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Abstract Callosobruchus maculatus is one of the most competitive stored grain pests, which causes a great loss to agricultural economy. However, due to an inadequacy of high-quality reference genome, the molecular mechanisms for olfactory and hypoxic adaptations to stored environments are unknown and require to be revealed urgently, which will contribute to the detection and prevention of the invasive pests C. maculatus. Here, we presented a high-quality chromosome-level genome of C. maculatus based on Illumina, Nanopore and Hi-C sequencing data. The total size was 1.2 Gb, and 65.17% (797.47 Mb) of it was identified to be repeat sequences. Among assembled chromosomes, chromosome 10 was considered the X chromosome according to the evidence of reads coverage and homologous genes among species. The current version of high-quality genome provides preferable data resources for the adaptive evolution research of C. maculatus.

The latest review published in Nature Reviews Drug Discovery by Michael W. Mullowney and co-authors focuses on the use of artificial intelligence techniques, specifically machine learning, in natural product drug discovery. The authors discussed various applications of AI in this field, such as genome and metabolome mining, structural characterization of natural products, and predicting targets and biological activities of these compounds. They also highlighted the challenges associated with creating and managing large datasets for training algorithms, as well as strategies to address these obstacles. Additionally, the authors examine common pitfalls in algorithm training and offer suggestions for avoiding them.

Abstract Diabetic retinopathy (DR) is an eye disease that causes blindness and vision loss in diabetic. Risk factors for DR include high blood glucose levels and some environmental factors. The pathogenesis is based on inflammation caused by interferon and other nuclear proteins. This review article provides an overview of DR and discusses the role of nuclear proteins in the pathogenesis of the disease. Some core proteins such as MAPK, transcription co-factors, transcription co-activators, and others are part of this review. In addition, some current advanced treatment resulting from the role of nuclear proteins will be analyzes, including epigenetic modifications, the use of methylation, acetylation, and histone modifications. Stem cell technology and the use of nanobiotechnology are proposed as promising approaches for a more effective treatment of DR.

Abstract Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 μmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.

Abstract Background Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. Methods An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays—informed by the literature—were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. Results Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. Conclusions This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. Trial registration N/A. Graphical Abstract

BackgroundThe gut microbiota significantly influences the onset and progression of juvenile idiopathic arthritis (JIA) and associated uveitis (JIAU); however, the causality remains unclear. This study aims to establish a causal link between gut microbiota and JIA or JIAU.MethodsUsing publicly available genome-wide association studies (GAWS) summary data, we conducted a two-sample Mendelian randomisation (MR) analysis employing various methods, namely inverse variance weighted (IVW), simple mode, weighted mode, weighted median and MR-Egger regression methods, to assess the causal association between JIA or JIAU and gut microbiota. Sensitivity analyses, including Cochrane’s Q test, MR-Egger intercept test, leave-one-out analysis and MR-PRESSO, were performed to evaluate the robustness of the MR results. Subsequently, reverse MR analysis was conducted to determine causality between gene-predicted gut microbiota abundance and JIA or JIAU.ResultsThe MR analysis revealed a causal association between gut microbiota abundance variations and JIA or JIAU risk. Specifically, the increased abundance of genus Ruminococcaceae UCG013 (OR: 0.055, 95%CI: 0.006–0.103, p = 0.026) and genus Ruminococcaceae UCG003 (β: 0.06, 95%CI: 0.003–0.117, p = 0.041) correlated with an increased risk of JIA, while genus Lachnospiraceae UCG001 (OR: 0.833, 95%CI: 0.699~0.993, p = 0.042) was associated with a reduced risk of JIA, among others. Sensitivity analysis confirmed MR analysis robustness.ConclusionsThis study provides substantial evidence supporting a causal association between genetically predicted gut microbiota and JIA or JIAU. It highlights the significant role of intestinal flora in JIA or JIAU development, suggesting their potential as novel biomarkers for diagnosis and prevention. These findings offer valuable insights to mitigate the impact of JIA or JIAU.

Abstract Background As new migraine therapies emerge, it is crucial for measures to capture the complexities of health-related quality of life (HRQoL) improvement beyond improvements in monthly migraine day (MMD) reduction. Investigations into the correlations between MMD reduction, symptom management, and HRQoL are lacking, particularly those that focus on improvements in canonical symptoms and improvement in patient-identified most-bothersome symptoms (PI-MBS), in patients treated with eptinezumab. This exploratory analysis identified efficacy measures mediating the effect of eptinezumab on HRQoL improvements in patients with migraine. Methods Data from the DELIVER study of patients with 2–4 prior preventive migraine treatment failures (NCT04418765) were inputted to two structural equation models describing sources of HRQoL improvement via Migraine-Specific Quality-of-Life Questionnaire (MSQ) scores. A single latent variable was defined to represent HRQoL and describe the sources of HRQoL in DELIVER. One model included all migraine symptoms while the second model included the PI-MBS as the only migraine symptom. Mediating variables capturing different aspects of efficacy included MMDs, other canonical symptoms, and PI-MBS. Results In the first model, reductions in MMDs and other canonical symptoms accounted for 35% (standardized effect size [SES] − 0.11) and 25% (SES − 0.08) of HRQoL improvement, respectively, with 41% (SES − 0.13) of improvement comprising “direct treatment effect,” i.e., unexplained by mediators. In the second model, substantial HRQoL improvement with eptinezumab (86%; SES − 0.26) is due to MMD reduction (17%; SES − 0.05) and change in PI-MBS (69%; SES − 0.21). Conclusions Improvements in HRQoL experienced by patients treated with eptinezumab can be substantially explained by its effect on migraine frequency and PI-MBS. Therefore, in addition to MMD reduction, healthcare providers should discuss PI-MBS improvements, since this may impact HRQoL. Health technology policymakers should consider implications of these findings in economic evaluation, as they point to alternative measurement of quality-adjusted life years to capture fully treatment benefits in cost-utility analyses. Trial registration ClinicalTrials.gov (Identifier: NCT04418765 ; EudraCT (Identifier: 2019–004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ). Graphical Abstract

Abstract Objective To analyze the risk factors affecting psychiatric behavior and study the psychobehavioral conditions of children with epilepsy. Method We randomly selected and enrolled 294 children with epilepsy who visited and were hospitalized in the pediatric clinic of Hebei General Hospital between January 2017 and January 2022, as the study participants. We comprehensively assessed their cognitive functions using the Gesell development schedule or Wechsler Intelligence Scales. The participants were divided into the study group (n = 123) with cognitive impairment and the control group (n = 171) with normal cognitive functions, for analysis. Results There were statistically significant differences between the two groups in disease course, frequency of epilepsy, status epilepticus, and the number of antiseizure medications (ASMs) used (P 0.05). Based on multivariate logistic regression analysis, the course of disease, frequency of onset, status epilepticus and number of ASMs used were identified as high-risk factors for cognitive impairment in children with epilepsy. Similarly, early onset, long course of disease, known etiology, and combination of multiple drugs have a negative impact on behavioral problems, school education, and social adaptability. Conclusion The course of disease, the frequency of onset, status epilepticus, and the number of ASMs used are high-risk factors for cognitive impairment in children with epilepsy, which can be prevented and controlled early. When selecting ASMs, their advantages and disadvantages should be weighed. Moreover, the availability of alternative treatment options must be considered. With the help of genomic technology, the causes of epilepsy should be identified as early as possible, and precision medicine and gene therapy for children with epilepsy should be actively developed.

Abstract For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.

Abstract The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of ~1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a mammalian cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 2449–3500, 2278–3257 and 1621–2904 protein groups are quantified in single A549 cells (n = 37), HeLa cells (n = 44) and U2OS cells (n = 27) under the DIA (MBR) mode, respectively. Benefiting from the flexible cell picking-up ability, we study HeLa cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight.

Abstract Background Single-nucleotide variants (SNVs) within gene coding sequences can significantly impact pre-mRNA splicing, bearing profound implications for pathogenic mechanisms and precision medicine. In this study, we aim to harness the well-established full-length gene splicing assay (FLGSA) in conjunction with SpliceAI to prospectively interpret the splicing effects of all potential coding SNVs within the four-exon SPINK1 gene, a gene associated with chronic pancreatitis. Results Our study began with a retrospective analysis of 27 SPINK1 coding SNVs previously assessed using FLGSA, proceeded with a prospective analysis of 35 new FLGSA-tested SPINK1 coding SNVs, followed by data extrapolation, and ended with further validation. In total, we analyzed 67 SPINK1 coding SNVs, which account for 9.3% of the 720 possible coding SNVs. Among these 67 FLGSA-analyzed SNVs, 12 were found to impact splicing. Through detailed comparison of FLGSA results and SpliceAI predictions, we inferred that the remaining 653 untested coding SNVs in the SPINK1 gene are unlikely to significantly affect splicing. Of the 12 splice-altering events, nine produced both normally spliced and aberrantly spliced transcripts, while the remaining three only generated aberrantly spliced transcripts. These splice-impacting SNVs were found solely in exons 1 and 2, notably at the first and/or last coding nucleotides of these exons. Among the 12 splice-altering events, 11 were missense variants (2.17% of 506 potential missense variants), and one was synonymous (0.61% of 164 potential synonymous variants). Notably, adjusting the SpliceAI cut-off to 0.30 instead of the conventional 0.20 would improve specificity without reducing sensitivity. Conclusions By integrating FLGSA with SpliceAI, we have determined that less than 2% (1.67%) of all possible coding SNVs in SPINK1 significantly influence splicing outcomes. Our findings emphasize the critical importance of conducting splicing analysis within the broader genomic sequence context of the study gene and highlight the inherent uncertainties associated with intermediate SpliceAI scores (0.20 to 0.80). This study contributes to the field by being the first to prospectively interpret all potential coding SNVs in a disease-associated gene with a high degree of accuracy, representing a meaningful attempt at shifting from retrospective to prospective variant analysis in the era of exome and genome sequencing.

Reducing the oral bioavailability of metal contaminants including As, Cd, , and Pb in foods can protect human health. Studies showed reduced metal bioavailability with elevated Ca and Fe intake; however, the effectiveness of enhancing food Ca and Fe bioavailability remains unknown. Based on a mouse bioassay and using metal accumulation in mouse tissues (kidneys and liver) as the bioavailability endpoint, this study investigated the roles of casein phosphopeptides (CPP, food nutrition fortifier) in lowering the As, Cd, and Pb bioavailability from consuming a metal-contaminated wheat. The CPP amendment at 0.10–0.50% in wheat promoted its Ca bioavailability, causing 33–62% and 59–80% decreases in the gene expression encoding for duodenal Ca and phosphate transporters in mice. This limited transcellular transport of Cd2+ and inorganic arsenate via Ca and phosphate transporters respectively, thus leading to 27% and 34% decreases in Cd and As contents in mouse kidneys fed with wheat at 0.50% CPP amendment. In addition, CPP promoted the colonization of Feacalibaculum and Bifidobacterium in mouse gut, likely promoting As excretion in feces by 81–112%. In contrast to As, and Cd, CPP failed to reduce Pb contents in mouse tissue after consuming CPP-amended wheat, probably by elevating wheat-Pb solubility in the intestinal fluid by 48–136%. However, co-amendment of 0.30% CPP and 500 ​μg ​g−1 Ca as Ca gluconate lowered the As, Cd, and Pb contents in mouse kidneys by 38–71%. The data indicate that fortifying Ca together with CPP in wheat can reduce human exposure to multi-metals via dietary intake.

Although advancements in n- and p-doping of gallium oxide (Ga2O3) are underway, the realization of functional pn diodes remains elusive. Here, we present the successful fabrication of a Ga2O3 pn diode utilizing ion implantation technology. The Ga2O3 epilayers were grown on c-plane sapphire substrates by metalorganic chemical vapor deposition (MOCVD). P-type conductivity Ga2O3 epilayer, confirmed by Hall effect analysis, was achieved by phosphorus (P) ion implantation followed with a rapid thermal annealing (RTA) process. This p-Ga2O3 epilayer reveals a significant reduction in resistivity ( 3kT/q) and remained very low at 2✕10−8 A, as the diode operated at 150oC. The behavior could be due to Ga2O3 being a wide bandgap material.

Autophagy is an evolutionarily conserved cellular recycling process that maintains cellular homeostasis. Despite extensive research in endocrine contexts, the role of autophagy in ovarian and testicular steroidogenesis remains elusive. The significant role of autophagy in testosterone production suggests potential treatments for conditions like oligospermia and azoospermia. Further, influence of autophagy in folliculogenesis, ovulation, and luteal development emphasizes its importance for improved fertility and reproductive health. Thus, investigating autophagy in gonadal cells is clinically significant. Understanding these processes could transform treatments for endocrine disorders, enhancing reproductive health and longevity. Herein, we provide the functional role of autophagy in testicular and ovarian steroidogenesis to date, highlighting its modulation in testicular steroidogenesis and its impact on hormone synthesis, follicle development, and fertility therapies.

Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology.

Abstract Background Alzheimer’s disease (AD) and vascular dementia (VaD) are two of the commonest causes of dementia in the elderly. Of the myriad biomolecules implicated in dementia pathogenesis, sphingolipids have attracted relatively scant research attention despite their known involvement in multiple pathophysiological processes. The potential utility of peripheral sphingolipids as biomarkers in dementia cohorts with high concomitance of cerebrovascular diseases is also unclear. Methods Using a lipidomics platform, we performed a case–control study of plasma sphingolipids in a prospectively assessed cohort of 526 participants (non-cognitively impaired, NCI = 93, cognitively impaired = 217, AD = 166, VaD = 50) using a lipidomics platform. Results Distinct patterns of sphingolipid alterations were found in AD and VaD, namely an upregulation of d18:1 species in AD compared to downregulation of d16:1 species in VaD. In particular, GM3 d18:1/16:0 and GM3 d18:1/24:1 showed the strongest positive associations with AD. Furthermore, evaluation of sphingolipids panels showed specific combinations with higher sensitivity and specificity for classification of AD (Cer d16:1/24:0. Cer d18:1/16:0, GM3 d16:1/22:0, GM3 d18:1/16:0, SM d16:1/22:0, HexCer d18:1/18:0) and VAD (Cer d16:1/24:0, Cer d18:1/16:0, Hex2Cer d16:1/16:0, HexCer d18:1/18:0, SM d16:1/16:0, SM d16:1/20:0, SM d18:2/22:0) compared to NCI. Conclusions AD and VaD are associated with distinct changes of plasma sphingolipids, warranting further studies into underlying pathophysiological mechanisms and assessments of their potential utility as dementia biomarkers and therapeutic targets.

Abstract Background Dyskeratosis congenita 1 (DKC1), a critical component of telomerase complex, is highly expressed in a variety of human cancers. However, the association of DKC1 with cancer occurrence and development stages is not clear, making a pan-cancer analysis crucial. Methods We conducted a study using various bioinformatic databases such as TIMER, GEPIA, UALCAN, and KM plotter Analysis to examine the different expressions of DKC1 in multiple tissues and its correlation with pathological stages. Through KEGG analysis, GO enrichment analysis and Venn analysis, we were able to reveal DKC1-associated genes and signaling pathways. In addition, we performed several tests including the CCK, wound healing assay, cell cycle arrest assay, transwell assay and Sa-β-gal staining on DKC1-deleted MDA-231 cells. Results Our study demonstrates that DKC1 has relatively low expression specificity in different tissues. Furthermore, we found that in ACC, KICH, KIRP and LIHC, the expression level of DKC1 is positively correlated with pathological stages. Conversely, in NHSC, KIRP, LGG, LIHC, MESO and SARC, we observed a negative influence of DKC1 expression level on the overall survival rate. We also found a significant positive correlation between DKC1 expression and Tumor Mutational Burden in 14 tumors. Additionally, we observed a significantly negative impact of DKC1 DNA methylation on gene expression at the promoter region in BRCA. We also identified numerous phosphorylation sites concentrated at the C-terminus of the DKC1 protein. Our GO analysis revealed a correlation between DKC1 and ribosomal biosynthesis pathways, and the common element UTP14A was identified. We also observed decreased rates of cell proliferation, migration and invasion abilities in DKC1-knockout MDA-MB-231 cell lines. Furthermore, DKC1-knockout induced cell cycle arrest and caused cell senescence. Conclusions Our findings suggest that the precise expression of DKC1 is closely associated with the occurrence and developmental stages of cancer in multiple tissues. Depletion of DKC1 can inhibit the abilities of cancer cells to proliferate, migrate, and invade by arresting the cell cycle and inducing cell senescence. Therefore, DKC1 may be a valuable prognostic biomarker for the diagnosis and treatment of cancer in various tissues.

Abstract Objectives To examine the characteristics of blood lymphocyte subsets in dermatomyositis-interstitial lung disease (DM-ILD) inflicted patients with positive anti-melanoma differentiation-associated gene 5 (anti-MDA5), as well as its prognosis value in this set of patients. Methods Data were retrospectively collected from 253 DM-ILD patients from three hospitals in China between January 2016 to January 2021. Patients were grouped into anti-MDA5 antibody positive group (MDA5+ DM-ILD) and anti-MDA5 antibody negative group (MDA5− DM-ILD) based on myositis-specific autoantibody test results. Demographic characteristics, lymphocyte subsets patterns and other clinical features were compared between the two groups. The association of lymphocyte subsets with 180-day mortality was investigated using survival analysis in MDA5+ DM-ILD. Results Out of 253 eligible patients with DM-ILD, 59 patients were anti-MDA5+ and 194 were anti-MDA5−. Peripheral blood lymphocyte count, CD3+ count, percentage of CD3+, CD3+CD4+ count, and CD3+CD8+ count was lower in MDA5+ DM-ILD than in MDA5− DM-ILD− (all P

Summary: Upcycling plastics presents an opportunity not only to reduce plastic waste, but also to provide an alternative carbon source to fossil fuels. Herein, we present a protocol to upcycle plastics with resin codes 2–7 using a commercially available base-metal photocatalyst. We first conducted batch reactions, followed by a continuous, segmented flow system for gram-scale upcycling into value-added platform chemicals. This protocol, employing tandem carbon-hydrogen bond oxidation/carbon-carbon bond cleavage reactions, can be useful for photocatalytically transforming plastics at ambient conditions.For complete details on the use and execution of this protocol, please refer to Li et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: Associations between oral health and systemic conditions have been well established in recent literature. Improvements in oral hygiene have consistently shown to significantly reduce the incidence of respiratory infections, which has high morbidity and mortality rates in the frail elderly. However, the simple low-cost intervention of good oral care remains overlooked in healthcare institutions and nursing homes, due to limited awareness and knowledge. Previous efforts for oral care training of non-dental healthcare professionals have been largely sporadic, with little impact and reach to the medical fraternity. Purpose: To overcome these challenges, we utilized a train-the-trainer model, where seven senior nurses from the long-term stay wards of a public community hospital were educated on the importance of good oral health and trained to administer a comprehensive oral care protocol in patients requiring assistance. The Oral Health Education Programme (OHEP) consisted of a full-day workshop on Common Dental Conditions, Oral Health Assessment Technique (OHAT), and oral hygiene instruction for normal and assisted tooth brushing in independent and mechanically ventilated patients respectively. Results: Majority of the nurses felt that the training was effective and applicable to their work. The number of patients with chronic respiratory infections in the wards were reduced after commencement of OHEP. Conclusion: This interprofessional education collaboration using the train-the-trainer model provides a standardized curriculum, while allowing autonomy for the trainers to customize modules relevant to their respective institutions. This partnership model between medical nurses and oral health professionals allows for better sustainability of the programme.

Limited evidence is available regarding the impact of ambient inhalable particulate matter (PM) on mental disorder (MD) or dementia-related deaths, particularly PM1, PM1–2.5, and coarse particles (PM2.5–10). Moreover, individual confounders have rarely been considered. In addition, evidence from low-pollution areas is needed but is inadequate. Using death records from the Death Registration System during 2015–2021 in Ningde, a coastal city in southeast China, we combined a conditional quasi-Poisson model with a distributed lag nonlinear model to estimate the nonlinear and lagged associations of PM exposure with MD or dementia-related deaths in Ningde, China, comprehensively controlling for individual time-invariant confounders using a time-stratified case-crossover design. The attributable fraction and number were calculated to quantify the burden of MD or dementia-related deaths that were related to PMs. We found J-shaped relationships between MD or dementia-related deaths and PMs, with different thresholds of 13, 9, 19, 33 and 12 μg/m3 for PM1, PM1–2.5, PM2.5, PM10 and PM2.5–10. An inter-quartile range increase for PM1, PM1–2.5, PM2.5, PM10 and PM2.5–10 above the thresholds led to an increase of 31.8% (95% confidence interval, 14.3–51.9%), 53.7% (22.4–93.1%), 32.6% (15.0–53.0%), 35.1% (17.7–55.0%) and 25.9% (13.0–40.3%) in MD-related deaths at lag 0–3 days, respectively. The associations were significant in the cool season rather than in the warm season and were significantly greater among people aged 75–84 years than in others. The fractions of MD-related deaths attributable to PM1, PM1–2.5, PM2.5, PM10 and PM2.5–10 were 5.55%, 6.49%, 7.68%, 10.66%, and 15.11%, respectively; however, only some of them could be protected by the concentrations recommended by the World Health Organisation or China grade I standard. Smaller associations and similar patterns were observed between PMs and dementia-related death. These findings suggest stricter standards, and provide evidence for the development of relevant policies and measures.

The potential of circular RNAs (circRNAs) as biomarkers and therapeutic targets is becoming increasingly evident, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored. Here, we investigated the function of circIGF1R and related mechanisms in cardiac regeneration. Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes, circRNAs associated with regeneration were identified. Our data showed that circIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and up-regulated after cardiac injury. The elevation was validated in patients diagnosed with acute myocardial infarction (MI) within 1 week. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from mice after apical resection and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis, while circIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry. RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circIGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation. This subsequently triggered the β-catenin signaling pathway, leading to the transcriptional activation of cyclin D1 and c-Myc. The roles of circIGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments. In conclusion, our study highlights the pivotal role of circIGF1R in facilitating heart regeneration and repair after ischemic insults. The circIGF1R/DDX5/β-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after MI, offering promising avenues for the development of regenerative therapies.

IntroductionThe heterogeneity of depressive and anxiety disorders complicates clinical management as it may account for differences in trajectory and treatment response. Self-schemas, which can be determined by Self-Referential Judgements (SRJs), are heterogeneous yet stable. SRJs have been used to characterize personality in the general population and shown to be prognostic in depressive and anxiety disorders.MethodsIn this study, we used SRJs from a Self-Referential Encoding Task (SRET) to identify clusters from a clinical sample of 119 patients recruited from the Institute of Mental Health presenting with depressive or anxiety symptoms and a non-clinical sample of 115 healthy adults. The generated clusters were examined in terms of most endorsed words, cross-sample correspondence, association with depressive symptoms and the Depressive Experiences Questionnaire and diagnostic category.ResultsWe identify a 5-cluster solution in each sample and a 7-cluster solution in the combined sample. When perturbed, metrics such as optimum cluster number, criterion value, likelihood, DBI and CHI remained stable and cluster centers appeared stable when using BIC or ICL as criteria. Top endorsed words in clusters were meaningful across theoretical frameworks from personality, psychodynamic concepts of relatedness and self-definition, and valence in self-referential processing. The clinical clusters were labeled “Neurotic” (C1), “Extraverted” (C2), “Anxious to please” (C3), “Self-critical” (C4), “Conscientious” (C5). The non-clinical clusters were labeled “Self-confident” (N1), “Low endorsement” (N2), “Non-neurotic” (N3), “Neurotic” (N4), “High endorsement” (N5). The combined clusters were labeled “Self-confident” (NC1), “Externalising” (NC2), “Neurotic” (NC3), “Secure” (NC4), “Low endorsement” (NC5), “High endorsement” (NC6), “Self-critical” (NC7). Cluster differences were observed in endorsement of positive and negative words, latency biases, recall biases, depressive symptoms, frequency of depressive disorders and self-criticism.DiscussionOverall, clusters endorsing more negative words tended to endorse fewer positive words, showed more negative biases in reaction time and negative recall bias, reported more severe depressive symptoms and a higher frequency of depressive disorders and more self-criticism in the clinical population. SRJ-based clustering represents a novel transdiagnostic framework for subgrouping patients with depressive and anxiety symptoms that may support the future translation of the science of self-referential processing, personality and psychodynamic concepts of self-definition to clinical applications.

Abstract Introduction Overuse of medication to treat migraine attacks can lead to development of a new type of headache or significant worsening of pre-existing headache, known as medication overuse headache. However, data concerning the burden of medication overuse (MO) in migraine are limited. This study aimed to assess the humanistic burden of MO in individuals with migraine from five European countries. Methods Data are from the 2020 National Health and Wellness Survey—a cross-sectional, population-based survey conducted in France, Germany, Italy, Spain, and the UK. Data were included from adults (≥ 18 years) with a self-reported diagnosis of migraine and at least one migraine attack and one headache in the past 30 days. MO was defined as (i) use of simple analgesics/over-the-counter medications on ≥ 15 days/month; or (ii) use of migraine medication, including combination analgesics, on ≥ 10 days/month. Humanistic burden of MO was assessed using the 12-Item Short-Form Health Survey (SF-12v2), EuroQol 5-Dimensions 5-Levels (EQ-5D), Short-Form 6-Dimensions (SF-6D), and Migraine Disability Assessment (MIDAS). The association of MO with humanistic burden was evaluated using generalized linear models adjusted for potential confounders in the full migraine population and in subgroups defined by headache frequency (monthly headache days [MHDs] 1–3, 4–7, 8–14, or ≥ 15). Results Among individuals with migraine, humanistic burden (SF-12v2, SF-6D, EQ-5D, and MIDAS) was higher in individuals who reported MO (n = 431) versus no MO (n = 3554), even after adjustment for confounding variables (p

Hydrogen sulfide (H2S) is one of the three known gas signal transducers, and since its potential physiological role was reported, the literature on H2S has been increasing. H2S is involved in processes such as vasodilation, neurotransmission, angiogenesis, inflammation, and the prevention of ischemia-reperfusion injury, and its mechanism remains to be further studied. At present, the role of post-translational processing of proteins has been considered as a possible mechanism for the involvement of H2S in a variety of physiological processes. Current studies have shown that H2S is involved in S-sulfhydration, phosphorylation, and S-nitrosylation of proteins, etc. This paper focuses on the effects of protein modification involving H2S on physiological and pathological processes, looking forward to providing guidance for subsequent research.

Abstract Advanced oxidation technology based on peroxonosulfate (PMS) has attracted extensive attention in water treatment research due to its fast reaction speed and wide pH range adaptability. Cobalt-based catalysts are considered to be one of the most effective reagents for PMS activation in various PMS activation methods. However, Co-ion leaching and difficulty in recovery have greatly hindered its practical applications. Herein, we developed a robust membrane constructed by nitrogen-doped carbon nanotubes embedded with cobalt nanoparticles (Co-NC) to concurrently address the Co-ion leaching and recovery issues. Based on our customization, continuous water flow reactor, the Co-NC membrane exhibited excellent catalytic activity and stability, in which it demonstrated a remarkable sterilization efficiency of 99.9999% against E. coli, and it retained a superior stability of 96.29% after 40 repeated cycles. Fewer attempts to put such efficient heterogeneous advanced oxidation processes (AOPs) into practical application, to mimic real-life applications, the performance of the Co-NC/PMS system was extended to the water taken from Qiuxi River. Remarkably, there is no deterioration in performance over 12 h of continuous real sewage processing. Mechanistic studies revealed that abundant high-valence metals (CoIV=O) were generated in the system, which can attack and penetrate into the cell membrane to destroy its intracellular defense system. This work provides useful insights into designing robust membranes with superior efficiency and stability for PMS-based advanced oxidation technology.

Abstract Background Nicotine dependence is a significant public health issue, and understanding the factors associated with nicotine dependence in this population is crucial for developing effective interventions. This study examined the association between family functioning and nicotine dependence levels of smoking fathers based on the McMaster model of family functioning (MMFF), providing evidence for future interventions. Methods In this study, we selected fathers of first- to fifth-grade students from 10 pilot elementary schools in Qingdao whose families smoked. We used the Fagerstrom test to assess nicotine dependence and the Family Assessment Device to evaluate family functioning. We performed univariate analysis to compare differences among those with different levels of nicotine dependence, and we used an ordinal logistic regression analysis to investigate the influences related to nicotine dependence. Results This study included 874 smokers, with 78.5% having mild nicotine dependence, 11.7% having moderate dependence, and 9.84% having severe dependence. Univariate analysis showed that smokers with severe dependence had lower education levels, higher prevalence of chronic diseases, more frequent alcohol consumption, and poorer family functioning compared to those with mild to moderate dependence. Ordinal logistic regression analysis showed that poorer general functioning scores (OR = 1.087, 95% CI: 1.008–1.173, P = 0.030), poorer behavioral control (OR = 1.124, 95% CI: 1.026–1.232, P = 0.012), more quit attempts, frequent alcohol consumption, and longer smoking duration may be associated with a higher likelihood of developing severe nicotine dependence. The older age of starting smoking and higher education level may be associated with a lower likelihood of developing severe nicotine dependence. However, it is important to note that the cross-sectional nature of this study precludes the determination of causal relationships. Conclusions This study finds that heavy nicotine dependence in smoking fathers is associated with risky behaviors and demographics such as longer smoking duration and frequent alcohol consumption. Targeted smoking cessation interventions are crucial for this group, taking these specific factors into consideration. Family functioning, particularly general functioning and behavioral control, may also be linked to nicotine dependence, indicating the need for further research in this area.

Abstract Accurate and stable short‐term passenger flow prediction is an indispensable part of current intelligent transportation systems. This paper proposes two deep learning prediction models based on convolutional neural networks (CNN) and long short‐term memory neural network (LSTM). Combining the CNN characteristics and the LSTM, the ConvXD‐LSTM extracts passenger flow features through CNN and then inputs the time series into the LSTM. The ConvLSTM converts the weight calculation of the LSTM into convolution operation to realize short‐term passenger flow prediction. Fuzhou Metro Line 1 passenger flow data was used for verification. The models were used to predict the passenger flow of subway stations and cross‐sections and compared with the traditional prediction models. In terms of prediction accuracy, ConvLSTM has the highest accuracy, followed by ConvXD‐LSTM. In terms of running time, ConvXD is the fastest and LSTM takes the longest. ConvXD‐LSTM and ConvLSTM are in the middle of the two models, achieving a good balance between accuracy and efficiency. Compared with ConvXD‐LSTM, ConvLSTM has a relatively simple network structure, which reduces the computational burden and improves the prediction accuracy.

Polycyclic aromatic hydrocarbons (PAHs) are persistent and harmful pollutants with high priority concern in agricultural fields. This work constructed a rice-crab coculture and bioaugmentation (RCM) system to remediate phenanthrene (a model PAH) contamination in rice fields. The results showed that RCM had a higher remediation performance of phenanthrene in rice paddy compared with rice cultivation alone, microbial addition alone, and crab-rice coculture, reaching a remediation efficiency of 88.92 % in 42 d. The concentration of phenanthrene in the rice plants decreased to 6.58 mg/kg, and its bioconcentration effect was efficiently inhibited in the RCM system. In addition, some low molecular weight organic acids of rice root increased by 12.87 %∼73.87 %, and some amino acids increased by 140 %∼1150 % in RCM. Bioturbation of crabs improves soil aeration structure and microbial migration, and adding Pseudomonas promoted the proliferation of some plant growth-promoting rhizobacteria (PGPRs), which facilitated the degradation of phenanthrene. This coupling rice-crab coculture with bioaugmentation had favorable effects on soil enzyme activity, microbial community structure, and PAH degradation genes in paddy fields, enhancing the removal of and resistance to PAH contamination in paddy fields and providing new strategies for achieving a balance between production and remediation in contaminated paddy fields.

This study utilized various phosphorus-ion implantation techniques, incorporating low, medium, and high doses, to investigate the electrical properties of unintentionally doped β-Ga2O3 epilayers. These epilayers were grown on sapphire substrates by metalorganic chemical vapor deposition.Specifically, the low-dose implantation involved phosphorus ions at concentrations of 1.6✕1013, 1✕1012 and 2.5✕1012 atoms/cm2, administered at implantation energies of 100, 50, and 40 keV, respectively. The medium-dose implantation utilized phosphorus ions at concentrations of 1.6✕1014, 1✕1013 and 2.5✕1013 atoms/cm2, at the same implantation energies. Finally, the high-dose implantation employed phosphorus ions at concentrations of 1.6✕1015, 1✕1014 and 2.5✕1014 atoms/cm2, with implantation energies of 100, 50, and 40 keV, respectively. The implantation parameters were also simulated using the Stopping and Range of Ions in Matter software, while the actual concentration of phosphorus ions was measured via secondary ion mass spectrometry. Subsequently, Ni and Au were deposited on the annealed phosphorus-implanted β-Ga2O3 epilayers, followed by rapid thermal annealing at 600 °C in a nitrogen environment for 1 min, for Hall measurement. The electrical properties of the phosphorus-implanted β-Ga2O3 epilayers were assessed through Hall measurements. Notably, the β-Ga2O3 epilayers implanted with middle and high doses displayed p-type behavior. The resistivity of the p-type β-Ga2O3 epilayers with middle and high doses measured 9.699 and 6.439 Ω cm, respectively, as determined by Hall measurements. Additionally, the hole carrier concentrations for these doses were measured as 1.612 × 1018 and 6.428 × 1017, respectively. Consequently, the phosphorus ion implantations using middle and high doses were proven effective in obtaining p-type Ga2O3. To further explore the defect formation energies and Fermi energies of substitutional phosphorus defects within the β-Ga2O3 lattices, first-principles density-functional simulations were employed.

The circular RNAs (circRNAs) involved in competitive endogenous RNA (ceRNA) mechanism are critical modulators affecting pathogenesis of thyroid carcinoma (TC). The study’s goal was to investigate the effects of circ 0003747 on the biological progression of papillary thyroid cancer (PTC). Normal thyroid cells Nthy-ori3–1 and TC derived cell lines were used in our study. Sanger sequencing and RNase R treatment were utilized for validating the circular structure of circ_0003747. In our work, circ_0003747 was found to be highly expressed in TC cells. Circ_0003747 knockdown reduced TC cell viability, proliferation, migration, and invasion while increasing cell apoptosis. Circ_0003747 targeted and negatively regulated miR-338-3p expression. Besides, miR-338-3p interacted with PLCD3 to repress its expression. Overexpression of miR-338-3p inhibited TC cell progression, and PLCD3 reversed these effects. Furthermore, PLCD3 overexpression reversed the effects of circ_0003747 knockdown on TC cells. Additionally, the knockdown of circ_0003747 remarkably suppressed tumour size and growth, restrained PLCD3 expression and promoted miR-338-3p expression in nude mice. In conclusion, circ_0003747 facilitated the biological progression of TC by modulating the miR-338-3p/PLCD3 axis, and it may be a new target for TC treatment. Abbreviations: TC: Thyroid carcinoma; PTC: Papillary thyroid carcinoma; CircRNAs: Circular RNAs; MiRNA: MicroRNA; EMT: Epithelial-mesenchymal transition; HCC: Hepatocellular carcinoma; PLCD3: Phospholipase C Delta 3; CeRNA: Competitive endogenous RNA

Background: Hydrogen sulfide (H2S) has been identified as the third gaseous signaling molecule. Endogenous H2S plays a key role in the progression of various types of cancer. However, the effect of endogenous H2S on the growth of esophageal cancer (EC) remains unknown. Methods: In this study, three kinds of H2S-producing enzymes inhibitors, DL-propargylglycine (PAG, inhibitor of cystathionine-γ-lyase), aminooxyacetic acid (AOAA, inhibitor of cystathionine-β-synthase), and L-aspartic acid (L-Asp, inhibitor of 3-mercaptopyruvate sulfurtransferase) were used to determine the role of endogenous H2S in the growth of EC9706 and K450 human EC cells. Results: The results indicated that the combination (PAG+AOAA+L-Asp) group showed higher inhibitory effects on the viability, proliferation, migration, and invasion of EC cells than PAG, AOAA, and L-Asp group. Inhibition of endogenous H2S promoted apoptosis via activation of mitogen-activated protein kinase pathway in EC cells. Endogenous H2S suppression triggered pyroptosis of EC cells by activating reactive oxygen species-mediated nuclear factor-κB signaling pathway. In addition, the combine group showed its more powerful growth-inhibitory effect on the growth of human EC xenograft tumors in nude mice without obvious toxicity. Conclusion: Our results indicate that inhibition of endogenous H2S production can significantly inhibit human EC cell growth via promotion of apoptosis and pyroptosis. Endogenous H2S may be a promising therapeutic target in EC cells. Novel inhibitors for H2S-producing enzymes can be designed and developed for EC treatment.

Precise regulation of photogenic electron transfer path plays an important role in improving photocatalytic carbon dioxide reduction efficiency and product selectivity. Herein, under the guidance of density functional theory calculation, the interface chemical bond (CoN2 bond) at the atomic level is designed, and g‐C3N4/CoCo‐layered double hydroxide (LDH) heterostructure is manufactured. CoCo‐LDH with water oxidation ability and g‐C3N4 were combined to construct S‐scheme heterojunction with redox ability. The valence band and conduction band of g‐C3N4 and CoCo‐LDH are precisely connected by the interfacial CoN2 bond, which realizes the high‐speed transfer of electron transport. Despite the absence of cocatalyst, the heterojunction exhibits high water oxidation and carbon reduction capacity due to the precise regulation of CoN2 bonds. Theoretical calculations and experimental results show that the addition of CoCo‐LDH: reduces the oxidation overpotential of water to provide more H protons; regulates the delocalization charge of g‐C3N4; and reduces the energy barrier of the CO2 intermediate (*COOH) in the reduction half‐reaction. The results show that the selectivity of carbon‐based substances in the products was 100%, and the optimal CO yield was 71.39 μmol g−1 h−1, which is among the highest values of g‐C3N4‐based photocatalysts.

Sunlight‐driven CO2 conversion into value‐added fuels emerges as an avant‐garde strategy to mitigate the imminent energy scarcity and global warming. Nevertheless, sluggish charge kinetics and rapid carrier recombination are deemed as the foremost bottlenecks of efficient CO2 photoreduction. In this contribution, the aforementioned shortcomings are addressed by assembling a homo–hetero architecture comprising oxygen‐defective ultrathin BiVO4 (BiVO4–Ov) and red/black phosphorus (RP/BP) homojunction with a built‐in nanoscale dual Z‐scheme electronic configuration. The development of BiVO4–Ov@RP/BP confers two electron relaying channels, that is, one from the RP/BP homojunction and another from the BiVO4–Ov/RP heterojunction, which warrant the efficient separation of electron–hole pairs. Besides, the ultrathin 2D and oxygen vacant nature of BiVO4–Ov exposes more active sites and renders electron trapping for efficient utilization of photogenerated charges. Amalgamating the desirable properties, the meticulously developed dual Z‐scheme homo–heterojunction system on the basis of surface defect‐engineered ultrathin BiVO4–Ov nanosheets integrated with RP/BP offers a new avenue for the exploration, design, and fabrication of new generation photocatalysts with exceptional photocatalytic activities. In particular, the BiVO4–Ov@RP/BP system demonstrates a remarkably high CH4 yield of 14.52 μmol g−1 after 6 h of visible light illumination, which resembles a leading‐edge photocatalytic performance among the existing BiVO4‐ and P‐based semiconductors.

Aims: This study aimed to investigate the association between the use of sodium-glucose transporter 2 inhibitors (SGLT-2i) and the risk of diabetic ketoacidosis (DKA), lower limb amputation (LLA), urinary tract infections (UTI), genital tract infections (GTI), bone fracture, and hypoglycemia in cohort studies.Methods: A systematic search was conducted in the PubMed and Embase databases to identify cohort studies comparing the safety of SGLT-2i versus other glucose-lowering drugs (oGLD) in patients with type 2 diabetes mellitus (T2DM). The quality of the studies was assessed using the Newcastle-Ottawa Scale. Primary endpoints were DKA and LLA, while secondary endpoints included UTI, GTI, bone fracture, and hypoglycemia. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated.Results: A total of 9,911,454 patients from 40 cohort studies were included in the analysis. SGLT-2i use was associated with a higher risk of DKA (HR: 1.21, 95% CI: 1.07–1.38, p = 0.003) and GTI (HR: 2.72, 95% CI: 2.48–2.98, p < 0.01). However, it was not associated with an increased risk of LLA (HR: 1.06, 95% CI: 0.92–1.23, p = 0.42), UTI (HR: 0.99, 95% CI: 0.89–1.10, p = 0.83), or bone fracture (HR: 0.99, 95% CI: 0.94–1.04, p = 0.66). Furthermore, SGLT-2i was associated with a reduced risk of hypoglycemia. Furthermore, compared to dipeptidyl peptidase 4 inhibitors, SGLT-2i as a class and individually was associated with an increased risk of DKA. Canagliflozin specifically increased the risk of LLA (HR: 1.19, 95% CI: 1.04–1.36, p = 0.01). The subgroup analysis suggested that SGLT-2i increased the risk of LLA among patients with a history of cardiovascular disease.Conclusion: SGLT-2i versus oGLD was associated with a similar occurrence of LLA, UTI, and bone fracture. However, SGLT-2i was associated with a higher risk of DKA and GTI than oGLD. These findings provide valuable information on the safety profile of SGLT-2i in patients with T2DM and can help inform clinical decision-making.

To investigate the overall damage characteristics and failure modes of a warship subjected to an underwater non-contact near-field explosion, a hull girder with a trapezoidal cross-section was designed, manufactured, and tested. The design criteria and parameters were determined according to the similarity criterion. Dynamic responses of the girder freely floating on water were obtained under varying conditions, including stand-off distance, charge mass, and position of attack. Damage morphologies of the girder model were obtained. Based on our analysis, basic conditions for sagging damage of the hull girder are proposed. The aim of this study was to determine an efficient method of attack resulting in the most severe damage to the ship hull. The experimental results show that the girder mainly exhibits a first-order response when the first wet frequency of the girder is close to the frequency of the explosion bubble pulsation. The largest deformation was observed when the underwater explosion occurred directly below the midspan of the girder compared to other explosions of the same intensity at different attack positions. When the ratio of stand-off to maximum bubble radius (λ) satisfies 0.7 ≤ λ＜2, the bubble mainly causes sagging damage instead of hogging. As λ decreases (1≤ λ＜2), the sagging damage increases under the same charge mass. However, as λ decreases further (0.7≤ λ＜1), the sagging deformation decreases. This is likely due to the impact of the liquid jet formed by the collapsing bubble, which causes the girder deformation to shift from sagging back to hogging deformation. The initial shock wave excites the high-frequency response of the girder structure but contributes very little to the overall velocity and displacement. However, bubble pulsation typically causes a low-frequency response, which will affect the velocity and displacement of the girder. The low-pressure region of the flow field formed by bubble pulsation and resonant coupling between the girder and the bubble are the predominant causes of damage to the overall girder structure.

Abstract Background Understanding the relationship between human evolution and environmental changes is the key to lifting the veil on human origin. The hypothesis that environmental changes triggered the divergence of humans from apes (ca. 9.3–6.5 million years ago, Ma) has been poorly tested because of limited continuous environmental data from fossil localities. Lufengpithecus (12.5-6.0 Ma) found on the southeastern margin of the Tibetan Plateau (SEMTP) across the ape–human split provides a good chance for testing this hypothesis. Results Here, we reconstructed the habitats of L. keiyuanensis (12.5–11.6 Ma) with comprehensive vegetation, climate, and potential food web data by palaeobotanical evidence, together with other multidisciplinary data and partly tested the environment-driven hypothesis by revealing the living conditions of Lufengpithecus. Conclusion A detailed comparison of hominoids on different continents reveals their behaviour and fate divergence across the ape–human split against the background of global climate change, i.e., the stable living conditions of SEMTP not only provided a so-called ‘refuge’ for arboreal Lufengpithecus but also acted as a ‘double-edged sword’, preventing their further evolution while vegetation shifts in East Africa probably stimulated the emergence of human bipedalism, and the intense climatic changes in Europe possibly prevented those hominoids from surviving that time interval. Our findings provide interesting insight into the environmental impacts on the behavioural evolution of hominoids.

Abstract Background Multiple sclerosis is a diffuse chronic demyelinating disease of the central nervous system. It is relatively uncommon in the Asian population and even more so in males. Despite the usual involvement of the brainstem, eight-and-a-half syndrome remains a rare first presentation in multiple sclerosis. Only a few cases have been reported previously, but none involving the Asian population. Eight-and-a-half syndrome, a neuro-ophthalmological condition, is characterized by one-and-a-half syndrome with ipsilateral lower facial nerve palsy, which localizes lesions to the pontine tegmentum. This case report demonstrates the first case of eight-and-a-half syndrome as the first presentation of multiple sclerosis in an Asian male. Case presentation A healthy 23-year-old Asian man presented with sudden onset of diplopia followed by left-sided facial asymmetry for 3 days. Assessment of extraocular movement revealed left conjugate horizontal gaze palsy. On right gaze, there was limited left eye adduction and horizontal nystagmus of the right eye. These findings were consistent with a left-sided one-and-a-half syndrome. Prism cover test revealed left esotropia of 30 prism diopters. Cranial nerve examination showed left lower motor neuron facial nerve palsy, while other neurological examination was normal. Magnetic resonance imaging brain showed multifocal T2 fluid attenuated inversion recovery hyperintense lesions, involving bilateral periventricular, juxtacortical, and infratentorial regions. A focal gadolinium contrast-enhanced lesion with open ring sign on T1 sequence was seen at the left frontal juxtacortical region. Multiple sclerosis was diagnosed on the basis of the clinical and radiological evidence, which fulfilled the 2017 McDonald criteria. Positive oligoclonal bands in cerebrospinal fluid analysis further confirmed our diagnosis. He had a complete resolution of symptoms 1 month after a course of pulsed corticosteroid therapy, and was subsequently placed on maintenance therapy with interferon beta-1a. Conclusion This case illustrates eight-and-a-half syndrome as the first presentation of a diffuse central nervous system pathology. A wide range of differential diagnoses needs to be considered in such a presentation as based on the patient’s demographics and risk factors.

Abstract Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m2) on Days 1 and 8 and oxaliplatin (85 mg/m2) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825). Trial registration Clinical trials: NCT03951597.

The study of synthetic biology focusing on biosensor systems has resulted from a growing interest in developing customized biological devices with desired cellular functions. Recently, biosensors have been used for a variety of medical applications such as disease diagnosis, prevention, rehabilitation, patient health monitoring, and human health management. Meanwhile, the ability to track biomarkers based on biosensors allows researchers and medical practitioners to provide patients with individualized treatment regimens and health management. Biosensors that respond to electrochemical, optical, thermal, piezoelectric and magnetic signals have been developed and utilized for various disease therapies and biomedical applications. This study reviews recent developments in biosensor-based therapeutic tools by sensing diverse biomarkers in many diseases (e.g. cancer, infections, metabolic diseases), such as physical biomarkers (e.g. pressure, temperature) and chemical biomarkers (e.g. dissolved oxygen, glucose). Additionally, we highlight the challenges and problems of biosensor-based therapeutics and possible solutions for biosensor engineering thereof. Current biosensors enable for coarsely programable personal treatment and health management, however, new sensors with optimized dose-response functions, for example, fast response and tight-control performances, could significantly boost versatile uses in medical treatment in the coming future.

Spinal cord injury is a severe and devastating disease, and spasticity is a common and severe complication that is notoriously refractory to treatment. However, the pathophysiological mechanisms underlying spasticity and its development remain largely unknown. The goal of the present study was to find differences, if any, in metabolites of the left precentral gyrus and basal ganglia of patients who have spinal cord injury with or without spasticity, and to explore the relationship between the brain metabolite concentrations and clinical status. Thirty-six participants were recruited for magnetic resonance spectroscopic examination: 23 with spinal cord injury (12 with spasticity and 11 without spasticity) and 13 healthy controls. We acquired localized proton spectra from the precentral gyrus and basal ganglia via 10 mm3 voxels. Notably, univariate linear regression analysis demonstrated that the lower that the N-acetylaspartate concentration (a marker for neuronal loss) was in the precentral gyrus of the patients, the lower their ASIA (American Spinal Injury Association) light-touch scores, pinprick scores, and motor scores. Additionally, longer durations of injury were associated with higher N-acetylaspartate levels in the precentral gyrus. Compared with the healthy participants and patients without spasticity, N-acetylaspartate levels in the patients with spasticity were significantly lower in both the precentral gyrus and basal ganglia. Lower N-acetylaspartate levels also correlated with greater sensory and motor dysfunction in the patients who had spinal cord injury with spasticity.

There are numerous universal portfolios generated in different studies using various divergence functions to achieve one goal, which is to maximize wealth. To extend the exploration, through this study, we have generated a new universal portfolio using the Hellinger distance. We conducted a comprehensive performance evaluation of our newly developed universal portfolio against common strategies such as the buy-and-hold strategy and the constant rebalanced portfolio. This evaluation used diverse stock price data from the Bursa Malaysia local platform for trading stocks, bonds, and other securities. Our empirical findings demonstrate that the Hellinger distance-based universal portfolio outperformed the traditional strategies in two out of three datasets over a period of 535 trading days. Specifically, the Hellinger portfolio shows a significant improvement in wealth accumulation, with data set X achieving the highest wealth increase and exhibiting nearly 99% allocation to the most profitable stock. These results highlight the potential of the Hellinger distance-based approach in improving the performance of universal portfolios and offer a promising tool for investment decision-making in today’s complex and unpredictable financial markets.

Some quasi-thermal (QT)-dominated gamma-ray bursts (GRBs) could be well described by a multicolor blackbody (mBB) function or a combined model of a BB plus a nonthermal (NT) component. In this analysis, two QT radiation-dominated bursts with known emission properties (GRB 210610B, likely from a hybrid jet, and GRB 210121A, with a spectrum consistent with nondissipative photospheric emission from a pure hot fireball) are used to make a comparison between these two models. To diagnose the magnetization properties of the central engine, the “top-down” approach proposed by Gao and Zhang is adopted. It is found that diagnoses based on these two models provide similar conclusions qualitatively; however, the model with mBB (or mBB+NT) may give more reasonable physical explanations. This implies that impacts from the GRB jet structure and geometrical broadening on the observed spectrum should be considered. However, conservatively, these methods may be not sensitive enough to distinguish between a pure hot fireball and a mildly magnetized hybrid jet. Some other information is necessary to provide more evidence when determining the jet properties for similar GRBs. Based on these considerations, we suggest that the photospheric emission of GRB 221022B is from a hot jet, where dissipation is caused by an internal shock mechanism due to the increasing Lorentz factor with time, which makes its prompt emission display typical evolution from thermal to NT.

Developing robust nonprecious metal‐based electrocatalysts toward hydrogen evolution reaction is crucial for large‐scale hydrogen production via electrochemical water splitting. Herein, surface high‐entropy NiFeCoCuTi alloy on column‐nanostructured nanoporous Ni skeleton is reported as multisite electrocatalyst for highly efficient hydrogen evolution in nonacidic environments by making use of surface heterogeneous atoms with distinct hydrogen and hydroxyl adsorption behaviors to accelerate water dissociation and mediate adsorption of hydrogen intermediates for combination into molecules. Associated with the column‐nanostructured nanoporous Ni skeleton that facilitates electron transfer/mass transportation and enables highly accessible and abundant electroactive sites, self‐supported monolithic nanoporous high‐entropy NiFeCoCuTi alloy electrode exhibits superior nonacidic hydrogen evolution reaction (HER) electrocatalysis, with low onset overpotentials and Tafel slopes. It only takes overpotential of as low as ≈209 mV to deliver ultrahigh current density of 2 A cm−2, along with exceptional stability for more than 240 h, in 1 m KOH electrolyte. These outstanding properties make nanoporous NiFeCoCuTi high‐entropy alloy (HEA) electrode attractive candidate as cathode material in the water electrolysis for large‐scale hydrogen production and suggest HEAs as ideal platform to develop multisite electrocatalysts.

Summary: Neurological diseases are one of the most pressing issues in modern times worldwide. It thus possesses explicit attention from researchers and medical health providers to guard public health against such an expanding threat. Various treatment modalities have been developed in a remarkably short time but, unfortunately, have yet to lead to the wished-for efficacy or the sought-after clinical improvement. The main hurdle in delivering therapeutics to the brain has always been the blood-brain barrier which still represents an elusive area with lots of mysteries yet to be solved. Meanwhile, nanotechnology has emerged as an optimistic platform that is potentially holding the answer to many of our questions on how to deliver drugs and treat CNS disorders using novel technologies rather than the unsatisfying conventional old methods. Nanocarriers can be engineered in a way that is capable of delivering a certain therapeutic cargo to a specific target tissue. Adding to this mind-blowing nanotechnology, the revolutionizing gene-altering biologics can have the best of both worlds, and pave the way for the long-awaited cure to many diseases, among those diseases thus far are Alzheimer’s disease (AD), brain tumors (glioma and glioblastoma), Down syndrome, stroke, and even cases with HIV. The review herein collects the studies that tested the mixture of both sciences, nanotechnology, and epigenetics, in the context of brain therapeutics using three main categories of gene-altering molecules (siRNA, miRNA, and CRISPR) with a special focus on the advancements regarding the new favorite, intranasal route of administration.

Abstract Intense ultraviolet (UV) exposure can cause phototoxic reactions, such as skin inflammation, resulting in injury. UV is a direct cause of DNA damage, but the mechanisms underlying transcriptional regulation within cells after DNA damage are unclear. The bioinformatics analysis of transcriptome sequencing data from UV‐irradiated and non‐UV‐irradiated skin showed that transcription‐related proteins, such as HSF4 and COIL, mediate cellular response to UV irradiation. HSF4 and COIL can form a complex under UV irradiation, and the preference for binding target genes changed because of the presence of a large number of R‐loops in cells under UV irradiation and the ability of COIL to recognize R‐loops. The regulation of target genes was altered by the HSF4–COIL complex, and the expression of inflammation and ageing‐related genes, such as Atg7, Tfpi, and Lims1, was enhanced. A drug screen was performed for the recognition sites of COIL and R‐loop. N6‐(2‐hydroxyethyl)‐adenosine can competitively bind COIL and inhibit the binding of COIL to the R‐loop. Thus, the activation of downstream inflammation‐related genes and inflammatory skin injury was inhibited.

Laccase activity secreted by Pleurotus eryngii Han 1787 and Lentinus edodes Han 1788 grown on six types of agroindustrial wastes was investigated. Maximum laccase activity of P. eryngii Han 1787 on Ulmus pumila, Juniperus formosana, Pinus tabuliformis, cottonseed shell, corncob, and leaf of corncob was nearly 5.77-fold, 2.37-fold, 2.78-fold, 2.81-fold, 11.53-fold, and 6.73-fold higher than that of L. edodes Han1788 on corresponding agroindustrial wastes. In general, the capacity of secreting laccase of P. eryngii Han 1787 was superior to that of L. edodes Han 1788. Furthermore, laccase activity of P. eryngii Han 1787 on the leaf of corncob, the corncob, Ulmus pumila, and Juniperus formosana was relatively stable during the whole fermentation process. Different fungi showed different preferences in different agroindustrial wastes to secret laccase on whole fermentation stage. The presence of leaf of corncob was useful for improving laccase activity of P. eryngii Han 1787, while L. edodes Han 1788 was more preferred to produce laccase along with the presence of Juniperus formosana. These results were preliminary conducive in laying the foundation for increasing industrial laccase-producing strains and producing low-cost laccase.

Laccase activity secreted by Pleurotus eryngii Han 1787 and Lentinus edodes Han 1788 grown on six types of agroindustrial wastes was investigated. Maximum laccase activity of P. eryngii Han 1787 on Ulmus pumila, Juniperus formosana, Pinus tabuliformis, cottonseed shell, corncob, and leaf of corncob was nearly 5.77-fold, 2.37-fold, 2.78-fold, 2.81-fold, 11.53-fold, and 6.73-fold higher than that of L. edodes Han1788 on corresponding agroindustrial wastes. In general, the capacity of secreting laccase of P. eryngii Han 1787 was superior to that of L. edodes Han 1788. Furthermore, laccase activity of P. eryngii Han 1787 on the leaf of corncob, the corncob, Ulmus pumila, and Juniperus formosana was relatively stable during the whole fermentation process. Different fungi showed different preferences in different agroindustrial wastes to secret laccase on whole fermentation stage. The presence of leaf of corncob was useful for improving laccase activity of P. eryngii Han 1787, while L. edodes Han 1788 was more preferred to produce laccase along with the presence of Juniperus formosana. These results were preliminary conducive in laying the foundation for increasing industrial laccase-producing strains and producing low-cost laccase.

Abstract Myocardial ischemia/reperfusion (I/R) injury is associated with the poor outcome and higher mortality after myocardial infarction. Recent studies have revealed that miR‐199a‐5p participates in the process of myocardial I/R injury, but the precise roles and molecular mechanisms of miR‐199a‐5p in myocardial I/R injury remain not well‐studied. Ferroptosis has been proposed to promote cardiomyocyte death, closely associated with myocardial I/R injury. Herein, the present study aimed to explore the function and mechanisms by which miR‐199a‐5p regulates whether miR‐199a‐5p contributes to ferroptosis‐induced cardiomyocyte death responding to oxygen–glucose deprivation/reoxygenation (OGD/R) injury, an in vitro model of myocardial I/R injury focusing on Akt/eNOS signaling pathway. The results found that ferroptosis‐induced cardiomyocyte death occurs and is accompanied by an increase in miR‐199a‐5p level in OGD/R‐treated H9c2 cells. MiR‐199a‐5p inhibitor ameliorated ferroptosis‐induced cardiomyocyte death as evidenced by the increased cell viability, the reduced reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) activity, malondialdehyde (MDA) and Fe2+ contents, and the up‐regulated glutathione (GSH)/glutathione disulphide (GSSG) ratio as well as glutathione peroxidase 4 (Gpx4) protein expression in H9c2 cells‐exposed to OGD/R, while miR‐199a‐5p mimic had the opposite effects. In addition, OGD/R led to the inhibition of Akt/eNOS signaling pathway, which was also blocked by miR‐199a‐5p inhibitor and aggravated by miR‐199a‐5p mimic. Furthermore, LY294002, an inhibitor of Akt/eNOS signaling pathway, abrogated miR‐199a‐5p inhibitor‐induced the reduction of ferroptosis‐induced cardiomyocyte death. In summary, our findings demonstrated that miR‐199a‐5p plays a central role in stimulating ferroptosis‐induced cardiomyocyte death during ischemic/hypoxic injury via inhibiting Akt/eNOS signaling pathway.