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Abstract Oral squamous cell carcinoma (OSCC) is a prevalent cancer worldwide, exhibiting unique regional prevalence. Despite advancements in diagnostics and therapy, the 5-year survival rate for patients has seen limited improvement. A deeper understanding of OSCC pathogenesis, especially its molecular underpinnings, is essential for improving detection, prevention, and treatment. In this context, noncoding RNAs, such as circular RNAs (circRNAs), have gained recognition as crucial regulators and potential biomarkers in OSCC progression. Our study highlights the discovery of previously uncharacterized circRNAs, including a SNX5 gene-derived circRNA, circSNX5, through deep sequencing of OSCC patient tissue transcriptomes. We established circSNX5’s tumor-specific expression and its strong correlation with patient survival using structure-specific and quantitative PCR analyses. In vitro and in vivo experiments underscored circSNX5 RNA’s regulatory role in cancer growth and metastasis. Further, our omics profiling and functional assays revealed that ADAM10 is a critical effector in circSNX5-mediated cancer progression, with circSNX5 maintaining ADAM10 expression by sponging miR-323. This novel circRNA-miRNA-mRNA regulatory axis significantly contributes to oral cancer progression and malignancy. Moreover, we discovered that circSNX5 RNA is produced via noncanonical sequential back-splicing of pre-mRNA, a process negatively regulated by the RNA-binding protein STAU1. This finding adds a new dimension to our understanding of exonic circRNA biogenesis in the eukaryotic transcriptome. Collectively, our findings offer a detailed mechanistic dissection and functional interpretation of a novel circRNA, shedding light on the role of the noncoding transcriptome in cancer biology and potentially paving the way for innovative therapeutic strategies.

Abstract Pressing environmental challenges require focused research on sustainable solutions in the domains of energy, water, food, land, and climate. The pigment eumelanin has recently been positioned as a promising candidate for solving issues in health, sensors, and energy storage. However, the low solubility of eumelanin in aqueous solvents, difficult film processibility, and high cost have hindered the material from wide deployment. Here, we propose melanin extracted from the black soldier fly, Hermetia illucens (Mel-BSF), as a sustainable alternative for the preparation of organic electrodes in energy storage applications. Mel-BSF displays pseudocapacitive behaviour with a high potential window, good electrochemical stability, and higher maximum capacity (91.8 mAh g−1) compared to synthetic eumelanin (17.3 mAh g−1) as the working electrode material in zinc-ion hybrid capacitors using an ionic liquid electrolyte. Structural and surface investigations reveal that additional aliphatic compounds, potentially lipids present after Mel-BSF refinement, significantly increase the film stability and redox centre availability.

Abstract The HBV core protein (HBc) is an important viral protein of HBV that plays an indispensable role in the lifecycle of HBV, including capsid assembly and transport, reverse transcription and virus release. In recent years, evidence has shown that HBc may be involved in the malignant progression of HCC. Thus, HBc is an attractive target for antiviral agents and provides a new strategy for the treatment of HBV-related HCC. Here, we identified a novel anti‐HBc compound—colchicine, an alkaloid compound—that promoted selective autophagic degradation of HBc through the AMPK/mTOR/ULK1 signalling pathway. We further confirmed that colchicine promoted the selective autophagy of HBc by enhancing the binding of HBc to the autophagy receptor p62. Finally, we evaluated the effects of colchicine on HBV replication and HBc-mediated HCC metastasis in vitro and in vivo. Our research indicated that the inhibitory effects of colchicine on HBV and HBV-related HCC depend on the selective autophagic degradation of HBc. Thus, colchicine is not only a promising therapeutic strategy for chronic hepatitis B but also a new treatment for HBV-related HCC.

Abstract Background The Diagnosis-Intervention Packet (DIP) payment system, initiated by China's National Healthcare Security Administration, is designed to enhance healthcare efficiency and manage rising healthcare costs. This study aims to evaluate the impact of the DIP payment reform on inpatient care in a specialized obstetrics and gynecology hospital, with a focus on its implications for various patient groups. Methods To assess the DIP policy's effects, we employed the Difference-in-Differences (DID) approach. This method was used to analyze changes in total hospital costs and Length of Stay (LOS) across different patient groups, particularly within select DIP categories. The study involved a comprehensive examination of the DIP policy's influence pre- and post-implementation. Results Our findings indicate that the implementation of the DIP policy led to a significant increase in both total costs and LOS for the insured group relative to the self-paying group. The study further identified variations within DIP groups both before and after the reform. In-depth analysis of specific disease groups revealed that the insured group experienced notably higher total costs and LOS compared to the self-paying group. Conclusions The DIP reform has led to several challenges, including upcoding and diagnostic ambiguity, because of the pursuit of higher reimbursements. These findings underscore the necessity for continuous improvement of the DIP payment system to effectively tackle these challenges and optimize healthcare delivery and cost management.

Abstract This study explores disparities and opportunities in healthcare information provided by AI chatbots. We focused on recommendations for adjuvant therapy in endometrial cancer, analyzing responses across four regions (Indonesia, Nigeria, Taiwan, USA) and three platforms (Bard, Bing, ChatGPT-3.5). Utilizing previously published cases, we asked identical questions to chatbots from each location within a 24-h window. Responses were evaluated in a double-blinded manner on relevance, clarity, depth, focus, and coherence by ten experts in endometrial cancer. Our analysis revealed significant variations across different countries/regions (p

Abstract Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2−/−/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD–induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3β pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.

Abstract In a battery pack, several lithium-ion batteries (LiBs) are connected in series and parallel so that sufficient voltage, current and power can be provided for applications. To ensure safe operation, when one of the LiB cells in a pack has its SoH below 80%, the entire pack will have to be discarded. Thus, ensuring all the LiB cells degrade similarly in a pack is crucial to maximize the potential of all the cells in a pack. There are several methods to perform screening on the LiB cells for such purpose, but there exist many practical challenges for estimating and predicting the degradation rate of the cells before they are chosen to be put in a pack which will be described in this work. This work provides solutions to some of these challenges and shows through experiments that one can screen the weak cells from production batch with just the first discharge cycle, and one can also predict the statistical distribution of the degradation rates of LiB cells in a production batch. On-line in-situ determination of the SoH of each cell connected in a pack is also made possible with a solution presented in this work, and this method is verified over many different types of LiB from various manufacturers.

Background Digital technologies proliferate in many people’s lives around the world with over 65% of these technology users being online. Children and youth are among the most prominent adopters of digital technologies in forms such as video gaming, social media, and online shopping. Problematic use of digital technologies can lead to poorer school/work performance, neglect of self-care skills, and comorbidities with other mental health issues. However, when used non-problematically, digital technology can also contribute to improving health and well-being. With the abundance of literature published, many reviews have sought to collate literature on treatment and interventions for children and youth with varying results. Thus, our proposed systematic review aims to synthesize current systematic reviews and meta-analyses on interventions and treatment of problematic digital technology use in children and youth (up to 25 years old). Methods As part of a three-paper series, a systematic search was completed in PsycINFO, Web of Science, and PubMed databases. Grey literature databases of the World Health Organization (IRIS database) and ClinicalTrials.gov were also searched. Furthermore, hand-searching of reference lists was also conducted. Title and abstract screening, followed by full-text screening, were completed by at least two independent reviewers. For this review, the extractions and the quality of selected reviews will be assessed using AMSTAR 2.0 by two authors independently and reviewed by two additional authors. Results Results will be presented in narrative and tabular form. The results of this study are expected to offer insights into the populations of children and youth studied, treatments/interventions provided, outcomes, results, limitations, and conclusions of literature from the past five years. Feasibility and generalizability of the reviews will also be discussed. Conclusions Methodological strengths and weaknesses of reviewed studies will point to gaps in knowledge and can be used to inform future areas of policy and research.

Abstract Enhancing fracture toughness and self‐healing within soft elastomers is crucial to prolonging the operational lifetimes of soft devices. Herein, it is revealed that tuning the polymer chain mobilities of carboxylated‐functionalized polyurethane through incorporating plasticizers or thermal treatment can enhance these properties. Self‐healing is promoted as polymer chains gain greater mobility toward the broken interface to reassociate their bonds. Raising the temperature from 80 to 120 °C, the recovered work of fracture is increased from 2.86 to 123.7 MJ m−3. Improved fracture toughness is realized through two effects. First, strong carboxyl hydrogen bonds dissipate large energies when broken. Second, chain mobilities enable the redistribution of localized stress concentrations to allow crack blunting, enlarging the size of dissipation zones. At optimal conditions of plasticizers (3 wt.%) or temperature (40 °C) to promote chain mobilities, fracture toughness improves from 16.3 to 19.9 and 25.6 kJ m−2, respectively. Insights of fracture properties at healed soft interfaces are revealed through double cantilever beam tests. These measurements indicate that fracture mechanics play a critical role in delaying complete failure at partial self‐healing. By imparting optimal polymer chain mobilities within tough and self‐healing elastomers, effective prevention against damage and better recovery are realized.

Abstract Background Progressive hepatitis B virus (HBV) infection can result in cirrhosis, hepatocellular cancer, and chronic hepatitis. While antiviral drugs that are now on the market are efficient in controlling HBV infection, finding a functional cure is still quite difficult. Identifying host factors involved in regulating the HBV life cycle will contribute to the development of new antiviral strategies. Zinc finger proteins have a significant function in HBV replication, according to earlier studies. Zinc finger protein 148 (ZNF148), a zinc finger transcription factor, regulates the expression of various genes by specifically binding to GC-rich sequences within promoter regions. The function of ZNF148 in HBV replication was investigated in this study. Methods HepG2-Na+/taurocholate cotransporting polypeptide (HepG2-NTCP) cells and Huh7 cells were used to evaluate the function of ZNF148 in vitro. Northern blotting and real-time PCR were used to quantify the amount of viral RNA. Southern blotting and real-time PCR were used to quantify the amount of viral DNA. Viral protein levels were elevated, according to the Western blot results. Dual-luciferase reporter assays were used to examine the transcriptional activity of viral promoters. ZNF148’s impact on HBV in vivo was investigated using an established rcccDNA mouse model. Results ZNF148 overexpression significantly decreased the levels of HBV RNAs and HBV core DNA in HBV-infected HepG2-NTCP cells and Huh7 cells expressing prcccDNA. Silencing ZNF148 exhibited the opposite effects in both cell lines. Furthermore, ZNF148 inhibited the activity of HBV ENII/Cp and the transcriptional activity of cccDNA. Mechanistic studies revealed that ZNF148 attenuated retinoid X receptor alpha (RXRα) expression by binding to the RXRα promoter sequence. RXRα binding site mutation or RXRα overexpression abolished the suppressive effect of ZNF148 on HBV replication. The inhibitory effect of ZNF148 was also observed in the rcccDNA mouse model. Conclusions ZNF148 inhibited HBV replication by downregulating RXRα transcription. Our findings reveal that ZNF148 may be a new target for anti-HBV strategies.

This research aims to bridge a gap in the existing literature by investigating the role of the blockchain-based metaverse in fostering decentralized sustainable management, leveraging the principles of stakeholder capitalism theory. By conducting a content analysis of thirty-two expert reports from the blockchain-based metaverse industry, the study identifies five key attributes that can potentially cultivate innovation and decentralized sustainable management within the business domain. These attributes include a creator economy, a persistent synchronous virtual environment, decentralization, an interoperable network, and a digitalized mindset. The research underscores the need for stakeholders to adopt a sustainable approach when navigating the blockchain-based metaverse, highlighting the potential benefits achievable in a decentralized, hybrid physical-digital environment. This work stands as a pioneering effort in conceptualizing a theoretical framework that encapsulates decentralized sustainable management within the blockchain-based metaverse, underpinned by the principles of stakeholder capitalism. Thus, it contributes significantly to the academic discourse on the sustainable implications of blockchain technology in new business models.

ABSTRACT: E2F transcription factor 5 (E2F5) gene is a transcription factor, plays an important role in the development of a variety of cells. E2F5 is expressed in human and mouse adipocytes, but its specific function in adipogenesis is unclear. Krüppel-like factor 7 (KLF7) facilitates proliferation and inhibits differentiation in chicken preadipocytes. Our previous KLF7 chromatin immunoprecipitation-sequencing analysis revealed a KLF7-binding peak in the 3′ flanking region of the E2F5, indicating a regulatory role of KLF7 in this region. In the present study, we investigated E2F5 potential role, the overexpression and knockdown analyses revealed that E2F5 inhibited the differentiation and promoted the proliferation of chicken preadipocytes. Moreover, we identified enhancer activity in the 3′ flanking region (nucleotides +22661/+22900) of E2F5 and found that KLF7 overexpression increased E2F5 expression and luciferase activity in this region. Deleting the putative KLF7-binding site eliminated the promoting effect of KLF7 overexpression on E2F5 expression. Further, E2F5 reversed the KLF7-induced decrease in preadipocyte differentiation and increase in preadipocyte proliferation. Taken together, our findings demonstrate that KLF7 inhibits differentiation and promotes proliferation in preadipocytes by enhancing E2F5 transcription.

Abstract Mg/Ca ratio in stalagmites primarily serves as an indicator of past hydrological conditions rather than temperature variations. Here, we present an Mg/Ca ratio record in a stalagmite from northern China, spanning ice age termination II. A unique finding is that Mg/Ca ratio shows a moderately strong positive correlation with cave air temperature obtained from clumped isotopes data in the same stalagmite. The stable hydrogeochemistry of source water and high temperature sensitivity of Mg partition coefficient plausibly explain this temperature dependence. Furthermore, we establish an Mg/Ca‐temperature calibration for stalagmites from mid‐latitudes, encompassing a temperature range between ∼2 and ∼15°C, where Mg/Ca = 14.221 × e0.073×T (R2 = 0.40). Applying this function to Mg/Ca ratio from similar stalagmites could tentatively provide a quantitative regional temperature record over millennial and centennial timescales. This research highlights Mg/Ca ratio in stalagmites as a potential palaeo‐temperature proxy and introduces, for the first time, a tentative Mg/Ca‐temperature calibration function for speleothems.

Background & Aims: Peripartum prophylaxis (PP) with tenofovir disoproxil fumarate (TDF) is the standard of care to prevent mother-to-child transmission of chronic hepatitis B (CHB) infection in mothers who are highly viremic. We investigated the maternal and infant outcomes in a large Chinese cohort of TDF-treated CHB pregnant participants. Methods: In this prospective study, treatment-naive mothers with CHB and highly viremic (HBV DNA ≥200,000 IU/ml) but without cirrhosis were treated with TDF at 24–28 weeks of pregnancy. In accordance with Chinese CHB guidelines, TDF was stopped at delivery or ≥4 weeks postpartum. Serum HBV DNA and alanine aminotransferase were monitored every 6–8 weeks to determine virological relapse (VR). Infants received standard neonatal immunization, and HBV serology was checked at 7–12 months of age. Results: Among 330 participants recruited (median age 30, 82.7% HBeAg+, median HBV DNA 7.82 log IU/ml), TDF was stopped at delivery in 66.4% and at ≥4 weeks in 33.6%. VR was observed in 98.3%, among which 11.6% were retreated with TDF. Timing of TDF cessation did not alter the risk of VR (99.0 vs. 96.9%), clinical relapse (19.5 vs. 14.3%), or retreatment (12.6 vs. 10.1%) (all p > 0.05). A similar proportion of patients developed alanine aminotransferase flare five times (1.1 vs. 2.1%; p = 0.464) and 10 times (0.5 vs. 0%; p = 0.669) above the upper limit of normal (ULN) in the early withdrawal and late withdrawal groups, respectively. No infants developed HBsAg-positivity. Conclusions: PP-TDF and neonatal immunization were highly effective in preventing mother-to-child transmission of HBV in mothers who are highly viremic. Timing of cessation of PP-TDF did not affect the risk of VR or retreatment. Impact and Implications: In pregnant mothers with chronic hepatitis B infection who are started on peripartum tenofovir to prevent mother-to-child-transmission (MTCT), the optimal timing for antiviral withdrawal during the postpartum period remains unknown. This prospective study demonstrates that stopping tenofovir immediately at delivery, compared with longer treatment duration of tenofovir, did not lead to an increased risk of virological relapse, retreatment, or transmission of the virus to the baby. Shortening the duration of peripartum antiviral prophylaxis from 12 weeks to immediately after delivery can be considered. The immediate withdrawal of peripartum tenofovir, combined with standard neonatal immunization schemes, is 100% effective in preventing MTCT among pregnant mothers with CHB who are highly viremic, with a high rate of vaccine response in infants.

Hydropower stations that are part of the grid system frequently encounter challenges related to the uneven distribution of power generation and associated benefits, primarily stemming from delays in obtaining timely load data. This research addresses this issue by developing a scheduling model that combines power load prediction and dual-objective optimization. The practical application of this model is demonstrated in a real-case scenario, focusing on the Shatuo Hydropower Station in China. In contrast to current models, the suggested model can achieve optimal dispatch for grid-connected hydropower stations even when power load data is unavailable. Initially, the model assesses various prediction models for estimating power load and subsequently incorporates the predictions into the GA-NSGA-II algorithm, specifically an enhanced elite non-dominated sorting genetic algorithm. This integration is performed while considering the proposed objective functions to optimize the discharge flow of the hydropower station. The outcomes reveal that the CNN-GRU model, denoting Convolutional Neural Network-Gated Recursive Unit, exhibits the highest prediction accuracy, achieving R-squared and RMSE (i.e., Root Mean Square Error) values of 0.991 and 0.026, respectively. The variance between scheduling based on predicted load values and actual load values is minimal, staying within 5 (m3/s), showcasing practical effectiveness. The optimized scheduling outcomes in the real case study yield dual advantages, meeting both the demands of ship navigation and hydropower generation, thus achieving a harmonious balance between the two requirements. This approach addresses the real-world challenges associated with delayed load data collection and insufficient scheduling, offering an efficient solution for managing hydropower station scheduling to meet both power generation and navigation needs.

Abstract Pancreatic cancer is highly lethal, of which 90% is pancreatic ductal adenocarcinoma (PDAC), with a 5-year survival rate of less than 12%, lacking effective treatment options and late diagnosis. Furthermore, the tumors show an intense resistance to cytotoxic chemotherapies. As autophagy is elevated in PDAC, targeting the autophagic pathway is regarded as a promising strategy for cancer treatment. Immunofluorescence and transmission electron microscopy were utilized to assess the autophagic flux. Label-free quantitative phosphoproteomics was used to figure out critically altered tyrosine phosphorylation of the proteins. Tumor-bearing mice were used to validate that SH2 TrM-(Arg)9 restrained the growth of tumor cells. SH2 TrM-(Arg)9 inhibited collagen-induced autophagy via blocking the DDR1/PYK2/ERK signaling cascades. SH2 TrM-(Arg)9 improved the sensitivity of PANC-1/GEM cells to gemcitabine (GEM). Inhibition of autophagy by SH2 TrM-(Arg)9 may synergized with chemotherapy and robusted tumor suppression in pancreatic cancer xenografts. SH2 TrM-(Arg)9 could enter into PDAC cells and blockade autophagy through inhibiting DDR1/PYK2/ERK signaling and may be a new treatment strategy for targeted therapy of PDAC.

Abstract Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients. Methods We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva). Results A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p

Abstract The marked increase in the incidence rate of brucellosis is a serious public health concern in Jiangsu Province. However, its temporal and spatial distribution has not been studied in depth. The main purpose of this study is to depict the demographic, temporal and spatial distribution patterns and clustering characteristics of brucellosis cases in Jiangsu Province, China, from 2006 to 2021 to develop and implement effective scientific prevention and control strategies. Data for human brucellosis cases in Jiangsu Province from 2006 to 2021 were obtained from the Nationwide Notifiable Infectious Diseases Reporting Information System (NIDRIS). Spatial autocorrelation analysis and temporal-spatial scan statistics were used to identify potential changes in the spatial and temporal distributions of human brucellosis in Jiangsu Province. During the years 2006–2021, 1347 brucellosis cases were reported in Jiangsu Province, with an average annual incidence rate of 0.1036 per 100,000 individuals. Middle-aged and elderly individuals (aged 40–69 years) were the main infected populations, accounting for 69.72% (939/1347) of all reported cases. The incidence of brucellosis in Jiangsu showed a long-term increasing trend and displayed pronounced seasonal variations, with the peak occurring between April and June annually. The incidence gradually expanded from the northern and southern areas to the central areas between 2006 and 2021. Global spatial autocorrelation analysis demonstrated a positive correlation in the incidence of brucellosis between 2008 and 2012–2021. Temporal-spatial clustering analysis showed that the primary cluster was detected in the northern, highly endemic regions of Jiangsu, and the three secondary clusters were in areas where there had been outbreaks of brucellosis. Human brucellosis remains a serious public health issue in Jiangsu Province. Northern and southern Jiangsu regions, with high rates of brucellosis, may require special plans and measures to monitor and control the disease. Additionally, the capacity to respond to outbreaks in high-incidence areas should be improved to prevent further brucellosis outbreaks.

Idiopathic granulomatous mastitis (IGM) is a rare condition characterised by chronic inflammation and granuloma formation in the breast. The aetiology of IGM is unclear. By focusing on the protein-coding regions of the genome, where most disease-related mutations often occur, whole-exome sequencing (WES) is a powerful approach for investigating rare and complex conditions, like IGM. We report WES results on paired blood and tissue samples from eight IGM patients. Samples were processed using standard genomic protocols. Somatic variants were called with two analytical pipelines: nf-core/sarek with Strelka2 and GATK4 with Mutect2. Our WES study of eight patients did not find evidence supporting a clear genetic component. The discrepancies between variant calling algorithms, along with the considerable genetic heterogeneity observed amongst the eight IGM cases, indicate that common genetic drivers are not readily identifiable. With only three genes, CHIT1, CEP170, and CTR9, recurrently altering in multiple cases, the genetic basis of IGM remains uncertain. The absence of validation for somatic variants by Sanger sequencing raises further questions about the role of genetic mutations in the disease. Other potential contributors to the disease should be explored.

The Hendy Test is widely used for assessing whether isotopic equilibrium was reached in speleothems by examining the δ18O and δ13C correlation along a single growth layer. However, stalagmite micro-layers are typically only a few micrometers thick and taper off from the center towards the sides, making it challenging to sample within the same growth layer in practice. To address this, we selected three caves in the monsoon region of China (Shihua Cave in the north, Heshang Cave in the central, and Baojinggong Cave in the south) to verify whether the modern cave calcite has reached equilibrium fractionation with drip water. We examined the spatial variations in the δ18O and δ13C values of farmed calcite on glass plates, which are analogous to a single growth layer. The δ18O and δ13C correlations of farmed calcite from different cave sites are consistently strong, suggesting that kinetic fractionation effects are prevalent, especially at the drip sites with lower drip rates due to longer CO2 degassing. The δ18O–δ13C covariations can also occur along speleothem growth axes on short time scales, while isotopic variations over longer time scales are still in response to climate change. We propose that the Hendy Test criteria might not be prerequisites to isotopic equilibrium, and a Replication Test provides a more reliable indication of the integrity of isotopic proxies in paleoclimate research.

The recent worldwide incidence of mpox infection and concerns about future emerging variants of mpox viruses highlight the need for the development of a new generation of mpox vaccines. To achieve this goal, we utilized our norovirus S nanoparticle vaccine platform to produce and evaluate two pseudovirus nanoparticles (PVNPs), S-L1 and S-J1. These PVNPs displayed the L1 neutralizing antigen target of the vaccinia virus and a yet-untested J1 antigen of the mpox virus, respectively, with the aim of creating an effective nanoparticle-based mpox vaccine. Each self-assembled PVNP consists of an inner shell resembling the interior layer of the norovirus capsid and multiple L1 or J1 antigens on the surface. The PVNPs improved the antibody responses toward the displayed L1 or J1 antigens in mice, resulting in significantly greater L1/J1-specific IgG and IgA titers than those elicited by the corresponding free L1 or J1 antigens. After immunization with the S-L1 PVNPs, the mouse sera exhibited high neutralizing antibody titers against the vaccinia virus, and the S-L1 PVNPs provided mice with 100% protection against mortality caused by vaccinia virus challenge. In contrast, the S-J1 PVNPs induced low neutralizing antibody titers and conferred mice weak protective immunity. These data confirm that the L1 protein is an excellent vaccine target and that the readily available S-L1 PVNPs are a promising mpox vaccine candidate worthy of further development.

Background: The management of the axilla in breast cancer patients with isolated chest wall recurrence (CWR) after mastectomy remains controversial. Although sentinel lymph node biopsy (SLNB) for restaging is feasible, its role is unclear. We aimed to determine if the omission of axillary restaging surgery in female patients with operable presumably isolated CWRs could result in an increased risk of second recurrences. Methods: In this retrospective multicentre study, patients who developed CWRs were reviewed. We excluded patients with suspected or concomitant regional/distant metastases, bilateral cancers and patients without CWR surgery. Patients’ demographics, pathological data and subsequent recurrences were collected from a prospective database and were compared between patients with axillary lymph node dissection (ALND) and/or SLNB versus no axillary operation at CWR. Findings: A total of 194 patients with CWRs were eligible. The median age at CWR was 56.0 (IQR 47.0–67.0) years old. At recurrence, 8 (4.1%), 5 (2.6%) and 181 (93.3%) patients had ALND, SLNB and no axillary operation, respectively. Patients with no axillary surgery during CWR were associated with, at primary cancer, a lower incidence of ductal carcinoma in situ as diagnosis (p = 0.007) and older age (p = 0.022). Subsequent ipsilateral axillary (p = 0.768) and second recurrences (p = 0.061) were not statistically different between patients with and without axillary surgery at CWR on median follow-up of 59.5 (IQR 27.3–105) months. Interpretation: In patients without evidence of concomitant regional or distant metastasis at CWR diagnosis, omission of axillary restaging surgery was not associated with an increased ipsilateral axillary or second recurrences on long-term follow-up.

Cotton is essential for the textile industry as a primary source of natural fibers. However, environmental factors like drought present significant challenges to its cultivation, adversely affecting both production levels and fiber quality. Enhancing cotton’s drought resilience has the potential to reduce yield losses and support the growth of cotton farming. In this study, the cotton calcium-dependent protein kinase GhCDPK16 was characterized, and the transcription level of GhCDPK16 was significantly upregulated under drought and various stress-related hormone treatments. Physiological analyses revealed that the overexpression of GhCDPK16 improved drought stress resistance in Arabidopsis by enhancing osmotic adjustment capacity and boosting antioxidant enzyme activities. In contrast, silencing GhCDPK16 in cotton resulted in increased dehydration compared with the control. Furthermore, reduced antioxidant enzyme activities and downregulation of ABA-related genes were observed in GhCDPK16-silenced plants. These findings not only enhanced our understanding of the biological functions of GhCDPK16 and the mechanisms underlying drought stress resistance but also underscored the considerable potential of GhCDPK16 in improving drought resilience in cotton.

Succession planning could ensure leadership continuity in an organization. Organizations start to realize the importance of strong leadership to maintain, grow, and sustain long-term business productivity. The semi-structured interview which lasts for thirty to forty minutes was used as the interview technique throughout this research because the semi-structured interview is more conversational and it also allowed the researcher to ask the questions in a more flexible way. The interview method found out the systematic succession planning system in University A. The primary data was from interviews that shows the systematic succession planning in University A, and the gathered data will show some of the practices. Overall, the succession planning management had followed up the seven-pointed model as proposed by Rothwell. The seven-pointed model as proposed by Rothwell had ensured the process of identifying a management position at the selected university. In this study, the research objective and research question has been answered by the researcher. The final results further explained the process of succession planning together with the recommendation of the study. Future research on succession planning in higher education can be improved to get better research results as if the data collection can be expanded to all levels of management in University A, as compared to this research which only covered the staff involved in the strategic position level.

IntroductionPharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related to CYP2D6 in children from the GUSTO cohort.MethodsBuffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with CYP2D6 were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of the CYP2D6 gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models’ performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites.ResultsOverall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model.DiscussionThe development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing.

Objective: Half of the patients with acute large artery occlusion (LAO) have poor outcomes after endovascular treatment (EVT). Early complications such as cerebral edema and symptomatic intracranial hemorrhage (sICH) can lead to early neurological deterioration (END), which correlates with hemodynamics. This study aimed to identify the hemodynamic predictors of END and outcomes in LAO patients after EVT. Methods: A total of 76 patients with anterior circulation LAO who underwent EVT and received transcranial Doppler (TCD) monitoring were included. Bilateral middle cerebral artery (MCA) blood flow velocities (BFVs) were measured repeatedly within 1 week. Mean flow velocities (MFV) and MFV index (ipsilateral MFV/contralateral MFV) were calculated. The primary outcome was the incidence of END within 72 h. The secondary outcome was the functional outcome at 90 days—a good outcome was defined as a modified Rankin scale (mRS) score of 0–2, while a poor outcome was defined as an mRS score of 3–6. Results: A total of 13 patients (17.1 %) experienced END within 72 h, including 5 (38.5 %) with cerebral edema, 5 (38.5 %) with sICH, and 3 (23.0 %) with infarct progression. Multivariable logistic regression analysis showed that a higher 24 h MFV index was independently associated with END (aOR 10.5; 95 % CI 2.28–48.30, p = 0.003) and a poor 90-day outcome (aOR 5.10; 95 % CI 1.38–18.78, p = 0.014). The area under the receiver operating characteristic (ROC) curve (AUC) of the 24 h MFV index for predicting END was 0.807 (95 % CI 0.700–0.915, p = 0.0005), the sensitivity was 84.6 %, and the specificity was 66.7 %. At the 1-week TCD follow-up, patients who had poor 90-day outcomes showed significantly higher 1-week iMFV [73.5 (58.4–99.0) vs. 57.7 (45.3–76.3), p = 0.004] and MFV index [1.24 (0.98–1.57) vs.1.0 (0.87–1.15) p = 0.007]. A persistent high MFV index (PHMI) was independently associated with a poor outcome (aOR 7.77, 95 % CI 1.81–33.3, p = 0.006). Conclusion: TCD monitoring within 24 h after EVT in LAO patients can help predict END, while dynamic follow-up within 1 week is valuable in predicting clinical outcomes.

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.

BackgroundAndrogen deprivation therapy (ADT) is the foundational treatment for metastatic prostate cancer (PCa). Androgen receptor (AR) axis-targeted therapies are a new standard of care for advanced PCa. Although these agents have significantly improved patient survival, the suppression of testosterone is associated with an increased risk of cardiometabolic syndrome. This highlights the urgency of multidisciplinary efforts to address the cardiometabolic risk of anticancer treatment in men with PCa.MethodsTwo professional organizations invited five urologists, five clinical oncologists, and two cardiologists to form a consensus panel. They reviewed the relevant literature obtained by searching PubMed for the publication period from April 2013 to April 2023, to address three discussion areas: (i) baseline assessment and screening for risk factors in PCa patients before the initiation of ADT and AR axis-targeted therapies; (ii) follow-up and management of cardiometabolic complications; and (iii) selection of ADT agents among high-risk patients. The panel convened four meetings to discuss and draft consensus statements using a modified Delphi method. Each drafted statement was anonymously voted on by every panelist.ResultsThe panel reached a consensus on 18 statements based on recent evidence and expert insights.ConclusionThese consensus statements serve as a practical recommendation for clinicians in Hong Kong, and possibly the Asia-Pacific region, in the management of cardiometabolic toxicities of ADT or AR axis-targeted therapies in men with PCa.

Background & Aims: Current antiviral drugs, including nucleoside analogs and interferon, fail to eliminate the HBV covalently closed circular DNA (cccDNA), which serves as a transcript template in infected hepatocytes. Silencing the HBV X protein, which plays a crucial role in cccDNA transcription, is a promising approach to inhibit HBV replication. Therefore, the identification of novel compounds that can inhibit HBx-mediated cccDNA transcription is critical. Methods: Initially, a compound library consisting of 715 monomers derived from traditional Chinese medicines known for their liver-protecting properties was established. Then, MTT assays were used to determine the cytotoxicity of each compound. The effect of candidates on Flag-HBx expression was examined by real-time PCR and western blotting in Flag-HBx transfected HepG2-NTCP cells. Ultimately, the antiviral effect of gambogic acid (GA) on HBV was observed in HBV-infected HepG2-NTCP cells. Mechanistically, the functional role of DTX1 in GA-induced HBV inhibition was examined using RNA-seq. Finally, the antiviral effect of GA was estimated in vivo. Results: Gambogic acid (GA), a natural bioactive compound with a myriad of biological activities, markedly reduced Flag-HBx expression. Potent and dose-dependent reductions in extracellular HBV RNAs, HBV DNA, HBsAg, HBeAg and HBc protein were discovered three days after GA treatment in HBV-infected cells, accompanied by the absence of significant cytotoxicity. Furthermore, our research revealed that GA exhibited a dose-dependent inhibition of HBx expression, which is a pleiotropic protein required for HBV infection in vivo. We explored the mechanisms underlying GA-mediated inhibition of HBV and confirmed that this inhibition is accomplished by upregulating the expression of the DTX1 gene and boosting the Notch signaling pathway. Finally, the inhibitory effect of GA on HBV replication was tested in vivo using a mouse model of hepatitis B virus recombinant cccDNA. Conclusions: Herein, we discovered GA, which is a natural bioactive compound that targets HBx to inhibit hepatitis B virus replication by activating the DTX1-Notch signaling pathway.