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Ethnopharmacological Relevance: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, mainly manifested as paresthesia. Tangzu granule (TZG) is derived from famous traditional Chinese medicine decoctions and optimized by long-term temporary practice. TZG has good efficacy in improving numbness, pain and pruritus of the lower extremities of DPN patients. However, the overall regulatory mechanisms underlying its effects on DPN remain unclear., Aim of the Study: This study aims to explore the potential mechanism of TZG for treating DPN., Materials and Methods: Sprague-Dawley (SD) rats were used to establish an in vivo model of DPN with streptozotocin (STZ) injection and high-fat diet (HFD) feeding. Additionally, sciatic glial RSC96 cells were induced with high glucose in vitro. SD rats in intervention group received TZG treatment for 12 weeks. After 12 weeks of treatment, sciatic nerve function was evaluated by intelligent hot plate meter and neuro electrophysiology detector. The morphological changes of sciatic nerve cells were observed by hematoxylin-eosin staining and transmission electron microscope. IL-1β, IL-18 inflammatory cytokines, pyroptosis and P2X7R/NLRP3 signaling pathway were observed by Western blotting, immunofluorescence staining and ELISA., Results: TZG improved nerve conduction velocity and sciatic neuropathy rational structural changes in DPN rats. It also inhibited RSC96 inflammatory response and cell death that induced by high glucose. This may be related to TZG inhibiting P2X7R, decreasing the activation of NLRP3 inflammasomes, down-regulating the levels of pyroptosis proteins such as caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N, and inhibiting the release of interleuki (IL)-18 and IL-1β inflammatory cytokines., Conclusions: TZG inhibited pyroptosis through P2X7R/NLRP3 signaling pathway, alleviated neuroinflammation, and showed protective effect in the treatment of DPN., 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.)

Background: Nitroxyl (HNO) is an emerging signaling molecule that plays a significant regulatory role in various aspects of plant biology, including stress responses and developmental processes. However, understanding the precise actions of HNO in plants has been challenging due to the absence of highly sensitive and real-time in situ monitoring tools. Consequently, it is crucial to develop effective and accurate detection methods for HNO. Establishing such methodologies will enable researchers to elucidate the functional roles of HNO in plant physiological processes, thereby advancing our knowledge of plant resilience and adaptation under environmental stressors., Result: Herein, we successfully constructed a near-infrared fluorescent probe, DCIF-HNO, based on the dicyanoisophorone platform as fluorophore and 2-(diphenylphosphino)benzoate as HNO recognition site for identifying HNO in plants. Probe DCIF-HNO exhibited rapid response, excellent selectivity, and high sensitivity to HNO in vitro spectroscopic tests, while also demonstrating low toxicity and biocompatibility. A rapid and portable smartphone sensing platform for HNO in actual samples was successfully constructed based on probe DCIF-HNO and color recognition application. Moreover, probe DCIF-HNO was successfully applied to plant cells and tissues, enabling real-time visualization and detection of HNO and revealing the complex network of HNO interactions during H 2 S/NO crosstalk in plants. Furthermore, the increase in HNO levels in plants response to high salt and Cr stress was observed using probe DCIF-HNO. Transcriptome sequencing and differential metabolites analysis were employed to gain insight into the mechanism of HNO production under Cr stress., Significance: Due to the optical properties and high-resolution imaging capabilities of DCIF-HNO, this study offers a novel framework for elucidating the signaling role of HNO in plant stress responses. The precise visualization of HNO dynamics enhances our understanding of the complex molecular pathways involved in plant adaptation to abiotic stressors. This research not only advances plant physiology but also has significant implications for developing strategies to enhance agricultural resilience in challenging environmental conditions., Competing Interests: Declaration of competing interest The authors declare that there are no known competing financial interests or personal relationships that can influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Advanced breast cancer is prone to bone metastasis, which is the most common bone metastatic tumor. Current clinical methods for diagnosing breast cancer bone metastases rely on serological markers, computed tomography and magnetic resonance imaging. However, these technologies cannot meet patients' needs due to the delayed screening, complex procedures and expensive equipment. Optical imaging currently exhibits inexhaustible and vigorous vitality in the field of diagnosis thanks to its advantages of simplicity, good controllability and high resolution. Nevertheless, the development of prominent chromophores for the diagnosis of breast cancer bone metastases is an appealing yet significantly challenging task. In this contribution, we rationally designed and synthesized three water-soluble aggregation-induced emission (AIE) luminogens, named PEGTPA-BTD, PEGTPA-NTD, and PEGTPA-NSD, by introducing different moieties as electron acceptors and PEGylated triphenylamine derivatives as electron donors and hydrophilic moieties. In vitro experiments showed that PEGTPA-NSD has a longer absorption and emission wavelength, where the emission wavelength can extend into NIR-II region. Besides, PEGTPA-NSD could self-assemble into stable nanoparticles in aqueous solution. Cell experiments showed that PEGTPA-NSD had no obvious dark toxicity to tumor cells or normal cells, and were easily taken in by tumor cells for cell imaging. What's more, PEGTPA-NSD NPs possessed excellent fluorescence imaging performance and biocompatibility in vivo for breast cancer bone metastases in NIR-I and NIR-II region, respectively. In summary, PEGTPA-NSD is the first reported aggregation-induced emission luminogens (AIEgens) that can self-assemble to nanoparticles in aqueous solution for NIR-I/NIR-II fluorescence imaging of breast cancer bone metastases. These findings would provide new strategies for optical diagnostic imaging of breast cancer bone metastases to better advance clinical technology development., 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.)

A concise synthetic strategy utilizing a Zr catalyst for the construction of cyctetryptomycin A and B is reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers with a Zr catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr catalyst required 1,2-bis(diphenylphosphino)ethane (dppe) as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations., (© 2024 Wiley-VCH GmbH.)

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.

There has been a sharp rise in the extent and scale of human activities since the mid-20th century, termed the "Great Acceleration", and nuclear activities are one of the defining technological processes for this period. 239,240 Pu released by atmospheric nuclear weapons tests provides an ideal chronostratigraphic marker for labeling this change due to its global fallout feature, temporal mutation, and long half-lives. However, the accumulation dynamics of plutonium from atmospheric deposition to preservation in the sediment is still controversial. Three sediment cores collected from two maar lakes with high-quality chronology were analyzed for 239,240 Pu. The first high-yield thermonuclear test (31st October 1952) and the highest global tests in 1961-1962 were identified, respectively, as the first rapidly increased 239,240 Pu in 1953 and peaked in 1963. In anoxic Lake Sihailongwan (SHLW), scavenging Pu from the water to sediment was accelerated due to the major particulate associated forms of Pu(III) and Pu(IV) and rapidly elevated dust flux when ice-melting occurred in every spring. The desorption of Pu from beneath sediment to the lake water and resorption by sediment particles were stronger in shallow and oxic Lake Huguangyan. Therefore, the first rapid increase of 239,240 Pu in 1953 and peak in 1963 accompanied by rapid scavenging and well preservation of plutonium provide a robust time marker for the "Great Acceleration", and this marker nearly permanently exists in such kind of lake sediment similar to Lake SHLW.

Rapid industrialization has led to the widespread accumulation of heavy metal-contaminated soils, posing significant environmental and health risks. Utilizing remediated soil for the production of sintered bricks offers a sustainable and effective solution. However, the migration and immobilization mechanisms of heavy metals during the sintering process, both within the tunnel kiln and the brick matrix, require detailed investigation. This study examined the distribution of heavy metals in the tunnel kiln and analyzed the differences in heavy metal content and leaching behavior between the inner and outer layers of the bricks. Bricks containing 15% remediated soil were prepared, and it was observed that the majority of heavy metals were effectively immobilized, with retention rates ranging from 90.6% to 99.9%. Selenium (Se), however, exhibited significant volatility, with a retention rate of only 64.3%. The outer layer of the brick body contained higher concentrations of As and Pb compared to the inner layer. Conversely, leaching tests showed lower leaching rates of Mn, Ni, Cu, and Zn in the inner layers, while As and Pb exhibited higher leaching rates in the inner layers. These findings underscore the varying migration and transformation behaviors of different heavy metals during sintering, both within the kiln and the brick layers. The study highlights the potential of doped sintered bricks as sustainable building materials, ensuring effective heavy metal stabilization with minimal environmental risk, and providing a promising pathway for the safe reuse of contaminated soils., 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 © 2025 Elsevier Ltd. All rights reserved.)

Flame retardant polybrominated diphenyl ethers (PBDEs) accumulate in human bodies through food and dust ingestion, and cause neurobehavioral deficits with obscure mechanism. We aimed to investigate NMDAR-CaMKⅡγ-mediated synapse-to-nuclear communication involved in BDE-209-induced cognitive impairment, and alleviation from exogenous melatonin. Decreased NMDAR subunits GluN2A and 2B, autophosphorylation of CaMKⅡα, and postsynaptic GluA1 trafficking were observed in the hippocampus of juvenile rats after maternal BDE-209 exposure. Moreover, nuclear shuttling of CaMKⅡγ with CaM, as well as downstream nuclear p-CaMKIV and p-CREB-dependent genes (Bdnf, c-Fos, Arc) expression were all causally down-regulated. These resulted in less dendritic spines in CA1 area and poor spatial learning and memory. Importantly, elevated miR-219a-5p in transcriptome sequencing was identified together with its targets Grin2b and Camk2g mRNA, further elucidated the reduction in GluN2B and CaMKⅡγ protein. These changes on synaptic plasticity caused by BDE-209 were reversed correspondingly under pretreatment of melatonin, partially via miR-219a inhibition. Collectively, our findings suggest that synaptonuclear signaling alterations potentially mediated neurobehavioral deficits induced by early-life BDE-209 exposure and the neuroprotection from melatonin, therefore provided a novel perspective for prevention., 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. On behalf of all co-authors, I would like to declare this work was original research that has not been published previously nor being considered for publication elsewhere, in whole or in part. No conflicts of interest exists in the submission of this manuscript. All other authors have read the manuscript and have agreed to submit it in its current form for consideration for publication in Food and Chemical Toxicology., (Copyright © 2025. Published by Elsevier Ltd.)

Oxidative stress and neuroinflammation are recognized as key factors in the development of neurodegenerative diseases, yet effective interventions and biomarkers to address oxidative stress and neuroinflammation in these conditions are limited. Uric acid (UA), traditionally associated with gout, is now gaining prominence as a potential target in neurodegenerative diseases. Soluble UA stands out as one of the most vital antioxidant compounds produced by the human body, accounting for up to 55% of the extracellular capacity to neutralize free radicals. While there is increasing evidence supporting the neuroprotective properties of UA in Parkinson's disease and Alzheimer's disease, gaps in knowledge still exist regarding the underlying mechanisms and how to effectively translate these benefits into clinical practice. Moreover, the current UA elevation therapy exhibits unstable antioxidant properties, individual variability, and even adverse effects, limiting its potential clinical applications. This review consolidates recent advancements in understanding how UA exerts neuroprotective effects on neurodegenerative diseases and emphasizes the dual roles of UA in managing oxidative stress and neuroinflammation. Additionally, the review elucidates the mechanisms through which UA confers neuroprotection. Based on this, the review underscores the significance of UA as a potential biomarker and aims to provide a comprehensive understanding of its potential as a therapeutic target, while also addressing possible challenges to clinical implementation., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The utilization of nonlinear optical (NLO) crystals plays a crucial role in the contemporary laser industry, and the advancement of novel NLO-active units is essential for the exploration of NLO materials. Two novel organic-inorganic hybrid iodates, designated as (C 3 N 2 H 5 ) 2 Mo 2 O 5 (IO 3 ) 4 ·3H 2 O ( 1 ) and (C 3 N 2 I 2 H 3 ) 2 Mo 2 O 5 (IO 3 ) 4 ·4H 2 O ( 2 ) were synthesized via mild hydrothermal methods, exhibiting band gaps of 3.75 and 3.00 eV, SHG response of 1.3 and 3.5 times that of KDP, and birefringence of 0.143 and 0.254@ 550 nm, respectively. The optical property enhancement can be attributed to the cationic modification strategy, as corroborated by the results of theoretical calculations.

Objectives: This study aimed to evaluate the incidence and clinical significance of coexistence of anti-aminoacyl-tRNA synthetase (anti-ARS) antibody in patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5 + DM)., Methods: We assessed a cohort of 246 consecutive patients with anti-MDA5 + DM. Clinical characteristics and survival rates were compared between patients with and without anti-ARS antibodies., Results: Of these 246 patients, 15 (15/246, 6.1%) were positive for anti-ARS antibodies. The anti-ARS-positive group had a higher proportion of mechanic's hands (53.3% vs 25.5%, P = 0.019), and the positivity rates for antinuclear antibody (ANA) (80.0% vs 50.6%, P = 0.033) and anti-Ro52 antibodies (93.3% vs 62.3%, P = 0.013) were also higher. However, the CRP levels were comparatively low [4.0 (0.5, 7.8) vs 6.0 (3.1, 12.2), P = 0.019]. In the overall population, no difference in survival rates was observed between anti-MDA5 + DM patients with or without anti-ARS antibodies (log-rank P = 0.339). The multivariate Cox regression analysis revealed that elevated lactate dehydrogenase (LDH) levels and the presence of rapidly progressive interstitial lung disease (RPILD) were associated with poor prognosis [hazard ratios of 1.002 (95% CI 1.001, 1.002, P < 0.001) and 11.096 (95% CI 5.006, 24.598, P < 0.001), respectively]., Conclusion: Among the 246 patients with anti-MDA5 + DM, only 15 patients (6.1%) tested positive for anti-ARS antibodies. The presence of anti-ARS antibodies is associated with the occurrence of mechanic's hands, as well as an increased positive rate of ANA and anti-Ro52 antibodies. Elevated LDH levels and the presence of RPILD are poor prognostic risk factors for patients with anti-MDA5 + DM. Key Points • The presence of anti-ARS antibodies is associated with the occurrence of mechanic's hands, as well as an increased positive rate of ANA and anti-Ro52 antibodies. • Elevated LDH levels and the presence of RPILD are poor prognostic risk factors for patients with anti-MDA5 + DM. • Understanding the clinical characteristics of these patients will help clinicians to develop individualised treatment plans for each patient., Competing Interests: Declarations. Patient consent for publication: Not required. Ethical approval: The study methods were approved by the Ethics Committee Board of the Second Affiliated Hospital of Soochow University (Approval No. JD-HG-2023–09). Disclosures: None., (© 2025. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

The rational design of efficient hydroxyl intermediate (*OH) adsorption catalysts for dopamine electrooxidation still faces a major challenge. To address this challenge, a CeO 2 -loaded CuO catalyst inspired by the f-p-d orbital hybridization strategy is designed to achieve efficient *OH adsorption and improve dopamine oxidation. The experimental results and theoretical calculations demonstrate that the f-p-d orbital hybridization regulates the electron distribution at the Ce-O-Cu interface, which facilitates electron transfer and optimizes the adsorption of *OH, thereby promoting dopamine oxidation. The designed electrochemical sensor exhibits excellent catalytic activity and sensitivity, reaching a limit of detection of 3.22 nM. This work provides a promising approach for designing highly active electrocatalysts with orbital hybridization for dopamine oxidation.

Purpose: Protein arginine methyltransferase 1 (PRMT1) is an integral constituent of numerous cellular processes. However, its role in corneal epithelial wound healing (CEWH) remains unclear. This study investigates the impact of PRMT1 on cellular mechanisms underlying corneal epithelial repair and its potential to improve wound healing outcomes., Methods: The murine CEWH model was established using an Alger brush. Corneal epithelial-specific Prmt1 knockout mice were generated using the Cre-lox system. Quantitative reverse transcription polymerase chain reaction and Western blot analyses determined the expression of candidate genes at mRNA and protein expression levels. Human corneal epithelial cells (HCECs) were transfected with siRNA using Lipofectamine RNAiMAX or infected with lentivirus to precisely alter the expression of PRMT1 or Annexin A3 (ANXA3). EdU and a scratch wound-healing assay evaluated the effects of PRMT1 or ANXA3 on HCEC proliferation and migration, respectively. Rescue experiment and chromatin immunoprecipitation assay validate the correlation between PRMT1 and ANXA3., Results: Prmt1 is significantly upregulated during CEWH, accompanied by an elevated global arginine methylation level. Knockdown of PRMT1 in HCECs or in vivo knockout impairs cell proliferation, migration, and the CEWH process. Furthermore, ANXA3 was identified as a critical target of PRMT1, with PRMT1 enhancing ANXA3 expression through histone arginine methylation at its promoter region, establishing a causal correlation between them. Moreover, PRMT1 can modulate the NF-κB and JNK signaling pathways via ANXA3., Conclusions: PRMT1 is a critical epigenetic regulator in CEWH, promoting wound healing by upregulating ANXA3 via histone arginine methylation. These findings highlight the potential of targeting PRMT1 to enhance corneal epithelial repair.

Ethnopharmacological Relevance: Nonalcoholic steatohepatitis (NASH) poses significant health risks; however, effective treatment options remain scarce. Yinchen-Gancao decoction (YG, a formula composed of Traditional Chinese Medicine Artemisia capillaris Thunb. and Glycyrrhiza uralensis Fisch.) ameliorated symptoms in NASH mouse models. However, the underlying mechanisms have not been elucidated., Aim of Study: This study aimed to assess the therapeutic efficacy of YG and explore the underlying mechanisms., Materials and Methods: YG was prepared and characterized, and then orally administered to high-fat diet (HFD) or high-fat high-sugar diet (HFHS) induced mice. Histopathological examinations and biochemical analyses were performed to evaluate the therapeutic effects. Fxr -/- mice were used to investigate the role of farnesoid X receptor (FXR) in the therapeutic effects of YG. The mechanism of action was explored by quantitative real-time PCR (RT-qPCR), western blotting, molecular docking, and cellular thermal shift assay (CETSA)., Results: YG improved liver histopathology and biochemical parameters in wild-type mice but only improved alanine aminotransferase (ALT) in Fxr -/- mice. YG upregulated FXR with Chlorogenic acid (CGA) identified as a bioactive constituent. In wild-type (WT) mice, YG downregulated de novo lipogenesis (DNL), fatty acid (FA) uptake, and upregulated FA β-oxidation. However, these effects were absent in the Fxr -/- mice. YG inhibited hepatic inflammation and endoplasmic reticulum stress (ERS) in both WT and Fxr -/- mice., Conclusion: Our study supported the use of YG as a promising therapeutic agent to attenuate NASH. Its mechanism of action involved the reduction of hepatic lipid accumulation (FXR-dependent) and the inhibition of hepatic inflammation and ERS., 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 © 2025. Published by Elsevier B.V.)

Thermogenic fat, including brown and beige fat, dissipates heat via thermogenesis and enhances energy expenditure. Thus, its activation represents a therapeutic strategy to combat obesity. Here, we demonstrate that levels of F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, negatively correlate with thermogenic fat functionality. FBXW7 overexpression in fat suppresses energy expenditure and thermogenesis, thus aggravates obesity and metabolic dysfunctions in mice. Conversely, FBXW7 depletion in fat leads to brown fat expansion and browning of white fat, and protects mice from diet induced obesity, hepatic steatosis, and hyperlipidemia. Mechanistically, FBXW7 binds to S6K1 and promotes its ubiquitination and proteasomal degradation, which in turn impacts glycolysis and brown preadipocyte proliferation via lactate. Besides, the beneficial metabolic effects of FBXW7 depletion in fat are attenuated by fat-specific knockdown of S6K1 in vivo. In summary, we provide evidence that adipose FBXW7 acts as a major regulator for thermogenic fat biology and energy homeostasis and serves as potential therapeutic target for obesity and metabolic diseases., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2025. The Author(s).)

Background and Purpose: The aim of this study was to assess the intracerebral hemorrhage (ICH) burden in 204 countries and territories worldwide from 1990 to 2021, disaggregated by sex, age, and sociodemographic index (SDI) at the global, regional, and country levels., Methods: Data from the 2021 Global Burden of Disease Study (GBD) were used to calculate age-standardized prevalence (ASPR), incidence (ASIR), death (ASDR), and disability-adjusted life year (DALY) rates for ICH. The estimated annual percentage change (EAPC) was used to assess time patterns. The Bayesian age-period-cohort (BAPC) model was employed to predict future ICH burden., Results: In 2021, the global ICH burden remained high, with a total of 16.6 million cases and an ASPR of 194.51 cases per 100,000 people. The ASIR was 40.83 cases per 100,000 people, the ASDR was 39.09 cases per 100,000 people, and the age-standardized DALY rate was 923.64 per 100,000 people. The low-SDI regions had the highest ASPR, ASIR, ASDR, and DALY rates. Geographically, western sub-Saharan Africa had the highest ASPR, Central Asia had the highest ASIR, and Oceania had the highest ASDR and DALY rates. High systolic blood pressure was the leading risk factor for ICH death, contributing to 57.9% of global fatalities., Conclusion: Despite the decline in the ASIR, there is an ongoing increase in the absolute number of ICH cases, with significant differences observed across age, sex, region, country, and SDI. More attention and emphasis should be placed on improving the ICH burden in low-SDI areas., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Hyaluronic acid (HA) nanogels have attracted widespread attention, aiming to improve cancer treatment paradigms and overcome the limitations of free-form drugs. However highly hydrophilic nature of HA nanogels limits their potential application where amphiphilic interactions are required for the delivery of hydrophobic drugs. In this study, we developed amphiphilic structure oxaliplatin (OXA) loaded oligo-hyaluronic acid (oHA)-PEG-Octane nanogel using stable disulfide bonds with ultrasonic re-emulsion method. 1,8-Mercaptooctane present in the organic phase underwent crosslinking with sulfhydryl groups conjugated on oHA and PEG in the inner aqueous phase through interfacial reactions, resulting in the formation of an amphiphilic structure of the nanogels. The nanogels demonstrated uniform size, stability, excellent biocompatibility, and achieved a high drug-loading capacity of 10.8 %. OXA NGs targeted tumor cells through CD44-mediated endocytosis, disassembled under the influence of high glutathione (GSH) levels within the tumor microenvironment (TME) and released OXA inside the reductive cytosol to trigger immunogenic cell death (ICD) of tumor cells. In vivo experiments showed OXA NGs could inhibit tumor growth. Furthermore, the amphiphilic hyaluronic acid nanohydrogel may have clinical potential due to its ability to accommodate various therapeutic agents; therefore, OXA NGs are a potential candidate for clinical translation., 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.)

The chemical instability of traditional organically-decorated superhydrophobic metal surfaces is a significant issue, severely limiting practical applications. This is due to the susceptibility of low surface energy coatings to ion permeation, decomposition, and exfoliation, especially in harsh environments. Here, organic coating-free, durable superhydrophobic surfaces on Al alloys by developing the paracrystalline state of a bionic anthill tribe structure is successfully achieved, using femtosecond laser element-doping microstructuring followed by repetitive annealing processes. Remarkably, the inherent superhydrophobic properties of the sample are maintained for ≈2000 h in a corrosive 3.5 wt.% NaCl aqueous solution, significantly surpassing the performance of traditional organic coatings. Moreover, this inherent superhydrophobicity remains nearly unchanged, even after rigorous electrochemical reaction measurements. Additional tests involving UV irradiation (>100 h), freezing cycles (>100 cycles), and acid/alkali resistance (>65 h) further demonstrate that the environmental adaptability of the surface far exceeds that of silane-coated surfaces. Ab initio calculations reveal that the formation of the paracrystalline state reduces surface energy and enhances chemical stability, thereby extending the durability of the superhydrophobic metal. These findings offer a powerful strategy for utilizing atomic-level structural rearrangements to design inherent superhydrophobic surfaces without the need for organic coatings., (© 2024 Wiley‐VCH GmbH.)

Background and Objective: Denosumab is widely used for osteoporosis and cancer treatment. However, hypocalcemia induced by denosumab is a frequent adverse event. The objective of this study is to comprehensively investigate the safety signals and the occurrence of hypocalcemia in real-world patient cases reported through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS)., Methods: Reports from January 1, 2017 to December 31, 2021 were extracted from the FAERS. Only cases of hypocalcemia suspected to denosumab were eligible in pharmacovigilance study. Denosumab-related hypocalcemia safety signal were identified to characterize their clinical features. A safety signal for hypocalcemia was evaluated using reporting odds ratios (ROR)., Results: Among the 102,413 cases related to denosumab, 1042 cases were reported with denosumab-related hypocalcemia. The affected patients were mainly elderly (median age 70 years) and male (n = 568, 63.5%). In available data, the median onset time of 23 (range 0-1601) days. Most patients required drug interruption (n = 226, 72.9%) and can achieve a recovered-resolved state (n = 318, 62.1%). For the whole database, denosumab exhibited a safety signal for hypocalcemia (ROR = 14.09, 95% Cl 13.18, 15.06). In the sensitivity analyses, denosumab also showed a safety signal for hypocalcemia in cancer (ROR = 21.28, 95% Cl 18.79, 24.11) and osteoporosis (ROR = 9.29, 95% Cl 6.80, 12.59). Compared with bisphosphonates, denosumab still has safety signal for hypocalcemia (ROR = 1.88, 95% Cl 1.67, 2.11)., Conclusions: This pharmacovigilance database analysis indicates a high safety signal for hypocalcemia associated with denosumab, particularly in cancer patients., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest. Ethical Approval: Not required., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Organic fouling and biofouling represents a critical challenge encountered by the membrane-based water treatment process. Herein, a piezoelectric PVDF membrane (PEM), capable of generating electrical responses to hydraulic pressure stimuli, was synthesized and employed for mitigating the fouling in surface water treatment. The surface-hydrophobilized PEM demonstrated sensitive and enhanced underwater output performance in response to increasing transmembrane pressure (TMP) during constant-flux filtration, with signals reaching up to ∼800 mV at a TMP of ∼80 kPa. This in-situ piezoelectric response significantly reduced TMP growth in both short-term (1 h) and long-term (15 days) filtration trials, demonstrating a strong capability to mitigate membrane fouling. Moreover, continuous piezoelectric stimulation effectively inhibited microbial activity and the accumulation of extracellular polymeric substances (EPS) on PEM surface, surpassing the dominant electrokinetic repulsion mechanisms observed in short-term trials. Microbial community analysis suggests that this evolution is primarily due to the targeted impact of piezoelectric stimulation on microbial metabolic behavior. The piezoelectric-induced electrical microenvironment inhibited the growth of microbes associated with high EPS production while promoting the proliferation of electrically active microbes involved in biopolymer digestion. In addition, the PEM demonstrated enhanced permeate quality throughout the filtration process, with DOC and UV 254 removal rates increasing from 11.7 % and 15.6 % initially to 28.6 % and 19.5 % by the 15th day, respectively. Given the performance and self-powered capability of PEM compared to current electrified antifouling methods that require an external power supply, these attributes are anticipated to hold practical significance in developing innovative and energy-efficient strategies for mitigating both organic fouling and biofouling., 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.)

Hydrogen sulfide (H 2 S) has emerged as a crucial signaling molecule in plant stress responses, playing a significant role in regulating various physiological and biochemical processes. In this study, we report an aggregation-induced emission (AIE)-based ratiometric fluorescent probe TPN-H 2 S for the highly selective detection of H 2 S in plant tissues. The probe exhibited excellent sensitivity and selectivity towards H 2 S over other analytes, enabling real-time monitoring of H 2 S dynamics in living cell. Furthermore, the AIE-based ratiometric probe TPN-H 2 S allowed for accurate quantification of H 2 S levels, providing valuable insights into the spatiotemporal distribution of Cys metabolism produces H 2 S. Importantly, the physiological pathways and signaling mechanisms of H 2 S production of was investigated in plant tissues under Cr and nano-plastics stress. Utilizing a high-throughput screening approach, we identified exogenous substances such as calcium chloride (CaCl 2 ) and abscisic acid (ABA) that could induce higher level of H 2 S production during the stress response in plants. Overall, those findings demonstrate the potential of the AIE-based ratiometric fluorescent probe TPN-H 2 S as a powerful tool for unraveling the role of H 2 S in plant stress responses and pave the way for further exploration of H 2 S-mediated signaling pathways in plants., 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.)

Ensuring the detection sensitivity of both RNA-derived and DNA-derived target genes in a single reaction has posed a significant challenge for on-site detection of plant pathogens. This challenge was addressed by developing a one-tube dual RT-RAA assay combined with LFS for the rapid on-site detection of pepper mild mottle virus (PMMoV) and four Colletotrichum species causing anthracnose in Solanaceous crops. By testing four different combinations of primer groups, two combinations were precisely adjusted within the dual RT-RAA system to balance amplification efficiency and maintain consistent levels of amplification in crude plant samples. Utilizing commercially accessible small-scale equipment and following a streamlined optimization strategy, the assay achieved a limit of detection of 0.32 copies/μL of target genes in the reaction. Importantly, it demonstrated no cross-reactivity with other plant pathogens, thereby affirming the high sensitivity and specificity of the developed dual RT-RAA-LFS detection assay. Moreover, the entire process took only 25 min from sample collection to the visible presentation of results. The assay was validated with 60 field samples and 10 seed samples, producing results consistent with reverse transcription quantitative polymerase chain reaction (RT-qPCR). Notably, it successfully detected PMMoV in systemic leaves without visible symptoms three days post-inoculation, underscoring its effectiveness in early disease detection. This streamlined strategy offers a valuable approach for rapid, low-cost, and highly sensitive on-site simultaneous detection of RNA genome-contained PMMoV and DNA genome-contained Colletotrichum species., 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 B.V. All rights reserved.)

Exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-ex) have become a hopeful substitute for whole-cell therapy due to their minimal immunogenicity and tumorigenicity. The present study aimed to investigate the hypothesis that hUCMSC-ex can alleviate excessive inflammation resulting from intracerebral hemorrhage (ICH) and facilitate the rehabilitation of the nervous system in rats. In vivo, hemorrhagic stroke was induced by injecting collagenase IV into the striatum of rats using stereotactic techniques. hUCMSC-ex were injected via the tail vein at 6 h after ICH model establishment at a dosage of 200 µg. In vitro, astrocytes were pretreated with hUCMSC-ex and then stimulated with hemin (20 μmol/mL) to establish an ICH cell model. The expression of TLR4/NF-κB signaling pathway proteins and inflammatory factors, including TNF-α, IL-1β, and IL-10, was assessed both in vivo and in vitro to investigate the impact of hUCMSC-ex on inflammation. The neurological function of the ICH rats was evaluated using the corner turn test, forelimb placement test, Longa score, and Bederson score on the 1st, 3rd, and 5th day. Additionally, RT-PCR was employed to examine the mRNA expression of TLR4 following hUCMSC-ex treatment. The findings demonstrated that hUCMSC-ex downregulated the protein expression of TLR4, NF-κB/P65, and p-P65, reduced the levels of pro-inflammatory cytokines TNF-α and IL-1β, and increased the expression of the anti-inflammatory cytokine IL-10. Ultimately, the administration of hUCMSC-ex improved the behavioral performance of the ICH rats. However, the results of PT-PCR indicated that hUCMSC-ex did not affect the expression of TLR4 mRNA induced by ICH, suggesting that hUCMSCs-ex may inhibit TLR4 translation rather than transcription, thereby suppressing the TLR4/NF-κB signaling pathway. We can conclude that hUCMSC-ex mitigates hyperinflammation following ICH by inhibiting the TLR4/NF-κB signaling pathway. This study provides preclinical evidence for the potential future application of hUCMSC-ex in the treatment of cerebral injury., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflict of interest. Ethical approval: The studies involving human participants were reviewed and approved by the Ethics Committee of the second Hospital of Hebei Medical University. The patients/participants provided their written informed consent to participate in this study. The animal study was reviewed and approved by the Ethics Committee of The Second Hospital of Hebei Medical University., (© 2024. The Author(s).)

Granuloma annulare (GA) is an idiopathic condition characterized by granulomatous inflammation in the skin. Prior studies have suggested that GA develops from various triggers, leading to a complex interplay involving innate and adaptive immunity, tissue remodeling, and fibrosis. Macrophages are the major immune cells comprising GA granulomas; however, the molecular drivers and inflammatory signaling cascade behind macrophage activation are poorly understood. Histologically, GA exhibits both palisaded and interstitial patterns on histology; however, the molecular composition of GA at the spatial level remains unexplored. GA is a condition without Food and Drug Administration-approved therapies despite the significant impact of GA on QOL. Spatial transcriptomics is a valuable tool for profiling localized, genome-wide gene expression changes across tissues, with emerging applications in clinical medicine. To improve our understanding of the spatially localized gene expression patterns underlying GA, we profiled the spatial gene expression landscape from 6 patients with GA. Our findings revealed mixed T helper 1 and T helper 2 signals comprising the GA microenvironment and spatially distinct M1 and M2 macrophage polarization characteristics. IFN-γ and TNF signals emerged as important regulators of GA granulomatous inflammation, and IL-32 emerged as a key driver of granulomatous inflammation. Overall, our spatial transcriptomics data indicate that GA exhibits mixed immune and macrophage polarization., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Given the impact of nonalcoholic fatty liver disease (NAFLD) on T cell activation and proliferation functions, we aim to explore the heterogeneity of follicular cytotoxic T (Tfc) cells in chronic hepatitis B (CHB) patients with NAFLD., Methods: 32 healthy controls (HCs), 36 treatment-naïve CHB patients, and 19 treatment-naïve CHB + NAFLD patients were recruited. We employed multicolor flow cytometry to assess the exhausted phenotype and functionality of Tfc cells. CD8 + T cells were subjected to single-cell RNA sequencing. Furthermore, we co-cultured peripheral blood mononuclear cells from CHB patients with HepG2.2.15 cells under different treatment to investigate the underlying mechanism., Results: We observed an increased expression of inhibitory receptors in Tfc cells compared to their counterparts in CHB patients. In CHB + NAFLD patients the memory identity and functional properties of Tfc cells were impaired. Enhanced lipid oxidation and oxidative stress were found in the Tfc of CHB + NAFLD patients. Tfc cells were predominantly present within the exhausted effector T cells in CHB + NAFLD patients, while in CHB patients, Tfc cells were mainly distributed within the precursors of exhausted T cells and central memory T cells. The effector memory phenotype of Tfc cells was diminished but could be partially restored after antioxidant treatment., Conclusion: We present the phenotype of Tfc cells in CHB patients, with or without NAFLD. Our findings provide evidence that the long-term memory identity and functionality of Tfc cells are impaired in CHB + NAFLD patients. Enhancing the characteristics of effector memory cells in Tfc through maintaining the redox balance may offer innovative therapeutic strategies for CHB + NAFLD patients., 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.)

Redox-active covalent organic frameworks (COFs) have been demonstrated as promising organic electrodes in many electrochemical devices. However, their inherently low conductivity significantly hinders the full utilization of their internal redox-active sites. To address this issue, a simple solvothermal method is used to in situ polymerize 2,4,6-triformylphloroglucinol (TP) and p-phenylenediamine (PA) on the surface of carbon nanotubes (CNTs), generating a nanocable-like COF-based nanocomposite, TpPa-COF@CNT nanocables, which contain abundant β-ketoenamine groups. By combining the high specific surface area and dense active sites of COFs with the superior conductivity of CNTs, the TpPa-COF@CNT nanocables as the anode in potassium-ion batteries displayed excellent performance. The reason is that the isomerization between the enolic and keto forms reinforces the stability of molecular architecture, while the transformation of active sites from C=N to C=O improves the K + adsorption capability. Notably, the TpPa-COF@CNT nanocable anode exhibits a high reversible capacity of 446.1 mAh g -1 at 0.1 A g -1 and maintains 282.5 mAh g -1 even after 2000 cycles at a higher current density of 2.0 A g -1 . Additionally, a full battery assembled with 3,4,9,10-Perylenetetracarboxylic dianhydride heat-treated at 450 °C as the cathode retains a reversible capacity of 273.6 mAh g -1 after 200 cycles at 0.1 A g -1 ., (© 2024 Wiley-VCH GmbH.)

Objective: This study aimed to evaluate the predictive performance of published amisulpride population pharmacokinetic (PopPK) models in schizophrenia patients with an external data set and establish remedial dosing regimens for nonadherent amisulpride-treated patients., Methods: A systematic search was conducted on PubMed, Embase, and Web of Science to identify PopPK models for evaluation. The evaluation process involved analyzing 390 serum concentration samples obtained from 361 Chinese adult inpatients diagnosed with schizophrenia. Model predictability was evaluated by prediction-based and simulation-based diagnostics. Based on validation results, a modified PopPK model was constructed to characterize amisulpride pharmacokinetic in our patients. Monte Carlo simulation was employed to investigate non-adherence scenarios and the impact of subsequently administered remedial regimens., Results: In the five assessed published models, four included trough concentrations from schizophrenia patients, and one combined single-dose data from healthy older adults and trough concentrations from older adults with Alzheimer's disease. The PE for population and individual predictions ranged from -92.89% to 27.02% and -24.82% to 4.04%, respectively. In the simulation-based diagnostics, the NPDE results indicated noticeable bias in all models. Therefore, a modified one-compartment model, with estimated creatinine clearance(eCLcr) as covariates on the apparent clearance (CL/F) of amisulpride, was developed. For delays in medication dosing, if the delay is within 12 hours, take half the missed dose right away, then resume the normal schedule; if the delay is up to 24 hours, just continue with the regular dosing schedule., Conclusion: Existing published models lack the necessary reliability for cross-center application. Future prospective studies are required to assess our model before integrating it into clinical practice. Model-based simulations provided a rational approach to propose remedial strategies for delayed or missed doses., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yan et al.)

Manganese (Mn) is an essential element for plant growth but can be toxic at high levels. Pecan (Carya illinoensis), an important nut-producing species, has been observed to exhibit tolerance to high Mn levels. In this study, pecan seedlings were exposed to a nutrient solution containing either 2 μM (control) or 1000 μM (excess) MnSO 4 to investigate the physiological mechanisms. Despite substantial increases in Mn concentration in all pecan tissues, the presence of excess Mn did not induce visible symptoms of Mn toxicity on pecan leaves, nor did it result in any changes in malondialdehyde (MDA) levels. Photosynthetic rate and chlorophyll fluorescence parameters also remained unchanged. Subsequent examination revealed more cell layers and greater cell numbers in leaf palisade mesophyll tissue of Mn-treated plants compared with the control group. Cell length, and cell area decreased significantly in response to excess Mn, but total chloroplast area was unchanged and chloroplast structure remained intact. Subcellular fractionation analysis demonstrated that the cell walls, and to a lesser extent the soluble fraction, contained the majority of the Mn in leaves. The presence of excess Mn caused a marked increase in leaf concentrations of malic acid and citric acid, potential chelators of Mn. Our results suggest that the majority of Mn was sequestered in the leaf cell walls and may have been present as less-toxic chelated organic acids, thereby safeguarding the primary Mn target, the chloroplast, and ultimately conferring robust Mn tolerance in pecan., 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 Masson SAS. All rights reserved.)

Background: Heart transplantation is a crucial intervention for severe heart failure, yet the challenge of organ rejection is significant. Bone marrow mesenchymal stem cells (BMSCs) and their exosomes have demonstrated potential in modulating T cells, dendtitic cells (DCs), and cytokines to achieve immunomodulatory effects. DCs, as key antigen-presenting cells, play a critical role in shaping immune responses by influencing T-cell activation and cytokine production. Through this modulation, BMSCs and their exosomes enhance graft tolerance and prolonging survival., Aim: To explore the immunomodulatory effects of exosomes derived from BMSCs overexpressing microRNA-540-3p (miR-540-3p) on cardiac allograft tolerance, focusing on how these exosomes modulating DCs and T cells activity through the CD74/nuclear factor-kappaB (NF-κB) pathway., Methods: Rat models were used to assess the impact of miR-540-3p-enhanced exosomes on immune tolerance in cardiac allografts. MiR-540-3p expression was manipulated in BMSCs, and derived exosomes were collected and administered to the rat models post-heart transplantation. The study monitored expression levels of major histocompatibility complex II, CD80, CD86, and CD274 in DCs, and quantified CD4 + and CD8 + T cells, T regulatory cells, and cytokine profiles., Results: Exosomes from miR-540-3p-overexpressing BMSCs lead to reduced expression of immune activation markers CD74 and NF-κB p65 in DCs and T cells. Rats treated with these exosomes showed decreased inflammation and improved cardiac function, indicated by lower levels of pro-inflammatory cytokines (interleukin-1β, interferon-γ) and higher levels of anti-inflammatory cytokines (interleukin-10, transforming growth factor β1). Additionally, miR-540-3p skewed the profiles of DCs and T cells towards immune tolerance, increasing the ratio of T regulatory cells and shifting cytokine secretion to favor graft acceptance., Conclusion: Exosomes derived from BMSCs overexpressing miR-540-3p significantly enhance immune tolerance and prolong cardiac allograft survival by modulating the CD74/NF-κB pathway, which regulates activities of DCs and T cells. These findings highlight a promising therapeutic strategy to improve heart transplantation outcomes and potentially reduce the need for prolonged immunosuppression., Competing Interests: Conflict-of-interest statement: The Yunan Labreal Biotech Ltd, co. provided the research materials in the animal experiment. Although the animal experiment was performed in the platform of a private company, they did not aware of or interfere the experimental propose and not participate in the writing, review, and publication of this manuscript. No economic interests were appeared., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Akkermansia muciniphila , a Gram-negative anaerobic bacterium colonizing the intestinal mucus layer, is regarded as a promising "next-generation probiotic". There is mounting evidence that diabetes and its complications are associated with disorders of A. muciniphila abundance. Thus, A. muciniphil and its components, including the outer membrane protein Amuc&#95;1100, A. muciniphila -derived extracellular vesicles (AmEVs), and the secreted proteins P9 and Amuc&#95;1409, are systematically summarized with respect to mechanisms of action in diabetes mellitus. Diabetes treatments that rely on altering changes in A. muciniphila abundance are also reviewed, including the identification of A. muciniphila active ingredients, and dietary and pharmacological interventions for A. mucinihila abundance. The potential and challenges of using A. muciniphila are also highlighted, and it is anticipated that this work will serve as a reference for more in-depth studies on A. muciniphila and diabetes development, as well as the creation of new therapeutic targets by colleagues domestically and internationally.

Understanding how children acquire syntactic structures from a limited set of grammatical rules and use them creatively to convey meaning has been a longstanding interest for scientific communities. Previous studies on syntactic development have revealed its close correlation with the development of vocabulary and working memory. Our study sought to elucidate how the relations between syntactic processing, word processing, and working memory were instantiated in the brain, and how earlier neural patterns might predict language abilities one year later. We employed functional near-infrared spectroscopy to examine among preschool children (N=50, M age =61.5 months) the neural activation associated with processing sentences of varying syntactic complexities, as well as tasks assessing word comprehension and working memory. The results revealed greater brain activation in the left inferior frontal gyrus (IFG) for syntactically complex as compared to simple sentences, and the activation magnitude was correlated with working memory. There was also a link between neural activity for sentence comprehension and word comprehension in bilateral superior temporal regions (STG). Moreover, the inter-regional and inter-hemispheric connectivity of IFG and STG/MTG could successfully predict children's future language comprehension one year later. The findings provide new insights into how the brain supports syntactic development and its interplay with word processing and working memory., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer metastasis is responsible for more than 90% of tumor-related deaths. Especially, metastatic breast cancer (MBC) is a common malignancy with a high mortality among women worldwide. It is urgent to develop effective drugs for the treatment of MBC. Herein, biomimetic chemotherapeutic drug-gene nanoparticles (named TPT-ASO VEGF @MM NPs) were constructed for the combination therapy of MBC. First, topotecan hydrochloride (TPT) and vascular endothelial growth factor antisense oligonucleotide (ASO VEGF ) were coself-assembled in water through electrostatic interaction to produce chemotherapeutic drug-gene nanoparticles (TPT-ASO VEGF NPs). Then, the nanoparticles were encapsulated within macrophage membranes (MM) to form biomimetic TPT-ASO VEGF @MM NPs with long circulation time in blood and active tumor-targeting ability. TPT-ASO VEGF @MM NPs can be effectively internalized by breast cancer cells and then the nanoparticles collapse to simultaneously release TPT and ASO VEGF . ASO VEGF can inhibit the expression of VEGF, impeding the process of neovascularization and blocking the metastatic pathway of cancer cells. Meanwhile, TPT can bind to the topoisomerase I-DNA complex to prevent DNA repair and replication, and further induce apoptosis of cancer cells. In addition, TPT can also affect hypoxia-inducible factor 1α (HIF-1α) expression and inhibit hypoxia-induced tumor metastasis to achieve synergistic therapy with ASO VEGF . In MBC mouse models, the in vivo inhibition rate of TPT-ASO VEGF @MM NPs for lung metastasis was 89.5%, with minor toxic side effects and the least number of metastatic nodules in the lungs. In summary, TPT-ASO VEGF @MM NPs would be a promising biomimetic nanodrug for chemo-gene combination therapy of MBC with high efficacy and safety in clinics.

Reversible electrodeposition and dissolution of manganese oxide (MnO 2 ) represent an emerging electrochromic system. However, challenges such as "dead MnO 2 " formation, limited optical modulation across a narrow wavelength range, and difficulties in scaling up have significantly hindered the development of MnO 2 reversible electrodeposition-based electrochromic windows. In this work, we introduced Fe 2+ /Fe 3+ mediator ions into the electrolyte to suppress the Jahn-Teller effect, thereby preventing the formation of "dead MnO 2 " and achieving stable and reversible MnO 2 deposition/dissolution. Furthermore, by employing WO 3 as the counter electrode, we developed a complementary electrochromic device based on ion insertion and metal oxide deposition. This complementary system exhibits color neutrality in the colored state and high optical contrast across the entire visible spectrum, with an average optical modulation of 67.3%, excellent cycling stability (85.0% retention after 3000 cycles), and capability to switch uniformly over areas as large as 100 cm 2 .

Paclitaxel (PTX) is a first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC) but it can induce indoleamine 2,3-dioxygenase (IDO) activation, which severely lowers down its immuno-chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap-Phe-Phe-Phe-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-T), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap-T is gradually converted to Nap-Phe-Phe-Phe-Lys-Ser-Thr(H 2 PO 3 )-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-Tp), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno-chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Immune checkpoint inhibitor (ICI) therapies have made considerable advances in cancer immunotherapy, but the complex and diverse spectrum of ICI-induced toxicities poses substantial challenges to treatment outcomes and computational analysis. Here we introduce DySPred, a dynamic graph convolutional network-based deep learning framework, to map and predict the toxicity profiles of ICIs at the population level by leveraging large-scale real-world pharmacovigilance data. DySPred accurately predicts toxicity risks across diverse demographic cohorts and cancer types, demonstrating resilience in small-sample scenarios and revealing toxicity trends over time. Furthermore, DySPred consistently aligns the toxicity-safety profiles of small-molecule antineoplastic agents with their drug-induced transcriptional alterations. Our study provides a versatile methodology for population-level profiling of ICI-induced toxicities, enabling proactive toxicity monitoring and timely tailoring of treatment and intervention strategies in the advancement of cancer immunotherapy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Although several case reports and small clinical trials have reported promising outcomes with Janus kinase (JAK) inhibitors for vitiligo, high-quality evidence and guidelines are lacking. We evaluated the efficacy and safety of JAK inhibitors for the treatment of vitiligo using a meta-analysis of randomized controlled trials (RCTs). We searched the PubMed, Embase, and Cochrane Library databases up to August 2023, with additional studies from ClinicalTrials.gov and company websites. We assessed outcomes, including percentage improvement in total vitiligo area score index (TVASI) and facial vitiligo area score index (FVASI); the proportion of patients achieving 50% improvement in TVASI (TVASI50) and 50% and 75% improvement in FVASI (FVASI50 and FVASI75); the risk of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), infections, and skin-related adverse events (AEs). Five studies with 1,550 participants were included. JAK inhibitors were associated with a higher proportion of TVASI50 (relative risk [RR] 2.67, 95% confidence interval [CI] 1.24-5.78) and FVASI75 (RR 3.97, 95%CI 2.62-6.02) responders than placebo. JAK inhibitors significantly increased the risk of skin-related AEs (RR 1.96, 95% CI 1.29-2.98) compared with placebo. However, the risk of TEAEs, SAEs, and infections was not significantly different between the JAK inhibitor and placebo groups. Subgroup analysis showed that JAK1 and JAK1/2 inhibitors were more effective than JAK3 inhibitors. However, there was insufficient evidence to suggest that the route of administration affects the efficacy and safety of JAK inhibitors in vitiligo. These findings indicate that JAK inhibitors are effective in repigmentation and well tolerated in patients with vitiligo., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This paper presents research on the security performance of a multi-user interference-based mixed RF/FSO system based on SWIPT untrusted relay. In this work, the RF and FSO channels experience Nakagami-m fading distribution and Málaga (M) turbulence, respectively. Multiple users transmit messages to the destination with the help of multiple cooperating relays, one of which may become an untrusted relay as an insider attacker. In a multi-user network, SWIPT acts as a charging device for each user node. In order to prevent the untrusted relays from eavesdropping on the information, some users are randomly assigned to transmit artificial noise in order to interfere with untrusted relays, and the remaining users send information to relay nodes. Based on the above system model, the closed-form expressions of secrecy outage probability (SOP) and average secrecy capacity (ASC) for the mixed RF/FSO system are derived. The correctness of these expressions is verified by the Monte Carlo method. The influences of various key factors on the safety performance of the system are analyzed by simulations. The results show that the security performance of the system is considerably improved by increasing the signal-interference noise ratio, the number of interfering users, the time distribution factor and the energy conversion efficiency when the instantaneous signal-to-noise ratio (SNR) of the RF link instantaneous SNR is low.

Background & Aims: Abnormal regulation of lncRNA is strongly linked to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise molecular mechanisms remain unclear. This study explores the roles of noncoding RNA activated by DNA damage (NORAD)/miR-511-3p/Rho-associated protein kinase 2 (Rock2) axis and the NORAD/ROCK2 interaction in the development of MASLD., Methods: In vitro and in vivo models of MASLD were created using high-fat diet-fed mice and free fatty acid (FFA)-treated hepatocytes. To examine the relationships between NORAD, miR-511-3p, and ROCK2, we employed bioinformatics, luciferase assays, RNA immunoprecipitation, and biotinylated NORAD pull-down assays. MASLD progression was assessed based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation, white fat growth, and liver fibrosis., Results: NORAD and ROCK2 were upregulated, while miR-511-3p was downregulated in MASLD liver tissues and FFA-treated hepatocytes. Mechanistically, NORAD competitively interacted with miR-511-3p to modulate Rock2 mRNA expression, and directly stabilized ROCK2 protein by abrogating its ubiquitination degradation. Functionally, liver-specific knockdown of NORAD or overexpression of miR-511-3p significantly slowed MASLD progression. Overexpression of NORAD or ROCK2 partially reversed miR-511-3p-induced inhibition of MASLD. Additionally, ROCK2 knockdown attenuated NORAD-induced worsening of MASLD. Moreover, overexpressing NORAD or ROCK2 or interfering miR-511-3p influenced resmetirom treatment to suppress MASLD development. Finally, metabolic changes in liver driven by the NORAD/miR-511-3p/Rock2 axis and NORAD/ROCK2 interaction also influenced white adipose growth, pancreatic β-cell dedifferentiation, and liver fibrosis., Conclusions: The NORAD/miR-511-3p/Rock2 axis and the NORAD/ROCK2 interaction play critical roles in MASLD progression, identifying potential therapeutic targets for its treatment., Competing Interests: Declaration of competing interest There is no conflict of interest related to the manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Esophageal cancer is a major malignancy with a high incidence and poor prognosis. To elucidate the mechanisms underlying its progression, particularly with respect to cell division and spindle orientation, we investigated the role of m6A modifications and the centrosomal protein CEP170. Using m6A-seq and RNA-seq of esophageal cancer tissues and adjacent normal tissues, we identified significant alterations in m6A modifications and gene expression, highlighting the upregulation and m6A enrichment of CEP170 in tumor tissues. Functional assays, including cell cycle synchronization, qPCR, immunoblotting, immunofluorescence, coimmunoprecipitation, methylated RNA immunoprecipitation, and cell proliferation assays, demonstrated that CEP170 plays a critical role in mitotic progression and spindle orientation. m6A-seq and RNA-seq revealed significant alterations in m6A modifications and gene expression in esophageal cancer. CEP170 was upregulated and highly enriched in m6A modifications in tumor tissues. Functional assays revealed that CEP170 plays a critical role in proper mitotic progression and spindle orientation. Knockdown of CEP170 led to spindle misorientation and impaired the stability of astral microtubules. Additionally, CEP170 affected the localization of the dynein/dynactin motor complex in the cell cortex. METTL3 was upregulated in tumor tissues and regulated CEP170 expression. RNA-seq upon CEP170 depletion revealed that ASPM was significantly downregulated, indicating its involvement as a downstream target of CEP170 in regulating cell proliferation and mitosis. Our findings provide novel insights into the molecular mechanisms by which CEP170 and m6A modifications regulate esophageal cancer progression, revealing that CEP170 is a potential therapeutic target., 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.)

Pancreatic β-cell apoptosis plays a crucial role in the development of type 2 diabetes. Cytochrome c oxidase subunit 6A2 (COX6A2) and Farnesoid X Receptor (FXR) have been identified in pancreatic β-cells, however, whether they are involved in β-cell apoptosis is unclear. Here, we sought to investigate the role of FXR-regulated COX6A2 in diabetic β-cell apoptosis. We found that COX6A2 expression was increased in islets from diabetic animals, whereas FXR expression was suppressed. Notably, overexpression of COX6A2 facilitated β-cell apoptosis, whereas its deficiency attenuated this process and ameliorates type 2 diabetes, suggesting a pro-apoptotic role of COX6A2 in β-cells. Mechanistically, increased COX6A2 interacted with and enhanced the expression of voltage-dependent anion channel 1 (VDAC1), thereby promoting the mitochondrial translocation of Bax, leading to the release of cytochrome c from the mitochondria to the cytoplasm and ultimately causing β-cell apoptosis. Moreover, FXR negatively regulated COX6A2 expression through the inhibition of histone acetyltransferase p300 occupancy, diminishing histone H3 acetylation at lysine 27 on the Cox6a2 promoter. Furthermore, the deficiency of FXR intensified β-cell apoptosis under diabetic situations. Thus, it is probable that in diabetogenic environments, reduced FXR expression contributes to enhanced COX6A2 expression, culminating in β-cell apoptosis. These findings emphasize the essential involvement of the FXR/p300 pathway-controlled COX6A2 in β-cell apoptosis, revealing a previously undiscovered mechanism underlying diabetic β-cell apoptosis., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: Ethics approval for animal work was provided by the Institutional Animal Care and Use Committee of Shenzhen University Medical School (Approval Number: IACUC-202300082). All methods performed in this study were in accordance with the relevant institutional guidelines and regulations. This study did not involve human participants, and therefore did not require any related ethical approval or consent to participate., (© 2024. The Author(s).)

Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematologic malignancies but has encountered challenges in effectively treating solid tumors. One major obstacle is the presence of the immunosuppressive tumor microenvironment (TME), which is mainly built by myeloid-derived suppressor cells (MDSCs). Recent studies have shown that MDSCs have a detrimental effect on CAR-T cells due to their potent immunosuppressive capabilities. Targeting MDSCs has shown promising results to enhance CAR-T immunotherapy in preclinical solid tumor models. In this review, we first highlight that MDSCs increase tumor proliferation, transition, angiogenesis and encourage circulating tumor cells (CTCs) extravasation leading to tumor progression and metastasis. Moreover, we describe the main characteristics of the immunosuppressive activities of MDSCs on T cells in TME. Most importantly, we summarize targeting therapeutic strategies of MDSCs in CAR-T therapies against solid tumors. These strategies include (1) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (2) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (3) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (4) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (5) CAR-T directly targeting MDSC selective antigens. In the near future, we are expected to witness the improvement of CAR-T cell therapies for solid tumors by targeting MDSCs in clinical practice., Competing Interests: Declarations. Ethics approval and consent to participate: The review did not involve any primary data collection or human subjects research, thus eliminating the need for ethical approval and participant consent. Consent for publication: All authors have agreed to publish this manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: CMTM6 has been closely associated with the onset and progression of various tumor types. However, the precise mechanism by which CMTM6 operates in hepatocellular carcinoma remains elusive, necessitating further investigation., Methods: Expression levels of CMTM6 in hepatocellular carcinoma tissues and cells were analyzed using immunohistochemistry and quantitative real-time PCR. The correlation between CMTM6 expression in hepatocellular carcinoma tissues and clinical pathological characteristics, as well as patient prognosis, was investigated. Proliferation and apoptosis of hepatocellular carcinoma cells with silenced or overexpressed CMTM6 were assessed, alongside measurements of β-catenin and Wnt1 protein expression levels. In vivo research was conducted utilizing a murine subcutaneous transplantation model. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to elucidate the regulatory mechanism of CMTM6. Additionally, CD66b expression levels in tumor tissue were examined using immunohistochemistry, and the immune infiltration of CMTM6 and tumor-associated neutrophils (TANs) was analyzed., Results: Elevated expression levels of CMTM6 in hepatocellular carcinoma tissues and cells were found to be associated with poor patient prognosis. Overexpression of CMTM6 in hepatocellular carcinoma cells was demonstrated to promote cellular proliferation and inhibit apoptosis. Mechanistically, CMTM6 expression levels in hepatocellular carcinoma tissues were observed to positively correlate with β-catenin expression. GSEA and KEGG analysis revealed significant enrichment of CMTM6 in the Wnt/β-catenin pathway, indicating its involvement in pathway regulation. Furthermore, CMTM6 was found to be associated with immune infiltration of TANs in hepatocellular carcinoma tissues., Conclusion: CMTM6 plays a pivotal role in the development and progression of hepatocellular carcinoma through regulation of the Wnt/β-catenin pathway via β-catenin. Moreover, CMTM6 demonstrates the capacity to promote immune infiltration of TANs in hepatocellular carcinoma tissues. Consequently, CMTM6 exhibits potential as both an early diagnostic marker and a novel therapeutic target for patients with hepatocellular carcinoma., Competing Interests: Declarations. Ethics approval and consent to participate: This study received approval from the Independent Ethics Committee of Tumor Hospital Affiliated to Xinjiang Medical University in 2023. The ethics approval number is G-2023032. Informed consent: Informed consent was obtained from all individual participants included in this study. The data supporting the conclusions presented in this article are incorporated within the manuscript. The raw datasets utilized and analyses performed in this study are available from the corresponding author upon submission of a reasonable request. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

One-dimensional nitrogen-doped carbon nanotube wrapped NiS 2 core-shell nanoboxes have been developed. The hollow interior and protective carbon layer significantly enhance sodium storage properties, showing high reversible capacities and superior cycling stability at high current densities. Density functional theory calculations indicated that the heterostructure remarkably enhances the charge transfer process.

Background: Raloxifene was approved for the treatment of postmenopausal osteoporosis; however, its safety profile remains inadequately understood. This study aimed to evaluate the safety signals associated with raloxifene., Research Design and Methods: Adverse events (AEs) related to raloxifene, spanning from the first quarter of 2004 to the fourth quarter of 2023, were extracted from the FDA Adverse Event Reporting System (FAERS) database. A disproportionality analysis was conducted using several methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM)., Results: The analysis yielded 7 229 reports related to raloxifene across 19 277 AEs. A total of 217 significantly disproportionate signals were identified, including muscle spasms and hot flashes. Notably, the study also uncovered novel AEs, including eye conditions like cataracts and macular degeneration, as well as gynecological issues like uterine polyps and hemorrhage. Additionally, the analysis confirmed that pulmonary embolism and deep vein thrombosis were the two most prevalent thromboembolic AEs., Conclusion: Our study reaffirmed some existing safety information regarding raloxifene while also unveiling novel risk signals. The findings provided crucial insights to enhance the rational use of the drug and inform safety regulatory strategies.

SiO is a widespread molecule found in interstellar space, and its dissociation requires a substantial input of energy due to its high bond energy of 8.34 eV. The present study initially demonstrated across a broad range of ultraviolet (UV) wavelengths (243-288 nm) the one-photon and two-photon dissociation of SiO molecules, which were generated from the laser ablation of a Si rod colliding with an oxygen molecular beam. The images of Si products obtained through time-sliced ion velocity mapping have revealed the existence of distinct dissociation channels, encompassing Si( 3 P) + O( 3 P), Si( 1 D) + O( 3 P), Si( 1 D) + O( 1 D) and Si( 1 S) + O( 1 D) from the photodissociation of vibrationally excited SiO(X 1 Σ + , v ) and low-lying electronically excited SiO(C 1 Σ - , D 1 Δ, a 3 Σ + , b 3 Π, d 3 Δ and e 3 Σ - ) states. These findings contribute to a more comprehensive understanding of silicon chemistry during the combustion of silica-rich meteorites in the Earth's atmosphere, and have wider implications in the fields of atmospheric chemistry, astrochemistry, and combustion science.

In this study, a homogeneous polysaccharide, named YDOP-1 was isolated form Dendrobium officinale using hot water extraction and ethanol precipitation method. YDOP-1 was characterized to be a typical O-acetyl-glucomannan with the molecular wight was 13,456 Da. Cell viability and colony forming assay showed that YDOP-1 possess moderate anti-gastric cancer effects. In order to further improve the anti-gastric cancer effects of YDOP-1, a selenium modification on YDOP-1 was performed. Energy dispersive spectrometer (EDS) and X-ray photoelectron spectroscopy (XPS) analysis demonstrated that the Se was successfully introduced into YDOP-1 by forming SeO bonds. Se modification significantly enhanced the anti-gastric cancer effects of YDOP-1, which could effectively inhibit the proliferation of MGC-803 cells via suppressing colony and inducing apoptosis by regulating the apoptosis proteins of Bax, Bcl-2, and Caspase-7. Our results indicated that the Se modified O-acetyl-glucomannan, YDOP-Se, was expected to be useful in the biomedicine field for the gastric cancer 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 B.V.)

Plants need to adapt to fluctuating atmospheric humidity and respond to both high and low humidity. Despite our substantial understanding of plant responses to low humidity, molecular mechanisms underlying the high humidity (HH) response are much less well understood. In this study, we investigated early responses to HH in Arabidopsis . Expression of CYP707A3 , encoding an abscisic acid (ABA) 8'-hydroxylase, is induced by HH within 10 min, which leads to a decrease in foliar ABA level. We identified that the combined action of CAMTA3 and CAMTA2 transcription factors regulate this response. This regulation requires a calmodulin (CaM)-binding domain of CAMTA3. Transcriptomes of HH-regulated genes are enriched in those related to calcium signaling, including cyclic nucleotide-gated ion channels (CNGCs). Moreover, HH induces CNGC2- and CNGC4-mediated increases in cytosolic Ca 2+ concentrations in leaves within a few minutes. We also found that CNGC2, CNGC4, and CAMTAs participate in HH-induced hyponastic movement of petioles. Taken together, our results indicate that CNGC2/CNGC4-Ca 2+ -CaM-CAMTA3/CAMTA2 acts as a primary regulatory module to trigger downstream HH responses., Competing Interests: Competing interests statement:The authors declare no competing interest.

Pythium spp. are soil-borne pathogens that cause damping-off and root rot diseases in many plant species such as cucumber. In the current study, the effect of dried roots-stems and leaves of Ageratina adenophora (Sprengel) R. King and H. Robinson (= Eupatorium adenophorum Sprengel) alone and in combination with pyrogenic biomass biochar to control Pythium aphanidermatum (Edson) Fitz was assessed. In four treatments of leaves, roots-stems, leaves + biochar, and roots-stems + biochar, it was observed that the treatment with leaves at an E max (maximal effective concentration on control fungi) of 79 g/kg of soil had the most antifungal effect on P. aphanidermatum . Also, the C max (the highest level of control) increased with time and reached 82.4% and 71% on days 30 and 60, respectively. The highest cucumber fresh fruit weight and the highest height of the stems in the greenhouse were observed in leaf treatment of A. adenophora . Biochar did not have any remarkable controlling effect on P. aphanidermatum , and its population increased. The main compounds extracted from the dried leaves and roots-stems of A. adenophora , including α-pinene, nonanone, hexahydronaphthalene, 3-undecanone, muurolene, and heneicosane, had antifungal properties. We concluded that the leaves of A. adenophora have the potential to be used as a bio-fumigant for P. aphanidermatum management.