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Objectives: This study aimed to investigate the histological and molecular characteristics of atypical central neurocytomas (CNs) and evaluate their clinical treatment outcomes, with the aim of identifying reliable biomarkers for differentiation and optimal treatment strategies., Methods: We conducted a retrospective study including 61 patients diagnosed with CNs. Clinical data, neuroimaging, and pathological findings were analyzed. RNA sequencing was performed on tumor tissues to identify differentially expressed genes., Results: Histological atypia and the Ki-67 index showed no significant impact on progression-free survival (PFS) or overall survival (OS). RNA sequencing identified significant genetic alterations in pathways such as neuroactive ligand-receptor interaction, cAMP, MAPK, and Ras signaling. Differently expressed genes included AMOTL1, PIK3R3, TGFBR1, SMO, COL4A6, MGP, SOX4, IGF2, SLIT1, and CKS2. The five-year OS rate (p = 0.015) and PFS rate (p = 2.00 × 10 -6 ) were significantly higher in the complete resection (CR) group compared to the incomplete resection (IR) group. Postoperative radiotherapy did not affect OS or PFS in the CR group. The five-year PFS rate (p = 3.80 × 10 -5 ) was significantly longer in patients in the CR group who did not receive radiotherapy compared to those in the IR group who did receive radiotherapy. The extent of surgical resection and operative approaches were found to be irrelevant to perioperative complications and dysfunctions at the last follow-up., Conclusion: CR is crucial for a better prognosis in patients with atypical CNs. Additional radiotherapy after CR offers little benefit. Histological atypia and the Ki-67 index are not effective in distinguishing between atypical and typical CNs. Identified genetic alterations provide insights into the aggressive behavior of atypical CNs, suggesting potential therapeutic targets and underscoring the need for further research to optimize treatment strategies., (© 2024. The Author(s).)

Introduction: Ankle fractures associated with disruption of the syndesmotic complex could potentially have poorer outcomes if missed or malreduced at the time of surgery. Favourable results have been reported for the suture button (SB) technique and may provide advantages over standard screw fixation of the syndesmosis, although this remains the gold standard method in many units., Aim: To compare the outcomes of syndesmotic screws (SS) with SB fixation of the syndesmosis during ankle fracture fixation at a high-volume orthopaedic department of a Scotland trauma unit., Method:  A cross-sectional, retrospective study looking at ankle fracture fixations was undertaken at the Clyde Trauma Unit, Paisley. Relevant information was obtained from electronic patient records for 457 ankle fracture patients between August 2019 and February 2022 and followed up for six months. The digital patient archive system (PACS) was used for evaluating radiographs. Patients were divided into two groups depending on whether they had an SS or SB fixation of their syndesmosis. We focused on the surgical and radiological outcomes following syndesmotic fixation as no functional scores following surgery were conducted on the patients., Result: Out of the entire study group, 26.3% (120/457 patients) required syndesmotic fixation. Within the syndesmotic fixation group, 70.8% (85/120 patients) underwent SS fixation, and 29.2% (35/120 patients) had an SB fixation. Both groups were statistically well-matched. Additionally, 21.1% (18/85) of SS fixation went on to have a second surgical procedure (four fixation failures, five planned removals, five for pain/stiffness, two infections, and two metalwork breakage/migration), whereas 8.6% (3/35) of the SB fixation group had a secondary procedure - two for fixation failures and one for infection., Conclusion: We reported a higher incidence of associated syndesmotic injury in our series of 457 ankle fractures than previously described. There were significantly fewer sequelae in the SB group compared to the SS fixation group (P = 0.0464). Although we did not observe a statistically significant difference in the rate of reoperation (P = 0.1184), this is likely due to the small numbers in the SB group. Our study suggests that SB fixation may be associated with a lower rate of reoperation for post-op complications such as metalwork failure, pain, and stiffness (21.1% SS vs 8.6% SB). Regardless of the fixation method used, accurate reduction of the ankle mortice and syndesmosis is a key step to a successful surgical outcome., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Integrated Research Application System (IRAS) issued approval project ID 339006. This study was exempt from the National Health Service (NHS) Research Ethics Committee review with Integrated Research Application System (IRAS) project ID 339006. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kong et al.)

Backgrounds: Abnormal metabolism is the hallmark of hepatocellular carcinoma. Targeting energy metabolism has become the major focus of cancer therapy. The natural product, sanguinarine, displays remarkable anti-tumor properties by disturbing energy homeostasis; however, the underlying mechanism has not yet been elucidated., Methods: The anticancer activity of sanguinarine was determined using CCK-8 and colony formation assay. Morphological changes of induced cell death were observed under electron microscopy. Necroptosis and apoptosis related markers were detected using western blotting. PKM2 was identified as the target by transcriptome sequencing. Molecular docking assay was used to evaluate the binding affinity of sanguinarine to the PKM2 molecule. Furthermore, Alb-Cre ERT2 ; PKM2 loxp/loxp ; Rosa26 RFP mice was used to construct the model of HCC-through the intervention of sanguinarine in vitro and in vivo-to accurately explore the regulation effect of sanguinarine on cancer energy metabolism., Results: Sanguinarine inhibited tumor proliferation, metastasis and induced two modes of cell death. Molecular docking of sanguinarine with PKM2 showed appreciable binding affinity. PKM2 kinase activity and aerobic glycolysis rate declined, and mitochondrial oxidative phosphorylation was inhibited by sanguinarine application; these changes result in energy deficits and lead to necroptosis. Additionally, sanguinarine treatment prevents the translocation of PKM2 into the nucleus and suppresses the interaction of PKM2 with β-catenin; the transcriptional activity of PKM2/β-catenin signaling and its downstream genes were decreased., Conclusions: Sanguinarine showed remarkable anti-HCC activity via regulating energy metabolism by PKM2/β-catenin signaling. On the basis of these investigations, we propose that sanguinarine might be considered as a promising compound for discovery of anti-HCC drugs.

Purpose: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS)., Patients and Methods: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m 2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D., Results: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m 2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%., Conclusion: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m 2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

The patient presented to the clinic with painful muscle swelling in the right lower extremity, which improved with immunosuppressive therapy. Initially, the condition was diagnosed as polymyositis but recurred soon after. After imaging and biopsy, the final diagnosis was primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). In this report, we discuss the challenges in diagnosing and treating this aggressive malignancy and review the literature on PSM-PTCL, NOS. Key Points • To date, there are few reports of PSM-PTCL, NOS, and our case is the tenth. • It is crucial to consider PSM-PTCL, NOS, when presenting with localized muscle edema and unexplained pain. • Histopathological examination is likely the most effective method for diagnosing this rare disease., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

We demonstrated a near-infrared exhaled breath sensor for real-time methane measurements by using tunable diode laser absorption spectroscopy (TDLAS), which can enable the noninvasive diagnosis of intestinal tract problems. The core component of the near-infrared TDLAS sensor is a two-mirror-based multipass cell with nine-circle patterns. An optical path length of 23.4 m was achieved in a volume of 233.3 cm 3 , which effectively improved the detection sensitivity and shortened the gas exchange time. The minimum detection limit was 0.37 ppm by applying wavelength modulation spectroscopy, which was 12.4 times greater than that of direct absorption spectroscopy. In addition, combined with wavelength modulation spectroscopy, the two-mirror-based multipass cell enabled sub-second gas exchange time of 0.6 s. Methane breath experiments were conducted with six volunteers, and the real-time measurement results and concentrations at the end of exhalation were analyzed. This study demonstrates that the developed sensor has high sensitivity, high selectivity, and fast response for breath methane measurements and has promising potential for noninvasive, real-time, and point-of-care disease diagnosis in clinical applications., Competing Interests: The authors declare no conflicts of interest., (© 2024 Optica Publishing Group.)

Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide. Due to the important role of mitochondrial metabolism in cancer progression, a clinical prognostic model based on mitochondrial metabolism and clinical features was constructed in this study to predict the prognosis of ESCC. Firstly, the mitochondrial metabolism scores (MMs) were calculated based on 152 mitochondrial metabolism-related genes (MMRGs) by single sample gene set enrichment analysis (ssGSEA). Subsequently, univariate Cox regression and LASSO algorithm were used to identify prognosis-associated MMRG and risk-stratify patients. Functional enrichment, interaction network and immune-related analyses were performed to explore the features differences in patients at different risks. Finally, a prognostic nomogram incorporating clinical factors was constructed to assess the prognosis of ESCC. Our results found there were differences in clinical features between the MMs-high group and the MMs-low group in the TCGA-ESCC dataset ( P <0.05). Afterwards, we identified 6 MMRGs (COX10, ACADVL, IDH3B, AKR1A1, LIAS, and NDUFB8) signature that could accurately distinguish high-risk and low-risk ESCC patients. A predictive nomogram that combined the 6 MMRGs with sex and N stage to predict the prognosis of ESCC was constructed, and the areas under the receiver operating characteristic (ROC) curve at 1, 2 and 3 years were 0.948, 0.927 and 0.848, respectively. Finally, we found that COX10, one of 6 MMRGs, could inhibit the malignant progression of ESCC in vitro . In summary, we constructed a clinical prognosis model based on 6 MMRGs and clinical features which can accurately predict the prognosis of ESCC patients.

A balanced excitation-inhibition ratio (E/I ratio) is critical for healthy brain function. Normative development of cortex-wide E/I ratio remains unknown. Here, we noninvasively estimate a putative marker of whole-cortex E/I ratio by fitting a large-scale biophysically plausible circuit model to resting-state functional MRI (fMRI) data. We first confirm that our model generates realistic brain dynamics in the Human Connectome Project. Next, we show that the estimated E/I ratio marker is sensitive to the gamma-aminobutyric acid (GABA) agonist benzodiazepine alprazolam during fMRI. Alprazolam-induced E/I changes are spatially consistent with positron emission tomography measurement of benzodiazepine receptor density. We then investigate the relationship between the E/I ratio marker and neurodevelopment. We find that the E/I ratio marker declines heterogeneously across the cerebral cortex during youth, with the greatest reduction occurring in sensorimotor systems relative to association systems. Importantly, among children with the same chronological age, a lower E/I ratio marker (especially in the association cortex) is linked to better cognitive performance. This result is replicated across North American (8.2 to 23.0 y old) and Asian (7.2 to 7.9 y old) cohorts, suggesting that a more mature E/I ratio indexes improved cognition during normative development. Overall, our findings open the door to studying how disrupted E/I trajectories may lead to cognitive dysfunction in psychopathology that emerges during youth., Competing Interests: Competing interests statement:The authors declare no competing interest.

Introduction: Ellagic acid (EA), commonly found in foods, offers significant health benefits in combating chronic diseases. However, its therapeutic potential is hindered by its extremely poor solubility and bioavailability., Method: In this study, EA nanoparticles (EA NPs) were produced using a sono-assembly method, without additional agents., Results: EA NPs exhibited stick-like nanoparticle structures with an average size of 147.3 ± 0.73 nm. EA NPs likely adopt a tunnel-type solvate structure, with 4 water participating in disruption of intramolecular hydrogen bonds in EA and establishment of intermolecular hydrogen bonds between EAs. Importantly, EA NPs exhibited remarkable enhancements in water solubility, with 120.7-fold increase in water, and 97.8-fold increase in pH 6.8 buffer. Moreover, ex vivo intestinal permeability studies demonstrated significant improvements (P < 0.5). These findings were further supported by in vivo pharmacokinetic studies, where EA NPs significantly enhanced the relative bioavailability of EA by 4.69 times., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Adaptive behavior relies both on specific rules that vary across situations and stable long-term knowledge gained from experience. The frontoparietal control network (FPCN) is implicated in the brain's ability to balance these different influences on action. Here, we investigate how the topographical organization of the cortex supports behavioral flexibility within the FPCN. Functional properties of this network might reflect its juxtaposition between the dorsal attention network (DAN) and the default mode network (DMN), two large-scale systems implicated in top-down attention and memory-guided cognition, respectively. Our study tests whether subnetworks of FPCN are topographically proximal to the DAN and the DMN, respectively, and how these topographical differences relate to functional differences: the proximity of each subnetwork is anticipated to play a pivotal role in generating distinct cognitive modes relevant to working memory and long-term memory. We show that FPCN subsystems share multiple anatomical and functional similarities with their neighboring systems (DAN and DMN) and that this topographical architecture supports distinct interaction patterns that give rise to different patterns of functional behavior. The FPCN acts as a unified system when long-term knowledge supports behavior but becomes segregated into discrete subsystems with different patterns of interaction when long-term memory is less relevant. In this way, our study suggests that the topographical organization of the FPCN and the connections it forms with distant regions of cortex are important influences on how this system supports flexible behavior., (Copyright © 2024 Wang et al.)

Food antigens elicit immune tolerance through the action of regulatory T cells (Tregs) in the intestine. Although antigens that trigger common food allergies are known, the epitopes that mediate tolerance to most foods have not been described. Here, we identified murine T cell receptors specific for maize, wheat, and soy, and used expression cloning to de-orphan their cognate epitopes. All of the epitopes derive from seed storage proteins that are resistant to degradation and abundant in the edible portion of the plant. Multiple unrelated T cell clones were specific for an epitope at the C-terminus of 19 kDa alpha-zein, a protein from maize kernel. An MHC tetramer loaded with this antigen revealed that zein-specific T cells are predominantly Tregs localized to the intestine. These cells, which develop concurrently with weaning, constitute up to 2% of the peripheral Treg pool. Bulk and single-cell RNA sequencing revealed that these cells express higher levels of immunosuppressive markers and chemokines compared to other Tregs. These data suggest that immune tolerance to plant-derived foods is focused on a specific class of antigens with common features, and they reveal the functional properties of naturally occurring food-specific Tregs., Competing Interests: Competing interests: D.R.L. consults and has equity interest in Vedanta, Immunai, Imidomics, Sonoma Biotherapeutics and Pfizer Pharmaceuticals. M.A.F. is a co-founder of Kelonia and Revolution Medicines, a member of the scientific advisory boards of the Chan Zuckerberg Initiative, Stand Up to Cancer, NGM Biopharmaceuticals, and TCG Labs/Soleil Labs, and an innovation partner at The Column Group. The remaining authors have no conflict of interest.

Endoscopic optical coherence tomography (OCT) possesses the capability to non-invasively image internal lumens; however, it is susceptible to saturation artifacts arising from robust reflective structures. In this study, we introduce an innovative deep learning network, ATN-Res2Unet, designed to mitigate saturation artifacts in endoscopic OCT images. This is achieved through the integration of multi-scale perception, multi-attention mechanisms, and frequency domain filters. To address the challenge of obtaining ground truth in endoscopic OCT, we propose a method for constructing training data pairs. Experimental in vivo data substantiates the effectiveness of ATN-Res2Unet in reducing diverse artifacts while preserving structural information. Comparative analysis with prior studies reveals a notable enhancement, with average quantitative indicators increasing by 45.4-83.8%. Significantly, this study marks the inaugural exploration of leveraging deep learning to eradicate artifacts from endoscopic OCT images, presenting considerable potential for clinical applications.

Bifenthrin (BF) is ubiquitous in aquatic environments, and studies have indicated that environmental concentrations of BF could cause neurotoxicity and oxidative damage in fish and decrease the abundance of aquatic insects. However, little information is available on the toxicity of BF in freshwater benthic mollusks. Bellamya aeruginosa (B. aeruginosa) is a key benthic fauna species in aquatic ecosystems, and has extremely high economic and ecological values. In this study, larval B. aeruginosa within 24 h of birth were exposed to 0, 30 or 300 ng/L of BF for 30 days, and then the toxic effects from molecular to individual levels were comprehensively evaluated in all the three treatment groups. It was found that BF at 300 ng/L caused the mortality of snails. Furthermore, BF affected snail behaviors, evidenced by reduced crawling distance and crawling speed. The hepatopancreas of snails in the two BF exposure groups showed significant pathological changes, including increase in the number of yellow granules and occurrence of hemocyte infiltration, epithelial cell thinning, and necrosis. The levels of ROS and MDA were significantly increased after exposure to 300 ng/L BF, and the activities of two antioxidant enzymes SOD and CAT were increased significantly. GSH content decreased significantly after BF exposure, indicating the occurrence of oxidative damage in snails. Transcriptomic results showed that differentially expressed genes (DEGs) were significantly enriched in pathways related to metabolism and neurotoxicity (e.g., oxidative phosphorylation and Parkinson disease), and these results were consistent with those in individual and biochemical levels above. The study indicates that environmental concentration of BF results in decreased survival rates, sluggish behavior, histopathological lesions, oxidative damage, and transcriptomic changes in the larvae of B. aeruginosa. Thus, exposure of larval snails to BF in the wild at concentrations similar to those used in this study might have adverse consequences at the population level. These findings provide a theoretical basis for further assessing the ecological risk of BF to aquatic gastropods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sepiapterin is an orally administered drug in development for the treatment of phenylketonuria, an inborn error of metabolism characterized by the deficiency of the phenylalanine-metabolizing enzyme phenylalanine hydroxylase. This study characterized the pharmacokinetics, safety, and tolerability of 2 clinical sepiapterin formulations (Phase 1/2, Phase 3) and the effects of food on the pharmacokinetics of the Phase 3 formulation in healthy participants. In Part A, 18 participants were randomized to one of 2 treatment sequences, each with 4 dosing periods comprising a single dose (20 or 60 mg/kg) of the Phase 1/2 or the Phase 3 formulation with a low-fat diet. In Part B, 14 participants were randomized to one of 2 sequences, each comprising 4 dosing periods of a single dose (20 or 60 mg/kg) of the Phase 3 formulation under fed (high-fat) or fasted conditions. Following oral administration, sepiapterin was quickly absorbed and rapidly and extensively converted to tetrahydrobiopterin (BH 4 ). BH 4 was the major circulating active moiety. Under low-fat conditions, the Phase 3 formulation was bioequivalent to the Phase 1/2 formulation at 20 mg/kg, while slightly lower BH 4 exposure (approximately 0.81×) for the Phase 3 formulation was observed at 60 mg/kg. BH 4 exposure increased to approximately 1.7× under the low-fat condition and approximately 2.8× under the high-fat condition at a dose of either 20 or 60 mg/kg for the Phase 3 formulation, compared with the fasted condition. Both sepiapterin formulations were well tolerated, with no serious or severe adverse events reported. All treatment-emergent adverse events were mild or moderate in severity., (© 2023 PTC Therapeutics Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

In recent years, there has been a growing recognition of the important role that long non-coding RNAs (lncRNAs) play in the immunological process of hepatocellular carcinoma (LIHC). An increasing number of studies have shown that certain lncRNAs hold great potential as viable options for diagnosis and treatment in clinical practice. The primary objective of our investigation was to devise an immune lncRNA profile to explore the significance of immune-associated lncRNAs in the accurate diagnosis and prognosis of LIHC. Gene expression profiles of LIHC samples obtained from TCGA database were screened for immune-related genes. The optimal immune-related lncRNA signature was built via correlational analysis, univariate and multivariate Cox analysis. Then, the Kaplan-Meier plot, ROC curve, clinical analysis, gene set enrichment analysis, and principal component analysis were performed to evaluate the capability of the immune lncRNA signature as a prognostic indicator. Six long non-coding RNAs were identified via correlation analysis and Cox regression analysis considering their interactions with immune genes. Subsequently, tumor samples were categorized into two distinct risk groups based on different clinical outcomes. Stratification analysis indicated that the prognostic ability of this signature acted as an independent factor. The Kaplan-Meier method was employed to conduct survival analysis, results showed a significant difference between the two risk groups. The predictive performance of this signature was validated by principal component analysis (PCA). Additionally, data obtained from gene set enrichment analysis (GSEA) revealed several potential biological processes in which these biomarkers may be involved. To summarize, this study demonstrated that this six-lncRNA signature could be identified as a potential factor that can independently predict the prognosis of LIHC patients.

Modern glycoproteomics experiments require the use of search engines due to the generation of countless spectra. While these tools are valuable, manual validation of search engine results is often required for detailed analysis of glycopeptides as false-discovery rates are often not reliable for glycopeptide data. Near-isobaric mismatches are a common source of misidentifications for the popular glycopeptide-focused search engine pGlyco3.0, and in this technical note we share a strategy and script that improves the accuracy of the search utilizing two manually validated datasets of the glycoproteins CD16a and HIV-1 Env as proof-of-principle., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

N-myc downstream-regulated gene 2 (NDRG2) has been recognised as a negative regulator of the progression of numerous tumours, yet its specific role in small-cell lung carcinoma (SCLC) is not fully understood. The purpose of the current study was to investigate the biological role and mechanism of NDRG2 in SCLC. Initial investigation using the Gene Expression Omnibus (GEO) dataset revealed marked downregulation of NDRG2 transcripts in SCLC. The decreased abundance of NDRG2 in SCLC was verified by examining clinical specimens. Increasing NDRG2 expression in SCLC cell lines caused significant changes in cell proliferation, cell cycle progression, colony formation, and chemosensitivity. NDRG2 overexpression decreased the levels of phosphorylated PTEN, AKT and mTOR. In PTEN-depleted SCLC cells, the upregulation of NDRG2 did not result in any noticeable impact on AKT or mTOR activation. Additionally, the reactivation of AKT reversed the antitumour effects of NDRG2 in SCLC cells. Notably, increasing NDRG2 expression retarded the growth of SCLC cell-derived xenografts in vivo. In conclusion, NDRG2 serves as an inhibitor of SCLC, and its cancer-inhibiting effects are achieved through the suppression of AKT/mTOR via the activation of PTEN. This work suggests that NDRG2 is a potential druggable target for SCLC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Observational studies have shown that obesity considerably affects the cardiovascular system. Thus we conducted this Mendelian randomization (MR) analysis to evaluate the causal effect of childhood obesity on heart failure (HF) and its risk factors., Methods and Results: We obtained genetic instruments from genome-wide association studies (GWAS) that investigated childhood obesity, HF, type 2 diabetes mellitus (T2DM), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), chronic kidney disease (CKD), valvular heart disease, myocarditis, hypertrophic cardiomyopathy, and hyperthyroidism. Inverse variance weighting (IVW), weighted median analysis, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were employed for MR analyses. In addition, the leave-one-out sensitivity test, MR-PRESSO global test, and Cochran's Q test were used for sensitivity analyses. Genetic evaluations showed that childhood obesity increases the risk of HF (odds ratio [OR] = 1.11, 95%CI: 1.05-1.17, p = 1.26 × 10 -4 ), T2DM (OR = 1.17, 95%CI: 1.12-1.23, p = 8.80 × 10 -12 ), AF (OR = 1.08, 95%CI: 1.05-1.12, p = 2.66 × 10 -7 ), MI (OR = 1.08, 95%CI: 1.04-1.13, p = 3.35 × 10 -4 ), and CAD (OR = 1.08, 95%CI: 1.03-1.13, p = 1.48 × 10 -3 ). We found no association between childhood obesity and CKD, valvular heart disease, myocarditis, hypertrophic cardiomyopathy, or hyperthyroidism. Sensitivity analysis and Bonferroni's correction showed consistent results., Conclusions: Our study provides new evidence for the relationship between childhood obesity and HF and its risk factors. The results indicate that individuals with a history of childhood obesity require more clinical attention to prevent the development of HF., Competing Interests: Conflicts of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/., (© The Author(s) 2024. Published by Oxford University Press.)

Identifying individual functional B cell receptors (BCRs) is common, but two-dimensional analysis of B cell frequency versus BCR potency would delineate both quantity and quality of antigen-specific memory B cells. We efficiently determine quantitative BCR neutralizing activities using a single-cell-derived antibody supernatant analysis (SCAN) workflow and develop a frequency-potency algorithm to estimate B cell frequencies at various neutralizing activity or binding affinity cutoffs. In an HIV-1 fusion peptide (FP) immunization study, frequency-potency curves elucidate the quantity and quality of FP-specific immunoglobulin G (IgG)+ memory B cells for different animals, time points, and antibody lineages at single-cell resolution. The BCR neutralizing activities are mainly determined by their affinities to soluble envelope trimer. Frequency analysis definitively demonstrates dominant neutralizing antibody lineages. These findings establish SCAN and frequency-potency analyses as promising approaches for general B cell analysis and monoclonal antibody (mAb) discovery. They also provide specific rationales for HIV-1 FP-directed vaccine optimization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Increasing evidence suggest a racial bias in pulse oximetry measurement, but this was under investigated in Asian pediatric populations., Methods: Via the Pediatric Intensive Care database, this retrospective study included pediatric patient records of arterial oxygen saturation (SaO 2 ) and oxygen saturation on pulse oximetry (SpO 2 ) measured within 10 min. Discrepancy was examined, and potential predictors of occult hypoxemia (defined as SaO 2 <88% with the paired SpO 2 ≥92%) as well as its association with outcomes were explored by logistic regression., Results: A total of 390 patients were included with 454 pairs of SaO 2 -SpO 2 readings. The study population consisted of Han Chinese (99.0%) and 43.6% were female. Occult hypoxemia was observed in 20.0% of the patients, with a mean SaO 2 of 71.4 ± 15.8%. Potential predictors of occult hypoxemia included female, being first admitted to cardiac ICU, congenital heart disease, increased heart rate, while patients with prior surgery records were less likely to experience occult hypoxemia. Patients with occult hypoxemia had numerically higher in-ICU mortality (16.7% versus 10.9%) and in-hospital mortality (17.9% versus 10.9%), but the associations were not statistically significant., Conclusions: There was a substantial proportion of hypoxemia that was not detected by pulse oximetry in the Chinese pediatric patients, which might be predicted by several characteristics and seemed to associate with mortality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: Regulatory T cells (Tregs) are involved in the maintenance of immune homeostasis and immune regulation. Clinical trials on the adoptive transfer of Tregs have been ongoing for > 10 years. However, many unresolved issues remain in the production of readymade Treg products and selection of patients. Hence, this study aimed to develop a method to expand off-the-shelf Tregs derived from umbilical cord blood (UCB-Tregs) in vitro without changing their phenotype and inhibitory function. In addition, the study intended to design an approach to precisely select patients who are more likely to benefit from the adoptive Treg transfer therapy., Methods: UCB-Tregs were isolated and cultured in a medium containing human recombinant IL-2 and rapamycin and then multiply restimulated with human T-activator CD3/CD28 dynabeads. The phenotype and suppressive capacity of Tregs were assessed on days 18 and 42. The relationship between the suppressive function of UCB-Tregs in vitro and clinical indicators was analyzed, and the ability of the in vitro suppressive capacity to predict the in vivo therapeutic effects was evaluated., Results: UCB-Tregs expanded 123-fold and 5,981-fold at 18 and 42 days, respectively. The suppressive function of UCB-Tregs on the proliferation of immune cells at 42 days was not significantly different compared with that of UCB-Tregs obtained at 18 days. The suppression rate of UCB-Tregs to PBMCs was negatively correlated with the course of diabetes. Moreover, the high-suppression group exhibited a better treatment response than the low-suppression group during the 12-month follow-up period., Conclusions: Multiply restimulated UCB-Tregs expanded at a large scale without any alterations in their classical phenotypic features and inhibitory functions. The suppressive function of Tregs in vitro was negatively correlated with the disease duration. The present study revealed the possibility of predicting the in vivo therapeutic effects via the in vitro inhibition assay. Thus, these findings provided a method to obtain off-the-shelf Treg products and facilitated the selection of patients who are likely to respond to the treatment, thereby moving toward the goal of precision treatment., (© 2024. The Author(s).)

Nuclear receptor binding SET domain (NSD) proteins are a class of histone lysine methyltransferases and implicated in multiple cancer types with aberrant expression and involvement of cancer related signaling pathways. In this study, a series of small-molecule compounds including compound 2 and 3 are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound 3 exhibits potent inhibitory activities in vitro towards the NSD2-SET and NSD3-SET with an IC 50 of 0.81 μM and 0.84 μM, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDs-targeted genes in non-small cell lung cancer cells at 100 nM. Compound 3 suppresses cell proliferation and reduces the clonogenicity in H460 and H1299 non-small cell lung cancer cells, and induces s-phase cell cycle arrest and apoptosis. These data establish our compounds as a valuable tool-kit for the study of the biological roles of NSDs in cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lianhua Piao, Yanong Daniel Wang, Jie Zhou, Yang Gao, Jin Fang, Qihui Li, Shan Chang, Ren Kong have patent pending to Primary Biotechnology Co., Ltd. and Suzhou Medinoah Co., Ltd. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: To date, no study has systematically explored the potential role of serum metabolites and lipids in the diagnosis of small cell lung cancer (SCLC). Therefore, we aimed to conduct a case-cohort study that included 191 cases of SCLC, 91 patients with lung adenocarcinoma, 82 patients with squamous cell carcinoma, and 97 healthy controls., Methods: Metabolomics and lipidomics were applied to analyze different metabolites and lipids in the serum of these patients. The SCLC diagnosis model (d-model) was constructed using an integrated machine learning technology and a training cohort (n = 323) and was validated in a testing cohort (n=138)., Results: Eight metabolites, including 1-mristoyl-sn-glycero-3-phosphocholine, 16b-hydroxyestradiol, 3-phosphoserine, cholesteryl sulfate, D-lyxose, dioctyl phthalate, DL-lactate and Leu-Phe, were successfully selected to distinguish SCLC from controls. The d-model was constructed based on these 8 metabolites and showed improved diagnostic performance for SCLC, with the area under curve (AUC) of 0.933 in the training cohort and 0.922 in the testing cohort. Importantly, the d-model still had an excellent diagnostic performance after adjusting the stage and related clinical variables and, combined with the progastrin-releasing peptide (ProGRP), showed the best diagnostic performance with 0.975 of AUC for limited-stage patients., Conclusion: This study is the first to analyze the difference between metabolomics and lipidomics and to construct a d-model to detect SCLC using integrated machine learning. This study may be of great significance for the screening and early diagnosis of SCLC patients., (© The Author(s) 2023. Published by Oxford University Press.)

The aim of this study is to explore whether Nrf2 antioxidant pathway negatively regulates the ChTLR15/NLRP3 inflammatory pathway stimulated by Eimeria tenella infection. Firstly, levels of molecules in the Nrf2/HO-1 pathway in DF-1 cells pre-treated with an optimized dose of Corilagine or probiotics Levilactobacillus brevis 23017 were quantified using real-time PCR (qRT-PCR) and Western blot. Then, DF-1 cells pre-treated with Corilagine or L. brevis 23017 were stimulated with E. tenella sporozoites, and mRNA levels of molecules in Nrf2/HO-1 and ChTLR15/NLRP3 pathways, protein levels of p-Nrf2, Nrf2, HO-1, ChTLR15 and ChNLRP3, levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were quantified. Further, expression level of Nrf2 and ChTLR15 in DF-1 cells was knocked down by RNA interfering (RNAi) method, and target cells were pre-treated with Corilagine or L. brevis 23017, followed by stimulation with E. tenella sporozoites, and the expression levels of key molecules in Nrf2/HO-1 and ChTLR15/NLRP3 pathways were quantified. The results showed that mRNA and protein levels of key molecules in the Nrf2/HO-1 pathway in DF-1 cells was significantly upregulated after pretreating with 15 μM Corilagine and supernatant of L. brevis 23017. After stimulating with E. tenella sporozoites, levels of molecules in the ChTLR15/NLRP3 pathway, levels of MDA and ROS in DF-1 cells pre-treated with 15 μM Corilagine or bacterial supernatant were all significantly down-regulated. The results from the knock-down experiment also displayed that Corrigine and L. brevis 23017 inhibited the activation of the ChTLR15/ChNLRP3 inflammatory pathway stimulated by E. tenella sporozoites through activating Nrf2/HO-1 antioxidant pathway. This study provides new ideas for the development of novel anticoccidial products., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome-coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase elevations observed in prior emvododstat clinical trials in patients with solid tumors, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on physiologically-based pharmacokinetic modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only eight patients experienced aminotransferase elevations, all of which were mild (grade 1), all resolving within a short period of time, and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safety. Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed., (© 2023 Simulations Plus Inc., PTC Therapeutics, Inc. and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Traditional molecular de novo generation methods, such as evolutionary algorithms, generate new molecules mainly by linking existing atomic building blocks. The challenging issues in these methods include difficulty in synthesis, failure to achieve desired properties, and structural optimization requirements. Advances in deep learning offer new ideas for rational and robust de novo drug design. Deep learning, a branch of machine learning, is more efficient than traditional methods for processing problems, such as speech, image, and translation. This study provides a comprehensive overview of the current state of research in de novo drug design based on deep learning and identifies key areas for further development. Deep learning-based de novo drug design is pivotal in four key dimensions. Molecular databases form the basis for model training, while effective molecular representations impact model performance. Common DL models (GANs, RNNs, VAEs, CNNs, DMs) generate drug molecules with desired properties. The evaluation metrics guide research directions by determining the quality and applicability of generated molecules. This abstract highlights the foundational aspects of DL-based de novo drug design, offering a concise overview of its multifaceted contributions. Consequently, deep learning in de novo molecule generation has attracted more attention from academics and industry. As a result, many deep learning-based de novo molecule generation types have been actively proposed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine condition in premenopausal women. Troxerutin, a common clinical anti-coagulant agent, was shown to work as a strong IL-22 boosting agent counteracting the hyperactivated gonadotrophin releasing hormone (GnRH) neurons and heightened GnRH release, the neuroendocrine origin of PCOS with unknown mechanism in rats. Exploring the off-label use of troxerutin medication for PCOS is thus sorely needed., Methods: Serum IL-22 content and hypothalamic IL-22 protein were detected. Inflammatory factor levels in hypothalamo-pituitary were evaluated. Immunofluorescence staining was employed to determine the activation and M1/M2-prone polarization of microglia in arcuate hypothalamus and median eminence. RNA-sequencing and transcriptome analysis were applied to explore the potential driver of microglia M2-polarization in response to IL-22 bolstering effect. The function of microglial IL-22/IL-22R1/IRF3 system was further verified using in vivo knockdown of IL-22R1 and a potent IRF3 inhibitor in BV2 microglial cell lines in vitro., Results: Troxerutin augmented serum IL-22 content, and its consequent spillover into the hypothalamus led to the direct activation of IL-22R1/IRF3 system on microglia, thereby promoted microglia M2 polarization in arcuate hypothalamus and median eminence, dampened hypothalamic neuroinflammation, inhibited hyperactive GnRH and rescued a breadth of PCOS-like traits in dihydrotestosterone (DHT) rats. The salutary effects of troxerutin treatment on hypothalamic neuroinflammation, microglial M1/2 polarization, GnRH secretion and numerous PCOS-like features were blocked by in vivo knockdown of IL-22R1. Moreover, evidence in vitro illustrated that IL-22 supplement to BV-2 microglia cell lines promoted M2 polarization, overproduction of anti-inflammatory marker and limitation of pro-inflammatory factors, whereas these IL-22 effects were blunted by geldanamycin, a potent IRF3 inhibitor., Conclusion: Here, the present study reported the potential off-label use of troxerutin medication, a common clinical anti-coagulant agent and an endogenous IL-22 enhancer, for multiple purposes in PCOS. The rational underlying the application of troxerutin as a therapeutic choice in PCOS derived from its activity as an IL-22 memetic agent targeting the neuro-endocrine origin of PCOS, and its promotive impact on microglia M2 polarization via activating microglial IL-22R1/IRF3 system in the arcuate hypothalamus and median eminence of DHT female rats., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Objective and Design: Pancreatic cancer is a highly malignant tumor that is well known for its poor prognosis. Based on glycosylation, we performed integrated quantitative N-glycoproteomics to investigate the synergistic anti-tumor effects of aspirin and gemcitabine on pancreatic cancer cells and explore the potential molecular mechanisms of chemotherapy in pancreatic cancer., Methods and Results: Two pancreatic cancer cell lines (PANC-1 and BxPC-3) were treated with gemcitabine, aspirin, and a combination (gemcitabine + aspirin). We found that the addition of aspirin enhanced the inhibitory effect of gemcitabine on the activity of PANC-1 and BxPC-3 cells. Quantitative N-glycoproteome, proteome, phosphorylation, and transcriptome data were obtained from integrated multi-omics analysis to evaluate the anti-tumor effects of aspirin and gemcitabine on pancreatic cancer cells. Mfuzz analysis of intact N-glycopeptide profiles revealed two consistent trends associated with the addition of aspirin, which showed a strong relationship between N-glycosylation and the synergistic effect of aspirin. Further analysis demonstrated that the dynamic regulation of sialylation and high-mannose glycoforms on ECM-related proteins (LAMP1, LAMP2, ITGA3, etc.) was a significant factor for the ability of aspirin to promote the anti-tumor activity of gemcitabine and the drug resistance of pancreatic cancer cells., Conclusions: In-depth analysis of N-glycosylation-related processes and pathways in pancreatic cancer cells can provide new insight for future studies regarding pancreatic cancer therapeutic targets and drug resistance mechanisms., (© 2023. Springer Nature Switzerland AG.)

Epilepsies are a group of neurological disorders characterized by abnormal spontaneous brain activity, involving multiscale changes in brain functional organizations. However, it is not clear to what extent the epilepsy-related perturbations of spontaneous brain activity affect macroscale intrinsic dynamics and microcircuit organizations, that supports their pathological relevance. We collect a sample of patients with temporal lobe epilepsy (TLE) and genetic generalized epilepsy with tonic-clonic seizure (GTCS), as well as healthy controls. We extract massive temporal features of fMRI BOLD time-series to characterize macroscale intrinsic dynamics, and simulate microcircuit neuronal dynamics used a large-scale biological model. Here we show whether macroscale intrinsic dynamics and microcircuit dysfunction are differed in epilepsies, and how these changes are linked. Differences in macroscale gradient of time-series features are prominent in the primary network and default mode network in TLE and GTCS. Biophysical simulations indicate reduced recurrent connection within somatomotor microcircuits in both subtypes, and even more reduced in GTCS. We further demonstrate strong spatial correlations between differences in the gradient of macroscale intrinsic dynamics and microcircuit dysfunction in epilepsies. These results emphasize the impact of abnormal neuronal activity on primary network and high-order networks, suggesting a systematic abnormality of brain hierarchical organization., (© 2024. The Author(s).)

Salmonella constitutes a prevalent alimentary pathogen, instigating zoonotic afflictions. Consequently, the prompt discernment of Salmonella in sustenance is of cardinal significance. Lateral flow assays utilizing colorimetric methodologies adequately fulfill the prerequisites of point-of-care diagnostics, however, their detection threshold remains elevated, generally permitting only qualitative discernment, an impediment to the preliminary screening of nascent pathogens. In response to this conundrum, we propose a lateral flow diagnostic predicated upon a streptavidin-biotin amplification system with recombinase polymerase amplification engineered for the expeditious and quantitative discernment of Salmonella enteritidis. Trace nucleic acids within a sample undergo exponential amplification via recombinase polymerase amplification to a level discernable, constituting the initial signal amplification. Subsequently, along the test line (T-line) of the lateral flow strip, the chromatic signal undergoes augmentation by securing a greater quantity of AuNPs through the magnification capacity of the streptavidin-biotin mechanism, affecting the second signal amplification. Quantitative results are procured via smartphone capture and transferred to computer software for precise calculation of the targeted quantity. The lateral flow strip exhibits a LOD at 19.41 CFU/mL for cultured S. enteritidis. The RSD of three varying concentrations were respectively 3.74 %, 5.96 %, and 4.25 %., (© 2023 Wiley-VCH GmbH.)

The fusion peptide (FP) on the HIV-1 envelope (Env) trimer can be targeted by broadly neutralizing antibodies (bNAbs). Here, we evaluated the ability of a human FP-directed bNAb, VRC34.01, along with two vaccine-elicited anti-FP rhesus macaque mAbs, DFPH-a.15 and DF1W-a.01, to protect against simian-HIV (SHIV) BG505 challenge. VRC34.01 neutralized SHIV BG505 with a 50% inhibitory concentration (IC 50 ) of 0.58 μg/ml, whereas DF1W-a.01 and DFPH-a.15 were 4- or 30-fold less potent, respectively. VRC34.01 was infused into four rhesus macaques at a dose of 10 mg/kg and four rhesus macaques at a dose of 2.5 mg/kg. The animals were intrarectally challenged 5 days later with SHIV BG505 . In comparison with all 12 control animals that became infected, all four animals infused with VRC34.01 (10 mg/kg) and three out of four animals infused with VRC34.01 (2.5 mg/kg) remained uninfected. Because of the lower potency of DF1W-a.01 and DFPH-a.15 against SHIV BG505 , we infused both Abs at a higher dose of 100 mg/kg into four rhesus macaques each, followed by SHIV BG505 challenge 5 days later. Three of four animals that received DF1W-a.01 were protected against infection, whereas all animals that received DFPH-a.15 were protected. Overall, the protective serum neutralization titers observed in these animals were similar to what has been observed for other bNAbs in similar SHIV infection models and in human clinical trials. In conclusion, FP-directed mAbs can thus provide dose-dependent in vivo protection against mucosal SHIV challenges, supporting the development of prophylactic vaccines targeting the HIV-1 Env FP.

Introduction: Depression is a common illness worldwide. However, the current treatments available for depression only achieve relative success, often come with several side effects, and are associated with high costs. Aurantii Fructus Immaturus (AFI) has a rich historical legacy in Traditional Chinese Medicine (TCM) for its traditional use as a treatment for depression. In this research, our primary objective is to examine the potential antidepressant properties and the mechanisms at play behind a particular bioactive compound found in AFI, which is referred to as carbon dots derived from AFI Carbonisata (AFIC-CDs). Methods: Extracted and isolated the AFIC-CDs from the decoction of AFIC, then characterized the morphological structure and functional groups comprehensively. We then utilized two distinct models to investigate the anti-depressive properties of AFIC-CDs: the chronic unpredictable mild stress (CUMS) model and the reserpine-induced pain-depression dyad model. In the CUMS model, we assessed immobile time and measured neurotransmitter levels in the mouse brain cortex. In the pain-depression dyad model, we evaluated immobile time, neurotransmitter levels, interleukin-1 (IL-1β) and tumor necrosis factor-α (TNF-α) levels, and the expression of mRNA of brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (Tph2). Results: AFIC-CDs were found to have abundant chemical groups, and their diameter ranged from 2 to 10 nm. In the CUMS model, AFIC-CDs demonstrated significant effects. They reduced the immobile time of the mice and increased the levels of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in the mouse brain cortex. In the pain-depression dyad model, the AFIC-CDs groups decreased the immobile time, showed effect in increasing both the neurotransmitters' levels and the expression of mRNA of BDNF and Tph2, and decreased the IL-1β and TNF-α levels in mouse brain cortex. Taken together, these results strongly indicate that AFIC-CDs possess significant antidepressant activity. Conclusion: AFIC-CDs demonstrate promising therapeutic potential in the treatment of depression, suggesting that they may become a valuable candidate for depression management. This not only extends the understanding of the biological activity of carbon dots (CDs) but also opens up new possibilities for the development of effective depression treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Dai, Li, Kong, Yuan, Li, Wang, Zhang, Kong and Zhao.)

Background: Abnormal mitochondrial pyruvate carrier 1 (MPC1) expression plays a key role in tumor metabolic reprogramming and progression. Understanding its significance in non-small cell lung cancer (NSCLC) is crucial for identifying therapeutic targets., Methods: TIMER 2.0 was utilized to assess the expression of MPC1 in both normal and cancer tissues in pan-cancer. Overall survival (OS) differences between high and low MPC1 expression were analyzed in NSCLC using the Cancer Genome Atlas (TCGA) datasets. We also examined the expression of MPC1 in NSCLC cell lines using western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addition, the tissue samples and clinical information of 80 patients with NSCLC from our hospital were collected. Immunohistochemistry (IHC) was used to assess MPC1 expression, and OS was evaluated using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic values of the clinical characteristics and MPC1expression ., Results: Analysis of public databases suggested that MPC1 was downregulated in NSCLC compared to that in normal lung tissue and predicted poor prognosis. In addition, the expression of MPC1 in NSCLC cell lines was lower than that in human bronchial epithelial (HBE) cells at both protein and mRNA levels. Further clinical analysis suggested that MPC1 expression was correlated with age, tumor T stage, and TNM stage. Kaplan-Meier analysis revealed that NSCLC patients with high MPC1 expression had a better prognosis, particularly in lung adenocarcinoma (LUAD), whereas no survival benefit was observed in lung squamous cell carcinoma (LUSC). Univariate and multivariate analyses suggested that MPC1 was an independent prognostic factor for patients with NSCLC., Conclusions: MPC1 is poorly expressed in NSCLC, particularly in LUAD, which predicts a poor prognosis and may serve as an independent prognostic factor. Further studies on MPC1 may reveal new targets for the treatment of NSCLC., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: Tetrahydrobiopterin (BH 4 ), a natural cofactor of aromatic amino acid hydroxylases, and sepiapterin, a natural precursor of BH 4 , are endogenously present in human plasma. This is the first report on methods for direct quantification of sepiapterin and BH 4 in human plasma by LC-MS/MS for pharmacokinetic assessment . Materials & methods: The analytes in plasma were harvested from blood that were treated with 10% ascorbic acid (AA) to a final concentration of 1% AA. Results & conclusion: The quantification methods were validated for calibration ranges of 0.75-500 ng/ml and 0.5-500 ng/ml for sepiapterin and BH 4 , respectively. Quantification of analytes was challenging due to their susceptibility to redox reactions. The validated methods were utilized successfully to support clinical development of sepiapterin.

Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5-aminoimidazole-4-carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m 2 ) was administered to patients with LMS via 1-hour intravenous (IV) infusion on Day 1 of every 21-day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (BIW), starting on Day 2 of every cycle, except for Cycle 2 (C2), where unesbulin was dosed either on Day 1 together with DTIC or on Day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in Cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached C max immediately or shortly after end of infusion at 1.0 and 1.4 hours (T max ), respectively. Coadministration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2-mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC C max by 69.4% and AUC inf by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m 2 IV DTIC q21d and 300 mg unesbulin BIW in a staggered regimen is well tolerated in patients with LMS., (This article is protected by copyright. All rights reserved.)

Examining the intricate interplay between ecosystem carbon-water coupling and soil moisture sensitivity serves as a crucial approach to effectively assess the dilemma arising from escalating global carbon emissions and concomitant water scarcity. Using the Lund-Potsdam-Jena Dynamic Global Vegetation Model (LPJ), this study investigated the potential effects of climate change and soil water content (SWC) on terrestrial ecosystem water use efficiency (WUE) across China from 1982 to 2060. The results revealed that: (1) WUE was higher in South China and Northeast China, but lower in Northwest China and it had shown a significant upward trend in the past 40 years, especially in Northwest China where grasslands were widely distributed. The increase in WUE was mainly closely related to the greening of vegetation. In the past 40 years, the area of net primary productivity (NPP), evapotranspiration (ET), and WUE showing an upward trend accounted for 85.85 %, 63.66 %, and 83.88 % of the total area of the country, respectively. Although ET also showed an increasing trend nationwide, the increase of NPP was more obvious; (2) The control experiment showed that WUE showed a significant increase trend in arid and semi-arid areas of Northwest China with the increase of CO 2 concentration, while SWC showed a significant drying trend, but both WUE and SWC showed an increasing trend in humid areas. The sensitivity of WUE to SWC was enhanced in arid and semi-arid areas, and the effect of soil drought was partially offset by the increase of WUE; (3) Future climate projections also indicated that the CO 2 fertilization effect will contribute to an increase in WUE while causing drier soil moisture conditions in the arid and semi-arid regions. Especially under the SSP5-8.5 scenario, CO 2 fertilization in Northwest China contributed more than 14 % to WUE from 2015 to 2060, while the impact on SWC depletion exceeded 3 %. This highlights the potential implications of rising atmospheric CO 2 concentration, as it may promote a significant rise in WUE and exacerbate the drying of soil moisture in these areas. These findings emphasize the need for careful attention and consideration in managing water resources in arid and semi-arid regions in the face of future climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Avian coccidiosis caused by Eimeria brings huge economic losses to the poultry industry. Although live vaccines and anti-coccidial drugs were used for a long time, Eimeria infection in chicken farms all over the world commonly occurred. The exploration of novel, effective vaccines has become a research hotspot. Eimeria parasites have complex life cycles, and effective antigens are particularly critical to developing anti-coccidial vaccines. Microneme proteins (MICs), secreted from microneme organelles located at the parasite apex, are considered immunodominant antigens. Eimeria tenella microneme 3 (EtMIC3) contains four conserved repeats (MARc1, MARc2, MARc3, and MARc4) and three divergent repeats (MARa, MARb, and MARd), which play a vital role during the Eimeria invasion. Enterococcus faecalis is a native probiotic in animal intestines and can regulate intestinal flora. In this study, BC1 and C4D domains of EtMIC3, BC1 or C4D fusing to dendritic cells targeting peptides, were surface-displyed by E. faecalis, respectively. Oral immunizations were performed to investigate immune protective effects against Eimeria infection., Competing Interests: The authors declare no conflict of interest.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies., Methods: Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4 + T cells, CD8 + T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated., Results: Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4 + T cells and tumor associated macrophages (TAMs) were increased in Caprin-1 High tissues. The extensive CD4 + T cells determined poor clinical outcome in Caprin-1 high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance., Conclusions: Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment., (© 2023. The Author(s).)

Background: Liver fibrosis represents an intermediate stage in the progression of liver disease, and as of now, there exists no established clinical therapy for effective antifibrotic treatment. Purpose: Our aim is to explore the impact of Carbon dots derived from Vaccaria Semen Carbonisata (VSC-CDs) on carbon tetrachloride-induced liver fibrosis in mice. Methods: VSC-CDs were synthesized employing a modified pyrolysis process. Comprehensive characterization was performed utilizing various techniques, including transmission electron microscopy (TEM), multiple spectroscopies, X-ray photoelectron spectroscopy (XPS), and high-performance liquid chromatography (HPLC). A hepatic fibrosis model induced by carbon tetrachloride was utilized to evaluate the anti-hepatic fibrosis effects of VSC-CDs. Results: VSC-CDs, exhibiting a quantum yield (QY) of approximately 2.08%, were nearly spherical with diameters ranging from 1.0 to 5.5 nm. The VSC-CDs prepared in this study featured a negative charge and abundant chemical functional groups. Furthermore, these particles demonstrated outstanding dispersibility in the aqueous phase and high biocompatibility. Moreover, VSC-CDs not only enhanced liver function and alleviated liver damage in pathomorphology but also mitigated the extent of liver fibrosis. Additionally, this study marks the inaugural demonstration of the pronounced activity of VSC-CDs in inhibiting inflammatory reactions, reducing oxidative damage, and modulating the TGF-β/Smad signaling pathway. Conclusion: VSC-CDs exerted significant potential for application in nanodrugs aimed at treating liver fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Dai, Dong, Yuan, Zhao, Wu, Kong, Li, Wang, Zhou, Yang, Kong, Zhao and Qu.)

Hepatocellular carcinoma (HCC) is often associated with poor outcomes due to lung metastasis. ICAM-1 + circulating tumor cells, termed circulating cancer stem cells (CCSCs), possess stem cell-like characteristics. However, it is still unexplored how their presence indicates lung metastasis tendency, and particularly, what mechanism drives their lung metastasis. Here, we demonstrated that a preoperative CCSC count in 5 mL of blood (CCSC 5 ) of >3 was a risk factor for lung metastasis in clinical HCC patients. The CSCs overexpressed with circ-CDYL entered the bloodstream and developed lung metastases in mice. Mechanistically, circ-CDYL promoted COL14A1 expression and thus ERK signaling to facilitate epithelial-mesenchymal transition. Furthermore, we uncovered that an RNA-binding protein, EEF1A2, acted as a novel transcriptional (co-) factor to cooperate with circ-CDYL and initiate COL14A1 transcription. A high circ-CDYL level is caused by HIF-1⍺-mediated transcriptional upregulation of its parental gene CDYL and splicing factor EIF4A3 under a hypoxia microenvironment. Hence, the hypoxia microenvironment enables the high-tendency lung metastasis of ICAM-1 + CCSCs through the HIF-1⍺/circ-CDYL-EEF1A2/COL14A1 axis, potentially allowing clinicians to preoperatively detect ICAM-1 + CCSCs as a real-time biomarker for precisely deciding HCC treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tumor cells overexpress programmed cell death ligand 1 (PD-L1) to impede immune responses and escape immune elimination. Development of effective combination regimens to sensitize immunotherapy is promising but always challenging. Herein, a self-reinforced photodynamic immunostimulator (designated as PCS) is constructed for metastatic breast cancer treatment through simultaneous downregulation and blockade of PD-L1. Specifically, PCS is prepared by encapsulating signal transducer and activator of transcription 3 (STAT3) inhibitor (Stattic) into photosensitizer (protoporphyrin IX) modified PD-L1 blockade peptide (CVRARTR) through drug self-assembly. PCS can facilitate the targeted drug accumulation in PD-L1 overexpressed breast cancer cells to block PD-L1 and inhibit the phosphorylation of STAT3 to downregulate PD-L1. Moreover, PCS increases intracellular oxidative stress to show a robust anti-proliferation effect through photodynamic therapy (PDT), which also triggers an immunogenic cell death (ICD) to expose the immunostimulatory signals. Consequently, the efficient PD-L1 inhibition and robust PDT of PCS synergistically suppress the malignant growth of breast cancer, and concurrently activate the systemic anti-tumor immunity for metastatic inhibition with no obvious side effects. Such a photodynamic immunostimulator may provide an effective combination regimen for therapies activated immunotherapy against metastatic breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Epithelial polarity is critical for proper functions of epithelial tissues, tumorigenesis, and metastasis. The evolutionarily conserved transmembrane protein Crumbs (Crb) is a key regulator of epithelial polarity. Both Crb protein and its transcripts are apically localized in epithelial cells. However, it remains not fully understood how they are targeted to the apical domain. Here, using Drosophila ovarian follicular epithelia as a model, we show that epithelial polarity is lost and Crb protein is absent in the apical domain in follicular cells (FCs) in the absence of Diamond (Dind). Interestingly, Dind is found to associate with different components of the dynactin-dynein complex through co-IP-MS analysis. Dind stabilizes dynactin and depletion of dynactin results in almost identical defects as those observed in dind-defective FCs. Finally, both Dind and dynactin are also required for the apical localization of crb transcripts in FCs. Thus our data illustrate that Dind functions through dynactin/dynein-mediated transport of both Crb protein and its transcripts to the apical domain to control epithelial apico-basal (A/B) polarity., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

To break through the simplification of three-dimensional printing (3DP) materials and realize the application of long-persistent phosphors in more fields, polylactic acid doped with Ca 2 BO 3 Cl: Eu 2+ , Dy 3+ was prepared in this study. The structure of the mixtures was analyzed and determined by infrared spectroscopy. The luminescence properties of phosphors and the composites were studied by fluorescence spectra and afterglow decay curve measurements. The yellow light of the mixtures could be attributed to the 5d-4f energy level transition of Eu 2+ . After the excitation of 254 nm ultraviolet lamp, the luminance and duration of the composites could be clearly observed. The mechanical properties of the composite filaments were tested, including maximal force and elasticity modulus. In particular, the influence of humidity on mechanical properties was analyzed in detail. The prepared composite filaments were printed into hollow dodecahedrons and presented in this study. Therefore, the composites had great properties and might be expected to put into practical applications of 3DP technology., Competing Interests: No competing financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem., (© 2023 The Authors. Proteins: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.)

The surface morphology of mature biofilms is heterogeneous and can be divided into concentric rings wrinkles (I), labyrinthine networks wrinkles (II), radial ridges wrinkles (III), and branches wrinkles (IV), according to surface wrinkle structure and distribution characteristics. Due to the wrinkle structures, channels are formed between the biofilm and substrate and transport nutrients, water, metabolic products, etc. We find that expansion rate variations of biofilms growing on substrates with high and low agar concentrations (1.5, 2.0, 2.5 wt.%) are not in the same phase. In the first 3 days' growth, the interaction stress between biofilm and each agar substrate increases, which makes the biofilm expansion rate decreases before wrinkle pattern IV (branches) comes up. After 3 days, in the later growth stage after wrinkle pattern IV appears, the biofilm has larger expansion rate growing on 2.0 wt.% agar concentration, which has the larger wrinkle distance in wrinkle pattern IV reducing energy consumption. Our study shows that the stiff substrate does not always inhibit the biofilm expansion, although it does in the earlier stage; after that, mature biofilms acquire larger expansion rate by adjusting the growth mode through the wrinkle evolution even in nutrient extremely depletion., Competing Interests: The authors declare no competing interests.