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Allopregnanolone (AlloP) is an example of neuroactive steroids (NAS), which is a potent allosteric activator of the γ-aminobutyric acid A (GABA A ) receptor. The mechanisms underlying the biological activity of AlloP and other NAS are only partially understood. Here, we present intrinsically fluorescent analogs of AlloP (MQ-323) and its 3β-epimer, epi-allopregnanolone (E-AlloP) (YX-11), and show, by a combination of spectroscopic and computational studies, that these analogs mimic the membrane properties of AlloP and E-AlloP very well. We found stereospecific differences in the orientation and dynamics of the NAS as well as in their impact on membrane permeability. However, all NAS are unable to condense the lipid bilayer, in stark contrast to cholesterol. Using Förster resonance energy transfer (FRET) and electrophysiological measurements, we show that MQ-323 but not YX-11 binds at the intersubunit site of the ELICα 1 GABA A receptor and potentiates GABA-induced receptor currents. In aqueous solvents, YX-11 forms aggregates at much lower concentrations than MQ-323, and loading both analogs onto cyclodextrin allows for their uptake by human astrocytes, where they become enriched in lipid droplets (LDs), as shown by quantitative fluorescence microscopy. Trafficking of the NAS analogs is stereospecific, as uptake and lipid droplet targeting is more pronounced for YX-11 compared to MQ-323. In summary, we present novel minimally modified analogs of AlloP and E-AlloP, which enable us to reveal stereospecific membrane properties, allosteric receptor activation, and intracellular transport of these neurosteroids. Our fluorescence design strategy will be very useful for the analysis of other NAS in the future.

Background: The prediction of ischaemic stroke in patients with heart failure with reduced ejection fraction (HFrEF) but without atrial fibrillation (AF) remains challenging. Our aim was to evaluate the performance of machine learning (ML) in identifying the development of ischaemic stroke in this population., Methods: We performed a post-hoc analysis of the WARCEF trial, only including patients without a history of AF. We evaluated the performance of 9 ML models for identifying incident stroke using metrics including area under the curve (AUC) and decision curve analysis. The importance of each feature used in the model was ranked by SAPley Additive exPlanations (SHAP) values., Results: We included 2213 patients with HFrEF but without AF (mean age 58 ± 11 years; 80% male). Of these, 74 (3.3%) had an ischaemic stroke in sinus rhythm during a mean follow-up of 3.3 ± 1.8 years. Out of the 29 patient-demographics variables, 12 were selected for the ML training. Almost all ML models demonstrated high AUC values, outperforming the CHA 2 DS 2 -VASc score (AUC: 0.643, 95% confidence interval [CI]: 0.512-0.767). The Support Vector Machine (SVM) and XGBoost models achieved the highest AUCs, with 0.874 (95% CI: 0.769-0.959) and 0.873 (95% CI: 0.783-0.953), respectively. The SVM and LightGBM consistently provided significant net clinical benefits. Key features consistently identified across these models were creatinine clearance (CrCl), blood urea nitrogen (BUN) and warfarin use., Conclusions: Machine-learning models can be useful in identifying incident ischaemic strokes in patients with HFrEF but without AF. CrCl, BUN and warfarin use were the key features., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Objectives: To investigate how post-traumatic growth (PTG) and moral sensitivity influence service behaviour among healthcare workers (HCWs) in mainland China post-COVID-19, with a focus on the mediating role of moral sensitivity., Design: Cross- sectional survey design., Setting: This study was conducted in 27 provinces across mainland China, from 16 March to 2 April 2023., Participants: 1,193 HCWs, including 378 physicians and 815 nurses, were selected using convenience and snowball sampling methods., Methods: The survey included the Post-traumatic Growth Inventory-Chinese version (PTGI-C), the Moral Sensitivity Questionnaire-Revised Chinese Version (MSQ-R-CV) and a service behaviour scale. Structural equation modelling was employed to analyse the data, focusing on the associations between PTG, moral sensitivity, and service behaviours., Results: The study found significant associations between PTG and moral sensitivity (r=0.49, p<0.01), with both factors positively influencing HCWs' service behaviours. Specifically, PTG had a direct effect on service behaviours ( β =0.172, p<0.01) and an indirect effect through moral sensitivity ( β =0.333, p<0.01), with moral sensitivity mediating 65.8% of PTG's impact on service behaviours. The model explained 56.0% of the variance in service behaviours, indicating a substantial influence of these psychological factors on professional conduct., Conclusions: The findings highlight the significant role of PTG and moral sensitivity in shaping the service behaviours of HCWs in the aftermath of the COVID-19 pandemic. The study suggests that enhancing PTG and moral sensitivity through targeted interventions could improve HCWs' service delivery and resilience, emphasising the importance of incorporating psychological and ethical training into healthcare practices to prepare for future public health crises., 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.)

Objectives: Frailty is a heterogeneous syndrome with distinct patterns. This study aimed to identify frailty risk patterns and their predictive value for mortality in older adults., Design: Prospective longitudinal study., Setting and Participants: Data were obtained from a 2017 survey of 609 independently mobile adults aged 65 years and older in suburban Japan, focusing on those at risk for at least 1 frailty dimension., Methods: Frailty assessments were extracted from the Kihon checklist, and subgroups were identified using latent class analysis. Associations between frailty patterns and 3-year mortality were assessed using Kaplan-Meier survival analysis and Cox proportional hazards modeling., Results: Three frailty patterns were identified: "high risk of cognitive impairment" (76.0%), "moderate risk of cognitive, physical, and oral dysfunction" (14.3%), and "high risk of cognitive, physical, and functional decline" (9.7%). We recorded 52 deaths during a mean follow-up time of 25.7 months (standard deviation: 12.6) and a median follow-up time of 26.5 months. Kaplan-Meier analysis showed significant survival differences among the groups (log-rank: P < .001). Compared with the high risk of cognitive impairment group, the moderate risk of cognitive, physical, and oral dysfunction group had a 145% higher mortality risk (adjusted hazard ratio, 2.45; 95% confidence interval, 1.22-4.90), while the high risk of cognitive, physical, and functional decline group exhibited a 220% higher risk of mortality (adjusted hazard ratio, 3.20; 95% confidence interval, 1.53-6.70)., Conclusions and Implications: The findings reveal the heterogeneity of frailty among community-dwelling Japanese older adults, with a high prevalence of cognitive impairment risk. The subgroup with risk of cognitive, physical, and functional decline had the highest mortality risk, highlighting the need for multidimensional assessment and intervention., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC), a prevalent and deadly cancer, poses a significant challenge with current treatments due to limitations such as poor stability, off-target effects, and severe side effects. Extracellular vesicles (EVs), derived from tumor cells, have the remarkable ability to home back to their cells of origin and can serve as Trojan horses for drug delivery. CD44, a cell surface glycoprotein, promotes cancer stem cell-like properties and is linked to poor prognosis and resistance to chemotherapy in HCC. Therefore, targeting CD44-expressing HCC cells is of interest in the development of novel therapeutic strategies for the treatment of HCC. In this study, we developed tumor cell-derived EVs (TEVs) functionalized with hyaluronic acid (HA) to serve as natural carriers for the precise delivery of doxorubicin (Dox), which specifically targets HCC cells expressing CD44. Our results demonstrated that HA-engineered EVs (HA-EVs) significantly enhanced Dox accumulation within HCC cells. In a mouse model, HA-EVs effectively delivered Dox to tumors, suppressing their growth and progression while minimizing systemic toxicity. This study demonstrates the potential of HA-functionalized EVs as a novel and targeted therapeutic platform for HCC, offering a valuable strategy for improving drug delivery and patient outcomes. This study presents a promising strategy to advance targeted chemotherapy for HCC and address the challenges associated with conventional treatments. Engineered HA-functionalized EVs offer a tailored and efficient approach to increase drug delivery precision, underscoring their potential as a novel therapeutic platform in the realm of HCC 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. Published by Elsevier Inc.)

Chlorophenols (CPs) are widely used in industries such as petrochemicals, insecticides, pharmaceuticals, synthetic dyes and wood preservatives. However, owing to the improper discharge and disposal, they have become major contaminants that are ubiquitously distributed in water, soil, and sewage sediments, posing a significant threat to ecosystems and human health. Consequently, accurate, sensitive and effective pretreatment and analysis methods for CPs are urgently required and have been actively explored in recent years. This review encompasses the pretreatment and detection methods for CPs in environmental samples from 2010 to 2024. The pretreatment methods for CPs primarily include solid-phase extraction, liquid-liquid extraction, solid-phase microextraction, liquid-phase microextraction, and QuEChERS. These methods are evolving towards more effective and environmentally friendly technologies, such as the miniaturization and automation of equipment, the development of innovative materials (including graphene, molecularly imprinted polymers, layered double hydroxides, porous organic polymers, and porous carbon), and the use of green solvents like deep eutectic solvents. Detection methods emphasize liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, sensors, and capillary electrophoresis. Advances in chromatographic columns, novel ion sources, and high-resolution mass spectrometry have significantly improved detection performance. In addition, the pros and cons of diverse techniques, critical comments and future perspectives are elaborated., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Reduning injection (RDN) is a traditional chinese medicine injection widely used in clinical practice. In this study, qualitative and quantitative analysis of RDN were conducted by UPLC-Orbitrap MS/MS simultaneously. Totally 118 compounds were identified and 34 compounds were quantified in RDN. The method with completed method validation proved the high sensitivity and efficiency of the method and it was applied to quantify compounds in RDN. Multivariate statistical analysis method selected 11 key variables that affect the content consistency of RDN. 20 batches with high biological potency were screened by cox-2 enzyme activity assay. Spectrum-effect relationship analysis and multivariate statistical analysis showed that 7 batches were high-quality selected after comprehensive quality evaluation and 9 compounds were key indicators for screening it. This strategy including fingerprint, qualitative analysis and multiple-component quantification could be well applied to modern quality evaluation of RDN, which could be valuable for the further quality control of more other traditional Chinese medicines., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, Wei xiao,mengyu qian, liang cao, xialin chen, jingqiu gu,zhenzhong wang has patent pending to wei xiao，mengyu qian, liang cao, xialin chen, jingqiu gu, zhenzhong wang. 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 B.V. All rights reserved.)

Non-small cell lung cancer (NSCLC), although considered non-immunogenic, is often resistant to chemotherapy agents during the course of treatment in clinical patients. Melittin (C 131 H 229 N 39 O 31 , CAS: 20449-79-0), the major component of honey bee venom, is a promising anticancer drug. However, the mechanism employed by melittin to reverse chemotherapy resistance of NSCLC cells remains unknown. In this study, the Cell Counting Kit 8, ethynyl deoxyuridine assay, and other assays were utilized to elucidate the melittin effects upon cell proliferation. Proteomics, lung cancer (LC) tissue chip, and Western blot analysis were used to identify potential targets of melittin. A549/DDP cells were employed to investigate the melittin effects against cisplatin resistance. Also, an in vivo animal experiment was conducted to further clarify the regulatory function of melittin towards cisplatin resistance of A549/DDP cells. Results showed that melittin inhibited malignant progression of A549/DDP cells by down-regulation of pyruvate dehydrogenase kinase 3 (PDK3)-mediated aerobic glycolysis and inhibition of heat shock factor 1 (HSF1) expression. The therapeutic effect of melittin was increased by combination with KNK437 and impaired chemotherapy resistance regarding A549/DDP cells via reversing aerobic glycolysis. The in vivo experiments confirmed that melittin incremented A549/DDP cell cisplatin sensitivities. Collectively, the data suggested that melittin suppressed aerobic glycolysis by regulating HSF1/PDK3, which incremented cisplatin sensitivity of A549/DDP cells. It may provide a new treatment method for chemotherapy resistance in clinical NSCLC patients., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The endogenous neurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) are allosteric modulators of γ-aminobutyric acid type A (GABA A ) and N -methyl-d-aspartate (NMDA) type glutamate receptors. Analogues of these endogenous steroid sulfates can be either positive or negative allosteric modulators (PAMs or NAMs, respectively) of these receptors, but there is limited information about the steroid-protein binding interactions that mediate these effects and photoaffinity labeling reagents (PALs) of sulfated steroids have not been reported previously. The synthesis of a panel of ten sulfated steroid analogues containing a diazirine group, five of which also contain an alkyne group for click chemistry reactions, for use in photoaffinity labeling studies to identify binding sites for steroid sulfates that are either positive or negative allosteric modulators is reported. Electrophysiological measurements on cultured rat hippocampal neurons were made to determine the modes of allosteric modulation in comparison to those of PS on both receptors. PALs with the activity profile of PS (NMDA PAM, GABA A NAM) were identified. Unexpectedly, PALs with PAM activity at both receptors were also found. Photolabeling of both receptors by two of the PALs was performed to demonstrate their utility, and by inference those of the other PALs, for future studies to identify binding sites for endogenous steroid sulfates on both receptors., Competing Interests: CFZ is a member of the Scientific Advisory Board of Sage Therapeutics and has equity in the company. DFC has equity in Sage Therapeutics and receives income from a license agreement between Washington University in St. Louis and Sage Therapeutics. Sage Therapeutics was not involved in this study. The other authors have no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Transmissible gastroenteritis virus (TGEV) is a porcine intestinal pathogenic coronavirus that can cause acute intestinal diseases in pigs, especially in suckling piglets under two weeks of age, with a mortality rate of 100 %. Dendritic cells (DCs) are important antigen-presenting cells (APCs) that are essential for the initiation and modulation of immune responses in animals. In this study, we used monocyte-derived porcine DCs as an in vitro model of APCs to further study the pathogenic mechanism of TGEV. Our results demonstrated that TGEV successfully replicates in monocyte-derived porcine DCs, whereas UV-inactivated TGEV failed to infect these cells. Importantly, TGEV infection of DCs led to significant upregulation of swine leukocyte antigen II DR (SLA-DR), a key molecule in the major histocompatibility complex class II (MHC-II) family. We further demonstrated that the ORF3b nonstructural protein of TGEV significantly enhances SLA-DR expression at the transcriptional level in porcine DCs. This study provides new insights into the pathogenic mechanisms of TGEV., Competing Interests: Declarations competing interests The authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: The efficacy of immune checkpoint inhibitors (ICIs) in cancer patients taking anti-hypertensive drugs is still not well established., Objective: To elucidate the effect of anti-hypertensive drugs on the clinical outcome of cancer patients receiving immunotherapy., Design: A retrospective cohort study and meta-analysis., Method: We conducted a real-world retrospective study of cancer patients treated with immunotherapy at two tertiary centers between January 2019 and June 2023, with primary outcomes being overall survival (OS) and progression-free survival (PFS). In addition, we performed a meta-analysis to synthesize currently relevant clinical studies., Results: A retrospective clinical study of 336 patients from 2 centers suggested that the use of anti-hypertensive drugs was related to a preferable OS (hazard ratio (HR) = 0.55, 95% confidence interval (CI): 0.33-0.90) compared to non-users. For PFS, no significant correlation was detected (HR = 0.71, 95% CI: 0.49-1.03). Further analysis revealed that renin-angiotensin system inhibitor (RASi) and calcium channel blocker (CCB) have a synergistic effect with ICIs. In addition, subgroup analysis found that the benefits of RASi or CCB in combination with ICIs are greater in women or patients ⩾65 years of age. There was better disease control in lung cancer patients using RASi, and a significantly longer OS was observed in patients with gastrointestinal tumors taking CCB. Meta-analysis suggested that anti-hypertensive drugs were associated with improved OS, but only the combination of RASi and immunotherapy showed a synergistic effect. No significant correlation with OS was found for other anti-hypertensive drugs, and there was no overall positive effect on PFS., Conclusion: Our study found that use of anti-hypertensive drugs, particularly RASi or CCB, was associated with improved OS in patients undergoing immunotherapy. The synergistic effects of RASi or CCB with ICIs were more pronounced in females or elderly. RASi or CCB exhibited different benefits in various types of tumors. These findings provide valuable insights for treating cancer patients with hypertension., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Ethnopharmacological Relevance: Tianshu capsule (TSC) is a traditional Chinese medicine (TCM) preparation and has significant clinical effect on migraine. The composition characteristics of TSC formula are worth exploring for the treatment of migraine., Aim of the Study: Identify the compounds in vivo after oral administration of TSC, Gastrodin (GAS), ferulic acid, senkyunolide G and senkyunolide I in the blood of healthy and migraine rats were used as representative compounds for time-dependent processes investigation. And we focus on explaining the characteristics of TSC treatment on migraine from a pharmacokinetic perspective., Materials and Methods: In this study, Ultra-high performance liquid chromatography with Orbitrap tandem mass spectrometry (UPLC-Orbitrap-MS/MS) system were used to detect the compounds in rat plasma and brain after oral administration of TSC. A sensitive, selective and reliable ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQ-MS/MS) system method was established for the simultaneous quantitative analysis of multi-components and evaluate the pharmacokinetic behavior of four main compounds., Results: A total of 46 compounds were significantly identified in vivo of rat, including 35 compounds in plasma, 7 compounds only in brain and 4 compounds both in plasma and brain. The quantitative method has been confirmed to be feasible for multi-components content determination, pharmacokinetic parameters indicated that the four compounds absorbed into blood rapidly, and senkyunolide I also cross the blood-brain barrier (BBB) quickly into brain. GAS has relatively high concentrations in plasma, and the parameters AUC 0-t , CL z/F displayed significant differences between the normal and migraine rats. And the AUC 0-t and C max of GAS and ferulic acid exhibited dose-dependent way., Conclusions: we added compounds for the pharmacokinetic study of TSC, providing powerful help for clinical medication in the treatment of migraine., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

The clinical success of KRAS G12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRAS G12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRAS G12C -mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The Arf gene family is essential for crop growth and development by regulating vesicle transport. However, few studies exist on the role of Arfs in the growth and yield formation of Brassica napus. Here we provide an exhaustive account of the phylogeny and expression of the 66 Arfs in rapeseed. We found that the expansion of Arf gene family is mainly through whole genome duplication, and some genes are loss during the expansion process. Expression analysis revealed that the Arfs in group X, with the exception of BnaC02.ARFA1B, BnaC06.ARFA1A.2, and BnaA07.ARFA1A.2, exhibited high expression levels across various tissues of B. napus at different developmental stages. These results indicate that the Arfss in group X were important in influencing rapeseed growth and development. We have found that Arfs in B. napus may have a more complex regulatory mechanism due to homologous recombination and gene sub-functionalization. Haplotype analysis indicated that Arfs regulate B. napus yield formation. We found high expression of BnaC07.ARFA1A in all tissues, and its overexpression significantly increased rapeseed silique number and yield. The comprehensive analysis will further characterize the functions of Arfs in B. napus and enhance regulatory networks for yield formation in B. napus., 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 article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dopamine (DA) is the most abundant biogenic amine present in the insect central nervous system, and regulates multiple functions in physiology and behaviors through dopamine receptors (DARs). The small brown planthopper Laodelphax striatellus is an important agricultural pest and causes serious damage by transmitting diverse plant viruses, such as rice stripe virus (RSV). However, DARs have not yet been molecularly characterized in planthoppers, and their roles in virus infection and transmission remain largely unknown in insect vectors. In this study, we cloned four LsDARs (LsDOP1, LsDOP2, LsDOP3 and LsDopEcR) from L.striatellus. LsDARs share considerable sequence identity with their orthologous DARs, and cluster nicely with their corresponding receptor groups. The transcript levels of LsDARs varied in different developmental stages and adult tissues, with the highest expressions in the egg stage and in the brain. The expression levels of LsDARs were significantly higher in RSV-viruliferous L.striatellus. Knockdown of LsDOP2 and LsDOP3 significantly downregulated the expressions of viral genes of capsid protein (CP) and RNA3 segment (RNA3), while LsDOP1 knockdown upregulated their expressions. Silencing LsDopEcR upregulated and then downregulated CP and RNA3 expressions. Moreover, LsDOP2 and LsDOP3 knockdown significantly decreased the vertical transmission rates of RSV. Meanwhile, DA injection promoted RSV transmission and accumulation. We further demonstrated that silencing of LsDARs significantly altered the expressions of vitellogenin (LsVg) and Vg receptor (LsVgR). Furthermore, the reproduction performance of L.striatellus was reduced by LsDOP2 and LsDOP3 knockdown, but increased by LsDopEcR knockdown, and not affected by LsDOP1 silencing. These results provide critical information concerning the roles of DARs in virus transmission and reproduction in L.striatellus, and open the way for the development of innovative strategies for planthopper control., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inland lakes are crucial for processing, storing, and releasing carbon dioxide (CO 2 ), and they play a significant role in the global carbon cycle and climate change. Studies have shown that inland lakes are mostly supersaturated in CO 2 , making them significant sources to the atmosphere. However, estimating CO 2 fluxes from inland lakes is still challenging due to large variations in surface water CO 2 partial pressure (pCO 2 ). Submerged aquatic vegetation (SAV) is widely found in aquatic ecosystems, especially in shallow lakes. However, their role in lake-wide carbonate chemistry has not been thoroughly investigated. Accurately measuring air-water CO 2 exchange and understanding the environmental factors that control these fluxes in vegetated ecosystems are essential for reducing uncertainties in global CO 2 emission estimates. In this study, high-resolution (3-h interval) field measurements were made along the nearshore of eastern Lake Taihu during the SAV growing seasons to examine their effects on surface water pCO 2 and air-water exchange. Our results showed evident daily variations in water chemistry and air-water fluxes. Daytime air-water CO 2 exchange switched from sinks in summer to sources in autumn. The vegetation sites were observed to be strong CO 2 sources consistently at night. The density of aquatic vegetation was found to be positively correlated with the daily range of pCO 2 , highlighting their role in regulating surface water carbonate chemistry. Negative correlations were found between water depth and surface pCO 2 . These results highlight the importance of aquatic vegetation and daily variations in reducing uncertainties in carbon budgets of shallow aquatic systems., 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.)

Hakka Huangjiu, a traditional Chinese rice wine, boasts a rich history and is known for its immunomodulatory, antibacterial, anti-aging and anti-fatigue effects. However, there is limited research on the primary active components and molecular mechanism of the bioactivity of Hakka Huangjiu. To address this gap, this study assessed the structural characteristics, antioxidant, and immunomodulatory activities of the polysaccharide-1 of Guangdong Hakka Huangjiu (HP1). Structural analysis revealed that HP1 had a low molecular weight polysaccharide of 5550 Da, primarily consisting of glucose (93.2 %), with smaller amounts of xylose, mannuronic acid and galactose. Methylation and NMR analysis suggested that the main glycosidic linkages present in HP1 are α-D-Glcp-(1→, →4)-α-D-Glcp-(1 → and →6) -α-D-Glcp-(1→. Furthermore, HP1 exhibited dose-dependent DPPH·, ABTS + and OH· scavenging activity. HP1 exhibited significant protection of HepG2 cells from H 2 O 2 damage. Additionally, HP1 induced the release of NO, TNF-α, IL-6 and iNOS in RAW264.7 cells. HP1 treatment significantly increased mRNA expression of TNF-α, IL-6, iNOS, COX-2, IL-1β and TGF-β1. These results suggested that polysaccharides HP1 may have potential as a novel natural antioxidant and immunomodulatory product for use in nutraceuticals and functional foods., 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.)

Triazoles, due to their high bactericidal performance, have been widely used in the agricultural, clinical, and chemical industry. However, triazoles have been proven to cause endocrine-toxic and organ impairment in humans as a potentially toxic substance. Besides, because of the improper use and difficulty of degradation, triazoles pesticide residues left in the environment could pose a threat to the environment. Therefore, the rapid, reliable, accurate, and high-sensitivity triazoles analysis methods are significantly essential to effectively monitor their presence in various samples and safeguard human health. This review aims to summarize and update the progress of the pretreatment and analytical methods of triazole fungicides in environmental samples from 2012 to 2024. Common pretreatment methods used to extract and purify targets include simple steps (e.g., protein precipitation and coated blade spray), liquid-liquid extraction, solid-phase extraction, and various microextraction methods such as liquid-phase microextraction and solid-phase microextraction, among others. Detection methods mainly include liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, supercritical fluid chromatography, sensing methods, and capillary electrophoresis. In addition, we elaborate and compare the advantages and disadvantages of different pretreatment and analytical methods, and their development prospects are discussed., Competing Interests: Declaration of Competing Interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To explore the value of whole tumour- and subregion-based radiomics of contrast-enhanced mammography (CEM) in differentiating the HER2 expression status of breast cancers., Methods: 352 patients underwent preoperative CEM from two centres were consecutively enroled and divided into the training, internal validation, and external validation cohorts. The lesions were divided into HER2-positive and HER2-negative groups. Besides the radiological features, radiomics features capturing the whole tumour-based (wITH) and subregion-based intratumoral heterogeneity (sITH) were extracted from the craniocaudal view of CEM recombined images. The XGBoost classifier was applied to develop the radiological, sITH, and wITH models. A combined model was constructed by fusing the prediction results of the three models., Results: The mean age of the patients was 51.1 ± 10.7 years. Two radiological features, four wITH features, and three sITH features were selected to establish the models. The combined model significantly improved the AUC to 0.80 ± 0.03 (95% CI: 0.73-0.86), 0.79 ± 0.06 (95% CI: 0.67-0.90), and 0.79 ± 0.05 (95% CI: 0.69-0.89) in the training, internal validation, and external validation cohorts, respectively (All P < 0.05). The combined model showed good agreement between the predicted and observed probabilities and favourable net clinical benefit in the validation cohorts., Conclusions: Both whole tumour- and subregion-based ITH radiomics features of CEM exhibited potential for differentiating the HER2 expression status. Combining conventional radiological features and ITH features can improve the model's performance., Competing Interests: Competing interests The authors declare no competing interests. Ethical The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board and Ethics Committee of Fudan University Shanghai Cancer Centre and the Third Affiliated Hospital of Soochow University. Individual consent for this retrospective analysis was waived., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: Atherogenic index of plasma (AIP) is a newly identified as marker of lipid metabolism and glucose metabolism, showing significant predictive value in individuals with cardiovascular disease. This study aimed to explore the correlation between AIP and early neurological deterioration (END) in ischemic stroke patients after mechanical thrombectomy (MT)., Methods: Patients with anterior circulation large artery occlusive stroke who underwent MT were retrospectively enrolled from 2 stroke center in China. The AIP is a logarithmically transformed ratio of triglycerides to high-density lipoprotein cholesterol. END was defined as an increase of ≥ 4 point in National Institutes of Health Stroke Scale within 24 hours after surgery. Multivariable regression analysis and restricted cubic spline was utilized to determine the association of AIP index with risk of END., Results: Of 601 patients (mean age, 70.2 ± 12.1 years; 62.1 % of male) enrolled, 91 (15.1 %) experienced postoperative END. After adjustment for potential confounders, higher AIP levels were significantly associated with an increased risk of END after MT treatment (Per 1-standard deviation increase; odd ratio, 1.474; 95 % confidence interval, 1.162-1.869, P = 0.001). Similar results were confirmed when the AIP was analyzed as a categorical variable. Restricted cubic spline further demonstrated a linear relationship between AIP and risk of END (P = 0.001 for linearity)., Conclusions: The present study found that a higher AIP index were associated with END in acute ischemic stroke patients following MT treatment for emergent large vessel occlusion., Competing Interests: Declaration of competing interest All the authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: Neurosteroids are allosteric modulators of GABA A currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABA A receptor., Experimental Approach: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABA A R, a chimeric receptor containing transmembrane domains of the α 1 -GABA A receptor. Tryptophan mutagenesis was used to identify specific interactions., Key Results: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3β-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites., Conclusions and Implications: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABA A R were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Osteosarcoma is a malignant bone tumor characterized by high metastatic potential and recurrence rates after therapy. The small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB), core components of a spliceosome, exhibit up-regulation across several cancer types. However, the precise role of SNRPB in osteosarcoma progression remains poorly elucidated. Herein, SNRPB expression was explored in human osteosarcoma tissues and normal bone tissues by immunohistochemical staining, revealing a notable up-regulation of SNRPB in osteosarcoma, correlating with diminished survival rates. The in vitro loss-of-function experiments showed that SNRPB knockdown significantly suppressed the osteosarcoma cell proliferation and migration, as well as tubule formation of human umbilical vascular endothelial cells, while enhancing osteosarcoma cell apoptosis. Mechanistically, SNRPB promoted the transcription of ribonucleotide reductase subunit M2 via E2F transcription factor 1. Further rescue experiments indicated that ribonucleotide reductase subunit M2 was required for SNRPB-induced malignant behaviors in osteosarcoma. Additionally, the function of SNRPB in osteosarcoma cell growth and apoptosis was confirmed to be associated with ataxia-telangiectasia mutated (ATM) signaling pathway activation. In conclusion, these findings provide initial insights into the underlying mechanisms governing SNRPB-induced osteosarcoma progression, and we propose SNRPB as a novel therapeutic target in osteosarcoma management., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In order to assess the antibiotic resistance of Escherichia coli and its transmission risk in a rice-frog coculture system in Zhejiang Province, this study collected E . coli from isolated soil, field water, and frog feces from the rice-frog coculture systems in four different areas of Zhejiang Province. The collected isolates were identified by 16S rRNA sequencing, while their antibiotic-resistant phenotypes were determined by Kirby-Bauer (K-B) method. PCR was used to identify the antibiotic-resistant genotypes and integrons, while conjugative transfer experiments were used to assess resistance transmission characteristics. The results showed a high prevalence of antibiotic resistance in the 82 strains of E . coli tested, primarily against tetracycline, sulfisoxazole, amoxicillin, and erythromycin. Most of these strains exhibited multidrug resistance, with the Fuyang area demonstrating the highest resistance rate compared to the other three areas. Further PCR analysis identified the sul1 gene as the most frequently detected resistance gene (63.41%), followed by bla TEM , tetA , and tetB . Among the 16 antibiotic resistance genes (ARGs) detected, the Fuyang isolates consistencly exhibited higher detection rate of 9 ARGs in comparison to the other regions. Additionally, the integrase gene intI1 displayed the highest detection rate, with 14 strains (34.15%) of integrase-positive bacteria carrying gene cassettes. Four different gene cassette compositions were observed, with dfrA1-aadA1 and dfrA17-aadA5 being the most common combinations. Conjugative transfer experiments demonstrated successful transfer of gene cassettes in 4 out of 14 donor bacteria, with conjugation transfer frequencies ranging from 4.32×10 -5 to 7.13×10 -4 . These findings revealed the severity of resistance in the Fuyang area among the four regions. Integrons play a significant role in mediating the resistance to multiple antibiotics in E . coli , facilitating the potential spread of resistance gene cassettes between different bacteria. Overall, this study provides valuable insights into the resistance status and transmission characteristics of E . coli in the rice-frog coculture system in Zhejiang Province, providing a theoretical basis for ensuring the food safety of rice crops.

We propose a two-stage estimation procedure for a copula-based model with semi-competing risks data, where the non-terminal event is subject to dependent censoring by the terminal event, and both events are subject to independent censoring. With a copula-based model, the marginal survival functions of individual event times are specified by semiparametric transformation models, and the dependence between the bivariate event times is specified by a parametric copula function. For the estimation procedure, in the first stage, the parameters associated with the marginal of the terminal event are estimated using only the corresponding observed outcomes, and in the second stage, the marginal parameters for the non-terminal event time and the copula parameter are estimated together via maximizing a pseudo-likelihood function based on the joint distribution of the bivariate event times. We derived the asymptotic properties of the proposed estimator and provided an analytic variance estimator for inference. Through simulation studies, we showed that our approach leads to consistent estimates with less computational cost and more robustness than the one-stage procedure developed in Chen YH (Lifetime Data Anal 18:36-57, 2012), where all parameters were estimated simultaneously. In addition, our approach demonstrates more desirable finite-sample performances over another existing two-stage estimation method proposed in Zhu H et al., (Commu Statistics-Theory Methods 51(22):7830-7845, 2021) . An R package PMLE4SCR is developed to implement our proposed method., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metals are crucial for solar energy applications, but their highly reflective surfaces limit solar energy absorption. The difficulty in manufacturing an ideal light-absorbing structure limits the incorporation of anti-reflective characteristics in metals. In this study, a femtosecond laser method was introduced to form micro-nano structures in metals, enhancing absorption by the application of silver nanoparticles and resulting in solar absorption rates of 97.2%, 98.3%, and 98.9% for aluminum, titanium, and steel, respectively. The solar reflectance was reduced by 82.3%, 62.6%, and 79.2%, respectively, compared to bare metal. Photothermal conversion and deicing tests verified a more efficient photothermal conversion ability in the composite micro-nanostructure surface. Compared to bare metal, the structure has more than twice the solar absorption efficiency and improves the deicing efficiency by 132%. The resultant material exhibits high photothermal conversion and deicing efficiencies, enhancing its potential for solar energy applications, particularly in photothermal, photovoltaic, and thermal solar technologies.

Schizophrenia is the most strongly stigmatized psychiatric diagnosis, with negative stereotypes including assumptions of incompetence and inability to recover. Individuals with cognitive impairment associated with schizophrenia (CIAS) have reported stigma experiences, suggesting that CIAS carries stigma in addition to the stigma associated with schizophrenia as a diagnostic label. While research has established that mental illness stigma more generally is linked with poor psychiatric and functional outcomes, no research has explored correlates of CIAS stigma. This study evaluated cognitive, psychiatric, and functional correlates of CIAS stigma among 54 individuals with schizophrenia spectrum disorders participating in a cognitive remediation trial. Participants with greater estimated cognitive decline reported higher levels of CIAS stigma experiences. Participants who reported higher levels of CIAS stigma also scored higher on a measure of depressive symptom severity. No significant associations were found between CIAS stigma and positive and negative psychosis symptoms or general psychopathology ratings. CIAS stigma was not associated with performance-based functional capacity or ratings of community functioning. Findings suggest that CIAS stigma is linked with the degree of cognitive decline and depressive symptom severity among individuals with schizophrenia spectrum disorders. Additional research is needed to elucidate directionality and the relationship between CIAS stigma and functioning outcomes., Competing Interests: Declaration of competing interest Dr. Medalia discloses receiving royalties from Oxford University Press, and having consultancies with Boehringer Ingelheim, Click Therapeutics and Medscape. Dr. Saperstein discloses receiving royalties from Oxford University Press. No conflict of interest for other authors., (Published by Elsevier B.V.)

Pomegranate ( Punica granatum L.) is an ancient fruit crop that has been cultivated worldwide and is known for its attractive appearance and functional metabolites. Fruit color is an important index of fruit quality, but the color formation pattern in the peel of evergreen pomegranate and the relevant molecular mechanism is still unknown. In this study, the contents of pigments including anthocyanins, carotenoids, and chlorophyll in the peel of 'Danruo No. 1' pomegranate fruit during three developmental stages were measured, and RNA-seq was conducted to screen key genes regulating fruit color formation. The results show that pomegranate fruit turned from green to red during development, with a dramatic increase in a* value, indicating redness and anthocyanins concentration, and a decrease of chlorophyll content. Moreover, carotenoids exhibited a decrease-increase accumulation pattern. Through RNA-seq, totals of 30, 18, and 17 structural genes related to anthocyanin biosynthesis, carotenoid biosynthesis and chlorophyll metabolism were identified from differentially expressed genes (DEGs), respectively. Transcription factors (TFs) such as MYB, bHLH, WRKY and AP2/ERF were identified as key candidates regulating pigment metabolism by K-means analysis and weighted gene co-expression network analysis (WGCNA). The results provide an insight into the theory of peel color formation in evergreen pomegranate fruit.

Background: Thyroid cancer is the most common endocrine neoplasm in China. Questions regarding the extent of patient involvement in shared decision-making (SDM) processes persist; this is particularly pertinent to patients considering treatment options for low-risk papillary thyroid cancer (PTC). In this study, we aimed to explore Chinese young adults' experiences of SDM relating to the choice of treatment for low-risk PTC. Methods: The study used a qualitative descriptive design and semistructured interviews. Interviews were conducted with 24 patients (ages ranging from 18 to 38 years; 4 men and 20 women) diagnosed with low-risk (PTC) between March 2023 and May 2024. Twenty-two of 24 patients' tumor size measured 1 cm or smaller; the largest tumor size measured 1.47 cm. Reflexive thematic analysis was used to identify key themes from the transcribed interviews. Results: The analysis revealed that the SDM experiences of young patients with low-risk PTC involve four themes: challenges in information sharing; reasons for information seeking; factors influencing decision making; and self-positioning in treatment decision making. Three self-positions relating to treatment decision making were identified. These included dependent positioning, which reflects a "paternalistic" decision-making pattern; collaborative positioning, reflecting a "sharing" of decision making; and autonomous positioning, reflecting an increased sense of personal responsibility for both managing their health and engagement in decision making. Limited treatment options being offered, overuse of medical terminology, and communication gaps between clinicians and patients were the main challenges described during the information-sharing process. Information that needs persisting after physician-patient consultations resulted in active information-seeking behavior. The key variables identified in this study that potentially affected the decision-making process were future personal considerations, language used to discuss cancer, and negative emotions. Conclusions: These results highlight the necessity of adopting flexible strategies when supporting collaborative treatment decision making in the context of the doctor-patient interaction for low-risk PTC. Based on these findings, clinicians can take measures to enhance the quality of SDM by inquiring about patients' role preferences, providing details of the full range of treatment options, and encouraging patients to share their preferences and concerns relating to possible treatment options.

Introduction: Early signs of mental health issues may develop into severe mental illnesses over time. The influence of parental emotional support on adolescent mental health problems is well acknowledged. However, prior research has predominantly focused on psychological symptoms, often neglecting the somatic symptoms associated with mental health. Additionally, there has been insufficient exploration of the mediating role of self-efficacy and the relationship between socioeconomic status (SES) and adolescent mental health, particularly within the context of Hong Kong., Methods: Using data from 3,613 adolescents aged 15 years from 109 schools in Hong Kong who participated in the Programme for International Student Assessment 2018, this study explored the relationship between parental emotional support and two dimensions of adolescent mental health symptoms (psychological and somatic symptoms), and the mediating effect of self-efficacy and the moderating role of SES., Results: We found that parental emotional support significantly reduced psychological and somatic symptoms, primarily by enhancing self-efficacy. MoreovSES moderated these relationships, with the impact of parental emotional support on psychological symptoms being more pronounced among adolescents from lower SES backgrounds., Discussion: This study deepens the understanding of the mechanisms underlying adolescent mental health in Hong Kong. By highlighting the importance of parental emotional support and self-efficacy, as well as the moderating effect of SES, the findings offer valuable insights for effective interventions aimed at improving adolescent mental health., 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 Qian, Jin, Lu and Zhao.)

Background: Plastids originated from an ancient endosymbiotic event and evolved into the photosynthetic organelles in plant cells. They absorb light energy and carbon dioxide, converting them into chemical energy and oxygen, which are crucial for plant development and adaptation. However, little is known about the plastid genome to light adaptation. Petrocosmea, a member of the Gesneriaceae family, comprises approximately 70 species with diverse light environment, serve as an ideal subject for studying plastomes adapt to light., Results: In this study, we selected ten representative species of Petrocosmea from diverse light environments, assembled their plastid genomes, and conducted a comparative genomic analysis. We found that the plastid genome of Petrocosmea is highly conserved in both structure and gene content. The phylogenetic relationships reconstructed based on the plastid genes were divided into five clades, which is consistent with the results of previous studies. The vast majority of plastid protein-coding genes were under purifying selection, with only the rps8 and rps16 genes identified under positive selection in different light environments. Notably, significant differences of evolutionary rate were observed in NADH dehydrogenase, ATPase ribosome, and RNA polymerase between Clade A and the other clades. Additionally, we identified ycf1 and several intergenic regions (trnH-psbA, trnK-rps16, rpoB-trnC, petA-psbJ, ccsA-trnL, rps16-trnQ, and trnS-trnG) as candidate barcodes for this emerging ornamental horticulture., Conclusion: We newly assembled ten plastid genomes of Petrocosmea and identified several hypervariable regions, providing genetic resources and candidate markers for this promising emerging ornamental horticulture. Furthermore, our study suggested that rps8 and rps16 were under positive selection and that the evolutionary patterns of NADH dehydrogenase, ATPase ribosome, and RNA polymerase were related to the diversity light environment in Petrocosmea. This revealed an evolutionary scenario for light adaptation of the plastid genome in plants., (© 2024. The Author(s).)

The design and preparation of effective nonprecious metal-based catalysts for the urea oxidation reaction (UOR) coupled with the hydrogen evolution reaction (HER) are of great significance to solve both energy shortage and environmental pollution problems. In this study, a novel hierarchical superhydrophilic and superaerophobicity three-dimensional nanorod-like bifunctional catalyst with a heterostructure (Ni 3 S 2 /VS 2 ) was prepared on nickel foam via a simple one-step hydrothermal method, serving as an excellent electrocatalyst for both UOR and HER. The formed heterostructure significantly alters the electronic structure, optimizing charge transfer and increasing the number of active sites, which enhances the electrocatalytic performance of Ni 3 S 2 /VS 2 . As a result, this catalyst requires an extremely low potential of 1.396 V at the current density of 100 mA cm -2 for UOR and only 164 mV overpotential at -10 mA cm -2 for HER. Notably, a constructed two-electrode electrolyzer system (Ni 3 S 2 /VS 2 ∥Ni 3 S 2 /VS 2 ) demonstrates extraordinary activity and long-term stability, achieving a current density of 10 mA cm -2 at a low cell voltage of 1.48 V, which is superior to majority of the reported catalysts. This work demonstrates that the formation of heterostructures can effectively enhance the catalytic activity of nanomaterials toward UOR and HER and provides a feasible strategy for fabricating highly efficient nonprecious metal overall urea electrocatalysts.

Background: Work-family conflict among physicians has many adverse consequences, like reduced work engagement and impaired well-being. However, relatively little research has been conducted on the impact of work-family conflict on specific pathways of physician well-being. The aim of this study was to determine the relationship between work-family conflict and employee well-being among physicians and to explore the mediating role of job satisfaction and work engagement in this relationship., Methods: Using data from a cross-sectional survey of 2,480 physicians in Jilin Province, China, partial least squares structural equation modeling (PLS-SEM) was applied in this study to examine the direct and indirect effects of work-family conflict on employee well-being and to assess the mediating roles of job satisfaction and work engagement therein., Results: The employee well-being score of physicians in Jilin Province was 5.16 ± 1.20. The univariate analysis results indicated significant disparities in employee well-being scores across different age groups, marital statuses, and professional titles. Work-family conflict was significantly negatively associated with employee well-being, while job satisfaction and work engagement were significantly positively associated with employee well-being. In addition, job satisfaction and work engagement were found to mediate the association between work-family conflict and employee well-being, and work engagement was considered to mediate the association between job satisfaction and employee well-being., Conclusions: Our study confirms that work-family conflict negatively affects physicians' employee well-being. Moreover, our investigation revealed that the association between work-family conflict and employee well-being is influenced by both job satisfaction and work engagement and that work engagement plays a mediating role in the link between job satisfaction and employee well-being. Therefore, we propose that hospital administrators should rationally allocate organizational resources and develop manageable schedules to enhance physicians' employee well-being., (© 2024. The Author(s).)

S-redox involving solvated polysulfides is accompanied by volumetric change and structural decay of the S-based cathodes. Here, we propose a synchronous construction strategy for consolidating Li, Se, S, and C elements within a composite cathode via a paradigm reaction of 8Li+2Se+CS 2 = 2Li 4 SeS+C. The obtained composite features crystalline Li 4 SeS encapsulated in a carbon nanocage (Li 4 SeS@C), exhibiting ultrahigh electrical conductivity, ultralow activation barrier, and excellent structural integrity, accordingly enabling large specific capacity (615 mAh g -1 ) and high capacity retention (87.3% after 350 cycles) at 10 A g -1 . TOF-SIMS demonstrates its superior volumetric efficiency to a similar derivative SeS@C (2Se+CS 2 = 2SeS+C), and DFT reveals its lower activation barrier than Li 2 S@C and Li 2 Se@C. This consolidation design significantly improves the electrochemical performance of S-based cathodes, and the paradigm reaction guarantees structural diversity and flexibility. Moreover, employing a synchronous construction mechanism to maximize the synergistic effect between element consolidation and carbon encapsulation opens up a new approach for developing robust S or chalcogenide cathodes.

Background: Noise-induced cochlear synaptopathy has recently emerged as a focus in hearing research., Purpose: This study aimed to examine the impact of repeated noise exposure on the quantification and mRNA expression levels of cochlear synapses., Methods: Measurements were conducted at baseline, 1 day, and 14 days post-exposure to 88 or 97 dB SPL noise (2 h/day for 7 days, frequency range 2-20 kHz). Auditory brainstem responses (ABRs), immunofluorescence and quantitative real-time PCR (qRT-PCR) were used to examine the results., Results: 1. Exposure to 88 dB SPL caused minimal changes in ABRs, ribbon morphology and medial olivocochlear (MOC) efferent synapses; elevation of synaptophysin(SYP) and α9α10 nAchR mRNA levels were observed. 2. Exposure to 97 dB SPL caused threshold shift and synaptopathy of ribbon and MOC; downregulation of α10nAchR, SYP and ctbp2 mRNA levels were observed., Conclusion: Noise-induced cochlear synaptic degeneration involves both afferent and efferent synaptopathy.

Background: Thyroid dysfunction plays an important role in the pathology of diabetes-associated cognitive dysfunction (DACD). However, thyroid hormone (TH) signaling and action changes in DACD brains remain unknown. This study evaluated the alternations in TH signaling and action in the brains of DACD mice and explored the beneficial effects of levothyroxine (L-T4) treatment. Methods: KK-Ay mice, serving as a spontaneous type 2 diabetes mellitus model, underwent intragastric administration of 10 ng/g and 20 ng/g of L-T4 solution or normal saline for 8 weeks. Age-matched C57BL/6J mice were used as normal controls. Cognitive and memory functions were examined through the open field and Morris water maze tests. Hippocampal TH signaling and pathogenic status were evaluated. The potential signaling pathways involved in the neuroprotective action of L-T4 were investigated through RNA sequencing and further verified through quantitative real-time PCR (qPCR), Western blotting (WB), immunofluorescence (IF), and fluorescent multiplex immunohistochemistry (mIHC) in vivo and vitro. Results: The expressions of hippocampal TH transporters (Mct8 and Oatp1c1), Dio2, and TH receptor were upregulated, whereas Dio3 as well as the TH-positive regulated genes MBP, Enpp2, and Klf9 were downregulated in DACD mice. Exogenous L-T4 partially alleviated cognitive and memory dysfunction and restored hippocampal neuronal activity by optimizing TH signaling. RNA sequencing provided insights into the role of type I interferon (IFN-I) signaling and necroptosis on the amelioration of hippocampal damage after L-T4 treatment. WB and qPCR further confirmed that the levels of key proteins for IFN-I signaling and necroptosis (p-STAT1, p-STAT2, IRF9, ZBP1, p-RIP3, and p-MLKL) were increased, but largely returned after L-T4 administration in vivo and T3 treatment in vitro . IF and mIHC revealed that IRF9 and p-MLKL colocalized in neurons, but not in astrocytes or microglia, of the hippocampus in DACD mice. The diabetes mellitus group had an increased number of IRF9 + p-MLKL + NeuN + cells, which decreased after L-T4 treatment. The elevated IFN-I signaling-mediated necroptosis in HT22 cells was also decreased by T3. Conclusion: We demonstrated abnormal hippocampal TH signaling and action in DACD. Promoting TH action with exogenous L-T4 ameliorated hippocampal impairment through inhibiting IFN-I signaling-induced necroptosis.

Anthocyanins are important secondary metabolites contributing to the red coloration of fruits, the biosynthesis of which is significantly affected by light. Glutathione S-transferases (GSTs) play critical roles in the transport of anthocyanins from the cytosol to the vacuole. Despite their importance, GST genes in mango have not been extensively characterized. In this study, 62 mango GST genes were identified and further divided into six subfamilies. MiGSTs displayed high similarity in their exon/intron structure and motif and domain composition within the same subfamilies. The mango genome harbored eleven pairs of segmental gene duplications and ten sets of tandemly duplicated genes. Orthologous analysis identified twenty-nine, seven, thirty-four, and nineteen pairs of orthologous genes among mango MiGST genes and their counterparts in Arabidopsis, rice, citrus, and bayberry, respectively. Tissue-specific expression profiling highlighted tissue-specific expression patterns for MiGST genes. RNA-seq and qPCR analyses revealed elevated expression levels of seven MiGSTs including MiDHAR1 , MiGSTU7 , MiGSTU13 , MiGSTU21 , MiGSTF3 , MiGSTF8 , and MiGSTF9 during light-induced anthocyanin accumulation in mango. This study establishes a comprehensive genetic framework of MiGSTs in mango fruit and their potential roles in regulating anthocyanin accumulation, which is helpful in developing GST -derived molecular markers and speeding up the process of breeding new red-colored mango cultivars.

The purpose of this research was to investigate the association between leisure activity and cognitive function in Chinese older adults, and to explore the mediating role of individual evaluation, anxiety and depression. Using cross-sectional data from the 2018 Chinese Longitudinal Healthy Longevity Survey (CLHLS), Pearson correlation analyses were employed to examine the relationships among various indicators. A multiple mediation model was constructed to investigate the mediating pathways through which leisure activities impact cognitive function in elderly individuals. Leisure activities, individual evaluation, anxiety, and depression were significantly correlated with cognitive function (p < 0.01). Leisure activities not only directly positively impacted cognitive function in elderly individuals (effect = 0.3780; 95% CI = [0.3459, 0.4101]), but also exerted indirect effects through five pathways. Individual evaluation, anxiety, depression, they plays a mediating role in the association between leisure activity and cognitive function in older adults in China. Leisure activities can positively impact cognitive function in elderly individuals by enhancing individual evaluation and subsequently reducing anxiety and depression., (© 2024. The Author(s).)

We analyzed the biological and genome characteristics of a phage infecting enteroinvasive Escherichia coli (EIEC), aiming to provide resources and a reference for the prevention and treatment of EIEC. With the EIEC preserved in our laboratory as the host bacterium, one strain of phage was isolated from the effluent sample from a chicken farm in Huzhou, Zhejiang and named ΦEP1. The titer, optimal multiplicity of infection, one-step growth curve, temperature, pH value, chloroform and bile salt sensitivity of ΦEP1 were determined by the double-layer agar plate method. The morphology of the phage was observed by transmission electron microscopy. The biocontrol effects of ΦEP1 in different food matrixes and the protective effect of this phage on Caco-2 cells were tested. The phage ΦEP1 showed the optimal multiplicity of infection of 0.1, the titer of 1.3×10 10 PFU/mL, strong tolerance to temperature, pH, chloroform, and bile salt, and a broad host spectrum. Furthermore, it expressed lysis activity against multiple strains of multiple antibiotic-resistant pathogenic E . coli and Shigella with different serotypes. Phage ΦEP1 had an incubation period of 10 min, an outbreak period of 80 min, and an outbreak volume of 48 PFU/cell. According to the morphology observed by transmission electron microscopy, phage ΦEP1 belonged to the order of Caudovirales , and it had a good protective effect on Caco-2 cells. Phage ΦEP1 had a genome of 87 182 bp with the GC content of 39.80%, 128 putative open reading frames, and no antibiotic resistance genes or virulence genes. ΦEP1 inhibited the growth of EIEC in artificially contaminated milk and beef and eliminated EIEC in cell protection experiments. It significantly increased the survival rate of Caco-2 cells and down-regulated the expression of interleukin (IL)-6 and IL-1β to reduce inflammation. We obtained an EIEC-targeting phage ΦEP1 with a high titer and strong tolerance to the environment, which provided a basis for the application of phages in food preservation and other fields.

Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics., Competing Interests: Declaration of interests A patent application related to this work has been filed by China Pharmaceutical University., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Salt-baked chicken was a traditional delicacy of Guangdong, but the effects of volatile flavor compounds at different stages of its processing remained unclear. This study utilized sensory analysis, e-nose, and GC-MS to investigate the changes in volatile flavor compounds during the processing of salt-baked chicken. The results indicated significant alterations in volatile flavor compounds at different stages of processing, resulting in flavor transitioning from the original flavor to salty, scorched, and fatty flavor. 75 volatile compounds were identified by GC-MS, with 15 key flavor compounds highlighted based on OAV, including aldehydes, alcohols, terpenes, heterocycles and esters. The research revealed the dynamic changes in volatile flavor compounds throughout the cooking process of salt-baked chicken and emphasized the important role of salt-baked in shaping its distinctive taste profile. These findings provided a theoretical foundation and practical guidance for enhancing and optimizing the authentic taste of this traditional dish, while fostering innovative advancements in prepared cuisine., 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 Published by Elsevier Ltd.)

Pediatric anesthesia presents greater challenges than does adult anesthesia. This bibliometric analysis aimed to analyze the top 100 most cited articles to be better understand the hot spots and prospects in pediatric anesthesia. Articles and reviews related to pediatric anesthesia were retrieved from the Web of Science Core Collection from 1990 to 2023. A bibliometric analysis of the top 100 most cited articles was also performed using information such as topics, author names, countries, institutions, publication years, and journals. A total of 32 831 articles were identified, with a total of 32 230 citations for the top 100 articles. The peak period for pediatric anesthesia research was from 2005 to 2009. The USA has emerged as the most active country in pediatric anesthesia research. Major journals published included Anesthesia and Analgesia , Anesthesiology , and Pediatrics , underscoring their authority in the field. Clinical studies on the top 100 most cited articles have focused on different stages of the perioperative period, the use of different anesthetic agents, and adverse outcomes in pediatric patients. The current study conducted a bibliometric analysis of the top 100 most cited articles in the field of pediatric anesthesia. Such insights are valuable for identifying research hot spots, assessing academic impact and collaboration in pediatric anesthesia, and guiding future research directions., Competing Interests: None declared., (Copyright © 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.)

Aims: Hyperglycemia is one of the adverse effects of tacrolimus (TAC), but the underlying mechanism is not fully identified. We used multi-omics analysis to evaluate the changes in the gut microbiota and metabolic profile of rats with TAC-induced diabetes., Methods: To establish a diabetic animal model, Sprague Dawley rats were divided randomly into two groups. Those in the TAC group received intraperitoneal injections of TAC (3 mg/kg) for 8 weeks, and those in the CON group served as the control. 16S rRNA sequencing was used to analyze fecal microbiota. The metabolites of the two groups were detected and analyzed by nontargeted and targeted metabolomics, including amino acids (AAs), bile acids (BAs), and short-chain fatty acids (SCFAs)., Results: The rats treated with TAC exhibited hyperglycemia as well as changes in the gut microbiota and metabolites. Specifically, their gut microbiota had significantly higher abundances of Escherichia-Shigella , Enterococcus , and Allobaculum , and significantly lower abundances of Ruminococcus , Akkermansia , and Roseburia . In addition, they had significantly reduced serum levels of AAs including asparagine, aspartic acid, glutamic acid, and methionine. With respect to BAs, they had significantly higher serum levels of taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), but significantly lower levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). There were no differences in the levels of SCFAs between the two groups. Correlations existed among glucose metabolism indexes (fasting blood glucose and fasting insulin), gut microbiota ( Ruminococcus and Akkermansia ), and metabolites (glutamic acid, hydroxyproline, GCDCA, TDCA, and TUDCA)., Conclusions: Both AAs and BAs may play crucial roles as signaling molecules in the regulation of TAC-induced diabetes., 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 Jiang, Qian, Zhen, Yang, Xu, Zuo, Jiang, Zhang and Hu.)

We designed and synthesized 27 new amide and dipeptide derivatives containing a substituted phenylalanine as negative allosteric modulators (NAMs) for the beta-2 adrenergic receptor (β 2 AR). These analogs aimed to improve the activity of our lead compound, Cmpd-15, by introducing variations in three key regions: the meta-bromobenzyl methylbenzamide (S1), para-formamidophenylalanine (S2), and 1-cyclohexyl-1-phenylacetyl (S3) groups. The synthesis involved the Pd-catalyzed β-C(sp 3 )-H arylation of N-acetylglycine with 1-iodo-4-substituent-benzenes as the key step. GloSensor cAMP accumulation assay revealed that six analogs (A 1 , C 5 , C 6 , C 13 , C 15 and C 17 ) surpass Cmpd-15 in β 2 AR allosteric function. This highlights the crucial role of the S1 region (meta-bromobenzyl methylbenzamide) in β 2 AR allostery while suggesting potential replaceability of the S2 region (para-formamidophenylalanine). These findings serve as a valuable springboard for further optimizing Cmpd-15, potentially leading to smaller, more active, and more stable β 2 AR-targeting NAMs., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Hexafluoropropylene oxide trimer acid (HFPO-TA) is an emerging environmental pollutant that can accumulate in air and surface water. Currently, it has been widely used in fluoropolymer industry, which could cause serious environmental pollution. Due to the high bioaccumulation, the accumulation of pollutants may have an adverse effect on the normal physiological function of the kidneys. However, the toxic effects of HFPO-TA on the kidney are unknown. In this study, we investigated the toxic effects of HFPO-TA exposure on the rat kidney and its mechanism of action. Male SD rats were divided into 4 groups: control group (Ctrl group), L group (0.125 mg/kg/d), M group (0.5 mg/kg/d) and H group (2 mg/kg/d). After 14 consecutive days of gavage, periodic acid‑silver methenamine (PASM) and hematoxylin-eosin (HE) staining were used to examine the structure of the kidneys. We also used transcriptome sequencing (RNA-seq) to identify differentially expressed genes (DEGs) in the testes of rats in both the control and high dose groups. Besides, expression of key proteins was analyzed by immunohistochemistry. The results indicated that HFPO-TA can lead to injured renal capsule, change glomerular shape and have a significant impact on the protein expression levels of AQP2, p-AQP2 and PPARα. Additionally, the level of total cholesterol (TC) was obviously decreased after HFPO-TA exposure. RNA-seq analysis showed that HFPO-TA primarily affected peroxisome proliferator-activated receptor (PPAR) signaling pathway that is associated with lipid metabolism and cyclic adenosine monophosphate (cAMP) signaling pathway. In summary, exposure to HFPO-TA can lead to kidney damage and lipid metabolism disorders., 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 Inc.)

Background: Our previous research showed that Porphyromonas gingivalis ( P. gingivalis ) infection can activate the inflammatory signaling pathway and promotes the malignancy development of esophageal squamous cell carcinoma (ESCC). However, the prognostic significance of inflammatory response-related genes (IRRGs) in P. gingivalis -infected ESCC requires further elucidation. Hence, our study constructed a prognostic signature based on P. gingivalis and IRRGs to forecast the survival of patients with ESCC, which may provide insight into new treatment options for ESCC patients., Methods: Differentially expressed genes (DEGs) were identified in P.gingivalis -infected and P.gingivalis -uninfected ESCC cell by RNA sequencing. A risk model was constructed and validated using the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database by using univariate Cox regression analysis, LASSO, and the multivariate Cox regression analysis. Kaplan-Meier analysis was carried out to compare the overall survival (OS) between high-risk and low-risk groups. Single-sample gene set enrichment analysis was used to analyze the immune cell infiltration. The Genomics of Drug Sensitivity in Cancer database was used to predict drug sensitivity., Results: There were 365 DEGs between the P.gingivalis -infected and P.gingivalis -uninfected groups. Four genes including DKK1, ESRRB, EREG, and RELN were identified to construct the prognostic risk model ( P  = .012, C-index = 0.73). In both the training and validation sets, patients had a considerably shorter OS in the high-risk group than those in the low-risk group ( P  < .05). A nomogram was established using the risk score, gender, and N stage which could effectively forecast the prognosis of patients ( P  = .016, C-index = 0.66). The high-risk group displayed lower immune infiltrating cells, such as activated dendritic cells, type 2 T helper cells, and neutrophils ( P  < .05). A total of 41 drugs, including dactinomycin, luminespib, and sepantronium bromide, had a significant difference in IC50 between the 2 subgroups., Conclusion: We demonstrated the potential of a novel signature constructed from 4 P. gingivalis -related IRRGs for prognostic prediction in ESCC patients., 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.)

Background: The relationship between selenium and renal function has always attracted widespread attention. Increased selenium level has been found to cause impaired renal function in our previous study, but the mechanism is not clear. In this study, we evaluate the potential mediating effects of plasma proteome in the association of selenium level and renal function to understand the mechanisms of selenium's effect on renal function., Methods: Utilizing two-sample two-step mediating mendelian randomization (MR) methodology to investigate the genetically causal relationship between selenium level and renal function as well as the role of the plasma proteome in mediating them. Additionally, the mediating proteins were enriched and analyzed through bioinformatics to understand the potential mechanisms of selenium effects on renal function., Results: In the MR analysis, an increase in selenium level was found to decrease estimated glomerular filtration rate (eGFR). Specifically, for each standard deviation (SD) increase in selenium levels, eGFR levels are reduced by 0.003 SD [Beta (95% CI): -0.003 (-0.004 ~ -0.001), P=0.001, with no observed heterogeneity and pleiotropy]. Through mediation analysis, 35 proteins have been determined mediating the genetically causal effects of selenium on the levels of eGFR, including Fibroblast growth factor receptor 4 (FGFR4), Fibulin-1, Cilia- and flagella-associated protein 45, Mothers against decapentaplegic homolog 2 (SMAD2), and E3 ubiquitin-protein ligase ZNRF3, and the mediation effect rates of these proteins ranged from 1.59% to 23.70%. In the enrichment analysis, 13 signal transduction pathways, including FGFR4 mutant receptor activation and Defective SLC5A5 causing thyroid dyshormonogenesis 1, were involved in the effect of selenium on eGFR levels., Conclusion: Our finding has revealed the underlying mechanism by which increased selenium level lead to deterioration of renal function, effectively guiding the prevention of chronic kidney disease and paving the way for future studies., 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 Fu, Qian, Yuan, Su, Ma, Li and Xu.)

Exposure to bisphenol A (BPA) during gestation and lactation is considered to be a potential risk factor for autism spectrum disorder (ASD) in both humans and animals. As a novel alternative to BPA, 4-hydroxy-4'-isopropoxydiphenylsulfone (BPSIP) is frequently detected in breast milk and placental barrier systems, suggesting potential transmission from the mother to offspring and increased risk of exposure. Gestation and lactation are critical periods for central nervous system development, which are vulnerable to certain environmental pollutants. Herein, we investigated the behavioral impacts and neurobiological effects of early-life exposure to BPSIP (0.02, 0.1, and 0.5 mg/kg body weight/day) in mice offspring. Behavioral studies indicated that BPSIP exposure induced ASD-like behaviors, including elevated anxiety-related behavior and decreased spatial memory, in both male and female pups. A distinct pattern of reduced social novelty was observed only in female offspring, accompanied by significant alterations in antioxidant levels. Transcriptome analysis demonstrated that differentially expressed genes (DEGs) were mainly enriched in pathways related to behaviors and neurodevelopment, which were consistent with the observed phenotype. Besides, a decrease in the protein levels of complex IV (COX IV) across all tested populations suggests a profound impact on mitochondrial function, potentially leading to abnormal energy metabolism in individuals with autism. Additionally, changes in synaptic proteins, evidenced by alterations in synapsin 1 (SYN1) and postsynaptic density protein-95 (PSD95) levels in the cerebellum and hippocampus, support the notion of synaptic involvement. These findings suggest that BPSIP may induce sex-specific neurotoxic effects that involve oxidative stress, energy generation, and synaptic plasticity.