Search

Diabetic microvascular dysfunction is evidenced by disrupted endothelial cell junctions and increased microvascular permeability. However, effective strategies against these injuries remain scarce. In this study, the type 2 diabetes mouse model was established by high-fat diet combined with streptozotocin injection in Rnd3 endothelial- specific transgenic and knockout mice. Echocardiography was employed to evaluate cardiac function. Microvascular corrosion casts, lanthanum nitrate perfusion, trans- endothelial electrical resistance, FITC-dextran permeability assay and laser speckle contrast imaging were performed to evaluate the integrity of endothelial cell junctions and microvascular function. RNA sequencing, mass spectrometry, co-immunoprecipitation, immunofluorescence and molecular docking were used to explore the downstream regulators of Rnd3. Evidence from gain/loss-of-function studies denoted a protective role for Rnd3 against microvascular dysfunction in diabetic heart. Endothelial-specific deletion of Rnd3 significantly exacerbated coronary microvascular barrier dysfunction under diabetic conditions, while Rnd3 overexpression effectively prevented these effects. Furthermore, Rnd3 overexpression also attenuated cardiac dysfunction in diabetic mice, as indicated by increased LVEF, LVFS, and E/A ratio. Rnd3 overexpression inhibited CMECs apoptosis and increased CMECs migration in response to HG-PA challenge. Rnd3 overexpression inhibited Rock1 activity and MLC phosphorylation in CMECs treated with HG-PA stimulus. Mechanically, Rnd3 recruited and interacted with the E3 ubiquitin ligase Trim40 which further facilitated the degradation of Rock1, thus inhibiting endothelial barrier hyperpermeability in HG-PA-stimulated CMECs. However, the cardioprotective effects of Rnd3 were largely abrogated by Trim40 deficiency in diabetic conditions. Collectively, Rnd3 alleviates microvascular hyperpermeability, maintains endothelial barrier integrity, and mitigates cardiac dysfunction by regulating the Rock1/MLC signaling pathway in the state of DCM., (© 2025 by the American Diabetes Association.)

Purpose: To evaluate the impact of maximal transurethral resection of bladder tumor (TURBT) on perioperative outcomes following radical cystectomy (RC)., Methods: This study included 310 patients who underwent RC for the diagnosis of bladder urothelial carcinoma. Of these, 146 patients had a history of maximal TURBT (TURBT group) and 164 did not (non-TURBT group). Patients in the TURBT group were categorized into four groups according to the time interval between the last TURBT and RC: ≤ 1 month, 1-3 months, 3-6 months, and > 6 months. Additionally, the TURBT group was stratified into a single TURBT group and multiple TURBT group. Perioperative outcomes were compared between the groups., Results: The median duration of pelvic drainage tube retention was longer in the TURBT group (11 vs. 9 days, p = 0.037). The incidence of Clavien-Dindo ≥ 3 complications (15.3% vs. 7.3%, p = 0.031) and ICU admission rate(10.4% vs. 4.5%, p = 0.048) were higher in the TURBT group. Statistically significant differences were observed in the incidence of Clavien-Dindo ≥ 3 complications (p = 0.007), reoperation rates (p = 0.041), incidence of sepsis (p = 0.022), and urinary complications (p = 0.024) across the four groups stratified by the time interval between TURBT and RC, with the 1-3 to months group demonstrating the highest incidence. There was no significant difference in perioperative outcomes between patients who underwent a single TURBT and those who underwent multiple TURBT., Conclusion: Patients with a history of maximal TURBT, especially those who underwent RC within 1-3 months after maximal TURBT, have an increased risk of unfavorable perioperative outcomes following RC., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Lanzhou University Second Hospital (Date.28 August 2023/No.2023A-536)., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Background and Objectives: Deep brain stimulation (DBS) is a well-established intervention for alleviating both motor and nonmotor symptoms of Parkinson disease. However, a common complication of stereotaxic DBS surgery is pneumocephalus, which can compromise electrode accuracy, complicate postoperative assessments, and negatively affect the long-term outcomes of DBS surgery. This report proposes a comprehensive and robust set of recommendations aimed at optimizing DBS surgical protocols to achieve zero pneumocephalus outcomes., Methods: A retrospective analysis was undertaken on 138 patients with Parkinson disease who underwent simultaneous bilateral stereotaxic DBS targeting either the subthalamic nucleus or the globus pallidus internus at a single institution. The study compared the pneumocephalus volume and postsurgical electrode tip displacement between the original surgical technique and a refined procedure that incorporated modified supine position, dural puncture, and liquid sealing., Results: With the implementation of the refined procedure, the volume of pneumocephalus significantly decreased from 14.40 ± 17.00 to 0.32 ± 1.02 mL, with 92.9% of patients showing no visible pneumocephalus or intracranial air less than 1 mL. In addition, the refined procedure was associated with less electrode tip displacement in the postoperative stage., Conclusion: The refined procedure effectively minimized the average pneumocephalus volume to approximately 0, and bilateral DBS electrodes exhibited enhanced stability during the postoperative stage., (Copyright © Congress of Neurological Surgeons 2025. All rights reserved.)

Nanozymes open up new avenues for amplifying signals in photoelectrochemical (PEC) biosensing, which are yet limited by the generated small-molecule signal reporters. Herein, a multifunctional nanoenzyme of Pt NPs/CoSAs@NC consisting of Co single atoms on N-doped porous carbon decorated with Pt nanoparticles is successfully synthesized for cascade catalytic polymerization of dopamine for constructing a highly sensitive photocurrent-polarity-switching PEC biosensing platform. Taking protein tyrosine phosphatase 1B (PTP1B) as a target model, Pt NPs/CoSAs@NC nanoenzymes are linked to magnetic microspheres via phosphorylated peptides. Upon dephosphorylation of PTP1B, Pt NPs/CoSAs@NC nanoenzymes with multiple enzyme-like activities, including peroxidase (POD)-like, catalase (CAT)-like, and oxidase (OXD)-like activities, are released and collected to induce the in situ cascade catalytic polymerization of dopamine on ZnCdS photoelectrode in the presence of H 2 O 2 . The generated polymer-molecule of polydopamine served as efficient signal reporter for simultaneously amplifying signal and switching photocurrent polarity, which not only improved the sensitivity but also enhanced the reliability. This biosensing platform is capable of sensitively quantifying PTP1B with ultralow detection limit (0.04 fM), wide linear range (0.1 fm-0.1 µm), and good applicability in complex biological samples. This work pioneers the utilization of nanozyme-based cascade catalytic polymerization strategy for improving sensitivity and reliability in biosensing technologies., (© 2025 Wiley‐VCH GmbH.)

Doxorubicin, a representative drug of the anthracycline class, is widely used in cancer treatment. However, Doxorubicin-induced cardiotoxicity (DIC) presents a significant challenge in its clinical application. Mitochondrial dysfunction plays a central role in DIC, primarily through disrupting mitochondrial dynamics. This study aimed to investigate the impact of Rnd3 (a Rho family GTPase 3) on DIC, with a focus on mitochondrial dynamics. Cardiomyocyte-specific Rnd3 transgenic mice (Rnd3-Tg) and Rnd3 LSP/LSP mice (N-Tg) were established for in vivo experiments, and adenoviruses harboring Rnd3 (Ad-Rnd3) or negative control (Ad-Control) were injected in the myocardium for in vitro experiments. The DIC model was established using wild-type, N-Tg, and Rnd3-Tg mice, with subsequent intraperitoneal injection of Dox for 4 weeks. The molecular mechanism was explored through RNA sequencing, immunofluorescence staining, co-immunoprecipitation assay, and protein-protein docking. Dox administration induced significant mitochondrial injury and cardiac dysfunction, which was ameliorated by Rnd3 overexpression. Further, the augmentation of Rnd3 expression mitigated mitochondrial fragmentation which is mediated by dynamin-related protein 1 (Drp1), thereby ameliorating the PANoptosis (pyroptosis, apoptosis, and necroptosis) response induced by Dox. Mechanically, the interaction between Rnd3 and Rho-associated kinase 1 (Rock1) may impede Rock1-induced Drp1 phosphorylation at Ser616, thus inhibiting mitochondrial fission and dysfunction. Interestingly, Rock1 knockdown nullified the effects of Rnd3 on cardiomyocytes PANoptosis, as well as Dox-induced cardiac remodeling and dysfunction elicited by Rnd3. Rnd3 enhances cardiac resilience against DIC by stabilizing mitochondrial dynamics and reducing PANoptosis. Our findings suggest that the Rnd3/Rock1/Drp1 signaling pathway represents a novel target for mitigating DIC, and modulating Rnd3 expression could be a strategic approach to safeguarding cardiac function in patients undergoing Dox treatment. The graphical abstract illustrated the cardioprotective role of Rnd3 in DIC. Rnd3 directly binds to Rock1 in cytoplasm and ameliorates mitochondrial fission by inhibiting Drp1 phosphorylation at ser616, thereby alleviating PANoptosis (apoptosis, pyroptosis, and necroptosis) in DIC., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: All experimental animal procedures were approved by the Animal Care and Use Committee of the Fourth Military Medical University and followed the Animal Research Advisory Committee of the National Institutes of Health guidelines (Approval ID: 20220617)., (© 2025. The Author(s).)

Introduction: The extraction of DNA is the basis of molecular biology research. The quality of the extracted DNA is one of the key factors for the success of molecular biology experiments., Objective: To select a suitable DNA extraction method for Chinese medicinal herbs and seeds., Methods: In this experiment, four commercial DNA extraction kits were used to extract the genomic DNA (gDNA) from the Pinellia ternata (Thunb.) Breit. powder; Arisaema amurense Maxim. powder as well as the seeds of Glycine max (L.) Merr. On the one hand, the concentration and purity of DNA extracted by these four kits were compared. On the other hand, nucleic acid amplification experiments were performed on three samples extracted by each of the four kits by Proofman-LMTIA methods, which is a novel nucleic acid isothermal amplification technique. The concentration and purity of DNA extracted by different kits were used to determine which methods were suitable for the dry powder of Chinese herbal medicines and seeds. The efficiency of the amplification curve to show whether the extracted DNA can be used in nucleic acid amplification experiments., Results: The results showed that the Proofman-LMTIA methods were of high specificity and the optimal reaction temperatures were 63, 59, and 59°C for P. ternata (Thunb.) Makino; A. amurense Maxim. and G. max (L.) Merr., respectively. The concentration and purity of the gDNAs extracted with all kits were within the acceptable ranges; meanwhile, the amplification of the gDNA extracted by Kit II was of the highest efficiency., Conclusion: In this experiment, the principle, concentration, purity, and time taken for extracting DNA with four kits were compared. The automated extraction kit based on the magnetic method is suitable for extracting DNA from Chinese medicinal herbs and seeds. The extracted DNA is suitable for nucleic acid amplification detection., (© 2024 John Wiley & Sons Ltd.)

Type 2 diabetes mellitus (T2DM) is associated with cellular abnormalities, tissue and organ dysfunctions, and periodontitis. This investigation examined the relationship between the oral microbiome and salivary biomarkers in T2DM patients with or without periodontitis. This cohort (35-80 years) included systemically healthy non-periodontitis (NP; n = 31), T2DM without periodontitis (DWoP; n = 32) and T2DM with periodontitis (DWP; n = 29). The oral microbiome [Operational Taxonomic Units (OTUs)] (16 s rRNA sequencing) and targeted host salivary biomarkers (immunoassays) were assessed. We identified 47 OTUs that were significantly different in abundance between NP samples and any disease subset or between disease subgroups. The most unique microbiome patterns were observed in the DWP group. Differences in genera/species abundance were also observed when T2DM patients were stratified by extent of periodontal inflammation and disease (i.e., generalized versus localized gingivitis/periodontitis). Salivary biomarkers showed significant elevations in MMP-8, MMP-9, resistin, IL-1β, IL-6, IFNα, and BAFF (THFSR13b) comparing generalized to localized periodontitis. Salivary analytes showed significant positive correlations with specific microbiome members, predominantly in DWP patients. Odds ratio analyses reinforced that a panel of biologic markers (IL-6, MMP-8) and bacteria (e.g., Bacteroidetes, Fusobacteria, Spirochaetes) discriminated the severity and extent of periodontal disease in this diabetic population., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The high-entropy concept affords an effective method to design and construct customized materials with desired characteristics for specific applications. Extending this concept to metal oxides, high-entropy oxides (HEOs) can be fabricated, and the synergistic elemental interactions result in the four core effects, i.e., the high-entropy effect, sluggish-diffusion effect, severe-lattice-distortion effect, and cocktail effect. All these effects greatly enhance the functionalities of this vast material family, surpassing conventional low- and medium-entropy metal oxides. For instance, the high phase stability, excellent electrochemical performance, and fast ionic conductivity make HEOs one of the hot next-generation candidate materials for electrochemical energy conversion and storage devices. Significantly, the extraordinary mechanical, electrical, optical, thermal, and magnetic properties of HEOs are very attractive for applications beyond catalysts and batteries, such as electronic devices, optic equipment, and thermal barrier coatings. This review will overview the entropy-stabilized composition and structure of HEOs, followed by a comprehensive introduction to the electrical, optical, thermal, and magnetic properties. Then, several typical applications, i.e., transistor, memristor, artificial synapse, transparent glass, photodetector, light absorber and emitter, thermal barrier coating, and cooling pigment, are synoptically presented to show the broad application prospect of HEOs. Lastly, the intelligence-guided design and high-throughput screening of HEOs are briefly introduced to point out future development trends, which will become powerful tools to realize the customized design and synthesis of HEOs with optimal composition, structure, and performance for specific applications.

Objective: Long-term inhalation of silica dust particles leads to lung tissue fibrosis, resulting in impaired gas exchange and increased mortality. Silica inhalation triggers the aging of epithelial cells (AECs), which is a key contributor to the development of pulmonary fibrosis. Myricetin, a flavonoid compound extracted from Myrica genus plants, possesses various biological activities, including antioxidant and immunomodulatory effects. However, the mechanisms underlying myricetin's ability to counter senescence and fibrosis need to be further studied., Experimental Approach: In vivo, the antifibrotic and anti-senescence effects of myricetin were evaluated using a silica-induced pulmonary fibrosis mouse model. To further elucidate the mechanisms by which myricetin counteracts silica-induced senescence, in vitro experiments were conducted using AECs., Results: Our studies revealed that myricetin treatment alleviated silica-induced mortality, improved lung function, and reduced the severity of pulmonary fibrosis in mice. Immunofluorescence analysis suggests its potential in mitigating senescence of AECs. Under laboratory conditions, myricetin intervened in the cellular senescence pathway induced by silica dust by modulating mitochondrial function. It acted through the PPARγ-PGC1α axis, effectively reducing silica-induced mitochondrial oxidative stress in AECs, promoting mitophagy, and maintaining mitochondrial dynamics. However, the efficacy of myricetin was reversed under PPARγ siRNA intervention. Additionally, myricetin exhibited an enhancing effect on PPARγ and autophagy in animal models. Treatment with PPARγ and PGC-1α siRNA elucidated the role of myricetin in promoting the formation of a positive feedback loop between PPARγ and PGC-1α. Additionally, the PPARγ inhibitor GW9662 verified the in vivo effects of myricetin., Conclusions: Myricetin activates PPARγ, forming a PPARγ-PGC-1α loop, which promotes mitophagy and maintains mitochondrial dynamics. This alleviates epithelial cell senescence induced by silica exposure, consequently mitigating silica-induced pulmonary fibrosis in mice.

In the field of polymer mechanochemistry, the activation of mechanophores within linear polymers in the bulk state is often limited by low activation rates. Herein, we demonstrate that the crystallization of polymers can significantly enhance the activation of mechanophores. Employing rhodamine-containing poly(lactic acid) (PLA) and polycaprolactone (PCL) as representative examples, our study reveals that the micromechanical force generated by crystallization is more effective in activating mechanophores than the macroscopic mechanical force induced by compression and ultrasonication, which is particularly pronounced for polymers with low molecular weights. Furthermore, the activation of the mechanophore is found to be positively correlated with the degree of crystallinity and polymer molecular weight, whereas the chirality of polymers does not influence the activation. This study offers new insights into mechanochemical reactions induced by polymer crystallization and provides a novel approach to enhancing mechanochemical reactivity.

Introduction: The Northern Territory (NT) of Australia has the highest rates of alcohol consumption and injury in the country. We aimed to: (i) describe the epidemiology of alcohol-related injury (ARI) hospitalisations in the NT; (ii) estimate the proportion of alcohol involvement in injury hospitalisations; and (iii) consider the influence of alcohol policies on ARI hospitalisation trends., Methods: We conducted a retrospective time-series study using coded hospitalisation data from NT public hospitals between 2007 and 2022. ARI hospitalisation was defined combining indicators for injury and acute alcohol use. We undertook descriptive analyses and calculated alcohol involvement against all injury hospitalisations. Annual percent changes (APC) were computed using joinpoint regression to examine the influence of alcohol policies on ARI hospitalisation trends by NT geographical regions (Central Australia and Top End)., Results: Alcohol use was associated with 22.6% of all injury hospitalisations. The most common cause of ARI hospitalisations was assault (46%). In Central Australia, a significant trend decline (APC -12.2; p = 0.011) was observed after 2017 following alcohol policies implemented between 2017 and 2018 (Banned Drinkers Register v2; Minimum Unit Price; and Police Auxiliary Liquor Inspectors). Consecutive years with the greatest decrease in Central Australia were 2013-2014 (APC -25.8) and 2018-2019 (APC -35.1); likely influenced by alcohol policies in effect at the time. In the Top End, a non-significant trend decline (APC -26.1; p = 0.186) was observed after 2020., Discussion and Conclusions: Alcohol policies implemented between 2017 and 2018 were associated with reduced ARI hospitalisations in Central Australia. Alcohol policies that demonstrated reduced harm should be sustained., (© 2024 Australasian Professional Society on Alcohol and other Drugs.)

Abstract: Efferocytosis refers to the process that phagocytes recognize and remove the apoptotic cells, which is essential for maintaining tissue homeostasis both in physiological and pathological conditions. Numerous studies have demonstrated that efferocytosis can prevent secondary necrosis and proinflammatory factor release, leading to the resolution of inflammation and tissue immunological tolerance in numerous diseases such as stroke. Stroke is a leading cause of death and morbidity for adults worldwide. Persistent inflammation triggered by the dead cells or cell debris is a major contributor to post-stroke brain damage. Effective efferocytosis might be an efficient strategy to minimize inflammation and restore brain homeostasis for neuronal regeneration and function recovery. In this review, we will discuss the phagocytes in the brain, the molecular mechanisms underlying efferocytosis, the role of efferocytosis in inflammation resolution, and the potential therapeutic applications targeting efferocytosis in stroke., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Adipsin (complement factor D, CFD), as the first described adipokine, is well-known for its regulatory effects in diabetic cardiovascular complications. However, its role in diabetic hind-limb ischemia was not clarified. This study aimed to evaluate the possible therapeutic effect of Adipsin in hind-limb ischemia in type 2 diabetic mice and to elucidate the molecular mechanisms involved., Methods: A high-fat diet and streptozotocin (HFD/STZ)-induced diabetic mouse model, and a transgenic mouse model with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg) were employed. Hindlimb ischemia was established by femoral artery ligation, and blood flow recovery was monitored using Laser Doppler perfusion imaging. Molecular mechanisms underlying Adipsin-potentiated angiogenesis were examined using RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses., Results: Adipsin expression was upregulated in non-diabetic mice following HLI, while suppressed in diabetic mice, indicating its potential role in ischemic recovery which is impaired in diabetes. Adipsin-Tg mice exhibited significantly improved blood flow recovery, increased capillary density, and enhanced muscle regeneration in comparison with non-transgenic (NTg) diabetic mice. Adipsin facilitated proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) under hyperglycemic and hypoxic conditions. Additionally, it enhanced phosphorylation of AKT, ERK, and eNOS pathways both in vivo and in vitro. RNA sequencing and co-immunoprecipitation/mass spectrometry (Co-IP/MS) analyses identified that Adipsin promoted angiogenesis by interacting with SERBP1, which disrupted the binding of SERBP1 to SERPINE1 mRNA, resulting in reduced SERPINE1 expression and the subsequent activation of the VEGFR2 signaling cascade., Conclusions: Adipsin promotes angiogenesis and facilitates blood perfusion recovery in diabetic mice with HLI by downregulating SERPINE1 through interaction with SERBP1. These findings elucidate a novel therapeutic potential for Adipsin in the management of PAD in diabetic patients, highlighting its role in enhancing angiogenesis and tissue repair., Competing Interests: Declarations. Ethics approval and consent to participate: All experimental animal procedures were approved by the Animal Care and Use Committee of the Air Force Medical University and followed the Animal Research Advisory Committee of the National Institutes of Health guidelines (Approval ID: 20201017). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Inhalable microorganisms in airborne fine particulate matter (PM 2.5 ), including bacteria and phages, are major carriers of antibiotic resistance genes (ARGs) with strong ecological linkages and potential health implications for urban populations. A full-spectrum study on ARG carriers and phage-bacterium linkages will shed light on the environmental processes of antibiotic resistance from airborne dissemination to the human lung microbiome. Our metagenomic study reveals the seasonal dynamics of phage communities in PM 2.5 , their impacts on clinically important ARGs, and potential implications for the human respiratory microbiome in selected cities of China. Gene-sharing network comparisons show that air harbours a distinct phage community connected to human- and water-associated viromes, with 57 % of the predicted hosts being potential bacterial pathogens. The ARGs of common antibiotics, e.g., peptide and tetracycline, dominate both the antibiotic resistome associated with bacteria and phages in PM 2.5 . Over 60 % of the predicted hosts of vARG-carrying phages are potential bacterial pathogens, and about 67 % of these hosts have not been discovered as direct carriers of the same ARGs. The profiles of ARG-carrying phages are distinct among urban sites, but show a significant enrichment in abundance, diversity, temperate lifestyle, and matches of CRISPR (short for 'clustered regularly interspaced short palindromic repeats') to identified bacterial genomes in winter and spring. Moreover, phages putatively carry 52 % of the total mobile genetic element (MGE)-ARG pairs with a unique 'flu season' pattern in urban areas. This study highlights the role that phages play in the airborne dissemination of ARGs and their delivery of ARGs to specific opportunistic pathogens in human lungs, independent of other pathways of horizontal gene transfer. Natural and anthropogenic stressors, particularly wind speed, UV index, and level of ozone, potentially explained over 80 % of the seasonal dynamics of phage-bacterial pathogen linkages on antibiotic resistance. Therefore, understanding the phage-host linkages in airborne PM 2.5 , the full-spectrum of antibiotic resistomes, and the potential human pathogens involved, will be of benefit to protect human health in urban areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cardiovascular disease remains the leading cause of high mortality in individuals with diabetes mellitus. Endothelial injury is a major contributing factor for vascular dysfunction in diabetes. However, the precise mechanisms underlying endothelial cell injury and their heterogeneity in diabetes remains elusive. In this study, single-cell sequencing is performed in heart tissues from leptin receptor knock-out (db/db) diabetic mice at various pathological stages. Through cell cluster identification, differential gene analysis, intercellular communication analysis, pseudo time analysis, and transcription factor analysis, a novel mechanism of cardiac vascular endothelial damage in diabetes is identified. Specifically, a single-cell transcription map of cardiac vascular endothelial cells is presented in db/db mice. Diverse cellular clusters are found to play vital roles under diabetes-induced damage, highlighting crucial transcription factors involved in their regulation. In addition, the essential transcription factor Ets1 is found to protect against vascular endothelial injury in db/db mice. In summary, the work provides a comprehensive understanding of the development of diabetic cardiac vascular endothelial damage and the heterogeneity of the cells involved. These findings offer valuable insights into potential treatments and assessments of diabetic cardiovascular endothelial damage., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Actinic keratoses (AK) may progress into squamous cell carcinoma. Many combination therapies were used to improve the clearance rate. However, there are limited studies on the efficacy and safety of lesion-directed Liquid nitrogen cryotherapy combined with field-directed photodynamic therapy (PDT)., Objective: This study is aimed to determine the efficacy and safety of Liquid nitrogen cryotherapy combined with PDT in Chinese patients with actinic keratosis., Methods: A total of 61 patients with AK were selected at the Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College between August 2018 and August 2023. They were randomly divided into PDT plus Liquid nitrogen cryotherapy group (LN-PDT) and control PDT group (C-PDT) with 30 patients and 31 patients, respectively. 27 patients in the LN-PDT group and 28 patients in the C-PDT group completed the clinical sessions. Efficacy, adverse effects, and cosmetic outcomes were recorded and compared between the two groups., Results: 3 months after the final treatment, the clearance rates for total AK lesions were 97.4 % (449/461) in the LN-PDT group and 93.4 % (456/488) in the C-PDT group (P < 0.05). For grade I AK lesions, the clearance rates were 99.2 % (234/237) for the LN-PDT group and 98.3 % (237/241) for the C-PDT group (P >0.05). For grade II lesions, the clearance rates were 97.5 % (156/160) for the LN-PDT group and 91.9 % (172/186) for the CPDT group (P < 0.05). For grade III lesions, the clearance rates of the LN-PDT and C-PDT groups were 87.5 % (58/64) and 78.7 % (47/61), respectively (P < 0.05). The two groups had no significant differences in pain, erythema, edema, hyperpigmentation and scarring. Cosmetic outcomes mainly were excellent or good in both groups with no significant difference., Conclusion: Liquid nitrogen cryotherapy combined with PDT showed higher efficacy on grade II and grade III AK lesions than PDT alone. The two groups have similar adverse effects and cosmetic outcomes., (Copyright © 2024. Published by Elsevier B.V.)

Enhancing crop salt tolerance through genetics and genomics is important for food security. It is environmentally friendly and cost-effective in maintaining crop production in farmlands affected by soil salinization and can also facilitate the utilization of marginal saline land. Despite the limited success achieved so far, it is becoming possible to bridge the gap between fundamental research and crop breeding owing to a deeper understanding of plant salt tolerance at both physiological and molecular levels. Therefore, we review the recent key progress in identifying the molecular mechanisms contributing to plant salt tolerance with a focus on balancing growth and salt resilience. With the accruing knowledge and the rapidly evolving tools (e.g. genome editing and artificial intelligence), it is reasonable to expect the future salt-tolerant crops in a few decades., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Spontaneous pregnancy loss (SPL) precedes an increased risk of reduced fertility, while its etiology mechanism remains largely unknown. Liver dysfunction presenting in early pregnancy may represent a pre-existing undiagnosed liver condition affecting fetal development. Here, we investigated whether maternal abnormal liver function in early pregnancy contributed to the incidence of SPL., Methods: Data on pregnant women were leveraged from the Maternal Health Care Information System in Shanghai City from 2017 to 2021. Liver dysfunction status was defined as having any elevated liver function biomarker levels (LFBs) at the first antenatal visit. SPL cases were defined as fetal death occurring before 28 weeks gestation. Generalized linear models were used to estimate crude and adjusted risk ratios (aRRs) and 95% confidence intervals (CIs)., Results: Among 10175 leveraged pregnant women, 918 (9.0%) SPL cases were recorded. Maternal liver dysfunction in early pregnancy was associated with a 49% increased risk of SPL (RR 1.49, 95% CI 1.22-1.84). This positive association persisted after adjustment for covariates (aRR 1.55, 95% CI 1.26-1.92). Higher γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels were also linked with increased risk of SPL in a linear fashion (aRRs per 1 standard deviation increase: 1.13, 95% CI 1.08-1.17; 1.13, 1.07-1.20, respectively). Similar magnitudes of associations were observed between normal weight and overweight pregnant women in subgroup analysis., Conclusion: We provide new evidence that maternal abnormal liver function in early pregnancy, as well as GGT and ALP, predisposes to an increased risk of SPL.

Traditional methods for identifying "hit" molecules from a large collection of potential drug-like candidates rely on biophysical theory to compute approximations to the Gibbs free energy of the binding interaction between the drug and its protein target. These approaches have a significant limitation in that they require exceptional computing capabilities for even relatively small collections of molecules. Increasingly large and complex state-of-the-art deep learning approaches have gained popularity with the promise to improve the productivity of drug design, notorious for its numerous failures. However, as deep learning models increase in their size and complexity, their acceleration at the hardware level becomes more challenging. Hyperdimensional Computing (HDC) has recently gained attention in the computer hardware community due to its algorithmic simplicity relative to deep learning approaches. The HDC learning paradigm, which represents data with high-dimension binary vectors, allows the use of low-precision binary vector arithmetic to create models of the data that can be learned without the need for the gradient-based optimization required in many conventional machine learning and deep learning methods. This algorithmic simplicity allows for acceleration in hardware that has been previously demonstrated in a range of application areas (computer vision, bioinformatics, mass spectrometery, remote sensing, edge devices, etc.). To the best of our knowledge, our work is the first to consider HDC for the task of fast and efficient screening of modern drug-like compound libraries. We also propose the first HDC graph-based encoding methods for molecular data, demonstrating consistent and substantial improvement over previous work. We compare our approaches to alternative approaches on the well-studied MoleculeNet dataset and the recently proposed LIT-PCBA dataset derived from high quality PubChem assays. We demonstrate our methods on multiple target hardware platforms, including Graphics Processing Units (GPUs) and Field Programmable Gate Arrays (FPGAs), showing at least an order of magnitude improvement in energy efficiency versus even our smallest neural network baseline model with a single hidden layer. Our work thus motivates further investigation into molecular representation learning to develop ultra-efficient pre-screening tools. We make our code publicly available at https://github.com/LLNL/hdbind ., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: We investigated neonatal seizures in three probands admitted to the neonatal intensive care units and their affected family members., Methods: Whole exome sequencing (WES) was performed along with confirmation by Sanger sequencing and segregation analysis. Copy number variant (CNV) analysis was also conducted. Neuroimaging, electroencephalography, and metabolic analysis revealed clinical phenotypes., Results: Bi-allelic variants c.1025T>C and c.1150G>A in MOCS1 were found in twin girls with molybdenum cofactor deficiency. The c.1025T>C variant was novel. A c.877C>T variant in KCNQ2 co-segregated with seizures in a family. A de novo 6.25 Mb duplication on 2q24.3 encompassing SCN1A, SCN2A, and SCN3A was identified in a proband who demonstrated normal development without seizures on follow-up., Significance: WES facilitated the molecular diagnosis of neonatal seizures in the study participants. Variants in the KCNQ2 and MOCS1 genes were classified as likely pathogenic based on our findings. The individual with a duplication of the sodium channel gene cluster on 2q24.3 exhibited additional phenotypes. Our investigation expanded the genotype-phenotype spectrum., (© 2024 International League Against Epilepsy.)

Background: Acute lung injury (ALI) is the most lethal disease associated with sepsis, and there is a lack of effective drug treatment. As the major cells of sepsis-induced ALI, macrophages polarize toward the proinflammatory M1 phenotype and secrete multiple inflammatory cytokines to accelerate the disease process through nuclear factor kappa-B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways. Taraxerone, the main component of the Chinese medicinal Sedum, possesses numerous biological activities. However, uncertainty remains regarding the potential of taraxerone to protect against sepsis-induced ALI. This study aimed to investigate the effects and mechanisms of taraxerone against ALI., Methods: An animal model for ALI was established by cecal ligation and puncture and treated with taraxerone via intraperitoneal administration. The protective effect of taraxerone on the lungs was analyzed using H&E staining, dihydroethidium staining, ELISA kits, cell counting, myeloperoxidase kit, malondialdehyde kit, glutathione kit, superoxide dismutase kit and flow cytometry. Western blotting, RT-PCR, flow cytometry, co-immunoprecipitation, and immunofluorescence were used to investigate the regulatory of taraxerone on SIRT1., Results: Our study demonstrates for the first time that taraxerone can activate SIRT1 in macrophages, promoting SIRT1 activity. This activation inhibited the NF-κB signaling pathway primarily through the dephosphorylation and deacetylation of p65. Simultaneously, taraxerone disrupted the NLRP3 inflammasome signaling pathway, thereby alleviating M1 polarization of macrophages and mitigating sepsis-induced pulmonary inflammation and oxidative stress. In vivo, EX527 was used to validate the anti-inflammatory and anti-oxidative stress effects of taraxerone mediated by SIRT1., Conclusion: SIRT1-mediated anti-inflammatory and anti-oxidative stress effects may be important targets for taraxerone in treating ALI., Competing Interests: Declarations Ethics approval and consent to participate The animal experimental protocol was approved by Ethics Committee of the Center for Scientific Research with Animal Models at Central South University (Certificate No.CSU-2022–0586). Consent for publication Not applicable. Competing interests The authors declare there are no competing interests., (© 2024. The Author(s).)

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as a negative immune regulator of T-cell receptor signaling. Deprivation of the HPK1 function suppresses tumor growth, providing an attractive strategy for cancer immunotherapy. Herein, we present a novel PROTAC-based HPK1 degrader compound DD205-291 with high selectivity and potency. DD205-291 showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, DD205-291 exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of DD205-291 at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, DD205-291 exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that DD205-291 is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.

Background: The triglyceride-glucose (TyG) index has garnered recognition as a surrogate marker for insulin resistance, a pivotal factor in the pathogenesis of various metabolic disorders. Despite its emerging role, the empirical evidence delineating its association with prediabetes mellitus (Pre-DM) remains scant. This research aims to clarify the link between the TyG index and the likelihood of Pre-DM development within a Chinese demographic., Methods: This investigation was structured as a retrospective cohort analysis, encompassing a sample of 179,177 Chinese adults. These individuals underwent medical examinations at the Rich Healthcare Group over a period spanning from 2010 to 2016. To ascertain the relationship between the TyG index and the incidence of Pre-DM, this study employed Cox regression analysis complemented by sensitivity and subgroup assessments. Furthermore, Cox proportional hazards regression with cubic spline functions and smooth curve fitting was incorporated to explore the existence of any non-linear connection within this association., Results: Upon adjusting for a comprehensive array of confounding variables, a statistically significant positive correlation between the TyG index and the risk of Pre-DM was identified (HR: 1.60, 95%CI 1.56-1.65, P < 0.001). The analysis illuminated a non-linear relationship, with an inflection point at a TyG index value of 8.78. For TyG index values below and above this inflection point, the HR was calculated to be 1.94 (95%CI 1.86-2.03) and 1.26 (95%CI 1.20-1.33), respectively. Sensitivity analyses further fortified the reliability of these findings., Conclusions: This comprehensive examination delineated a significantly positive, non-linear correlation between the TyG index and the risk of Pre-DM within a Chinese population. Individuals with TyG index values below 8.78 have a significantly increased risk of developing prediabetes. These findings underscore the TyG index's potential efficacy as a predictive tool for assessing Pre-DM risk in clinical practice., (© 2024. The Author(s).)

Background and Aims: Many studies have shown a link between physical activity (PA) and nonalcoholic fatty liver disease (NAFLD). However, more research is needed to investigate the relationship between different types of PA and NAFLD. This study aimed to explore the potential link between different types of PA, hepatic steatosis, and liver fibrosis., Study: A cross-sectional study was conducted using the data set from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. A multiple linear regression model was used to examine the linear relationship between different types of PA, the controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). In addition, smoothing curve fitting and threshold effect analysis were used to depict their nonlinear relationship., Results: This study involved 5933 adults. Multiple linear regression analysis revealed a significantly negative correlation between leisure-time PA and CAP, while the relationship between occupation-related PA, transportation-related PA, and CAP was not significant. Subgroup analysis further revealed that leisure-time PA was significantly negatively correlated with CAP in women and younger age groups (under 60 y old), while the relationship was not significant in men and older age groups. In addition, there was a significant negative correlation between leisure-time PA and liver fibrosis in men., Conclusions: Leisure-time PA can prevent hepatic steatosis, and women and young people benefit more. Occupation-related PA is not associated with hepatic steatosis and cannot replace leisure-time PA. In men, increasing leisure-time PA is more effective in preventing liver fibrosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Resolving the intricate details of biological phenomena at the molecular level is fundamentally limited by both length- and time scales that can be probed experimentally. Molecular dynamics (MD) simulations at various scales are powerful tools frequently employed to offer valuable biological insights beyond experimental resolution. However, while it is relatively simple to observe long-lived, stable configurations of, for example, proteins, at the required spatial resolution, simulating the more interesting rare transitions between such states often takes orders of magnitude longer than what is feasible even on the largest supercomputers available today. One common aspect of this challenge is pathway discovery, where the start and end states of a scientific phenomenon are known or can be approximated, but the mechanistic details in between are unknown. Here, we propose a representation-learning-based solution that uses interpolation and extrapolation in an abstract representation space to synthesize potential transition states, which are automatically validated using MD simulations. The new simulations of the synthesized transition states are subsequently incorporated into the representation learning, leading to an iterative framework for targeted path sampling. Our approach is demonstrated by recovering the transition of a RAS-RAF protein domain (CRD) from membrane-free to interacting with the membrane using coarse-grain MD simulations.

An electride, characterized by unique interstitial anionic electrons (IAEs), offers promising avenues for modulating its superconductivity. The pressure-dependent coupling between IAEs and orbital electrons significantly affects the superconducting transition temperature ( T c ). However, existing research has predominantly concentrated on pressures within 300 GPa. To advance the understanding, we propose investigating the Li-S system under ultrahigh pressure to unveil novel electride superconductors. Five stable Li-rich electrides with diverse IAE topologies, including one Li 7 S, three Li 9 S, and one Li 12 S phases, are identified through structural search calculations. Among the Li 9 S phases, in the C 2/ c phase (600 GPa), the IAEs are connected to the S atomic extra-nuclear electrons with the unconventional d orbital attribute due to the extreme pressure, while two low-pressure R -3 (25 GPa) and C 2/ m (400 GPa) phases have interconnected IAEs. Due to its unique IAE attributes, C 2/ c Li 9 S exhibits the highest T c of 53.29 K at 600 GPa. Its superconductivity results from the coupling of the S d , Li p electrons, and IAEs with the low-frequency phonons associated with the attraction between IAEs and the Li-S framework. Our work enhances insights into IAEs within electrides and their role in facilitating superconductivity.

Single- and few-layer graphene-based thermal interface materials (TIMs) with extraordinary high-temperature resistance and ultra-high thermal conductivity are very essential to develop the next-generation integrated circuits. However, the function of the as-prepared graphene-based TIMs would undergo severe degradation when being transferred to chips, as the interface between the TIMs and chips possesses a very small interfacial thermal conductance. Here, a "2.5D" all-carbon interface containing rich covalent bonding, namely a sp 2 /sp 3 hybrid interfaces is designed and realized by a plasma-assisted chemical vapor deposition with a function of ultra-rapid quenching. The interfacial thermal conductance of the 2.5D interface is excitingly very high, up to 110-117 MWm -2  K -1 at graphene thickness of 12-25 nm, which is even more than 30 % higher than various metal/diamond contacts, and orders of magnitude higher than the existing all-carbon contacts. Atomic-level simulation confirm the key role of the efficient heat conduction via covalent C-C bonds, and reveal that the covalent-based heat transport could contribute 85 % to the total interfacial conduction at a hybridization degree of 22 at %. This study provides an efficient strategy to design and construct 2.5D all-carbon interfaces, which can be used to develop high performance all-carbon devices and circuits., (© 2024 Wiley-VCH GmbH.)

Advancing the compositional space of a compound class can result in intriguing superconductors, such as LaH 10 . Herein, we performed a comprehensive first-principles structural search on a binary B-C system with various chemical compositions. The identified diamond-like BC 15 , named d -BC 15 , is thermodynamically superior to the synthesized BC 3 and BC 5 . Interestingly, d -BC 15 shows anisotropic superconductivity resulting from three distinct Fermi surfaces. Its predicted critical temperature ( T c ) is 43.6 K at ambient pressure, beyond the McMillan limit. d -BC 15 reaches a maximum of around 75 K at 0.43% hole doping due to the substantially enhanced density of states at the Fermi level. Additionally, d -BC 15 demonstrates superhard characteristics with a Vickers hardness of 75 GPa. The calculated tensile and shear stresses are 72 and 73 GPa, respectively. The combination of high superconductivity and superhardness in d -BC 15 offers new insights into the design of multifunctional materials.

Compared to conventional fibers, electrospun porous nanofibers with hierarchical structures often involve additional active sites, interfaces, and internal spaces which boost the performances of functional materials. Here in this study, coaxial composite cellulose acetate@silk fibroin (CA@SF) fibrous membranes are constructed through an electrostatic spinning technique combining solvent-induced phase separation. Hierarchical core-shell structures on the fibers are achieved, which significantly increases the surface area and benefits the mechanical property, flux, as well as the electroless deposition of Ag nanoparticles. The total electromagnetic shielding efficiency of the sandwiched hierarchical CA@SF@Ag composite membrane with a thickness of only 100 μm reaches up to 100 dB, surpassing around 82% beyond nonhierarchical ones. To be noticed, when post-treated by ethanol, the membrane enables an enhanced tensile strength of up to 10 MPa with a thickness of only 50 μm. Our findings pave the way to the application of electrospun fiber membranes in the field of ultrathin electromagnetic shielding films.

Vitexin is a natural flavonoid glycoside compound extracted from the leaves and seeds of Vitex negundo. It is widely distributed in the leaves and stems of numerous plants and exhibites remarkable anti-tumor, anti-inflammatory, and anti-hypertensive properties. However, whether vitexin presents the anti-aging and senescence prevention effect has not been fully elucidated. The purpose of this study is to investigate the effect of vitexin on progeria mice and cellular senescence, as well as its underlying molecular mechanisms. To generate a premature aging/senescence model in vivo and in vitro, we used D-galactose (D-gal), hydrogen peroxide (H 2 O 2 ), and adriamycin (ADR), respectively. Our findings demonstrated that vitexin potentially delays D-gal-induced progeria mice; similar effects were observed in stress-induced premature senescent fibroblasts in culture. Interestingly, this effect of vitexin is closely correlated with the reduction of the senescence-associated secretory phenotype (SASP) and the inhibition of the SASP-related JAK2/STAT3 pathway. Furthermore, we determined that vitexin meets the pharmacological parameters using the freely available ADMET web tool. Collectively, our findings demonstrate that vitexin possesses anti-senescence and anti-aging properties due to the inhibition of SASP and suppression of JAK2/STAT3 signaling pathway., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The multimode assay based on multiple response mechanisms has received great attention to effectively improve the accuracy of a sensing platform. However, multifunctional sensing materials for simultaneously satisfying the multiple-mode detections are still in shortage due to the incompatibility of the signal transduction mechanisms in different modes. Here, taking human papillomavirus 16 (HPV-16) DNA (TDNA) as the model due to its important role in cervical cancer, a novel multifunctional material, ethyl violet (EV)@NH 2 -MIL-88B(Fe) (ENM) hybrids, have been successfully prepared, which could simultaneously satisfy CRISPR-Cas12a-assisted photoelectrochemical (PEC)-fluorescent (FL)-colorimetric (CL) triple-mode detection of TDNA. Based on the TDNA-induced trans-cleavage ability of CRISPR-Cas12a and efficient separation of magnetic beads, ENM was obtained from the single-stranded DNA-surrounded streptavidin-modified magnetic beads-ENM (SMB-ssDNA-ENM) and decomposed by pyrophosphate to get free EV, 2-aminoterephthalic acid (NH 2 -BDC), and Fe 3+ . Thus, TDNA was sensitively detected based on the EV-enhanced PEC signal of SnS 2 nanosheets (PEC mode), fluorescent signal of NH 2 -BDC (FL mode), and characteristic absorption peak at about 720 nm of Fe 3+ -induced Prussian blue (PB) (CL mode). The designed PEC-FL-CL triple-mode biosensing platform had good performance for the detection of TDNA with a wide linear range (0.1 fM-100 nM) and ultralow detection limits (0.07 fM for PEC, 0.03 fM for FL and 0.09 fM for CL). Additionally, the developed PEC-FL-CL triple-mode biosensing platform has great potential for applications in early disease diagnosis and bioanalysis, as it can be easily extended to other DNA assays through modification of the crRNA sequence within the CRISPR-Cas12a system.

Soil salinity is detrimental to plant growth and remains a major threat to crop productivity of the world. Plants employ various physiological and molecular mechanisms to maintain growth under salt stress. Identification of genes and genetic loci underlying plant salt tolerance holds the key to breeding salt tolerant crops. CIPK-CBL pathways regulate adaptive responses of plants (especially ion transport) to abiotic stresses via fine-tuned Ca 2+ signal transduction. In this study, we showed that over-expression of OsCIPK17 in Arabidopsis enhanced primary root elongation under salt stress, which is in a Ca 2+ dependent manner. Further investigation revealed that, under salt stress, OsCIPK17 transcript level was significantly induced and its protein moved from the cytosol to the tonoplast. Using both Y2H and BiFC, tonoplast-localised OsCBL2 and OsCBL3 were shown to interact with OsCIPK17. Interestingly, over-expressing salt-induced OsCBL2 or OsCBL3 in Arabidopsis led to enhanced primary root elongation under salt stress. In this process, OsCIPK17 was shown recruited to the tonoplast (similar to the effect of salt stress). Furthermore, transgenic Arabidopsis lines individually over-expressing OsCIPK17, OsCBL2 and OsCBL3 all demonstrated larger biomass and less Na  +  accumulation in the shoot under salt stress. All data combined suggest that OsCIPK17- OsCBL2/3 module is a major component of shoot Na + exclusion and therefore plant salt tolerance, which is through enhanced Na  +  compartmentation into the vacuole in the root. OsCIPK17 and OsCBL2/3 are therefore potential genetic targets that can be used for delivering salt tolerant rice cultivars., 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 Masson SAS.)

Controlling the growth of microbial consortia is of great significance in the biomedical field. Selective bacterial growth is achieved by fabricating silk inverse opal (SIO) scaffolds with varying pore sizes ranging from 0.3 to 4.5 µm. Pore size significantly influences the growth dynamics of bacteria in both single and mixed-strain cultures. Specially, the SIO-4.5 µm scaffold is observed to be more favorable for cultivating S. aureus, whereas the SIO-0.3 µm scaffold is more suitable for cultivating E. coli and P. aeruginosa. By adjusting the secondary conformation of silk fibroin, the stiffness of the SIO substrate will be altered, which results in the increase of bacteria on the SIO by 16 times compared with that on the silk fibroin film. Manipulating the pore size allows for the adjustment of the S. aureus to P. aeruginosa ratio from 0.8 to 9.3, highlighting the potential of this approach in regulating bacterial culture., (© 2024 Wiley‐VCH GmbH.)

Background: Relative fat mass (RFM) is a newly developed, sex-specific anthropometric formula designed to estimate total body fat percentage. However, research investigating the correlation between RFM and the risk of non-alcoholic fatty liver disease (NAFLD) remains limited. This study evaluates the association between RFM and the risk of NAFLD within the Japanese population., Methods: This study including 14,250 Japanese adults who underwent physical examinations at Murakami Memorial Hospital between 2004 and 2015. We employed binary logistic regression to elucidate the direct relationship between RFM levels and the incidence of NAFLD. Additionally, a generalized additive model (GAM) coupled with smooth curve fitting techniques was utilized to map the non-linear association., Results: The cohort had an average age of 43.53 ± 8.89 years, with a male majority of 52.00%. NAFLD was identified in 17.59% of the participants. After adjusting for confounding factors, a significant positive correlation between RFM and NAFLD risk was observed (OR: 1.15, 95%CI: 1.10-1.21, P < 0.0001 for females; OR: 1.15, 95%CI: 1.10-1.19, P < 0.0001 for males). Additionally, a non-linear relationship between RFM and the incidence of NAFLD was detected in both genders. The RFM threshold was identified as 34.95 for women and 23.40 for men. RFM was positively associated with the risk of NAFLD when RFM was below the respective threshold (OR: 1.29, 95%CI: 1.19-1.40, P < 0.0001 for females; OR: 1.23, 95%CI: 1.17-1.29, P < 0.0001 for males), whereas no significant association was found when RFM was above the threshold (OR: 1.05, 95%CI: 0.98-1.12, P = 0.1829 for females; OR: 1.01, 95%CI: 0.95-1.08, P = 0.7392 for males)., Conclusion: Our findings suggest a positive, nonlinear relationship between RFM and the risk of NAFLD, with a saturation effect. These results imply that maintaining RFM at a lower level may be advantageous in mitigating the risk of NAFLD., (© 2024. The Author(s).)

Pseudorabies virus (PRV) infection causes systemic inflammatory responses and inflammatory damages in infected animals, which are associated with the activation of inflammasome and pyroptosis in infected tissues. Here, we identified a critical function of PRV non-structural protein UL4 that enhanced ASC-dependent inflammasome activation to promote pyroptosis. Whereas, the deficiency of viral UL4 was able to reduce ASC-dependent inflammasome activation and the occurrences of pyroptosis. Mechanistically, the 132-145 aa of UL4 permitted its translocation from the nucleus to the cytoplasm to interact with cytoplasmic ASC to promote the activation of NLRP3 and AIM2 inflammasome. Further research showed that UL4 promoted the phosphorylation levels of SYK and JNK to enhance the ASC phosphorylation, which led to the increase of ASC oligomerization, thus promoting the activation of NLRP3 and AIM2 inflammasome and enhanced GSDMD-mediated pyroptosis. In vivo experiments further showed that PRV UL4 (132DVAADAAAEAAAAE145) mutated strain (PRV-UL4mut) infection did not lead to a significant decrease in viral titers at 12 h. p. i, but it induced lower levels of IL-1β, IL-18, and GSDMD-NT, which led to an alleviated inflammatory infiltration and pathological damage in the lungs and brains, and a lower death rate compared with wild-type PRV strain infection. Taken together, our findings unravel that UL4 is an important viral regulator to manipulate the inflammasome signaling and pyroptosis of host cells to promote the pathogenicity of PRV, which might be further exploited as a new target for live attenuated vaccines or therapeutic strategies against pseudorabies in the future., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The triglyceride-glucose (TyG) index, recognized for its cost-efficiency and simplicity, serves as an accessible indicator of insulin resistance. Yet, its correlation with the risk of prediabetes and diabetes (Pre-DM/DM) in the Chinese demographic remains uncertain. Consequently, our study explored the association between the TyG index and the development of Pre-DM/DM within the Chinese population., Methods: The retrospective cohort study was carried out utilizing data from a health screening initiative. The study included 179541 adults over 20 who underwent medical examinations at the Rich Healthcare Group over a period spanning from 2010 to 2016. The correlation between the TyG index and Pre-DM/DM risk was investigated using Cox regression analysis. Furthermore, Cox proportional hazards regression with cubic spline functions and smooth curve fitting was incorporated to explore their non-linear connection., Results: The mean age of study participants was 41.18 ± 12.20 years old, and 95255 (53.05%) were male. During a median follow-up of 3.01 years, 21281 (11.85%) participants were diagnosed with Pre-DM/DM. After adjusting the potential confounding factors, the results showed that the TyG index was positively correlated with incident Pre-DM/DM (HR: 1.67, 95%CI: 1.62-1.71, P< 0.001). Additionally, a non-linear association was observed between the TyG index and the onset of Pre-DM/DM, with an inflection point identified at 8.73. Hazard ratios (HR) to the left and right of this inflection point were 1.95 (95%CI: 1.86-2.04) and 1.34 (95%CI: 1.27-1.42), respectively. Furthermore, sensitivity analyses confirmed the stability of these findings., Conclusion: The TyG index exhibited a non-linear positive relationship with the risk of Pre-DM/DM. These findings imply that maintaining the TyG index at a lower, specified threshold may be beneficial in mitigating the onset of Pre-DM/DM., 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 Cao, Hu, Xiao, Zan, Chang, Han, Zhang and Wang.)

Background: Acute myeloid leukemia (AML) is the most common type of acute leukemia among adults with the recommend therapy of combination of cytarabine and idarubicin in the induction phase. The uncoordinated pharmacokinetics prevent adequate control of drug ratio following systemic administration. Therefore, the dual-loaded liposomes containing cytarabine and idarubicin for synergistic effects were proposed and investigated. Methods: The molar ratio of cytarabine and idarubicin for synergistic effects was investigated. The dual-loaded liposomes were prepared and characterized by particle size, zeta potential, encapsulation efficiency, cryo-Transmission electron microscopy (cryo-TEM), and in vitro stability. The in vitro cytotoxicity and cell uptake of liposomes were determined within CCRF-CEM cells. The PK experiments was carried out in male SD rats. The in vivo antitumor effect was carried out within CD-1 nude female mice. The antitumor mechanism of liposomes was investigated. Results: The synergistic molar ratios were found to be in the range of 20:1~40:1. The size distribution of the dual-loaded liposomes was approximately 100 nm with PDI ≤ 0.1, a zeta potential of approximately -30 mV, an entrapment efficiency of cytarabine and idarubicin of >95% with spherical structure and uniform distribution, and in vitro stability for 21 d. The drugs in the liposomes can be quickly uptaken by the leukemia cells. The PK experiments showed that the molar ratio of cytarabine to idarubicin in plasma was maintained at 30:1 within 4 h. The efficacy of liposomes was significantly enhanced. Conclusions: The dual-loaded liposomes containing cytarabine and idarubicin showed enhanced antitumor efficacy.

Subarachnoid hemorrhage (SAH) induced acute impairment of the glymphatic system, but few have investigated the dysfunction of the meningeal lymphatic system and their contribution to the pathophysiology of SAH. In addition, most studies were conducted in rodent animals. We aimed to investigate the impact of SAH on glymphatic and meningeal lymphatic function in a large animal model using beagles and to evaluate the effects of intermittent cistern magna CSF drainage on these systems. Methods: The SAH model was created in beagles via endovascular perforation using a digital subtraction angiography machine. Intermittent cistern magna CSF drain was performed daily from 1 d to 3 d after SAH. We examined CSF pressure, neuronal death, enlargement of perivascular space (PVS), hydrocephalus, and neurological and cognitive deficits before and after SAH. The dynamics of glymphatic and meningeal lymphatic functions were analyzed by quantifying the signal intensity of dimeglumine gadopentetate (Gd-DTPA) using T1-weighted magnetic resonance imaging (MRI). Measurements were taken before SAH and at 1 h, 1 week, and 2 weeks post-SAH. Results: SAH in beagles caused significant blood clots, neuronal death, increased CSF pressure, hydrocephalus, and neurological and cognitive deficits. MRI revealed dilated ventricles and enlarged PVS post-SAH. The glymphatic system's function, assessed by Gd-DTPA distribution, showed reduced CSF influx and glymphatic impairment after SAH, particularly in the ipsilateral hemisphere, persisting for a week with partial recovery at 2 weeks. For lymphatic clearance, Gd-DTPA rapidly filled the olfactory bulbs, optic nerves, facial and vestibulocochlear nerves, and spinal nerves under normal conditions. SAH caused delayed and reduced Gd-DTPA efflux outflow in these areas, disrupting lymphatic clearance. Despite initial dysfunction, increased hemoglobin levels in cervical lymph nodes indicated active blood clearance post-SAH, with recovery by 2 weeks. Treatment with intermittent cistern magna CSF drain significantly ameliorated the glymphatic and meningeal lymphatic dysfunction after SAH. Conclusion: SAH impaired both glymphatic and meningeal lymphatic functions in beagles, with better restoration of lymphatic function post-SAH, which may contribute to functional recovery after SAH. External CSF drain is an effective therapeutic approach to facilitate the recovery of glymphatic and meningeal lymphatic function following SAH., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Various small molecule GLP1R agonists have been developed and tested for treating type 2 diabetes (T2DM) and obesity. However, many of these new compounds have drawbacks, such as potential hERG inhibition, lower activity compared to natural GLP-1, limited oral bioavailability in cynomolgus monkeys, and short duration of action. Recently, a new category of 3-phenyloxetane derivative GLP1R agonists with enhanced hERG inhibition has been discovered. Using an AIDD/CADD method, compound 14 ( DD202-114 ) was identified as a potent and selective GLP1R agonist, which was chosen as a preclinical candidate (PCC). Compound 14 demonstrates full agonistic efficacy in promoting cAMP accumulation and possesses favorable drug-like characteristics compared to the clinical drug candidate Danuglipron. Additionally, in hGLP-1R knock-in mice, compound 14 displayed a sustained pharmacological effect, effectively reducing blood glucose levels and food intake. These findings suggest that compound 14 holds promise as a future treatment option for T2DM and obesity, offering improved properties.

Objective: The relationship between body fat mass and bone mineral density (BMD) remains controversial. This research aimed to explore the linear or non-linear relationship between body fat mass and BMD among adults in the United States., Methods: This cross-sectional study identified adults aged 18 years or older in the National Health and Nutrition Examination Survey from 2011 to 2018. After adjusting for covariates, linear relationships between body fat mass and BMD in different genders were tested by generalized linear models, and potential non-linear relationships were explored by generalized additive models and piecewise linear regression models., Results: The research included 4691 (57.9% of the total sample) males and 3417 (42.1% the of total sample) females. In both males and females, we found a negative association between android or total body fat mass and lumbar spine BMD and a positive association between appendicular, android, gynoid, or total body fat mass and whole body BMD (all P < 0.05). The relationships between body fat mass in all regions and lumbar spine BMD were U-shaped in males and inverted U-shaped in females (all P non-linear  < 0.05). Inverted U-shaped relationships existed between body fat mass in all regions and whole body BMD in females (all P non-linear  < 0.05)., Conclusions: Body fat mass was negatively and linearly associated with lumbar spine BMD, but positively associated with whole body BMD. Body fat mass had a U-shaped relationship with lumbar spine BMD in males and an inverted U-shaped association with lumbar spine and whole body BMD in females., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The misregulation of protein phosphatases is a key factor in the development of many human diseases, notably cancers. Here, based on a 100 MHz quartz crystal microbalance (QCM) biosensing platform, the dephosphorylation process of phosphopeptide (P-peptide) caused by protein tyrosine phosphatase 1B (PTP1B) was monitored in real time for the first time and PTP1B activity was assayed rapidly and sensitively. The QCM chip, coated with a gold (Au) film, was used to immobilized thiol-labeled single-stranded 5'-phosphate-DNAs (P-DNA) through Au-S bond. The P-peptide, specific to PTP1B, was then connected to the P-DNA via chelation between Zr 4+ and phosphate groups. When PTP1B was injected into the QCM flow cell where the P-peptide/Zr 4+ /MCH/P-DNA/Au chip was placed, the P-peptide was dephosphorylated and released from the Au chip surface, resulting in an increase in the frequency of the QCM Au chip. This allowed the real-time monitoring of the P-peptide dephosphorylation process and sensitive detection of PTP1B activity within 6 min with a linear detection range of 0.01-100 pM and a detection limit of 0.008 pM. In addition, the maximum inhibitory ratios of inhibitors were evaluated using this proposed 100 MHz QCM biosensor. The developed 100 MHz QCM biosensing platform shows immense potential for early diagnosis of diseases related to protein phosphatases and the development of drugs targeting protein phosphatases., 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: We aimed to evaluate the trajectory of skin barrier properties in full-term newborns during the first four days after birth., Methods: Based on the MKNFOAD cohort (NCT02889081), transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin pH, and sebum content at five anatomical sites (cheek, forehead, volar forearm, abdomen, and dorsal lower leg) were examined once within 96 h after birth in 384 full-term infants. Multivariable linear regression analysis was performed to assess variations in these skin barrier parameters with age adjusted for gestational age, neonate's sex, parents' allergy history, delivery mode, amniotic fluid characteristics, and birth weight. The regression coefficient (ß) and 95% confidence interval were reported., Results: We analyzed a total of 384 neonates including 198 (51.6%) boys. TEWL values remained stable and showed no significant association with age (days). pH values exhibited a declining trend with age (p for trend <0.001). Both SCH values and sebum content grew with age (p for trend <0.001)., Conclusion: During the first four days after birth, the skin TEWL remained stable, pH decreased, and the SCH and sebum content increased over time. These findings provide insights into the neonatal skin physiological development at the beginning of life., Impact: From birth to 96 h, TEWL was stable, pH showed a steep decline, SCH and sebum content increased. This study provides the first evidence of skin adaptation in the newborn due to changes in utero to after birth in the first 4 days of life in an Asian population. These findings will provide a new theoretical basis for neonatal skin physiology and clinical strategies for guiding newborn skin care., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Purpose: To evaluate the therapeutic efficacy of intravenous amoxicillin clavulanate potassium combined with nebulized budesonide and ambroxol hydrochloride in pediatric community-acquired pneumonia (CAP) and its impact across various microbial strains and clinical symptoms. The primary objective of this study is to evaluate the efficacy of intravenous amoxicillin-clavulanate combined with nebulized budesonide and ambroxol hydrochloride in the treatment of pediatric community-acquired pneumonia (CAP), and to analyze their impact on different microbial strains and clinical symptoms. Secondary objectives include assessing the treatment's effect on the improvement of clinical symptoms, hospital stay duration, and the levels of inflammatory markers., Design: Prospective, single-center study., Methods: Fifty-six children with CAP, aged under 6 years, from Affiliated Maternity and Child Health Care Hospital of Nantong University were included. Patients were treated with conventional therapy and the study medication. Clinical characteristics, microbiological data, symptom improvement, and hospitalization times were analyzed., Findings: Young children, particularly under 1 year, exhibited a higher incidence of multiple microbial infections and severe clinical manifestations. Treatment with budesonide and ambroxol hydrochloride led to significant clinical improvement across all age groups, with notable efficacy against various pathogens., Conclusions: Nebulized budesonide and ambroxol hydrochloride are effective in treating pediatric CAP, offering a promising therapeutic option, particularly for young children with severe presentations., (© 2024. The Author(s).)

Objective: It has been recognized that there is a nexus among Trisomy 8 (T8), Behcet's disease (BD), and myelodysplastic syndrome (MDS). We reported a series of inflammatory features in 2 children with T8 without hematological involvement., Methods: 2 children with trisomy 8 who were excluded from MDS were retrospectively collected from the Department of Rheumatology and Immunology, Children's Hospital of Nanjing Medical University, Nanjing., Results: Patients developed a range of inflammatory manifestations before a diagnosis of T8. The clinical manifestations of T8 patients vary from normal to severely disabled. Glucocorticoids and thalidomide can effectively relieve inflammation in patients with T8., Conclusion: The early clinical manifestations of T8 in children lack specificity, and the diagnosis is mainly based on karyotype analysis, gastrointestinal endoscopy and bone marrow aspiration findings. Active and effective immunoregulatory therapy and long-term follow-up can improve the prognosis of patients with T8., 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., (© 2024 Zhang, Zhao, Pan, Jin, Fan and Yu.)

Background: Neuroinflammatory responses are closely associated with poststroke prognosis severity. This study aimed to develop a predictive model, combining inflammation-derived markers and clinical indicators, for distinguishing functional outcomes in patients with subacute ischemic stroke., Methods and Results: Based on activities of daily living assessments, ischemic stroke participants were categorized into groups with little effective (LE) recovery and obvious effective (OE) recovery. Initial biocandidates were identified by overlapping differentially expressed proteins from proteomics of clinical serum samples (5 LE, 5 OE, and 6 healthy controls) and differentially expressed genes from an RNA sequence of the ischemic cortex in middle cerebral artery occlusion mice (n=3). Multidimensional validations were conducted in ischemia-reperfusion models and a clinical cohort (15 LE, 11 OE, and 18 healthy controls). Models of robust biocandidates combined with clinical indicators were developed with machine learning in the training data set and prediction in another test data set (15 LE and 11 OE). We identified 194 differentially expressed proteins (LE versus healthy controls) and 174 differentially expressed proteins (OE versus healthy controls) in human serum, and 5121 differentially expressed genes (day 3) and 5906 differentially expressed genes (day 7) in middle cerebral artery occlusion mice cortex. Inflammation-derived biomarkers TIMP1 (tissue inhibitor metalloproteinase-1) and galactosidase-binding protein LGLAS3 (galectin-3) exhibited robust increases under ischemic injury in mice and humans. TIMP1 and LGALS3 coupled with clinical indicators (hemoglobin, low-density lipoprotein cholesterol, and uric acid) were developed into a combined model for differentiating functional outcome with high accuracy (area under the curve, 0.8)., Conclusions: The combined model is a valuable tool for evaluating prognostic outcomes, and the predictive factors can facilitate development of better treatment strategies.

Aqueous zinc-ion capacitors (AZICs) are considered potential energy storage devices thanks to their ultrahigh power density, high safety, and extended cycling life. Carbon-based materials widely used as cathodes in AZICs face challenges, such as inappropriate pore sizes, poor electrolyte-electrode wettability, and insufficient vacancy defects and active sites. These limitations hinder efficient energy storage capacity and long-term stability. To address these issues, the B and F co-doped hierarchical porous carbon cathode materials (BFPC) are constructed through a facile annealing treatment process. The BFPC-2//Zn device exhibited high capacities of 222.4 and 118.3 mAh g -1 at current densities of 0.2 and 10 A g -1 , respectively. Notably, the BFPC-2//Zn device demonstrated long-term cycling stability with a high capacity retention of 96.9 % after 20,000 cycles at 10 A g -1 . Additionally, the assembled BFPC-2 based AZICs displayed a maximum energy density of 175.8 Wh kg -1 and an ultrahigh power density of 17.3 kW kg -1 . Mechanism studies revealed that the exceptional energy storage ability and charge-transfer process of the BFPC cathode are attributed to the synergistic effect of B and F heteroatoms and the coupling effect between vacancy defects and pore size. This work presents a novel design strategy by incorporating B and F active sites into hierarchical porous carbon materials, providing enhanced energy storage capabilities for practical application in AZICs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this study, characteristic components of 15 natural flavors was analyzed by the polar-gradient extraction (PGE) technique in combination with GC-MS and chemometrics pattern recognition. The obtained results were utilized for the traceability of 4 functional fragrance formulations. The optimal PGE system consisting of 5 different polar solvents, was developed based on similarity-intermiscibility theory. Four chemometrics pattern recognition models including PCA, HCA, PLS-DA, and OPLS-DA were constructed based on the characteristic component database constituting 15 natural flavors. These models were used to trace 4 functional fragrance formulations. The experimental results obtained were found to be satisfactory and accurate. The combination of PGE technique and chemometric pattern recognition methods provides theoretical guidance for the analysis of characteristic components of natural flavors and the traceability of functional fragrance formulations. This approach can be promoted in various fields such as food, traditional Chinese medicine, and cosmetics., 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.)