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Metabolic reprogramming plays a critical role in hepatocarcinogenesis. However, the mechanisms regulating metabolic reprogramming in primary liver cancer (PLC) are unknown. Differentially expressed miRNAs between PLC and normal tissues were identified using bioinformatic analysis. RT-qPCR was used to determine miR-10b-5p and SCL38A2 expression levels. IHC, WB, and TUNEL assays were used to assess the proliferation and apoptosis of the tissues. The proliferation, migration, invasion, and apoptosis of PLC cells were determined using the CCK-8 assay, Transwell assay, and flow cytometry. The interaction between miR-10b-5p and SLC38A2 was determined using dual-luciferase reporter assay. A PLC xenograft model in BALB/c nude mice was established, and tumorigenicity and SLC38A2 expression were estimated. Finally, liquid chromatography - mass spectrometry (LC-MS) untargeted metabolomics was used to analyze the metabolic profiles of xenograft PLC tissues in nude mice. miR-10b-5p was a key molecule in the regulation of PLC. Compared with para-carcinoma tissues, miR-10b-5p expression was increased in tumor tissues. miR-10b-5p facilitated proliferation, migration, and invasion of PLC cells. Mechanistically, miR-10b-5p targeted SLC38A2 to promote PLC tumor growth. Additionally, miR-10b-5p altered the metabolic features of PLC in vivo . Overexpression of miR-10b-5p resulted in remarkably higher amounts of lumichrome, folic acid, octanoylcarnitine, and Beta-Nicotinamide adenine dinucleotide, but lower levels of 2-methylpropanal, glycyl-leucine, and 2-hydroxycaproic acid. miR-10b-5p facilitates the metabolic reprogramming of PLC by targeting SLC38A2, which ultimately boosts the proliferation, migration, and invasion of PLC cells. Therefore, miR-10b-5p and SLC38A2 are potential targets for PLC diagnosis and treatment.

Background: Altered phospholipid metabolism plays a key role in changing the immune microenvironment and severely affecting T-cell function. LPCAT3 is one of the vital enzymes regulating phospholipid metabolism. This study aims to verify the effect of LPCAT3 on HBV replication in vitro and the chronic progression of hepatitis B infection based on the results of lipidomic., Methods: Untargeted lipidomic analysis was employed to scrutinize discrepancies in lipid metabolites between 40 HBV-infected patients and those who spontaneously cleared the virus. Subsequently, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot assay (ELISPOT), western blotting (WB) and quantitative polymerase chain reaction (qPCR) were utilized to investigate LPCAT3 expression and assess HBV replication and endoplasmic reticulum stress (ERS)., Results: A comparative analysis between HBV-infected patients and those experiencing spontaneous clearance revealed significant disparities in 24 lipid metabolites. Among these, phosphatidylcholine (PC) and lysophosphatidylcholine (LPC), constituting half (12/24) of the identified metabolites, were identified as substrates and products of LPCAT3. In vitro studies demonstrated that inhibiting LPCAT3 led to elevated expression levels of hepatitis B surface antigen (HBsAg), HBV-DNA, and interferon-γ (IFN-γ) (P < 0.05), indicative of heightened HBV replication. Furthermore, LPCAT3 inhibition significantly upregulated the expression of genes associated with ERS (P < 0.05)., Conclusions: Inhibiting LPCAT3 significantly correlates with HBV replication and induces inflammation by enhancing ERS. We hypothesize that LPCAT3 serves as a potential biomarker for hepatitis B virus replication and chronic progression. Furthermore, these findings elucidate the malignant progression of HBV infection from the standpoint of lipid metabolism, offering a novel insight for subsequent mechanistic exploration or therapeutic studies., Lay Summary: LPCAT3 inhibition enhances endoplasmic reticulum stress and HBV replication by altering the membrane phospholipid composition and promotes chronic hepatitis B progression., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Despite the growing recognition of the impact of urban environments on social health, limited research explores the combined associations of multiple urban exposures, particularly in dense cities. This study examines the interplay between greenspace, air pollution, and social health as well as the underlying pathways and population heterogeneity in Hong Kong using cross-sectional survey data from 1977 adults and residential environmental data. Social health includes social contacts, relations, and support. Greenspace used street-view greenness (SVG), park density, and the normalized difference vegetation index (NDVI). 100-m daily ground NO 2 and O 3 , indicative of air pollution, were derived using a spatiotemporal deep learning model. Mediators involved physical activity and negative emotions. Main analyses were performed in a 1000-m buffer with multivariate logistical regressions, stratification, interaction, and Partial Lease Square - Structural Equation Modelling (PLS-SEM). Multi-exposure models revealed positive associations between park density/SVG and social contacts, as well as between SVG and social relations, while O 3 was negatively associated with social relations/support. Significant moderators included age, birthplace, employment, and education. PLS-SEM indicated direct positive associations between SVG and social contacts/relations and significant indirect negative associations between NO 2 /O 3 and social health via negative emotions. This study adds to urban health research by exploring complex relationships between greenspace, air pollution, and social health, highlighting the role of the environment in fostering social restoration., 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.)

Background: Studies have linked air pollution to lung cancer incidence and mortality, but few have compared these associations, which may differ due to cancer survival variations. We aimed to evaluate the association between long-term air pollution exposure and lung cancer incidence and compare findings with previous lung cancer mortality analyses within the same cohorts., Methods: We analyzed four population-based administrative cohorts in Denmark (2000-2015), England (2011-2017), Norway (2001-2016) and Rome (2001-2015). We assessed residential exposure to annual average fine particulate matter (PM 2.5 ), nitrogen dioxide (NO₂), black carbon (BC), and warm-season ozone (O 3 ) using Europe-wide land use regression models. We used Cox proportional hazard models to evaluate cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer incidence identified using hospital admission records (English and Roman cohorts) or cancer registries (Danish and Norwegian cohorts). We evaluated the associations at low exposure levels using subset analyses and natural cubic splines. Cohort-specific HRs were pooled using random-effects meta-analyses, separately for incidence and mortality., Results: Over 93,733,929 person-years of follow-up, 111,949 incident lung cancer cases occurred. Incident lung cancer was positively associated with PM 2.5 , NO 2 and BC, and negatively associated with O 3 . The negative O 3 association became positive after adjustment for NO 2 . Associations were almost identical or slightly stronger for lung cancer incidence than mortality in the same cohorts, with respective meta-analytic HRs (95% CIs) of 1.14 (1.06, 1.22) and 1.12 (1.02, 1.22) per 5 μg/m 3 increase in PM 2.5 , and 1.10 (1.04, 1.16) and 1.09 (1.02, 1.16) per 10 μg/m 3 increase in NO 2 . Positive associations persisted for both incidence and mortality at low pollution levels with similar magnitude., Conclusions: We found similarly elevated risks of lung cancer incidence and mortality in association with residential exposure to PM 2.5 , NO 2 and BC in meta-analyses of four European administrative cohorts, which persisted at low pollution levels., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure to increased air pollution, noise, and reduced surrounding greenness have been suggested as potential environmental risk factors for hypertension in adults, but limited evidence exists regarding early-life exposure, particularly from prospective studies. We investigated independent and joint associations of childhood exposure to these factors with incident hypertension in early adulthood in a US nationwide cohort. Study participants were from the Growing Up Today Study (GUTS) established in 1996 (GUTSI) and 2004 (GUTSII), who were ages 9-14 (GUTSI) or 10-17 (GUTSII) at enrollment. Incident hypertension was identified by self-report on questionnaires from 2010 to 2021. We estimated residential exposures to air pollution (from spatiotemporal models), noise, and surrounding greenness throughout childhood (10-18y). We applied Cox proportional hazards models adjusted for potential confounders to assess hazard ratios (HRs) and 95% confidence intervals (CIs) associated with each interquartile range (IQR) change in exposure. We performed a quantile g-computation to assess the joint association of simultaneous exposure to the mixture. We considered potential effect modification by sex, maternal history of hypertension, overweight/obese status at age 18, urbanicity, and neighborhood socioeconomic status. Among 17,762 participants, 1530 hypertensive cases occurred during an average follow-up of 12.8 years. HRs for all exposures were small with CIs including unity. A joint HR of 1.03 (95% CI: 0.95, 1.11) was associated with a one-quartile increase across simultaneous exposure to the environmental mixture. The joint associations were stronger among non-obese participants or participants living in less advantaged neighborhoods: HRs of 1.07 (95% CI: 0.97, 1.18) and 1.08 (95% CI: 0.98, 1.18), respectively. In conclusion, we did not identify an independent or joint association between childhood exposure to air pollution, noise, and surrounding greenness and early adulthood hypertension. However, a positive joint association was suggested among non-obese participants or those living in less advantaged neighborhoods., 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.)

Ischemic stroke is characterized by high morbidity and mortality and a lack of effective therapeutic interventions. Leptin plays an important role in regulating oxidative stress, angiogenesis, hematopoiesis, etc. Although recent studies have found a neuroprotective effect of leptin, little is known about its role in cerebral ischemia. This study explores the possible roles and potential preventative mechanisms of leptin in cerebral ischemia-reperfusion injury (CIRI). An in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was used to replicate the CIRI model, low (0.5 mg/kg), medium (1 mg/kg) and high (2 mg/kg) concentrations of leptin were injected intraperitoneally immediately after inserting the embolic line. After 1.5 h of ischemia and 24 h of reperfusion, we examined the neural function of the mice, collected brain tissue for histological examination, and screened for the optimal concentrations of leptin intervention. On this basis, we observed the changes of cortical apoptosis injury, intracellular calcium fluorescence intensity and astrocyte glial fibrillary acidic protein (GFAP) expression and morphological changes. In addition, we also tested the expression of transporters and metabolism-related enzymes (VGLUT-1, VGLUT-2, GLAST, GLT-1, GS, ATP1α1), the expression of inflammatory factors and the content of glutamate (Glu). Compared with the I/R group, we found that leptin improved neurological deficits, reduced the area of infarcts, maintained the normal morphology of astrocytes (AST), downregulated the expression of VGLUT-1, and upregulates the expression of GLT-1 and GLAST, thereby reducing the content of Glu in the synaptic cleft. Our studies suggest that leptin may have a neuroprotective effect by decreasing the excitotoxicity of glutamate., 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 B.V. All rights reserved.)

Photolyase and cryptochrome belong to a group of structurally similar flavoproteins but with two distinct functions of DNA repair as a photoenzyme and signal transduction as a photoreceptor, respectively, under blue-light illumination. Here, we studied a recently discovered bifunctional Chlamydomonas reinhardtii cryptochrome (CraCRY) with focus on its repair of UV-induced pyrimidine-pyrimidone (6-4) photoproduct (6-4PP). We used femtosecond spectroscopy and site-directed mutagenesis to map out the critical elementary steps by following the dynamics of initial reactants, various intermediates, and final products. We observed initial direct ultrafast electron tunneling from the hydroquinone flavin cofactor to 6-4PP in 300 ps through an intervening adenine as a mediator, minimizing the electron bifurcation of a two-step hopping pathway bridged also by the adenine as an intermediate. The subsequent proton transfer (PT) from the neighboring histidine to anionic 6-4PP in 2 ns is critical and competes with the futile back electron transfer in 151 ps. Mutations of either of two histidines in the active site nearly abolish repair, indicating their essential role on repair reactivity and structural integrity. These results elucidate the electron-coupled PT mechanism and the repair photocycle of this bifunctional cryptochrome at the molecular level, further supporting that the hydroquinone flavin is the active state in vivo for dual functions or one of the two functions is excessive., Competing Interests: Competing interests statement:The authors declare no competing interest.

In this study, a series of novel thieno [3, 2-b]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5-1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T 1/2 value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome sequencing of spontaneously compound 6c-resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2-b]pyridinone derivatives. Overall, this study identified thieno [3, 2-b]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Following the relaxation of control measures for COVID-19 in China in December 2022, there was a resurgence of influenza A among children in Linyi. This research aims to analyze the epidemiology and genetic characteristics of influenza A viruses circulating among children in Linyi from April 2022 to March 2024. Throat swab specimens were collected from children with influenza-like illness (ILI), and the types of influenza were identified. The hemagglutinin (HA) genes of influenza A viruses were amplified using reverse transcription-polymerase chain reaction (RT-PCR) and then sequenced. Subsequently, the gene characteristics and phylogenetics of these sequences were analyzed. A total of 6258 cases of influenza A were tested from 54,926 children with ILI over two years, showing three epidemic waves: one in summer 2022 and two in spring and winter 2023. The epidemic waves in summer 2022 and winter 2023 were caused by influenza A(H3N2) viruses. In spring 2023, influenza A(H1N1)pdm09 viruses accounted for 77.1% and A(H3N2) viruses accounted for 22.9%, respectively. The influenza A(H1N1)pdm09 viruses belonged to clade 6B.1A.5a.2a, while the influenza A(H3N2) viruses evolved from clade 3C.2a1b.2a.1a to 3C.2a1b.2a.2a.3a.1. Compared with the vaccine strain of the Northern Hemisphere of the current year, multiple amino acid substitutions and glycosylation sites changes were observed in the HA protein that most likely resulted in antigenic drift. The influenza A viruses have been circulating and evolving persistently in Linyi from 2022 to 2024. Continuous surveillance is essential for comprehending the dynamics of influenza in the post-COVID-19 era., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical statement: This study was in compliance with the Helsinki Declaration and approved by the Ethics Committee of Women and Children’s Health Care Hospital of Linyi. The specimens involved in this research were all obtained from the remaining specimens for clinical test. Specimens collection in this study was agreed by the patient’s guardian with prior written informed consent. The research is not for commercial use., (© 2024. The Author(s).)

Aim: This study was designed to investigate the response of the respiratory structures to orthognathic surgery in patients with Class III malocclusion, with a specific emphasis on the vertical placement of the hyoid bone. The correlations of these changes were also analysed, followed by further subgroup analyses based on preoperative conditions., Materials and Methods: Dolphin software was used to obtain cephalometric landmarks, airway and hyoid bone measurements from pre- and postoperative CBCT scans of 31 patients. Statistical analyses included paired t-tests and Pearson's correlation analysis., Results: Stomatological mandibular values and the nasopharynx height showed significant changes. Pearson's correlation identified significant correlations between changes in B and H horizontal coordinates (p < 0.05), as well as between changes in H longitudinal coordinates and specific airway dynamics (p < 0.05). Patients with a lower preoperative hyoid position experienced a more pronounced decrease in hypopharyngeal airway volume after surgery compared to those with a higher preoperative hyoid position, as evidenced by the significant mean differences and p values (p < 0.01)., Conclusions: Class III patients experienced airway constriction following orthognathic surgery, particularly those with a lower preoperative hyoid bone position, who showed a more significant decrease in hypopharyngeal airway volume postsurgery compared to those with a higher preoperative hyoid position. These findings underscored the importance of individualised surgical planning and highlighted the need for further research with dynamic assessments to optimise respiratory outcomes., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Backgound: Traumatic brain injury (TBI) is a severe neurological disorders, which invloving complicated molecular mechanisms, such as endoplasmic reticulum (ER) stress and ferroptosis. , However, the mechanism underlying TBI remains unclear., Objectives: The Objective was to determine the effect of VPA on ER stress and ferroptosis, and affirm the relationship between ER stress and ferroptosis. Methods: The expression levels of GRP78, ATF6, CHOP and GPX4 in brain tissues were detected via western blot, histological staining, and immunofluorescence. The effect of VPA on ER stress and ferroptosis on OS cellswas evaluated in vitro and in vivo., Results: In our study, we found that VPA suppressed ER stress after TBI by inhibiting the GRP78-ATF6-CHOP signaling pathway, which ameliorated ferroptosis by reversing the reduction of the ferroptosis protein GPX4. Furthermore, tissue defects, bleeding, and iron accumulation also reduced. Moreover, 4-phenylbutyric acid was used to further confirm our assumption., Conclusion: VPA plays a neuroprotective role by inhibiting ER stress levels and subsequently inhibiting ferroptosis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objectives: The US Food and Drug Administration (FDA) issued a warning about buprenorphine-induced dental caries of unknown mechanism in 2022. To investigate the potential mechanism, the association between local buprenorphine exposure and dental biofilm formation will be explored in this study., Methods: Female F344 rats were dosed with sublingual buprenorphine film or intravenous injection to explore the oral cavity exposure of the buprenorphine. The buprenorphine distribution in salivary glands after the sublingual and intravenous administration was also evaluated. To investigate the effects of buprenorphine exposure on dental caries formation, buprenorphine's impact on the biofilm formation of S. mutans in vitro was measured., Results: The absolute sublingual bioavailability of buprenorphine in rats was 17.8% with a high ratio of oral fluid exposure to blood concentration in the pharmacokinetic study. Salivary gland concentrations of buprenorphine and its active metabolite norbuprenorphine were significantly higher than their blood concentrations after both sublingual (s.l.) and intravenous (i.v.) administration. Correlation analysis showed that the oral fluid concentration of buprenorphine and norbuprenorphine was highly correlated to salivary gland concentration rather than blood concentration. These data indicate that the salivary gland serves as an accumulation organ for buprenorphine, allowing prolonged oral fluid exposure to buprenorphine. Lastly, buprenorphine and its metabolites contributed to the biofilm formation of S. mutans in high concentration., Conclusions: Sublingual administration substantially increased the salivary gland distribution of buprenorphine and norbuprenorphine. Depot effects following sublingual dosing and salivary gland accumulation likely sustained high oral fluid exposure to buprenorphine and stimulated the biofilm formation of S. mutans., Competing Interests: The authors report no conflict of interests. Dr Ming Hu is the cofounder of Sanarentero LLC. Dr. Vesna Tumbas Saponjac has a financial interest in Sanarentero LLC. Sanarentero is not involved in deciding the research direction of this project., (Copyright © 2024 American Society of Addiction Medicine.)

Background: To investigate the accuracy of quantitative blood oxygen level-dependent (qBOLD) magnetic resonance imaging (MRI) in identifying hypoxia within glioblastoma and explore dynamic changes in oxygenation status of glioblastoma with and without metformin administration., Methods: Three healthy and seven C6-bearing rats underwent 7-T qBOLD MRI. Oxygen extraction fraction (OEF) and cerebral metabolism rate of O 2 (CMRO 2 ) were calculated from qBOLD data. Tumor tissues were stained using hypoxia-inducible factor-1 α (HIF-1 α ) and pimonidazole. The correlation between the hypoxia markers and corresponding qBOLD-based parameters was analyzed. Six C6-bearing rats were divided into metformin-treated and control groups for a longitudinal study of qBOLD imaging changes, with scans conducted on the 12th, 15th, and 18th day post-tumor implantation., Results: In healthy rats, gray matter showed higher values than white matter in T2, T2*, cerebral blood volume (CBV), and cerebral blood flow (CBF), whereas OEF was lower. Glioblastoma tissues exhibited elevated T2, T2*, CBV, and CBF but decreased OEF and CMRO 2 relative to normal-appearing white matter. No significant correlation was found between staining scores from HIF-1 α and pimonidazole. T2* and T2 values were negatively correlated with pimonidazole scores in tumor regions. As the tumor progressed, OEF values increased with intra-tissue variations, whereas CMRO 2 decreased. Metformin delayed the reduction of T2 and T2* values, with significant differences in OEF and CMRO 2 values compared to controls on day 18., Conclusion: T2* and T2 values were significantly associated with the hypoxia status in glioma. Metformin could potentially mitigate the progression of hypoxia in glioblastoma, which can be tracked by qBOLD parameters., Relevance Statement: This study demonstrates the potential of qBOLD parameters in assessing glioma dynamic oxygen metabolism and the efficacy of metformin as an anti-hypoxic agent, providing insights into improving glioblastoma treatment strategies., Key Points: The study investigated qBOLD imaging's accuracy in identifying hypoxia status within glioblastoma. qBOLD effectively assesses hypoxia and its dynamic evolution in glioblastoma. qBOLD parameters assist in identifying a suitable patient demographic for metformin treatment., Competing Interests: Declarations. Ethics approval and consent to participate: All studies were approved by the Institutional Animal Care and Use Committee of the Medical School of Fudan University (2023-HSYY-539JZS). Consent for publication: Not applicable. Competing interests: One of the authors (Pu-Yeh Wu) is an employee of GE Healthcare. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: Clobazam (CLB) is an effective, safe and well-tolerated adjunctive treatment for refractory epilepsy. However, the cost-effectiveness of CLB in China remains unclear., Aim: The aim of this study was to evaluate the cost-effectiveness of CLB as an adjunctive therapy for patients with refractory epilepsy in China., Method: A Markov model was established to simulate the lifetime epilepsy process in patients. The epilepsy remission rate, health state utility and mortality data were derived from clinical trials and the literature. The costs were collected from the health care system in the hospital. The primary outcome was the incremental cost-effectiveness ratio (ICER), which was calculated by comparing CLB as an add-on therapy with conventional therapy and was assessed in the context of the Chinese health system. One-way and probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty, and several scenario analyses were also conducted., Results: Compared with maintaining conventional therapy, adding CLB as an adjuvant therapy increased the cost of Chinese Yuan (CNY) 1770.17 over a lifetime, with an incremental quality-adjusted life years (QALYs) value of 1.02, resulting in an ICER of CNY 1737.10 per QALY gained. The daily dose of CLB had the strongest effect on the ICER. The probabilistic sensitivity analyses revealed that the probability of CLB being cost-effective was 77.35% at a willingness to pay (WTP) of CNY 85698/QALY., Conclusion: CLB is a cost-effective add-on therapy for refractory epilepsy in the Chinese population., Competing Interests: Conflicts of interest: The authors have no conflicts of interest to declare., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Probiotic therapy with Lactobacillus reuteri and Lactobacillus rhamnosus (LGG) demonstrates potential as an adjunctive treatment for autism spectrum disorder (ASD). In a rat model of ASD induced by lipopolysaccharide (LPS) injection during pregnancy, we evaluated the effects of these probiotics on offspring. Administration of L. reuteri or LGG for three weeks post-birth improved social deficits and reduced anxiety in LPS-exposed rats. Additionally, probiotics significantly modified short-chain fatty acid profiles, increasing butyric acid levels and decreasing propionic acid levels. They also enhanced colonic barrier integrity by upregulating tight junction proteins, including ZO-1, Occludin, and Claudin4. RNA sequencing identified differential gene expression in pathways related to inflammation, the HPA axis, and reactive oxygen species metabolism, with NADPH oxidase 1 (NOX1) emerging as a crucial gene. Validation studies confirmed that Lactobacillus strains reduced inflammatory cytokines, inhibited corticosterone secretion, increased antioxidant levels, and suppressed the NF-κB/NOX1 pathway. In an H 2 O 2 -induced oxidative stress model using Caco-2 cells, pre-treatment with L. reuteri, LGG, or NF-κB inhibitors enhanced cellular antioxidants, inhibited NF-κB/NOX1 activation, and improved barrier function. Overall, L. reuteri and LGG administration improved social behavior, bolstered colonic barrier function, and mitigated HPA axis overactivation in LPS-exposed rats, while also alleviating oxidative stress in the colon and Caco-2 cells. These findings suggest that L. reuteri and LGG have substantial clinical potential for ASD treatment by targeting multiple pathophysiological mechanisms, including inflammation, HPA axis dysregulation, and oxidative stress, thereby presenting a promising adjunctive therapeutic strategy for enhancing social behavior and gut health in ASD., 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.)

Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: This article was approved by the ethics committee of Children’s Hospital, Zhejiang University School of Medicine (2023-IRB-0284-P-01). Informed consent: Written informed consent was obtained from the parents of the patient for the publication of information and imaging findings.

Channa asiatica is an economically valuable fish species and excellent model for studying hypoxic tolerance. However, the underlying genetic and molecular mechanisms are poorly understood. In this study, we assembled a high-quality C. asiatica genome (23 chromosomes, totaling 722 Mb) using a combination of Illumina short-read, PacBio long-read, and Hi-C sequencing. Repetitive elements accounted for 28.39%of the C. asiatica genome, and 23,949 protein-coding genes were predicted, with 96.63 % of these functionally annotated. Moreover, a comparative genomic analysis of 12 fish genomes showed that gene families associated with oxygen binding and transport were expanded in C. asiatica. In addition, transcriptome analysis revealed that multiple oxidative stress pathways were activated when C. asiatica was exposed to air. In conclusion, this study provided high-quality genome assembly and transcriptome data, both serving as critical resources for researching the genetic basis of hypoxic tolerance in C. asiatica., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: Almonertinib is primarily metabolized by CYP3A4, so it could interact with a variety of drugs metabolized by CYP3A4, leading to the changes of systemic exposure., Objective: For the purpose of this experiment, an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay with accuracy and simplicity was optimized and fully validated for the simultaneous quantitative determination of almonertinib and its metabolite HAS-719, and drug-drug interactions (DDI) between almonertinib and nicardipine in vivo and in vitro was researched., Materials and Methods: Detection of analytes was achieved by UPLC-MS/MS coupled with multiple reaction monitoring (MRM) in the positive ion mode with ion transitions of m/z 526.01 → 72.04 for almonertinib, m/z 512.18 → 455.08 for HAS-719 and m/z 447.16 → 128.11 for IS, respectively., Results: There was favourable linearity in the 0.5-200 ng/mL calibration range for almonertinib and 0.5-100 ng/mL for HAS-719. The lower limit of quantification (LLOQ) for both analytes was 0.5 ng/mL. The precision, accuracy, stability, matrix effect and extraction recovery required for methodological validation were consistent with the requirements of FDA guideline. Then, the UPLC-MS/MS assay was employed successfully on the interactions of almonertinib and nicardipine in vivo and in vitro . The half-maximal inhibitory concentration (IC 50 ) was 1.19 μM in rat liver microsomes (RLM), where nicardipine inhibited the metabolism of almonertinib with a mixed inhibitory mechanism. In pharmacokinetic experiments of rats, it was observed that nicardipine could significantly alter the pharmacokinetic profiles of almonertinib, including AUC (0-∞), AUC (0-t) and C max , but had no effect on the metabolism of HAS-719., Conclusion: According to the findings, it was indicated that nicardipine could inhibit the metabolism of almonertinib in vitro and in vivo .

Eye drops are envisaged as the most promising non-invasive formulation for the treatment of the ocular posterior segment diseases, while it is hindered by a series of complex ocular barriers, both static and dynamic in nature. In this context, we propose a single molecule nanomedicine based on host-guest chemistry to achieve highly efficient drug delivery targeted to ocular posterior segment. Sulfonated azocalix[4]arene (SAC4A) serves as the single molecule carrier, owing the multiple features of small size (24.0 Å in length, 21.2 Å in width, 14.8 Å in height with a Van der Waals volume of 930 Å 3 ), negative charge, hydrophilicity, loading universality and hypoxia-triggered release. As a proof-of-concept, an eye drop formed by the complexation of SAC4A with sunitinib (SUN) is prepared to treat wet age-related macular degeneration (wAMD). SAC4A successfully transports SUN to the ocular posterior segment (the amount of SUN reaching the retinal-choroid tissue in the SUN@SAC4A group was 2.47 times larger than that in the SUN group at 30 min), significantly enhancing its anti-choroidal neoangiogenesis effect of SUN to wAMD, which played a key role in the treatment. We believe that the single molecule nanomedicine paradigm is highly amenable for treating various ocular posterior segment diseases in the future., (Copyright © 2024. Published by Elsevier B.V.)

Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, marked by hormonal imbalances and disruptions in glucose and lipid metabolism. Emerging research has indicated a correlation between lipids and PCOS, yet the specific lipid profiles or associated genes identified in various studies vary, and observational data alone cannot establish causation. Therefore, our study seeks to establish a causal association between lipidome and PCOS., Methods: Data from genome-wide association studies, liposomes, metabolites, and PCOS-related information were collected. Four rounds of double-sample bidirectional intermediate Mendelian Randomization analyses including liposomes to disease, liposomes to metabolites, metabolites to disease, and reverse Mendelian Randomization analysis of lipids, total effect values and intermediary effect values were calculated. The proportion mediated by the intermediary effect was determined by dividing the intermediary effect value by the total effect value., Results: The analyses revealed that three liposomes and nine metabolites were causally associated with PCOS. Specifically, phosphatidylcholine and 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol were identified as independent risk factors for PCOS through further Mendelian Randomization analysis. The risk of developing PCOS increased by 32% for every one standard deviation increase in phosphatidylcholine and by 17% for every one standard deviation increase in 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol. Furthermore, the study revealed that phosphatidylcholine can influence the development of PCOS with 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol acting as a mediator, explaining 4.97% of the effect., Conclusions: This study confirmed a causal relationship between phosphatidylcholine and 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol with PCOS, where phosphatidylcholine can influence the occurrence of PCOS with 1-Stearoyl-2-Oleoyl-Glycosylphosphatidylinositol as a mediator.

Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Given that ponatinib can induce significant cardiotoxicity when taken, and that most Chinese medicines have cardioprotective effects, it is possible to administer them in combination in clinic to alleviate adverse effects. The quantitative determination of ponatinib and its metabolite N-desmethyl ponatinib was optimized and fully verified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). And the drug-drug interactions (DDI) of ponatinib with lycopene and shikonin, both in vivo and in vitro, were studied. The results of bioanalytical methodology showed that ponatinib and N-desmethyl ponatinib had good linearity in plasma samples, and their selectivity, accuracy, precision, stability, matrix effect and recovery were all satisfied with the need of quantitative analysis of samples. In animal experiments, compared with the control group, lycopene and shikonin significantly changed the pharmacokinetic parameters of ponatinib, including AUC (0-t) , AUC (0-∞) and CL z/F , while having no effect on the pharmacokinetic parameters of N-desmethyl ponatinib. In vitro interaction studies indicated that lycopene showed mixed inhibition mechanism on ponatinib metabolism in both rat liver microsomes (RLM) and human liver microsomes (HLM). And, shikonin displayed mixed inhibition mechanism in RLM and competitive inhibition mechanism in HLM, respectively. In summary, the UPLC-MS/MS method can accurately and sensitively quantify ponatinib and N-desmethyl ponatinib, and provide further reference for clinical drug combination between ponatinib and lycopene or shikonin., 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 B.V. All rights reserved.)

Myocardial infarction (MI) is a lethal cardiovascular disease worldwide. Emerging evidence has revealed the critical role of gut dysbiosis and impaired gut-brain axis in the pathological progression of MI. Tanshinone IIA (Tan IIA), a traditional Chinese medicine, has been demonstrated to exert therapeutic effects for MI. However, the effects of Tan IIA on gut-brain communication and its potential mechanisms post-MI are still unclear. In this study, we initially found that Tan IIA significantly reduced myocardial inflammation, apoptosis and fibrosis, therefore alleviating hypertrophy and improving cardiac function following MI, suggesting the cardioprotective effect of Tan IIA against MI. Additionally, we observed that Tan IIA improved the gut microbiota as evidenced by changing the α-diversity and β-diversity, and reduced histopathological impairments by decreasing inflammation and permeability in the intestinal tissues, indicating the substantial improvement of Tan IIA in gut function post-MI. Lastly, Tan IIA notably reduced lipopolysaccharides (LPS) level in serum, inflammation responses in paraventricular nucleus (PVN) and sympathetic hyperexcitability following MI, suggesting that restoration of Tan IIA on MI-induced brain alterations. Collectively, these results indicated that the cardioprotective effects of Tan IIA against MI might be associated with improvement in gut-brain axis, and LPS might be the critical factor linking gut and brain. Mechanically, Tan IIA-induced decreased intestinal damage reduced LPS release into serum, and reduced serum LPS contributes to decreased neuroinflammation with PVN and sympathetic inactivation, therefore protecting the myocardium against MI-induced injury., Competing Interests: Declarations Conflict of interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper. Ethical Approval All the animal experiments were approved by Xi’an Jiaotong University Laboratory Animal Administration Committee and were carried out strictly in accordance with Xi’an Jiaotong University Guidelines for Animal Experimentation. Consent to Participate Authors give full consent to participate. Consent for Publication Authors give full consent for publication., (© 2024. The Author(s).)

CD8 + T cells play a critical role in cancer immune-surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain-3 (Tim-3). Here Siglec-G is identified as a coinhibitory receptor that limits CD8 + T cell function. Siglec-G is highly expressed on tumor-infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec-G-SHP2 axis in CD8 + T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec-G in inhibiting CD8 + T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Social isolation not only increases the risk of mortality in later life but also causes depressive symptoms, cognitive and physical disabilities. Although RNA m6A modifications are suggested to play key roles in brain development, neuronal signaling and neurological disorders, both the roles of m6A and the enzymes that regulate RNA m6A modification in social isolation induced abnormal behavior is unknown. The present study aims to explore the possible epitranscriptomic role of RNA m6A modifications and its enzymes in social isolation induced impaired behavior., Methods: 3-4 weeks mice experiencing 8 weeks social isolation stress (SI) were used in the present study. We quantified m6A levels in brain regions related to mood and cognitive behavior. And the expression of hippocampal m6A enzymes was also determined. The role of hippocampal m6A and its enzymes in SI induced abnormal behavior was further verified by the virus tool., Results: SI led to not only depressive and anxiety-like behaviors but also cognitive impairment, with corresponding decreases in hippocampal m6A and METTL14. Hippocampal over-expression METTL14 with lentivirus not only rescued these behaviors but also enhanced the hippocampal m6A level. Hippocampal over-expression METTL14 resulted in increased synaptic related genes., Conclusions: We provide the first evidence that post-weaning social isolation reduces hippocampal m6A level and causes altered expression of m6A enzyme in mice. Importantly, hippocampal METTL14 over-expression alleviated the SI-induced depression/anxiety-like and impaired cognitive behaviors and enhanced m6A level and synaptic related genes expression., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest or any known competing financial interests or personal relationships that may bias the performance or interpretation of the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To report a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) followed by massive unilateral uveal proliferation., Methods: Retrospective case report., Results: A 47-year-old female with history of metastatic ovarian carcinoma initially presented with bilateral vision loss and multifocal red patches on posterior poles consistent with BDUMP. Five years later, she presented with bilateral neovascular glaucoma and unilateral iris and ciliary body mass concerning for malignancy. Enucleation revealed diffuse uveal growth involving almost the entirety of the uveal tract., Conclusions: BDUMP can rarely be associated with uveal proliferation. Routine examinations are recommended to monitor for any changes concerning malignancy.

Context: The global prevalence of type 2 diabetes mellitus (T2DM) has increased significantly in recent decades. Despite numerous studies and systematic reviews, there is a gap in comprehensive and up-to-date evaluations in this rapidly evolving field., Objective: This review provides a comprehensive and current overview of the efficacy of Traditional Chinese Medicine (TCM) in treating T2DM., Methods: A systematic review was conducted using PubMed, Web of Science, Wanfang Data, CNKI, and Medline databases, with a search timeframe extending up to November 2023. The search strategy involved a combination of subject terms and free words in English, including 'Diabetes,' 'Traditional Chinese Medicine,' 'TCM,' 'Hypoglycemic Effect,' 'Clinical Trial,' and 'Randomized Controlled Trial.' The studies were rigorously screened by two investigators, with a third investigator reviewing and approving the final selection based on inclusion and exclusion criteria., Results: A total of 108 relevant papers were systematically reviewed. The findings suggest that TCMs not only demonstrate clinical efficacy comparable to existing Western medications in managing hypoglycemia but also offer fewer adverse effects and a multitarget therapeutic approach. Five main biological mechanisms through which TCM treats diabetes were identified: improving glucose transport and utilization, improving glycogen metabolism, promoting GLP-1 release, protecting pancreatic islets from damage, and improving intestinal flora., Conclusions: TCM has demonstrated significant protective effects against diabetes and presents a viable option for the prevention and treatment of T2DM. These findings support the further exploration and integration of TCM into broader diabetes management strategies.

Background: To clarify the psychological experience and coping strategies in patients with acute pancreatitis in pregnancy (APIP) and propose interventional measures to improve pregnancy outcomes in these women. With an increasing trend of pregnant women in advanced ages and multiparous women, the incidence of APIP has significantly increased. Pregnancy accompanied by concurrent pancreatitis may subject these women to notable psychological stress, which is a factor that has been infrequently reported in previous studies., Methods: APIP patients were interviewed from December 2020 to June 2021. Data were collected through semi-structured interviews based on an outline, including six questions. The interviews were recorded and analyzed using qualitative content analysis until data saturation was reached., Results: Ten APIP patients were interviewed and four themes were identified, including excessive psychological burden, uncomfortable experience, urgent requirement for adequate medical resources, and importance of social support., Conclusion: Patients with APIP suffer from significant psychological stress due to their medical conditions and management. They desired adequate medical resources and social support. The local health department, hospital administrators, and medical staff should understand the psychological requirements and provide adequate healthcare and education that are easily accessible to these APIP patients. In addition, family support should also be encouraged to promote APIP patients' recovery.

The inhibition of amino acids on the formation of protein-bound HAs was assessed in both model systems and roast beef patties, and the synergism between these amino acids was also investigated. The amino acids can promote the formation of protein-bound HAs at low addition amount, and the total content of protein-bound HAs increased from 444.05 ± 4.98 ng/g of the control group to 517.36 ± 16.51 ng/g when 0.05 % cysteine was added. Amino acid combinations exhibited stable inhibitory effects, with the maximum inhibitory rate of 64 % in the treatment with histidine-proline combination (1:4). The synergistic inhibition may be caused by simultaneously scavenging intermediates and competing for the binding sites of muscle proteins, and the reaction with protein-bound HAs to form adduct can serve as supporting factors to co-mitigate the promotion in protein-bound HAs from increased protein solubility. These findings proposed the potential mitigation strategies against protein-bound HAs formation., 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.)

Context: Diabetic retinopathy (DR) is one of the leading causes of vision impairment and blindness among diabetic patients globally. Despite advancements in conventional treatments, the quest for more holistic approaches and fewer side effects persists. Traditional Chinese medicine (TCM) has been used for centuries in managing various diseases, including diabetes and its complications., Objective: This review evaluated the efficacy and underlying mechanisms of TCM in the management of DR, providing information on its potential integration with conventional treatment methods., Methods: A comprehensive literature review was conducted using PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI) with the search terms 'traditional Chinese medicine', 'diabetic retinopathy', 'clinical efficacies' and their combinations. Studies published before 2023 without language restriction were included, focusing on clinical trials and observational studies that assessed the effectiveness of TCM in DR treatment., Results: The review synthesized evidence of empirical traditional Chinese formulas, traditional Chinese patent medicines, and isolated phytochemicals on DR treatment. The key mechanisms identified included the reduction of oxidative stress, inflammation, and neovascularization, as well as the improvement in neurovascular functionality and integrity of the retinal blood barrier., Conclusions: TCM shows promising potential to manage DR. More large-scale, randomized controlled trials are recommended to validate these findings and facilitate the integration of TCM into mainstream DR treatment protocols.

Objectives: This study investigated variations in Medicare payments for Alzheimer's disease and related dementia (ADRD) by race, ethnicity, and neighborhood social vulnerability, together with cost variations by beneficiaries' enrollment in Accountable Care Organizations (ACOs)., Methods: We used merged datasets of longitudinal Medicare Beneficiary Summary File (2016-2020), the Social Vulnerability Index (SVI), and the Medicare Shared Savings Program (MSSP) ACO to measure beneficiary-level ACO enrollment at the diagnosis year of ADRD. We analyzed Medicare payments for patients newly diagnosed with ADRD for the year preceding the diagnosis and for the subsequent 3 years. The dataset included 742,175 Medicare fee-for-service (FFS) beneficiaries aged 65 and older with a new diagnosis of ADRD in 2017 who remained in the Medicare FFS plan from 2016 to 2020., Results: Among those newly diagnosed, Black and Hispanic patients encountered higher total costs compared to White patients, and ADRD patients living in the most vulnerable areas experienced the highest total costs compared to patients living in other regions. These cost differences persisted over 3 years postdiagnosis. Patients enrolled in ACOs incurred lower costs across all racial and ethnic groups and SVI areas. For ADRD patients living in the areas with the highest vulnerability, the cost differences by ACO enrollment of the total Medicare costs ranged from $4,403.1 to $6,922.7, and beneficiaries' savings ranged from $114.5 to $726.6 over three years post-ADRD diagnosis by patient's race and ethnicity., Conclusions: Black and Hispanic ADRD patients and ADRD patients living in areas with higher social vulnerability would gain more from ACO enrollment compared to their counterparts., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cerebral ischemia-reperfusion injury produces excessive reactive oxygen and nitrogen species, including superoxide, nitric oxide, and peroxynitrite (ONOO - ). We recently developed a new ONOO - -triggered metal-free carbon monoxide donor (PCOD585), exhibiting a notable neuroprotective outcome on the rat middle cerebral artery occlusion model and rendering an exciting intervention opportunity toward ischemia-induced brain injuries. However, its therapeutic mechanism still needs to be addressed. In the pharmacological study, we found PCOD585 inhibited neuronal Bcl2/Bax/caspase-3 apoptosis pathway in the peri-infarcted area of stroke by scavenging ONOO - . ONOO - scavenging further led to decreased Acyl-CoA synthetase long-chain family member 4 and increased glutathione peroxidase 4, to minimize lipoperoxidation. Additionally, the carbon monoxide release upon the ONOO - reaction with PCOD585 further inhibited the neuronal Iron-dependent ferroptosis associated with ischemia-reperfusion. Such a synergistic neuroprotective mechanism of PCOD585 yields as potent a neuroprotective effect as Edaravone. Additionally, PCOD585 penetrates the blood-brain barrier and reduces the degradation of zonula occludens-1 by inhibiting matrix metalloproteinase-9, thereby protecting the integrity of the blood-brain barrier. Our study provides a new perspective for developing multi-functional compounds to treat ischemic stroke., Competing Interests: Declarations. Ethics Approval: The animal experiment was conducted by the national and institutional guidelines on ethics and biosafety, and the protocol was approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University (License ID: 201907W079). Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Renal fibrosis contributes to chronic renal failure and a decline in the quality of life. Bushen Huoxue (BSHX) formula is a Traditional Chinese Medicine used to treat chronic renal failure. However, its mechanisms of action remain unclear., Methods and Results: In this study, a rat model of renal fibrosis was constructed by 5/6 nephrectomy in vivo , and histopathological changes were analyzed using hematoxylin-eosin and Masson's trichrome staining. Angiotensin II (Ang II) was used to establish an in vitro renal fibrosis cell model in vitro . Pyroptosis was measured using flow cytometry. Related markers of fibrosis and NOD-like receptor protein 3 (NLRP3) inflammasome activation were measured using western blotting and enzyme-linked immunosorbent assay. Treatment with BSHX (0.25, 0.5, and 1 g/kg) significantly inhibited renal fibrosis and damage in 5/6 nephrectomized rats and simultaneously reduced oxidative stress and NLRP3 inflammasome activation. Similarly, BSHX treatment reduced the levels of hydroxyproline, transforming growth factor-β, matrix metalloproteinase 2, and matrix metalloproteinase 9 and inactivated the Smad2/3 signaling pathway in Ang II-treated HK-2 cells. Our data also showed that treatment with BSHX reduced NLRP3 inflammasome activation and pyroptosis in Ang II-treated HK-2 cells. Moreover, fibrosis and pyroptosis in HK-2 cells induced by NLRP3 overexpression were reduced by treatment with BSHX., Conclusions: BSHX significantly reduced renal fibrosis and pyroptosis, and its mechanism was mainly associated with the inhibition of reactive oxygen species (ROS)/NLRP3-mediated inflammasome activation.

In this study, seventeen isobavachalcone (IBC) derivatives (1-17) were synthesised, and evaluated for their cytotoxic activity against three human lung cancer cell lines. Among these derivatives, compound 16 displayed the most potent cytotoxic activity against H1975 and A549 cells, with IC50 values of 4.35 and 14.21 μM, respectively. Compared with IBC, compound 16 exhibited up to 4.11-fold enhancement of cytotoxic activity on human non-small cell lung cancer H1975 cells. In addition, we found that compound 16 suppressed H1975 cells via inducing apoptosis and necroptosis. The initial mechanism of compound 16 induced cell death in H1975 cells involves the increasing of Bax/Bcl-2 ratio and Cyt C protein level, down-regulating of Akt protein level, and cleaving caspase-9 and -3 induced apoptosis; the up-regulation of RIP3, p-RIP3, MLKL, and p-MLKL levels induced necroptosis. Moreover, compound 16 also caused mitochondrial dysfunction, thereby decreasing cellular ATP levels, and resulting in excessive reactive oxygen species (ROS) accumulation.

Objectives: Cognitive-behavioral stress management (CBSM) is an effective psychological intervention to relieve psychological and symptomatic distress. This study aimed to investigate the effect of CBSM in anxiety, depression, and post-traumatic stress disorder (PTSD) in parents of pediatric acute myeloid leukemia (AML) patients., Methods: Totally, 56 pediatric AML patients and 100 parents were randomized into the CBSM group (28 patients and 49 parents) and the normal control (NC) group (28 patients and 51 parents) to receive corresponding interventions for 10 weeks. The questionnaire scores were assessed at month M0, M1, M3, and M6., Results: In parents of pediatric AML patients, self-rating anxiety scale score at M1 ( p  = 0.034), M3 ( p  = 0.010), and M6 ( p  = 0.003), as well as anxiety at M3 ( p  = 0.036) and M6 ( p  = 0.012) were decreased in the CBSM group versus the NC group. Self-rating depression scale score at M3 ( p  = 0.022) and M6 ( p  = 0.002), as well as depression at M6 ( p  = 0.019) were declined in the CBSM group versus the NC group. Symptom checklist-90 (a psychotic status questionnaire) score at M3 ( p  = 0.031) and M6 ( p  = 0.019) were declined in the CBSM group versus the NC group. Regarding PTSD, the impact of the events scale-revised score at M3 ( p  = 0.044) and M6 ( p  = 0.010) were decreased in the CBSM group versus the NC group. By subgroup analyses CBSM (versus NC) improved all outcomes in parents with anxiety at M0 and depression at M0 (all p  < 0.050), but could not affect the outcomes in parents without anxiety or depression at M0 (all p  > 0.050)., Conclusion: CBSM reduces anxiety, depression, and PTSD in parents of pediatric AML patients.

AUXIN/INDOLE-3-ACETIC ACIDs are transcriptional repressors for auxin signalling. Aux/IAAs of Arabidopsis thaliana display some functional redundancy. The IAA3/SHY2 clade (IAA1, IAA2, IAA3 and IAA4) show strong sequence similarity, but no higher-order mutants have been reported. Here, through CRISPR/Cas9 genome editing, we generated loss-of-function iaa1/2/3/4 mutants. The quadruple mutants only exhibited a weak phenotype. Thus, we additionally knocked out IAA7/AXR2 and IAA16, which are coexpressed with IAA1/2/3/4. Remarkably, under white light control conditions, the iaa1/2/3/4/7/16 mutants exhibited a shade avoidance-like phenotype with over-elongated hypocotyls and petioles and hyponastic leaves. The sextuple mutants were highly sensitive to low light intensity, and the hypocotyl cells of the mutants were excessively elongated. Transcriptome profiling and qRT-PCR analyses revealed that the sextuple mutation upregulated IAA19/MSG2 and IAA29, two shared shade/auxin signalling targets. Besides, genes encoding cell wall-remodelling proteins and shade-responsive transcription regulators were upregulated. Using dual-luciferase reporter assays, we verified that IAA2/IAA7 targeted the promoters of cell wall-remodelling genes to inhibit their transcription. Our work indicates that the IAA1/2/3/4/7/16 gene set is required for the optimal integration of auxin and shade signalling. The mutants generated here should be valuable for exploring the complex interactions among signal sensors, transcription activators and transcription repressors during hormone/environmental responses., (© 2024 John Wiley & Sons Ltd.)

Drug transmission through the blood-brain barrier (BBB) is considered an arduous challenge for brain injury treatment following the return of spontaneous circulation after cardiac arrest (CA-ROSC). Inspired by the propensity of melanoma metastasis to the brain, B16F10 cell membranes are camouflaged on 2-methoxyestradiol (2ME2)-loaded reactive oxygen species (ROS)-triggered "Padlock" nanoparticles that are constructed by phenylboronic acid pinacol esters conjugated D-a-tocopheryl polyethylene glycol succinate (TPGS-PBAP). The biomimetic nanoparticles (BM@TP/2ME2) can be internalized, mainly mediated by the mutual recognition and interaction between CD44v6 expressed on B16F10 cell membranes and hyaluronic acid on cerebral vascular endothelial cells, and they responsively release 2ME2 by the oxidative stress microenvironment. Notably, BM@TP/2ME2 can scavenge excessive ROS to reestablish redox balance, reverse neuroinflammation, and restore autophagic flux in damaged neurons, eventually exerting a remarkable neuroprotective effect after CA-ROSC in vitro and in vivo. This biomimetic drug delivery system is a novel and promising strategy for the treatment of cerebral ischemia-reperfusion injury after CA-ROSC., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To explore the associations and gender differences between health anxiety, eHealth literacy and self-reported health in Chinese university students., Methods: 1,205 university students aged 18-22 years were voluntarily recruited to respond to an online self-report questionnaire., Results: The severity level of health anxiety among university students was ranked as lifestyle anxiety, psychological anxiety, appearance anxiety, physical anxiety. There were significant gender differences in appearance anxiety, and yet no in eHealth literacy of university students. eHealth literacy was positively associated with self-reported health; health anxiety was negatively associated with self-reported health. Female's eHealth literacy, lifestyle, psychological and physical anxiety, and male's eHealth literacy, appearance anxiety significantly impacted on their self-reported health., Conclusion: The lower eHealth literacy or the more health anxiety, the worse their self-reported health. The findings underscored the importance for university students to improve eHealth literacy and reduce health anxiety. Appropriate interventions with gender differences were urgently needed.

Objective: To summarize the characteristics and risk factors for infection in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)., Methods: PubMed, Embase, and Cochrane Library databases were searched for relevant articles from database inception to November 2023. The prevalence, odds ratio (OR), and mean difference (MD) with 95 % confidence intervals (CIs) were pooled using a random-effects model. Sensitivity and subgroup analysis were also performed., Results: Forty-one studies with 5343 patients with AAV were included, of whom 2890 patients experienced an infection. The pooled prevalence was 54.6 % (95 % CI, 48.4 % to 61.1 %) for all infections and 35.8 % (95 % CI, 31.0 % to 40.8 %) for severe infections; and prevalence of Pneumocystis jirovecii pneumonia, aspergillosis, candidiasis, cryptococcosis, herpes zoster, cytomegalovirus, and specific bacterial infections were pooled. The respiratory system was the most common infection site, followed by blood, urinary tract, skin and soft tissue, and digestive infections. Risk factors for infection included older age, end-stage renal disease, dialysis, diabetes, smoking, kidney and lung involvement, leukopenia; higher Birmingham Vasculitis Activity Score, and serum creatinine and C-reactive protein levels; and lower hemoglobin levels, and platelet and CD4 counts. In addition, use of cyclophosphamide, steroid pulse therapy, plasma exchange, and higher initial glucocorticoid dose were associated with significantly increased risk of infection., Conclusion: In patients with AAV, therapy should take risk factors for infection into account. Risk factors should be modified wherever possible. Physicians should be familiar with the common infection sites and pathogens, and consider empiric therapy covering common pathogens for life-threatening infections., 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. Published by Elsevier B.V.)

Indium phosphide (InP) is a representative of environmentally friendly quantum dots (QDs), and quantum dot light-emitting diodes (QLEDs) based on InP QDs are prime candidates for next-generation display applications. However, there are numerous nonradiative sites on the surface of InP QDs, which compromise the operational stability of QLEDs. Herein, we employed cysteamine (CTA) molecules for post-treatment of QD films, effectively passivating surface defects and nonradiative sites, thereby enhancing stability. This treatment enabled a long T 95 lifetime of over 1,200 h at an initial luminance of 1,000 cd m -2 . Additionally, CTA-treated QDs induced the formation of an interface dipole, elevating the energy levels of QDs and reducing the injection barrier for holes. Moreover, the dipole moment at the interface hindered electron injection, achieving a more balanced carrier injection in the device. Consequently, we achieved a peak external quantum efficiency (EQE) of 21.21%.

Background: Axial spondyloarthritis (ax-SpA) is an autoinflammatory disease affecting multiple organs. While emphasizing the treatment of chronic diseases, it has been found that the prevalence of mental disorders and insomnia in patients is also increasing. We investigated mood status, sleep quality and the health-related quality of life (HRQoL) in these patients., Methods: A total of 94 pairs ax-SpA patients and age- and sex-matched healthy controls were included in this cross-sectional study. Demographic and clinical data were collected. We assessed the disease activity by the Ankylosing Spondylitis Disease Activity Score, including C-reactive protein (ASDAS-CRP), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI). The Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI) and the Medical Outcomes Survey Sheet Form-36 (SF-36) were used to evaluate mood status and quality of sleep and life, respectively. We evaluated the factors related to anxiety and depression scores, sleep disturbance scores and quality of life scores, and the predictors of anxiety, depression and sleep disturbance were analyzed., Results: Forty-five active patients and forty-nine relieved patients were enrolled. We found that the median HADS anxiety (HADS-A), depression (HADS-D) subscale scores and PSQI score were significantly higher in active ax-SpA than in inactive patients, and were significantly higher than those in controls (HADS-A 9 vs. 5 vs. 3, p < 0.001; HADS-D 8 vs. 5 vs. 3, p < 0.001; PSQI 10 vs. 6 vs. 3, p < 0.001). Moreover, the HADS-A scores were positively correlated to positive HLA-B27 (p = 0.042), pain (p = 0.002) and the BASFI score (p = 0.012), HADS-D scores were positively correlate to disease course (p < 0.001) and PSQI scores were significantly positively correlated to the BASFI score (p = 0.009). Logistic regression analysis showed that BASFI was a risk factor for anxiety, age was a protective factor for depression and disease course was a risk factor for depression. The optimal cut-off value of BASFI in predicting anxiety was 1.55 with an area under the curve value of 0.8488 (p < 0.001), and the optimal cut-off value of age and the course of the disease in predicting depression was 50.5 years old with an area under the curve value of 0.62 (p = 0.0482) and 54 months with an area under the curve value of 0.7988 (p < 0.001). In addition, disease activity was negatively correlated with SF-36 dimensions, and anxiety, depression and sleep disturbance in ax-SpA patients also had significant negative effects on HRQoL (p < 0.05)., Conclusions: Patients with active ax-SpA tend to be more anxious, depressed and sleep disturbed, and have worse HRQoL than patients in remission. Patients with ax-SpA are more likely to be anxious with worse spinal function, more likely to be depressed with younger age and longer course of disease. Therefore, the assessment of mental health, sleep and HRQoL should also be included in the long-term management of patients with ax-SpA. Key Points • Active ax-SpA patients tend to have more anxiety, depression, sleep disturbances and worse HRQoL compared with patients in remission • The optimal cut-off value of BASFI in predicting anxiety was 1.55, the age and the course of the disease in predicting depression was 50.5 years old and 54 months., Competing Interests: Declarations. Ethics approval and consent to participate: The ethics committee at institution approved the study and was carried out in line with the Principles of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent for participation in the survey and the use of data for publication. Consent for publication: All authors approve of the manuscript and have provided consent of authorship. Disclosures: None., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

The damnification of mitochondrion is often considered to be an important culprit of inflammatory bowel disease (IBD), however, there are fewer reports of mechanisms of mitochondria-mediated IBD treatment. Therefore, we first proposed to reboot mitochondrial energy metabolism to treat IBD by capturing the double-sided factor of ROS and creatine (Cr)-assisted energy adjustment. Herein, an oral Cr-modified selenium-based hyaluronic acid (HA) nanogel (HA Se -Cr nanogel) was fabricated for treatment of IBD, through ROS elimination and energy metabolism upgradation. More concretely, due to IBD lesion-specific positive charge and the high expression of CD44, HA Se -Cr nanogel exhibited dual targeted inflammatory bio-functions, and ROS-driven degradation properties in high-yield ROS levels in inflammation areas. As expected, multifunctional HA Se -Cr nanogel could effectively ameliorate IBD-related symptoms, such as mitochondrial biological function restoration, inhibition of M1-like macrophage polarization, gut mucosal reconstruction, microbial ecological repair, etc., thus excellently treating IBD. Overall, the proposed strategy underlined that the great potentiality of HA Se -Cr nanogel by restarting mitochondrial metabolic energy in colitis lesions, providing new a pavement of mitochondrion-mediated colitis treatment in clinical applications., Competing Interests: Declarations. Ethics approval and consent to participate: All animal care and experimental protocols comply with the relevant laws, regulations and standards concerning animal welfare ethics. This project has been supervised and approved by Laboratory Animal Welfare and Ethics Committee of Shanghai Jiaotong University (ICCUC NO. 2020-09-XLM-03). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: The transparency of the cornea is determined by the extracellular matrix, which is secreted by corneal stromal keratocytes (CSKs). Human-induced pluripotent stem cell (hiPSC)-derived keratocytes (hiPSC-CSKs) can be used in cell-based therapy for treating corneal blindness. Our goal was to develop an effective small molecule-based technique for differentiating hiPSCs into keratocytes., Methods and Analysis: hiPSCs were cultured in chemically defined medium, and embryoid bodies (EBs) were generated; these EBs were induced into CSKs using keratocyte-differentiated medium. The expression of keratocyte-specific markers was assessed using quantitative RT-PCR, immunostaining and Western blotting., Results: We found that the expression of genes encoding keratocyte markers, including aldehyde dehydrogenase 1 family member A1 (ALDH1A1), lumican and keratocan, was upregulated. Immunostaining showed positive staining for ALDH1A1 and keratocan in the hiPSC-CSK samples. Similarly, western blot analysis indicated that ALDH1A1 and keratocan expression levels were significantly greater in the hiPSC-CSKs than in the control cells. In addition, hiPSC-CSKs were not transformed into fibroblasts or myofibroblasts., Conclusion: We established an innovative and effective method to generate CSKs via the EB-based differentiation of hiPSCs, which might be employed for cell-based therapy of corneal stromal opacities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We conducted a study on radiation exposure in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) treated with [ 177 Lu]Lu-DOTA-TATE in China for the first time, aiming to provide guidance and reference for radiation protection in this regard. A total of 30 GEP-NENs patients who received [ 177 Lu]Lu-DOTA-TATE therapy were recruited in the study. We measured the external dose rate (EDR) values of each patient during the injection and 0-6 h post-administration period, as well as the radiation dose (RD) values to healthcare nurses and the surrounding environment. We performed a double exponential curve fitting and estimated the RD to the public from patients discharged at different times after [ 177 Lu]Lu-DOTA-TATE therapy., Results: Among the 30 patients, 27 patients completed 4 cycles of [ 177 Lu]Lu-DOTA-TATE treatments, the estimated RD to the public indicated that for adult family members, children above 10 years old, children aged 3-10 and coworkers of the patients, patients could begin daily contact at least 24 h, 48 h, 144 h and 192 h after injection to ensure that the total RD values after four treatments not exceed the limit. During the hospitalization of patients receiving [ 177 Lu]Lu-DOTA-TATE, the cumulative dose received by the administering nurses and to the ward environment were both well below the national RD limits., Conclusions: This study conducted a fitting analysis of the decay pattern of EDR values in GEP-NENs patients undergoing [ 177 Lu]Lu-DOTA-TATE therapy, in order to establish guidelines for patient discharge timing and provide recommendations for radiation protection for the general public after patient discharge. Trial registration A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With GEP-NETs, NCT05459844. https://clinicaltrials.gov/study/NCT05459844?cond=NCT05459844&rank=1 . Registered 5 July 2022., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of FUSCC (Approval No. 2210262-2). All patients provided written informed consent to participate in the study. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent for publication: Written informed consent for publication was obtained from all study participant. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

DNA is considered as a prospective candidate for the next-generation data storage medium, due to its high coding density, long cold-storage lifespan, and low energy consumption. Despite these advantages, challenges remain in achieving high-fidelity, fully integrated, and cost-efficient DNA storage system. In this study, a homemade digital microfluidics-based compact DNA data storing pipeline is orchestrated to complete the entire process from synthesis to sequencing. The synthetic half employs phosphoramidite chemistry on 200-nm magnetic beads, where the dimethyltrityl protecting group is removed by droplet manipulation of trichloroacetic acid. The sequencing counterpart relies on pyrophosphate releasing originated from polymerase-catalyzed primer extension, which leads to photon-countable chemiluminescence signal in 2.5-μL drops of trienzyme cascading reactions. Further resequencing plus plurality voting can improve the nucleobase accuracy beyond 95%. As a proof-of-concept trial, semantic information is saved in DNA via the Huffman coding and Reed-Solomon error-correction, and then robustly retrieved from this streamlined platform. As a result, it took a total of 6.5 h to writing and reading 8.3 bytes of data, equal to a storaging speed of 48 min/byte, much quicker than the previously reported. This bead-based miniaturized device promises an unattended protocol for achieving high-throughput, full-packaged, and above all, neatly precision DNA storage., (© 2024 Wiley‐VCH GmbH.)

Objective: To compare the diagnostic value of [ 18 F]AlF-LNC1007, [ 18 F]FDG, and [ 18 F]AlF-NOTA-FAPI-04 PET/CT in breast cancer. Methods: 33 patients with highly suspected or already diagnosed but untreated breast cancer were enrolled in the study and underwent [ 18 F]AlF-LNC1007 (30 patients), [ 18 F]FDG (22 patients), and [ 18 F]AlF-NOTA-FAPI-04 (8 patients) PET/CT. Quantitative measurements included the SUV max and tumor-to-background ratio (TBR) for all lesions and background tissues. The Chi-square test was used for intergroup diagnostic efficacy, and the Wilcoxon test was used for intergroup SUV max or TBR. Diagnostic efficacy for lymph node metastasis was evaluated using receiver operating characteristic (ROC) analysis. Results: Compared to [ 18 F]FDG, [ 18 F]AlF-LNC1007 had a higher positive predictive value (100% vs 91%, P = 0.0004) in lymph node metastases (42 vs 46) and higher sensitivity (100 vs 76%, P = 0.0003) in bone metastases (33 vs 25) but lower sensitivity (93 vs 100%, P = 0.001) in liver metastases. Apart from liver metastases, [ 18 F]AlF-LNC1007 PET/CT had higher SUV max in primary tumor and other metastases, with no statistical difference in TBR. Compared to [ 18 F]AlF-NOTA-FAPI-04 PET/CT, [ 18 F]AlF-LNC1007 had less false-positive and a higher positive predictive value in bone metastases (99 vs 95%, P = 0.0003) but had lower SUV max ( P < 0.01) in all primary and metastases lesions. The TBR difference between [ 18 F]AlF-LNC1007 and [ 18 F]AlF-NOTA-FAPI-04 was statistically significant only in bone metastases (5.97 vs 5.02, P = 0.001). The comparison of lymph node detection efficacy between [ 18 F]AlF-LNC1007 and [ 18 F]FDG PET/CT showed significant differences in SUV max cutoff values for diagnosing lymph node metastases (2.62 vs 3.90), sensitivity (95.2% vs 66.67), and specificity (100% vs 85.00) (all P < 0.001). Conclusion: [ 18 F]AlF-LNC1007 demonstrated superior efficacy compared to [ 18 F]FDG and [ 18 F]AlF-NOTA-FAPI-04 and higher uptake than [ 18 F]FDG in primary tumor, lymph node and bone metastases, and higher TBR than [ 18 F]AlF-NOTA-FAPI-04, especially in bone metastases. [ 18 F]AlF-LNC1007 also showed high specificity in differentiating inflammatory and metastatic lymph nodes.

Background: The COVID-19 pandemic has had a profound impact on global mental health, particularly affecting vulnerable groups such as pregnant women. Post-traumatic stress disorder (PTSD) in this population may potentially hinder infant physical development, underscoring the necessity for specific interventions. This study seeks to explore the prevalence of PTSD among pregnant women during the pandemic and its implications for infant physical development, thereby providing evidence to mitigate the adverse effects of the pandemic on maternal and child health., Methods: A prospective cohort study was carried out involving 450 pregnant women from December 2022 to February 2023. Data included demographic details, PTSD evaluation using the PTSD Checklist-Civilian version (PCL-C) scale, coping mechanisms, and infant growth indicators at three months postpartum. Statistical methods included descriptive statistics, univariate analysis, and multivariate analysis of covariance (ANCOVA) to control for confounding factors., Results: The study enrolled a total of 450 pregnant women. Following exclusions and follow-up attrition, 422 pregnant women were analyzed. There were 72 pregnant women with PTSD and 350 without PTSD. There was no statistically significant difference in birth weight between the two groups of participants. Three months after birth, infants of PTSD-positive mothers exhibited significantly lower weight percentiles at three months (P < 0.001), adjusted for birth weight, feeding method, and coping strategies. Multivariate analysis affirmed a 9.44-point reduction in weight percentile among infants in the PTSD-positive group (95% CI: 4.01-14.87, P = 0.001)., Conclusion: Pregnant women suffering from PTSD during the pandemic are at risk of giving birth to infants with impaired physical growth. These findings highlight the critical need for mental health support for pregnant women to foster optimal infant development and to guide public health policies and clinical practices., Competing Interests: Declarations. Ethics approval and consent to participate: This study adheres to the principles of the Declaration of Helsinki, and the study protocol were approved by the ethical review boards of China-Japan Friendship Hospital. Informed consent to participate was obtained from the parents or legal guardians of any participant under the age of 16. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objectives: Atypical thymic carcinoids (ATCs) are rare mediastinal malignancies that lack established treatment guidelines. Capecitabine and temozolomide (CapTem) has demonstrated significant efficacy in pancreatic neuroendocrine neoplasms (NENs), while its applicability and effectiveness in ATCs remain underexplored. This study seeks to investigate the efficacy, safety, and prognostic factors associated with CapTem in ATC patients., Design and Methods: Thirty-eight ATC patients treated with CapTem at our center were analyzed. We assessed the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse effects. We also examined patients' clinicopathological characteristics and their correlations with CapTem efficacy., Results: The cohort achieved a 15.8% ORR and 89.5% DCR, with a median PFS of 13.0 months. Multivariate analysis identified the platelet-to-lymphocyte ratio (PLR) as a significant independent prognostic factor for PFS, with a PLR ⩾ 235 associated with shorter PFS (7 months vs. undefined, p  = 0.0004). Age was an independent prognostic factor for OS, with patients over 50 years experiencing shorter OS (36 months vs. undefined, p  = 0.015). Safety analysis showed rare severe toxicities and no treatment-related fatalities., Conclusion: CapTem is an effective and well-tolerated treatment for ATC patients. Pretreatment PLR and age appear to be potential prognostic markers for CapTem therapy; however, these results warrant validation in larger patient cohorts., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

The precise asymmetric photochemical transformation of organic compounds containing multiple reactive sites presents significant progress in synthetic chemistry. Herein, we report an unprecedented visible-light-induced cascade transformation of tropolone cyclic triene derivatives by using chiral photoactive metal-organic cages (cPMOCs) as enzyme-mimicking multipocket photocatalysts. The cage-confined photocatalysis promotes three successive elementary steps, i.e ., enantioselective [2 + 2] photocycloaddition with chalcone, regio-, and diastereoselective α-ketol rearrangement, and a stereoselective 1,3-acyl shift, resulting in bicyclo[3.2.2]nonane skeleton with multichiral-centers unattainable by other methods. This study demonstrates how complex synthetic challenges of peri-, chemo-, and stereoselectivities could be subtly manipulated by cage-confined supramolecular catalysis for exploration of new reactivities.

Fruit appearance of eggplant is a key commercial trait, and the precise selection of new varieties with diverse aesthetics aligns with current breeding objectives. However, functional genomics research in eggplant remains underdeveloped. Here, we assembled the first telomere-to-telomere (T2T) eggplant genome, as well as chloroplast and mitochondrial genomes for the inbred line 'NO211'. The 1.06-Gb SmT2T genome is anchored to 12 chromosomes, nine of which are gap-free, totaling three gaps. This assembly harbors 36,505 genes and 64.08 % repetitive sequences, identifying 12 centromeres and 22 telomeres. Utilizing the SmT2T genome for bulked segregant analysis (BSA) and forward genetic approach with green-striped 'NO211' and pure green 'P13' as parents, the green stripe (GS) locus was finely mapped to a 9-Kb region on Chr4, containing a single gene, eggplant.04G07850 (GLK protein). Sequence analysis and qRT-PCR revealed that a single-base deletion in the exon of SmGLK in 'P13' led to premature stop codon, and SmGLK expression was significantly higher in the pericarp of 'NO211' compared to 'P13'. A marker was developed and validated in 36 germplasms, demonstrating co-segregation with green-striped rind trait. This study provides an ideal reference genome for eggplant functional genomics studies, facilitating mechanistic research on peel stripe formation and molecular-assisted selection for fruit appearance., 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 B.V. All rights reserved.)