte Carlo simulation of unit states of the system under various working conditions, the promotion of the frequency regulation capacity with high wind power penetration (WPP) is verified.

Abstract Background Randomized controlled trials have found that once-weekly insulin resulted in greater glycemic control compared to once-daily insulin in patients with type 2 diabetes. However, no direct comparisons have been made between different types of once-weekly insulin thus far. This systematic review and network meta-analysis aimed to evaluate the effect of the two most advanced once-weekly insulin analogues, namely insulin icodec and insulin Fc, in patients with type 2 diabetes. Methods We conducted a thorough search in the databases PubMed, Embase, and the Cochrane Central Register of Controlled Trials. The search included articles published from the beginning to October 10, 2023, with no language limitations. Our aim was to conduct a systematic review of randomized controlled trials that investigated the effectiveness and safety of once-weekly insulin in individuals with type 2 diabetes. Our primary outcome was to evaluate excellent glycemic control, defined as patients achieving glycated hemoglobin levels below 7%. Results We identified a total of 7 trials involving 2829 patients. The results showed that once-weekly insulin icodec is more effective than once-weekly insulin Fc (RR 1.59 [95% CI 1.08–2.38]), once-daily degludec (RR 1.43 [95% CI 1.14–1.83]), and once-daily glargine (RR 1.15 [95% CI 1.00-1.41]). Moreover, the incidence of severe hypoglycemia was lower with once-weekly insulin icodec compared to once-daily degludec (RR 0.00016 [95% CI 0 to 0.41]). However, no significant difference in the incidence of severe hypoglycemia was observed between once-weekly insulin icodec and once-daily glargine (RR 0.39 [95% CI 0.03 to 4.83]). Conclusions In patients with type 2 diabetes, once-weekly insulin icodec achieved superior glycemic control compared to once-weekly insulin Fc, with no significant difference in the occurrence of hypoglycemia. The ranking probability results have shown that one weekly icodec seems to be the preferred option in patients with type 2 diabetes. Trial registration PROSPERO Identifier: CRD42023470894.