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Background: Recent studies have shown that KIR + CD8 + T cells play a role in suppressing autoimmunity by eliminating pathogenic CD4 + T cells. However, their specific role in type 1 diabetes (T1D) remains unclear., Methods: In this study, we enrolled 108 patients diagnosed with T1D and 86 healthy individuals. We conducted flow cytometric analysis to examine the various subtypes of KIR + CD8 + T cells derived from peripheral blood mononuclear cells. Additionally, CD8 + T cells were isolated from the peripheral blood of T1D patients to assess the functions of different KIR + CD8 + T cell subtypes. To investigate the influence of lipids on the characteristics and activities of these T cell subtypes, the isolated CD8 + T cells were cultured with varying concentrations of palmitic acid (PA). Furthermore, we utilized an NSG (NOD scid gamma) mouse adoptive transfer model to assess the impact of dietary lipid intake on the functionality of KIR2DL5 + CD8 + T cells in vivo., Results: We observed variations in circulating KIR + CD8 + T cell subtypes between patients with T1D and healthy controls. Notably, we observed a significant negative correlation between the frequencies of circulating KIR + CD8 + T cells and the titers of ZnT8 autoantibodies in individuals with T1D. Among these subtypes, KIR2DL5 + CD8 + T cells demonstrated a positive association with dietary fat intake, characterized by increased perforin expression and reduced PD-1 expression. Importantly, KIR2DL5 + CD8 + T cells exhibited enhanced proliferative capacity compared to other KIR + CD8 + T cell subsets. Palmitic acid (PA) was found to enhance the activation of KIR2DL5 + CD8 + T cells and strengthened their ability to suppress CD4 + T cell proliferation in T1D patients. Moreover, dietary lipid intake significantly enhanced the functionality of KIR2DL5 + CD8 + T cells in an NSG mouse adoptive transfer model., Conclusion: Our findings suggest that lipid intake enhances the functionality of human KIR2DL5 + CD8 + T cells and may offer implications for immunotherapy in T1D., 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.)

Cancer constitutes a significant threat to patients' lives worldwide. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) that boost antitumor immunity by targeting immune checkpoint components, has emerged as a promising strategy for its treatment in recent years. However, the objective response rates of the ICIs are unsatisfactory. As the primary route, systemic administration of ICIs is often accompanied by immune-related adverse events. Local delivery of ICIs serves as a potential therapeutic strategy that can improve the efficacy while simultaneously reducing side effects through precise drug release at the tumor site. Initial validation of direct local application of ICIs for tumors in clinical trials has indicated reduced side effects and improved efficacy, while low bioavailability remains a challenge. Furthermore, research on various carriers, including nanoparticles, microneedles, hydrogels, combined platforms, and implantable devices for local release of ICIs has exhibited applying potential in treating murine tumors, among which combined platforms such as combined hydrogel system hold the highest promise due to their encompassment of the advantages of multiple carriers. These carriers, by incorporating ICIs and other therapeutics, could manage cancers more potently, which needs to be confirmed in clinical trials after the refinement of their biocompatibility. This review summarizes the latest research advancements regarding local administration of ICIs, with a particular focus on the carriers for local delivery as well as the combination therapies, thus providing novel insights and research guidance for scholars to enhance the efficacy of locally delivered ICIs on managing multiple cancers in the future.

Extracellular vesicles (EVs) had been described as a next-generation drug delivery system, due to the compelling evidence that they can facilitate the transfer of a variety of biomolecules between cells. The most frequently used strategy for loading protein cargoes is the endogenous engineering of EVs through genetic fusion of the protein of interest (POI) and scaffold proteins with high EV-sorting ability. However, the lack of scaffold proteins had become a major issue hindering the promotion of this technology. Herein, we proposed novel screening criteria that relax the inclusion requirement of candidate scaffold proteins and eventually identified a new scaffold protein, PLXNA1. The truncated PLXNA1 not only inherits the high EV-sorting ability of its full-length counterpart but also allows the fusion expression of POI in both outer surface and luminal areas, individually or simultaneously. In conclusion, our screening criteria expanded the range of potential scaffold proteins. The identified scaffold protein PLXNA1 showed great potential in developing therapeutic EVs., (© 2024 Echo Biotech Co Ltd. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

During space flight, prolonged weightlessness stress exerts a range of detrimental impacts on the physiology and psychology of astronauts. These manifestations encompass depressive symptoms, anxiety, and impairments in both short-term memory and motor functions, albeit the precise underlying mechanisms remain elusive. Recent studies have revealed that hindlimb unloading (HU) animal models, which simulate space weightlessness, exhibited a disorder in memory and motor function associated with endogenous formaldehyde (FA) accumulation in the hippocampus and cerebellum, disruption of brain extracellular space (ECS), and blockage of interstitial fluid (ISF) drainage. Notably, the impairment of the blood-brain barrier (BBB) caused by space weightlessness elicits the infiltration of albumin and hemoglobin from the blood vessels into the brain ECS. However, excessive FA has the potential to form cross-links between these two proteins and amyloid-beta (Aβ), thereby obstructing ECS and inducing neuron death. Moreover, FA can inhibit N-methyl-D-aspartate (NMDA) currents by crosslinking NR1 and NR2B subunits, thus impairing memory. Additionally, FA has the ability to modulate the levels of certain microRNAs (miRNAs) such as miRNA-29b, which can affect the expression of aquaporin-4 (AQP4) so as to regulate ECS structure and ISF drainage. Especially, the accumulation of FA may inactivate the ataxia telangiectasia-mutated (ATM) protein kinase by forming cross-linking, a process that is associated with ataxia. Hence, this review presents that weightlessness stress-derived FA may potentially serve as a crucial catalyst in the deterioration of memory and motor abilities in the context of microgravity., (© 2024. The Author(s).)

Oral leukoplakia (OLK) is the most emblematic oral potentially malignant disorder that may precede the diagnosis of oral squamous cell carcinoma (OSCC) and has an overall malignant transformation rate of 9.8 %. Early intervention is crucial to reduce the malignant transformation rate from OLK to OSCC but the lack of effective local pharmaceutical preparations poses a challenge to clinical management. Rapamycin is speculated to prevent OLK from carcinogenesis and its inherent lipophilicity facilitates its penetration into stratum corneum. Nevertheless, hydrophilic hydrogels frequently encounter challenges when attempting to deliver lipophilic drugs. Furthermore, the oral cavity presents a complex environment defined by oral motor functions, saliva secretion cycles, dynamic fluctuations, and protective barriers comprising mucus and lipid layers. Consequently, addressing issues of muco-penetration and muco-adhesion is imperative for developing an effective drug delivery system aiming at delivering rapamycin to target oral potentially malignant disorders. Here, a dual-function hydrogel drug delivery system integrating adhesion and lipophilicity was successfully developed based on polyvinyl alcohol (PVA) and dioleoyl phosphatidylglycerol (DOPG) via dynamic boronic ester bonds. Rheological experiments based on orthogonal design revealed that PVA-DOPG hydrogels exhibited ideal adhesive strength (around 6 kPa) and could adhere to various surfaces in both dry and wet conditions. PVA-DOPG hydrogels also significantly promoted lipophilic molecules' penetration into stratum corneum (integrated fluorescence density of 6.95 ± 0.52 × 10 6 and mean fluorescence depth of 0.96 ± 0.07 mm) of ex-vivo porcine buccal mucosa ( p  < 0.001). Furthermore, PVA-DOPG hydrogels incorporating rapamycin inhibited malignant transformation of OLK mouse model induced by 4-Nitroquinoline N-oxide (4-NQO), distinct improvements in survival (the neoplasm incidence density at the 40th day is 0.0091) ( p  < 0.05), decrease in neoplasm incidence density of 36.36 % and inhibition rate in neoplasm volume of 75.04 ± 33.67 % have been demonstrated, suggesting the hydrogels were valuable candidates for potential applications in the management of OLK., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Objective: Given their neural crest origin, gingival mesenchymal stem cells (GMSCs) possess high neurogenic potential, which makes them suitable for cell replacement therapy against neurodegenerative diseases. This study investigated whether GMSCs can be transdifferentiated into neurons in vitro using a protocol involving small molecules VCRFY (VPA, CHIR99021, Repsox, Forskolin, and Y-27632). The regulatory mechanisms of key signaling pathways were also investigated., Methods: Neuronal induction of GMSCs was conducted using a small molecules-based protocol over 7 days, which included the evaluation of cell morphology, proliferation, expressions of neurogenic markers, and intracellular calcium oscillation. The activation of canonical the Wnt signaling pathway was assessed by examining the protein content and subcellular localization of β-catenin., Results: Small molecules-treated GMSCs displayed neuronal morphology and increased expression of neurogenic markers, including class III beta-tubulin (TUJ1), neuron-specific enolase (NSE), microtube-associated protein 2 (MAP2), and neurofilament medium (NFM), verified through RT-qPCR, western blotting, and immunocytochemistry. Based on the results of Fluo-4 AM calcium flux assay, small molecules-treated GMSCs exhibited enhanced electrophysiological activity. GMSC proliferation halted after 2 days of treatment. Among the small molecules, CHIR99021 exhibited the highest neuronal induction efficiency. Furthermore, activation of the Wnt/β-catenin signaling pathway augmented neuronal differentiation., Conclusions: Small molecule-based cellular reprogramming can efficiently generate neurons from GMSCs, with Wnt/β-catenin signaling to play a critical role in neuronal induction., 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 Ltd.)

Perovskite solar cells (PSCs) are gaining prominence in the photovoltaic industry due to their exceptional photoelectric performance and low manufacturing costs, achieving a significant power conversion efficiency of 26.4%, which closely rivals that of silicon solar cells. Despite substantial advancements, the effective area of high-efficiency PSCs is typically limited to about 0.1 cm 2 in laboratory settings, with efficiency decreasing as the area increases. The limitation poses a major obstacle to commercialization, as large-area, high-quality perovskite films are crucial for commercial applications. This paper reviews current techniques for producing large-area perovskites, focusing on slot-die coating, a method that has attracted attention for its revolutionary potential in PSC manufacturing. Slot-die coating allows for precise control over film thickness and is compatible with roll-to-roll systems, making it suitable for large-scale applications. The paper systematically outlines the characteristics of slot-die coating, along with its advantages and disadvantages in commercial applications, suggests corresponding optimization strategies, and discusses future development directions to enhance the scalability and efficiency of PSCs, paving the way for broader commercial deployment.

The incidence rate of chronic heart failure has increased significantly in China and has a large impact on patients' lives. The purpose of the study was to validate the Chronic Heart Failure Health-Related Quality of Life Questionnaire (CHFQOLQ-20) cross-culturally and test its reliability and validity in patients with chronic heart failure. This study was conducted by investigating 622 patients with chronic heart failure from August 2023 to January 2024, and the data were tested for validity using SPSS 25.0 and AMOS 23.0. The final psychometric validation of the CHFQOLQ-20 was performed. The Chinese version of the CHFQOLQ-20 had a Cronbach's α of 0.908, a split-half reliability of 0.870, and a retest reliability of 0.892. An exploratory factor analysis yielded four common factors with a cumulative ANOVA of 59.355%, and the validated factor analysis with one correction resulted in a better-fitting model (χ 2 /df = 2.020, RMSEA = 0.057, CFI = 0.920, TLI = 0.907). The scale is a reliable assessment tool that can be used in future clinical practice., (© 2024. The Author(s).)

Nucleoside-derived supramolecular hydrogels based on G 4 -structures have been extensively developed in the biomedical sector and recognized for superior excellent biocompatibility and biodegradability. However, limited longevity and stability present a significant challenge. Chemical modifications in the molecular structure have been shown to enhance the longevity stability of G 4 -structure-based supramolecular hydrogels, but the precise way in which the molecular structure impacts the stability of the G 4 -structures and consequently affects the properties of the hydrogel remains to be elucidated. This issue represents a notable challenge in the field, which restricts their further applications to some extent. In this study, single crystals of Gd, αGd and αGd* were cultivated and compared with G. Notably, before this study, the single crystal structures of all natural nucleosides, with the exception of Gd, had been determined. The investigation into the molecular structure and supramolecular self-assembly properties of four guanosine analogs at the atomic scale revealed that the formation of G-quartets is critical for their ability to form hydrogels. The stability of the sugar ring geometry conformation (an intrinsic factor) and the disorder and strength of the hydration effect (extrinsic factors) are vital for maintaining the stability of the G 4 -structures. The rapid cooling changes the molecular geometry conformation, and the organic solvent changes the hydration effect, which can improve the longevity stability of G 4 -structure-based supramolecular hydrogels instead of chemical modifications. Consequently, the lifespan of the hydrogels was extended from 2 h to over one week. This advancement is expected to offer significant insights for future research in designing and developing G 4 -structure-based supramolecular hydrogels.

Background: Dyslipidemia is prominently associated with adverse outcomes in patients with coronary artery disease (CAD). The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is a novel comprehensive lipid index. However, limited evidence exists on the relationship of the NHHR with the risk of adverse outcomes in patients with CAD. This study aimed to explore the associations between the NHHR and adverse outcomes and identify the optimal NHHR ranges linked to the lowest adverse outcome risk in patients with CAD undergoing percutaneous coronary intervention (PCI)., Methods: Among 2253 patients with CAD undergoing PCI, 2251 with available total cholesterol and HDL-C levels were analyzed. Furthermore, all patients were classified into quintiles based on the NHHR. The primary outcome was the incidence of MACCEs, comprising cardiac mortality, acute myocardial infarction, stroke, and repeat revascularization. Multivariable logistic regression analysis was used to assess the relationship between the NHHR and MACCEs. Moreover, restricted cubic spline (RCS) analysis was performed to quantify nonlinearity. Lastly, the consistency between these associations was confirmed by conducting subgroup and interaction analyses., Results: A total of 270 patients experienced MACCEs over a median follow-up of 29.8 months (interquartile range, 25.6-34 months). After adjustment for confounding variables, the adjusted ORs (95% CIs) of the patients in quintiles 2, 3, 4, and 5 were 0.79 (0.52-1.20), 0.64 (0.42-0.99), 1.00 (0.67-1.48), and 1.17 (0.74-1.64), respectively (reference group: quintile 1). Additionally, RCS analysis demonstrated a U-shaped relationship between the NHHR and MACCEs, with an inflection point at an NHHR of 3.119 using a two-piecewise regression model. This relationship was consistent across the various subgroups, while significant interactions were not observed in these associations.The ORs and 95% CIs to the left and right of the inflection point were 0.734 (0.551-0.978) and 1.231 (1.038-1.460), respectively., Conclusions: This study reveals a U-shaped association between baseline NHHR and MACCE incidence in patients with CAD undergoing PCI., (© 2024. The Author(s).)

Isoguanosine (isoG) is a natural structural isomer of guanosine (G) with significant potential for applications in ionophores, genetics, gel formation, and cancer therapy. However, the cost of commercially available isoG on a gram scale is relatively high. To date, a detailed method for the large-scale preparation of high-purity isoG has not been reported. This study presented a simple and convenient approach for the large-scale synthesis of isoG through the diazotization of 2,6-diaminopurine riboside with sodium nitrite and acetic acid at room temperature. Further, this method could synthesize isoG derivatives (2'-fluoro-isoguanosine (1) and 2'-deoxy-isoguanosine (2)) from 2,6-diaminopurine nucleoside derivatives using diazotization. The structural information of natural and modified nucleosides is crucial for the modification and substitution of DNA/RNA. This study obtained the single-crystal structure of isoG for the first time and analyzed it in detail using microcrystal electron diffraction. The three-dimensional supramolecular structure of isoG adopted similarly base-pair motifs from π-π stacking interaction of diverse layers, intramolecular hydrogen bonding, and distinct hydrogen bonding interactions from sugar residues. This study has contributed to further isoG modification and its applications in medicinal chemistry and materials., (© 2024 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

A specialised microenvironment, termed niche, provides extrinsic signals for the maintenance of residential stem cells. However, how residential stem cells maintain niche homeostasis and whether stromal niche cells could convert their fate into stem cells to replenish lost stem cells upon systemic stem cell loss remain largely unknown. Here, through systemic identification of JAK/STAT downstream targets in adult Drosophila testis, we show that Escargot (Esg), a member of the Snail family of transcriptional factors, is a putative JAK/STAT downstream target. esg is intrinsically required in cyst stem cells (CySCs) but not in germline stem cells (GSCs). esg depletion in CySCs results in CySC loss due to differentiation and non-cell autonomous GSC loss. Interestingly, hub cells are gradually lost by delaminating from the hub and converting into CySCs in esg-defective testes. Mechanistically, esg directly represses the expression of socs36E, the well-known downstream target and negative regulator of JAK/STAT signalling. Finally, further depletion of socs36E completely rescues the defects observed in esg-defective testes. Collectively, JAK/STAT target Esg suppresses SOCS36E to maintain CySC fate and repress niche cell conversion. Thus, our work uncovers a regulatory loop between JAK/STAT signalling and its downstream targets in controlling testicular niche homeostasis under physiological conditions., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

In recent years, there has been extensive research into drug delivery systems aimed at enhancing drug utilization while minimizing drug toxicities. Among these systems, oral patches/films have garnered significant attention due to their convenience, noninvasive administration, ability to bypass hepatic first-pass metabolism, thereby enhancing drug bioavailability, and their potential to ensure good compliance, particularly among special patient populations. In this review, from the perspective of the anatomical characteristics of the oral cavity and the advantages and difficulties of oral drug delivery, we illustrate the design ideas, manufacturing techniques, research methodologies, and the essential attributes of an ideal oral patch/film. Furthermore, the applications of oral patches/films in both localized and systemic drug delivery were discussed. Finally, we offer insights into the future prospects of the oral patch/film, aiming to provide valuable reference for the advancement of oral localized drug delivery systems., (© 2024 Wiley Periodicals LLC.)

Background: There are few studies on the safety of sub-maximal exercise testing of aerobic exercise in apparently healthy Chinese populations. The purpose of this study was to explore the frequency of exercise electrocardiography (ECG) abnormalities and the corresponding exercise intensities, as well as the associated influencing factors, during a symptom-limited stepwise incremental cardiopulmonary exercise test (CPET) in an apparently healthy Chinese population., Methods: A cross-sectional study was done in four communities, one urban and one rural in the North (Beijing) and in the South (Hezhou, Guangxi) of China from 1 January 2017 to 31 December 2018, respectively. Total of 1642 participants was recruited, 918 were eligible and completed demographic indicators, routine blood indicators, physical activity status, symptom-limited CPET and exercise ECG were included in the analysis., Results: Of the exercise ECG outcomes, 10 (1.1%) were positive and occurred at exercise intensities ≥ 62.50% heart rate reserve (HRR); 44 (4.8%) were equivocal and 864 (94.1%) were normal. Individuals with Cardiovascular Disease Risk Factor (CVDRF) = 3-4 were 2.6 times more likely to have a equivocal and abnormal exercise ECG than those with CVDRF = 0-2. Exercise ECGs of individuals with CVDRF = 5-7 were 5.4 times more likely to be positive and abnormal than exercise ECGs of individuals with CVDRF = 0-2., Conclusions: The exercise intensity of 62.5% HRR can be used as a safe upper limit for safe participation in exercise in apparently healthy Chinese population; the greater the number of CVDRFs, the greater the likelihood of cardiovascular risk during exercise., (© 2024. The Author(s).)

Introduction: Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer's disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates., Area Covered: This review provides an overview of PDE9 inhibitors in patents from 2018 to the present., Expert Opinion: Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

In this study, we redefine the diagnostic landscape of diabetic ulcers (DUs), a major diabetes complication. Our research uncovers new biomarkers linked to immunogenic cell death (ICD) in DUs by utilizing RNA-sequencing data of Gene Expression Omnibus (GEO) analysis combined with a comprehensive database interrogation. Employing a random forest algorithm, we have developed a diagnostic model that demonstrates improved accuracy in distinguishing DUs from normal tissue, with satisfactory results from ROC analysis. Beyond mere diagnosis, our model categorizes DUs into novel molecular classifications, which may enhance our comprehension of their underlying pathophysiology. This study bridges the gap between molecular insights and clinical practice. It sets the stage for transformative strategies in DUs management, marking a significant step forward in personalized medicine for diabetic 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 Elsevier B.V. All rights reserved.)

Background: Integrins are upregulated on endothelial cells and T-lymphocytes in autoimmune thyroid disease (AITD), potentially contributing to immune response localization. The role of integrins on B-cells in AITD remains unclear., Methods: Peripheral blood samples were collected from healthy controls (n = 56), patients with Graves' disease (GD) (n = 37) and Hashimoto's thyroiditis (HT) (n = 52). Ultrasound-guided fine-needle aspiration (FNA) of the thyroid was performed in patients with non-autoimmune thyroid disease (nAITD) (n = 19), GD (n = 11), and HT (n = 40). Integrins α4β7, α4β1, and αEβ7 in B cells were measured by flow cytometry. Serum zonulin levels were quantified via ELISA. Associations of integrins on B cells with thyroid hormones, thyroid autoantibodies, AITD duration, and zonulin were analyzed., Results: HT patients exhibited lower α4β7 and higher α4β1 expression on B cells compared to healthy controls and GD patients. While α4β7 was predominant on circulating B cells, the dominant integrin expressed on intrathyroidal B cells varied with specific thyroid diseases. In GD patients, α4β7 and α4β1 expression on circulating B cells correlated positively and negatively with thyroid function and thyroid stimulating immunoglobulins (TSI) levels, respectively. Intrathyroidal α4β1 + B cells positively correlated with TSH levels in HT patients. Additionally, serum zonulin was elevated in HT patients, and intrathyroidal α4β7 + B cells and α4β1 + B cells correlated negatively and positively with zonulin levels, respectively. Integrin αEβ7 on B cells showed no significant association with AITD., Conclusion: Integrins expressed on B cells potentially play a role in the pathogenesis of AITD and might serve as immune biomarkers for the disease., 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.)

Rationale: In the era of burgeoning digital technology, healthcare is a challenging transformative change towards virtual and digital platforms. Internet-based healthcare services are emerging as a popular trend within the medical area. User experience (UX) is paramount for the healthcare service, as it significantly influences experience satisfaction and fosters user viscosity. Gaining a profound understanding of users' demands and crafting services that align with their expectations is essential., Methods: Consequently, exploring an effective design approach for the digital healthcare service that prioritizes UX along with utilizing a comprehensive evaluation methodology to handle UX data, is of profound importance. This study introduces a design methodology for Internet-based healthcare products grounded in the UX and mental (UX-M) model. Aiming to refine the Internet-based healthcare product design by integrating insights from the experience data, it employs the Delphi-ANP and the fuzzy comprehensive evaluation to determine evaluation indexes and conduct experiential assessments., Results: The UX evaluation results of existing schemes are compared with the proposed design scheme of the intelligent guidance and internet hospital. The findings indicate that the UX evaluation of Internet-based medical services with the proposed method outperforms the existing schemes., Conclusions: On the one hand, UX research of Internet-based healthcare products can significantly enhance service satisfaction for patients utilizing online medical treatments. On the other hand, the analysis of experience-based evaluation empowers designers to refine and improve UX design of Internet-based medical services. Such research endeavors are critical for enhancing the overall quality of service offerings and elevating user satisfaction in the digital healthcare landscape., (© 2024 John Wiley & Sons Ltd.)

Mercury (Hg) is detrimental to human health, but its impact on lipid biomarkers remains a subject of controversy. This study sought to delineate a clear link between blood Hg and lipid biomarkers correlated with cardiovascular disease (CVD), including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), in hypertensive adults in the USA., Methods: This cross-sectional research gathered data from a total of 4415 participants sourced from the National Health and Nutrition Examination Survey (NHANES). The Holm-Bonferroni stepdown procedure was utilized to control the type I error rate in multiple comparisons. We employed multivariable linear regression models to assess the correlation between blood Hg and lipid biomarkers. Subsequently, subgroup analyses were conducted, categorized by both gender and race. Additionally, we used smooth curve fittings and generalized additive models to confirm the presence of non-linear relationships. When non-linearity was detected, we applied a recursive algorithm to calculate the inflection points. Finally, we established a weighted two-piecewise linear regression model to illustrate the associations on either side of the inflection point., Results: In our multivariable linear regression models, clear associations emerged. Specifically, positive correlations were observed between blood mercury and TC (β = 0.025; 95% CI 0.009 to 0.041; corrected P = 0.011), LDL-C (β = 0.022; 95% CI 0.007 to 0.036; corrected P = 0.012), and HDL-C (β = 0.007; 95% CI 0.001 to 0.013; corrected P = 0.058). However, there was no significant correlation with TG (β =  - 0.007; 95% CI - 0.018 to 0.004; corrected P = 0.526). Notably, it has been demonstrated that distinct inverted U-shaped and U-shaped curves exist when stratified by gender in our analysis., Conclusions: Blood Hg exhibited a positive correlation with TC, LDL-C, and HDL-C in hypertensive adults in the USA. Nonetheless, no significant association was observed with TG., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Research on the phonological development of children with autism spectrum disorder (ASD) has not yet reached consistent conclusions, and systematic studies from different language groups are needed. This study aimed to systematically investigate the characteristics of phonological development in 3-6 year-old Mandarin-speaking children with ASD. We analyzed 10 min speech samples from 21 children with ASD, 18 development level-matched children with developmental disorders (DD), and 15 chronological age-matched typically developing (TD) children during semi-structured parent-child free play based on Mandarin phonological features. The children with ASD had a significantly smaller inventory than those with TD on the initial and final inventories. The children with ASD had only a significantly smaller initial inventory than those with DD in Phases 2 and 4. Compared with TD children, children with ASD used a higher proportion of V 1 and V 1 V 2 C and a smaller proportion of V 1 V 2 V 3 , CV 1 C, and CV 1 V 2 C. No significant differences existed between ASD and DD children in the proportion of any syllable structure, but V 1 V 2 V 3 , CV 1 , and CV 1 V 2 C numbers were significantly fewer than in DD children. Children with ASD were significantly greater than children with TD in the diversity of V 1 V 2 , CV 1 , and overall syllables. ASD children had significantly fewer different types of syllables in both V 1 V 2 C and CV 1 than did DD children and significantly greater diversity in CV 1 and overall syllables than did DD children. These preliminary data suggest that the gap between TD and ASD children's language abilities increased with age, and this gap was reflected in initial, final, and syllable complexity and diversity. Children with DD and ASD showed similar language abilities, and children with DD showed detailed differences from those with ASD regarding initial, syllable complexity and diversity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Eleocharis vivipara, an amphibious sedge in the Cyperaceae family, has several remarkable properties, most notably its alternate use of C 3 photosynthesis underwater and C 4 photosynthesis on land. However, the absence of genomic data has hindered its utility for evolutionary and genetic research. Here, we present a high-quality genome for E. vivipara, representing the first chromosome-level genome for the Eleocharis genus, with an approximate size of 965.22 Mb mainly distributed across 10 chromosomes. Its Hi-C pattern, chromosome clustering results, and one-to-one genome synteny across two subgroups indicates a tetraploid structure with chromosome count 2n = 4x = 20. Phylogenetic analysis suggests that E. vivipara diverged from Cyperus esculentus approximately 32.96 million years ago (Mya), and underwent a whole-genome duplication (WGD) about 3.5 Mya. Numerous fusion and fission events were identified between the chromosomes of E. vivipara and its close relatives. We demonstrate that E. vivipara has holocentromeres, a chromosomal feature which can maintain the stability of such chromosomal rearrangements. Experimental transplantation and cross-section studies showed its terrestrial culms developed C 4 Kranz anatomy with increased number of chloroplasts in the bundle sheath (BS) cells. Gene expression and weighted gene co-expression network analysis (WGCNA) showed overall elevated expression of core genes associated with the C 4 pathway, and significant enrichment of genes related to modified culm anatomy and photosynthesis efficiency. We found evidence of mixed nicotinamide adenine dinucleotide - malic enzyme and phosphoenolpyruvate carboxykinase type C 4 photosynthesis in E. vivipara, and hypothesize that the evolution of C 4 photosynthesis predates the WGD event. The mixed type is dominated by subgenome A and supplemented by subgenome B. Collectively, our findings not only shed light on the evolution of E. vivipara and karyotype within the Cyperaceae family, but also provide valuable insights into the transition between C 3 and C 4 photosynthesis, offering promising avenues for crop improvement and breeding., (© 2024 The Author(s). Journal of Integrative Plant Biology published by John Wiley & Sons Australia, Ltd on behalf of Institute of Botany, Chinese Academy of Sciences.)

Force-related discoloration materials are highly valuable because of their characteristics of visualization, easy operation, and environment friendliness. Most force-related discoloration materials focus on polymers and depend on bond scission, which leads to insensitivity and unrecoverable. Small-molecule systems based on well-defined molecular structures and simple composition with high sensitivity would exhibit considerable mechanochromic potential. However, to date, researches about force-related discoloration materials based on small molecule solution remain limited and are rarely reported. In this study, we developed a repeatable and instantaneous discoloration small molecule solution system by simple one-pot synthesis method. It exhibited an instantaneous chromic change from yellowish to dark green under shaking and reverting back to yellow within 1 minute after removal of the shaking. Experimental results confirmed that the discoloration mechanism is attributed to the oscillation accelerating the production of unstable ortho-OH phenoxyl radical. The newly developed shaking-induced discoloration small molecule system (SDSMS) promises in field of mechanical force sensing and optical encryption., (© 2024 Wiley-VCH GmbH.)

The rational design of photocatalysts for improving the conversion of solar energy into hydrogen is a promising route for achieving carbon neutrality. Herein, we couple plasmonic titanium nitride (TiN) with highly crystalline potassium-doped polymeric carbon nitride (PPCN) to construct a PPCN/TiN ohmic junction. Such an ohmic junction not only broadens the absorption spectrum but also inhibits the recombination of electrons and holes. In addition, Pt nanoparticles are introduced into this ohmic junction to form plasmonic Pt-PPCN/TiN, improving the capture of hot electrons generated by TiN and thereby promoting the dissociation of the O-H bond in H 2 O. The energy barrier decreases from 0.7 to 0.2 eV. Enhanced separation of carrier, activation of water molecules, and capture of hot electrons are jointly promoting photo-thermo catalytic hydrogen production. Therefore, under full-spectrum irradiation, the hydrogen production rate of Pt-PPCN/TiN reaches 19 085 μmol g -1 h -1 . This novel plasmonic photocatalyst is promising for full-spectrum photo-thermo catalytic hydrogen production.

Verticillium dahliae, a soil-borne fungal pathogen, compromises host innate immunity by secreting a plethora of effectors, thereby facilitating host colonization and causing substantial yield and quality losses. The mechanisms underlying the modulation of cotton immunity by V. dahliae effectors are predominantly unexplored. In this study, we identified that the V. dahliae effector Vd6317 inhibits plant cell death triggered by Vd424Y and enhances PVX viral infection in Nicotiana benthamiana. Attenuation of Vd6317 significantly decreased the virulence of V. dahliae, whereas ectopic expression of Vd6317 in Arabidopsis and cotton enhanced susceptibility to V. dahliae infection, underscoring Vd6317's critical role in pathogenicity. We observed that Vd6317 targeted the Arabidopsis immune regulator AtNAC53, thereby impeding its transcriptional activity on the defense-associated gene AtUGT74E2. Arabidopsis nac53 and ugt74e2 mutants exhibited heightened sensitivity to V. dahliae compared to wild-type plants. A mutation at the conserved residue 193L of Vd6317 abrogated its interaction with AtNAC53 and reduced the virulence of V. dahliae, which was partially attributable to a reduction in Vd6317 protein stability. Our findings unveil a hitherto unrecognized regulatory mechanism by which the V. dahliae effector Vd6317 directly inhibits the plant transcription factor AtNAC53 activity to suppress the expression of AtUGT74E2 and plant defense., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Climate change is threatening fragile alpine ecosystems and their resident ungulates, particularly the wild yak (Bos mutus) that inhabits alpine areas between the tree line and glaciers on the Tibetan Plateau. Although wild yaks tend to shift habitats in response to changes in climatic factors, the precise impacts of climate change on their habitat distribution and climate refugia remain unclear. Based on over 1000 occurrence records, the maximum entropy (MaxEnt) algorithm was applied to simulate habitat ranges in the last glacial maximum (LGM), Mid-Holocene, current stage, and three greenhouse gas emission scenarios in 2070. Three habitat patches were identified as climate refugia for wild yaks that have persisted from the LGM to the present and are projected to persist until 2070. These stable areas account for approximately 64% of the current wild yak habitat extent and are sufficiently large to support viable populations. The long-term persistence of these climate refugia areas is primarily attributed to the unique alpine environmental features of the Tibetan Plateau, where relatively stable arid or semi-arid climates are maintained, and a wide range of forage resource supplies are available. However, habitat loss by 2070 caused by insufficient protection is predicted to lead to severe fragmentation in the southeastern and northwestern Kunlun, Hengduan, central-western Qilian, and southern Tanggula-northern Himalaya Mountains. Habitat disturbance has also been caused by increasing anthropogenic effects in the southern Tanggula and northern Himalaya Mountains. We suggest that sufficient protection, transboundary cooperation, and community involvement are required to improve wild yak conservation efforts. Our combined modeling method (MaxEnt-Zonation-Linkage Mapper-FRAGSTAT) can be utilized to identify priority areas and linkages between habitat patches while assessing the conservation efficiency of protected areas and analyzing the coupled relationship between climate change and anthropogenic impacts on the habitat distribution of endangered species., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest. The work is all original research carried out by the authors. All authors agree with the contents of the manuscript and its submission to the journal., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Current label-free surface-enhanced Raman spectroscopy (SERS) assay for the detection and analysis of organophosphorus pesticides has achieved initial success, but the application still faces constraints of substrate portability and specificity. To this end, this paper demonstrates a method for portable, rapid, and specific detection of low concentrations of fenthion pesticides based on a solid substrate of gold nanoparticle monolayers combined with molecularly imprinted polymers (MIPs). The nano-monolayers were transferred to the surface of mercapto-silicon wafers by interfacial self-assembly technique to form a stable connection with S-Au bonds and, at the same time, prevent nanoparticles from dropping off during the surfactant removal process. Then, the fenthion MIPs were directly generated on the surface of the monolayer film by spin-coating with a pre-polymerization solution and ultraviolet-induced polymerization. Tests showed that the molecular imprint was able to accurately bind to fenthion, but not other molecules, in a mixture of structural analogs, achieving a low concentration detection of 10 -8  mol/L. The composite substrate maintained a signal uniformity of a relative standard deviation (RSD)  =  7.05% and a batch-to-batch reproducibility of RSD  =  10.40%, making it a potential pathway for the extended application of SERS technology., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Glioblastoma is characterized by high aggressiveness, frequent recurrence, and poor prognosis. Histone acetylation-associated genes have been implicated in its occurrence and development, yet their predictive ability in glioblastoma prognosis remains unclear., Results: This study constructs a histone acetylation risk model using Cox and LASSO regression analyses to evaluate glioblastoma prognosis. We assessed the model's prognostic ability with univariate and multivariate Cox regression analyses. Additionally, immune infiltration was evaluated using ESTIMATE and TIMER algorithms, and the SubMAP algorithm was utilized to predict responses to CTLA4 inhibitor. Multiple drug databases were applied to assess drug sensitivity in high- and low-risk groups. Our results indicate that the histone acetylation risk model is independent and reliable in predicting prognosis., Conclusions: Low-risk patients showed higher immune activity and longer overall survival, suggesting anti-CTLA4 immunotherapy suitability, while high-risk patients might benefit more from chemotherapy. This model could guide personalized therapy selection for glioblastoma patients., (© 2024. The Author(s).)

This study aimed to investigate the effect of the microstructure of shale on fracture initiation and extension during hydraulic fracturing. The Longmaxi Formation shale reservoir in the Sichuan Basin was considered as the research object; its structure was modeled from a microscopic perspective, and a zero-thickness cohesive unit was embedded within the solid unit. Numerical simulations were performed to study the effect of mineral content on the microextension of the hydraulic fracture, extension behavior, and evolution law of shale. The results showed that changes in the mineral content resulted in changes in the forces between molecules within the minerals, which, in turn, affected the shale's brittleness. The percentages of brittle mineral content in the Long I, II, and III reservoir sections are 60.37, 47.60, and 53.56%, respectively. The fracture initiation pressures of the three reservoirs were 29.22, 31.42, and 30.22 MPa, respectively, and a linear correlation was found between the fracture initiation pressures and the brittle mineral contents of the reservoir sections. An increase in the reservoirs' percentage of brittle mineral content facilitated the fracture initiation, with a corresponding gradual decrease in the resistance to fracture initiation. The pore pressures of the fractures in the three reservoirs after fracture initiation were 0.90, 1.18, and 1.00 MPa, respectively. The larger the percentage of brittle minerals was, the lower was the fracture pore pressure. The greater the length, number, area, and width of the cracks were, the more likely they were to form longer and wider cracks. Hence, reservoirs with a high percentage of brittle minerals should be prioritized as the target formations for hydraulic fracturing operations. The results of this study reveal how the mineral content affects the extension of microscopic hydraulic fractures in shale reservoirs. As such, this work can provide a theoretical basis for rationally selecting a hydraulic fracturing operation layer in shale gas reservoirs., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Diaphorina citri Kuwayama ( D . citri ) is one of the major pests in the citrus industry, which spreads Citrus Huanglongbing disease. It has developed resistance to chemical insecticides. Therefore, searching for greener solutions for pest management is critically important. The main aim of this study was to evaluate the repellent and insecticidal efficacy of essential oils (EOs) from four species of Myrtaceae plants: Psidium guajava (PG), Eucalyptus robusta (ER), Eucalyptus tereticornis (ET), and Baeckea frutescens (BF) against D. citri and to analyze their chemical compositions. GC-MS analysis was performed, and the results indicated that the EOs of PG, ER, ET, and BF were rich in terpenoids, ketones, esters, and alcohol compounds. The repellent rate of all four EOs showed that it decreased with exposure time but increased with the concentration of EOs from 80.50% to 100.00% after treating D. citri for 6 h with four EOs at 100% concentration and decreased to 67.71% to 85.49% after 24 h of exposure. Among the compounds from the EOs tested, eucalyptol had the strongest repellent activity, with a 24 h repellency rate of 100%. The contact toxicity bioassay results showed that all EOs have insecticidal toxicity to D. citri ; the LC50 for nymphs was 36.47-93.15 mL/L, and for adults, it was 60.72-111.00 mL/L. These results show that when PG is used as the reference material, the ER, ET, and BF EOs have strong biological activity against D. citri , which provides a scientific basis for the further development of plant-derived agrochemicals., Competing Interests: The authors declare no conflicts of interest.

PA28γ overexpression is aberrant and accompanied by poor patient prognosis in various cancers, the precise regulatory mechanism of this crucial gene in the tumor microenvironment remains incompletely understood. In this study, using oral squamous cell carcinoma as a model, we demonstrated that PA28γ exhibits high expression in cancer-associated fibroblasts (CAFs), and its expression significantly correlates with the severity of clinical indicators of malignancy. Remarkably, we found that elevated levels of secreted IGF2 from PA28γ + CAFs can enhance stemness maintenance and promote tumor cell aggressiveness through the activation of the MAPK/AKT pathway in a paracrine manner. Mechanistically, PA28γ upregulates IGF2 expression by stabilizing the E2F3 protein, a transcription factor of IGF2. Further mechanistic insights reveal that HDAC1 predominantly mediates the deacetylation and subsequent ubiquitination and degradation of E2F3. Notably, PA28γ interacts with HDAC1 and accelerates its degradation via a 20S proteasome-dependent pathway. Additionally, PA28γ + CAFs exert an impact on the tumor immune microenvironment by secreting IGF2. Excitingly, our study suggests that targeting PA28γ + CAFs or secreted IGF2 could increase the efficacy of PD-L1 therapy. Thus, our findings reveal the pivotal role of PA28γ in cell interactions in the tumor microenvironment and propose novel strategies for augmenting the effectiveness of immune checkpoint blockade in oral squamous cell carcinoma., 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.)

Efficient, low-cost photocatalysts with mild synthesis conditions and stable photocatalytic behavior have always been the focus in the field of photocatalysis. This study proves that non-quantum-dot Cs 2 PbI 2 Cl 2 -based materials, created by a simple method, can be successfully employed as new high-efficient photocatalysts. The results demonstrate that two-dimensional Cs 2 PbI 2 Cl 2 perovskite can achieve over three times higher photocatalytic performance compared to three-dimensional CsPbBr 3 perovskite. Moreover, the photocatalytic performance of Cs 2 PbI 2 Cl 2 can be further improved by constructing a heterojunction structure, such as Cs 2 PbI 2 Cl 2 /CsPbBr 3 . Cs 2 PbI 2 Cl 2 can connect well with CsPbBr 3 through a simple method, resulting in tight bonding at the interface and efficient carrier transfer. Cs 2 PbI 2 Cl 2 /CsPbBr 3 exhibits notable 5-fold and 10-fold improvements in photocatalytic performance and rate compared to CsPbBr 3 . Additionally, Cs 2 PbI 2 Cl 2 /CsPbBr 3 demonstrates superb stable catalytic performance, with nearly no decrease in photocatalytic performance after 7 months (RH = 20% ± 10, T = 25 °C ± 5). This study also reveals that the photocatalytic process based on Cs 2 PbI 2 Cl 2 /CsPbBr 3 can directly oxidize organic matter using holes, without relying on the generation of intermediate reactive oxygen species from water or oxygen (such as ·OH or ·O 2 - ), showcasing further potential for achieving high photocatalytic efficiency and selectivity in anhydrous/anaerobic catalytic reactions and treating recalcitrant pollutants.

Heavy metal pollution poses a significant risk to human health and wreaks havoc on agricultural productivity. Phytoremediation, a plant-based, environmentally benign, and cost-effective method, is employed to remove heavy metals from contaminated soil, particularly in agricultural or heavy metal-sensitive lands. However, the phytoremediation capacity of various plant species and germplasm resources display significant genetic diversity, and the mechanisms underlying these differences remain hitherto obscure. Given its potential benefits, genetic improvement of plants is essential for enhancing their uptake of heavy metals, tolerance to harmful levels, as well as overall growth and development in contaminated soil. In this study, we uncover a molecular cascade that regulates cadmium (Cd 2+ ) tolerance in cotton, involving GhRCD1, GhbHLH12, GhMYB44, and GhHMA1. We identified a Cd 2+ -sensitive cotton T-DNA insertion mutant with disrupted GhRCD1 expression. Genetic knockout of GhRCD1 by CRISPR/Cas9 technology resulted in reduced Cd 2+ tolerance in cotton seedlings, while GhRCD1 overexpression enhanced Cd 2+ tolerance. Through molecular interaction studies, we demonstrated that, in response to Cd 2+ presence, GhRCD1 directly interacts with GhbHLH12. This interaction activates GhMYB44, which subsequently activates a heavy metal transporter, GhHMA1, by directly binding to a G-box cis-element in its promoter. These findings provide critical insights into a novel GhRCD1-GhbHLH12-GhMYB44-GhHMA1 regulatory module responsible for Cd 2+ tolerance in cotton. Furthermore, our study paves the way for the development of elite Cd 2+ -tolerant cultivars by elucidating the molecular mechanisms governing the genetic control of Cd 2+ tolerance in cotton., (© 2024 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: Previous studies have suggested that adequate myocardial reperfusion after percutaneous coronary intervention (PCI) can improve the inhomogeneity of myocardial repolarization. However, it remains unclear whether no-reflow (NR) following emergency PCI involves disadvantages related to ventricular repolarization indices. The present study aimed to determine the effect of NR on QT dispersion (QTd) in patients with ST-segment elevation myocardial infarction (STEMI) and to evaluate the prognostic value of the relative reduction of QTd on ventricular arrhythmia events (VAEs)., Methods: A prospective case-control study was conducted. According to the inclusion criteria, 275 patients with STEMI who underwent primary PCI treatment at the First People's Hospital of Anqing affiliated to Anhui Medical University from January 2020 to May 2023 were enrolled. According to whether NR occurred during PCI, these patients were divided into two groups: an NR group and a non-NR group. Subsequently, the QT intervals were measured before and at 12 hours after PCI. Afterward, the QTd, corrected QTd (QTcd), and the relative reduction of QTd and QTcd 12 hours pre- and postprocedure (ΔQTd-R and ΔQTcd-R, respectively) were calculated. Finally, multivariable logistic regression analysis was performed to predict the risk of VAE occurrence., Results: In the non-NR group, there was a significant decrease from baseline in postprocedure QTd (48±17 vs. 73±22 ms; P=0.009) and QTcd (54±19 vs. 80±23 ms; P=0.01); in contrast, the NR group showed no significant difference in QTd (64±20 vs. 75±23 ms; P=0.58) or QTd (70±22 vs. 82±26 ms; P=0.45). Furthermore, the ΔQTd-R and ΔQTcd-R were both lower in the NR group than in the non-NR group (P<0.05); however, the rate of VAEs was higher in the NR group than in the non-NR group (15.2% vs. 6.2%; P=0.02). The multivariable logistic regression analysis results revealed that each increase of 12% in ΔQTcd-R was an independent predictor of VAEs (odds ratio: 0.547; 95% confidence interval: 0.228-0.976)., Conclusions: The NR phenomenon following primary PCI in patients with STEMI leads to the defective recovery of QTd and QTcd. Furthermore, ΔQTcd-R can be viewed as an effective indicator for evaluating the myocardial repolarization inhomogeneity, and short-term clinical outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-398/coif). The authors have no conflicts of interest to declare., (2024 Cardiovascular Diagnosis and Therapy. All rights reserved.)

(1) Background: The benefits of weight management are widely recognized, and prolonged fasting duration has become a common method for weight control. The suitability of time-restricted eating (TRE) for elderly individuals remains controversial. This study aims to examine the correlation between fasting duration and mortality within a nationally representative cohort of elderly individuals in the United States. (2) Methods: Data were extracted from a prospective cohort study conducted as part of the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Participants aged over 60 with complete data on dietary intake and mortality follow-up information were included. Fasting duration was assessed using two 24 h dietary recalls. All the participants were categorized into fasting duration quartiles. Mortality outcomes were ascertained through the National Death Index. Cox proportional hazards regression models were utilized to analyze the association between fasting duration and mortality. (3) Results: The final analysis included 10,561 elderly participants (mean age 69.89, 45.58% male). Individuals with the longest fasting duration (over 12.38 h) had a significantly higher risk of CVD mortality compared to those with a normal fasting duration (10.58-12.38 h). This elevated CVD mortality risk was particularly pronounced in males, individuals over 70 years old, and non-shift workers. A non-linear relationship was observed between fasting duration and all-cause mortality and CVD mortality. (4) Conclusions: Prolonged fasting periods are associated with a higher risk of CVD mortality in the elderly population, although this correlation is not evident for all-cause, cancer, or other-cause mortality. A fasting duration of 11.49 h correlates with the lowest mortality risk. Additionally, elderly individuals with the shortest fasting duration exhibit elevated hazard ratios for both cancer and other-cause mortality. As with any health intervention, clinicians should exercise caution when recommending a fasting regimen that is personalized to the health condition of people who are older. Further research through randomized controlled trials should be conducted to comprehensively investigate the impact of TRE on mortality.

Chromosome segregation is an essential cellular process that has the potential to yield numerous targets for drug development. This pathway is presently underutilized partially due to the difficulties in the development of robust reporter assays suitable for high throughput screening. In bacteria, chromosome segregation is mediated by two partially redundant systems, condensins and ParABS. Based on the synthetic lethality of the two systems, we developed an assay suitable for screening and then screened a library of fungal extracts for potential inhibitors of the ParABS pathway, as judged by their enhanced activity on condensin-deficient cells. We found such activity in extracts of Humicola sp. Fractionation of the extract led to the discovery of four new analogues of sterigmatocystin, one of which, 4-hydroxy-sterigmatocystin (4HS), displayed antibacterial activity. 4HS induced the phenotype typical for parAB mutants including defects in chromosome segregation and cell division. Specifically, bacteria exposed to 4HS produced anucleate cells and were impaired in the assembly of the FtsZ ring. Moreover, 4HS binds to purified ParB in a ParS-modulated manner and inhibits its ParS-dependent CTPase activity. The data describe a small molecule inhibitor of ParB and expand the known spectrum of activities of sterigmatocystin to include bacterial chromosome segregation.

Atopic dermatitis (AD), a chronic and recurrent inflammatory skin disorder, presents a high incidence and imposes a substantial economic burden. Preventing its recurrence remains a significant challenge in dermatological therapy owing to poorly understood underlying mechanisms. In our study, we adopted a strategy of tracing the mechanisms of recurrence from clinical outcomes. We developed a mouse model of recurrent AD and applied clinically validated treatment regimens. Transcriptomic analyses revealed a pronounced enrichment in the glutathione metabolic pathway in the treated group. Through integrated bioinformatics and in vivo validation, we identified glutathione S-transferase alpha 4 (GSTA4) as a pivotal mediator in AD recurrence. Immunohistochemical analysis demonstrated decreased GSTA4 expression in lesions from patients with AD. Functionally, in vitro overexpression of GSTA4 significantly curtailed AD-like inflammatory responses and ROS production. Moreover, we discovered that NRF2 transcriptional activity regulates GSTA4 expression and function. Our treatment notably augmented NRF2-mediated GSTA4 transcription, yielding pronounced anti-inflammatory and ROS-neutralizing effects. Conclusively, our findings implicate GSTA4 as a critical factor in the recurrence of AD, particularly in the context of oxidative stress and chronic inflammation. Targeting the NRF2-GSTA4 axis emerges as a promising anti-inflammatory and antioxidative strategy for preventing AD recurrence., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Group B Streptococcus (GBS) is a leading cause of morbidity and mortality in young infants worldwide. This study aimed to investigate candidate GBS vaccine targets, virulence factors, and antimicrobial resistance determinants., Methods: We used whole-genome sequencing to characterize invasive GBS isolates from infants < 3 months of age obtained from a multicenter population-based study conducted from 2015 to 2021 in China., Results: Overall, seven serotypes were detected from 278 GBS isolates, four (Ia, Ib, III, V) of which accounted for 97.8 %. We detected 30 sequence types (including 10 novel types) that were grouped into six clonal complexes (CCs: CC1, CC10, CC17, CC19, CC23 and CC651); three novel ST groups in CC17 were detected, and the rate of CC17, considered a hyperinvasive neonatal clone complex, was attached to 40.6 % (113/278). A total of 98.9 % (275/278) of isolates harbored at least one alpha-like protein gene. All GBS isolates contained at least one of three pilus backbone determinants and the pilus types PI-2b and PI-1 + PI-2a accounted for 79.8 % of the isolates. The 112 serotype III/CC17 GBS isolates were all positive for hvgA. Most of the isolates (75.2 %) were positive for serine-rich repeat glycoprotein determinants (srr1or srr2). Almost all isolates possessed cfb (99.6 %), c1IE (100 %), lmb (95.3 %) or pavA (100 %) gene. Seventy-seven percent of isolates harboured more than three antimicrobial resistance genes with 28.4 % (79/278) gyrA quinoloneresistancedeterminants mutation, 83.8 % (233/278) carrying tet cluster genes and 77.3 % (215/278) carrying erm genes which mediated fluoroquinolone, tetracycline and clindamycin resistance, respectively.", Conclusions: The findings from this large whole-genome sequence of GBS isolates establish important baseline data required for further surveillance and evaluating the impact of future vaccine candidates., 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 Ltd.)

Background: Programmed cell death is an important mechanism for the development of hepatic ischemia and reperfusion (IR) injury, and multiple novel forms of programmed cell death are involved in the pathological process of hepatic IR. ERRFI1 is involved in the regulation of cell apoptosis in myocardial IR. However, the function of ERRFI1 in hepatic IR injury and its modulation of programmed cell death remain largely unknown., Methods: Here, we performed functional and molecular mechanism studies in hepatocyte-specific knockout mice and ERRFI1-silenced hepatocytes to investigate the significance of ERRFI1 in hepatic IR injury. The histological severity of livers, enzyme activities, hepatocyte apoptosis and ferroptosis were determined., Results: ERRFI1 expression increased in liver tissues from mice with IR injury and hepatocytes under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Hepatocyte-specific ERRFI1 knockout alleviated IR-induced liver injury in mice by reducing cell apoptosis and ferroptosis. ERRFI1 knockdown reduced apoptotic and ferroptotic hepatocytes induced by OGD/R. Mechanistically, ERRFI1 interacted with GRB2 to maintain its stability by hindering its proteasomal degradation. Overexpression of GRB2 abrogated the effects of ERRFI1 silencing on hepatocyte apoptosis and ferroptosis., Conclusions: Our results revealed that the ERRFI1-GRB2 interaction and GRB2 stability are essential for ERRFI1-regulated hepatic IR injury, indicating that inhibition of ERRFI1 or blockade of the ERRFI1-GRB2 interaction may be potential therapeutic strategies in response to hepatic IR injury., (© 2024. The Author(s).)

Bioelectronics, which converges biology and electronics, has attracted great attention due to their vital applications in human-machine interfaces. While traditional bioelectronic devices utilize nonliving organic and/or inorganic materials to achieve flexibility and stretchability, a biological mismatch is often encountered because human tissues are characterized not only by softness and stretchability but also by biodynamic and adaptive properties. Recently, a notable paradigm shift has emerged in bioelectronics, where living cells, and even viruses, modified via gene editing within synthetic biology, are used as core components in a new hybrid electronics paradigm. These devices are defined as "living synthelectronics," and they offer enhanced potential for interfacing with human tissues at informational and substance exchange levels. In this Perspective, the recent advances in living synthelectronics are summarized. First, opportunities brought to electronics by synthetic biology are briefly introduced. Then, strategic approaches to designing and making electronic devices using living cells/viruses as the building blocks, sensing components, or power sources are reviewed. Finally, the challenges faced by living synthelectronics are raised. It is believed that this paradigm shift will significantly contribute to the real integration of bioelectronics with human tissues., (© 2024 Wiley‐VCH GmbH.)

Purpose: This study aimed to evaluate the reliability and validity of the translated Chinese version of the Communication Complexity Scale (C-CCS) in a Chinese sample of preschool-aged children with minimal verbal skills., Methods: A total of 120 children with autism spectrum disorders or children with developmental delays aged 2 to 5 years with minimal verbal skills (i.e., produced less than 20 functional words) were recruited to complete the C-CCS. First, we tested the protocol with 20 children and shortened it based on their results. Second, the interrater reliability, test-retest reliability, and concurrent validity for 100 participants were examined. C-CCS scores were compared with scores from the Chinese Communicative Development Inventories (CCDI) for concurrent validity., Results: Ten C-CCS interactive scripts were administered to 100 participants. Intraclass correlation coefficients (ICC) between independent observers were high. The ICCs for overall optimal scores, optimal BR scores and optimal JA scores were 0.978, 0.971 and 0.977 respectively. Agreement for scores within scripted opportunities and communication level were high-Kappa coefficients 0.869 and 1.000 respectively. The test-retest reliability was high ( r  = 0.911). A moderate correlation was found between the C-CCS and the CCDI ( r  = 0.401)., Conclusions: The results indicate that C-CCS could be used as a measurement tool in research and clinical practice to describe communication levels in children with minimal verbal skills in China.

In this research, SCAPS-1D simulation software (Version: 3.3.10) was employed to enhance the efficiency of CsSnX 3 (X = Cl, Br, I) all-inorganic perovskite solar cells. By fine-tuning essential parameters like the work function of the conductive glass, the back contact point, defect density, and the thickness of the light absorption layer, we effectively simulated the optimal performance of CsSnX 3 (X = Cl, Br, I) all-inorganic perovskite solar cells under identical conditions. The effects of different X-site elements on the overall performance of the device were also explored. The theoretical photoelectric conversion efficiency of the device gradually increases with the successive substitution of halogen elements (Cl, Br, I), reaching 6.09%, 17.02%, and 26.74%, respectively. This trend is primarily attributed to the increasing size of the halogen atoms, which leads to better light absorption and charge transport properties, with iodine (I) yielding the highest theoretical conversion efficiency. These findings suggest that optimizing the halogen element in CsSnX 3 can significantly enhance device performance, providing valuable theoretical guidance for the development of high-efficiency all-inorganic perovskite solar cells.

Soil salinization is a major abiotic stress factor that negatively impacts plant growth, development, and crop yield, severely limiting agricultural production and economic development. Cotton, a key cash crop, is commonly cultivated as a pioneer crop in regions with saline-alkali soil due to its relatively strong tolerance to salt. This characteristic renders it a valuable subject for investigating the molecular mechanisms underlying plant salt tolerance and for identifying genes that confer salt tolerance. In this study, focus was placed on examining a salt-tolerant variety, E991, and a salt-sensitive variety, ZM24. A combined analysis of transcriptomic data from these cotton varieties led to the identification of potential salt stress-responsive genes within the glutathione S-transferase (GST) family. These versatile enzyme proteins, prevalent in animals, plants, and microorganisms, were demonstrated to be involved in various abiotic stress responses. Our findings indicate that suppressing GhGSTF9 in cotton led to a notably salt-sensitive phenotype, whereas heterologous overexpression in Arabidopsis plants decreases the accumulation of reactive oxygen species under salt stress, thereby enhancing salt stress tolerance. This suggests that GhGSTF9 serves as a positive regulator in cotton's response to salt stress. These results offer new target genes for developing salt-tolerant cotton varieties.

Ethnopharmacological Relevance: Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder that poses a significant global health challenge. There is a lack of safe and effective medications to treat AD. Astragalus membranaceous is a traditional Chinese medicine widely used in clinical treatment of skin diseases. Calycosin (CA), derived from the root of Astragalus membranaceous, exhibits dual attributes of anti-inflammatory and antioxidant properties, suggesting its promise for addressing cutaneous inflammation. Nonetheless, the precise mechanisms underlying CA's therapeutic actions in AD remain elusive., Aim of the Study: This study aimed to evaluate the efficacy and safety of CA in treating AD while also delving into the mechanistic underpinnings of CA's action in AD., Materials and Methods: The cell viability and anti-inflammatory impacts of CA in vitro were first gauged using CCK-8 and RT-qPCR. The potential mechanisms of CA were then probed using modular pharmacology. Flow cytometry was employed to ascertain the differentiation of Treg and Th17 cells derived from naïve T cells, as well as the proportions and mean fluorescence intensity (MFI) of human iTreg cells. The expressions of IL-10 and TGF-β1 were measured and Treg suppression assay was performed. The in vivo therapeutic efficacy of topical CA application was assessed using a calcipotriol (MC903)-induced AD mouse model. The expression metrics of inflammatory cytokines, IL-17A, FOXP3, and RORγt were authenticated via immunohistochemistry, RT-qPCR, Western blot, and ELISA., Results: CA exhibited a favorable safety profile and reduced the mRNA expressions of Th2 inflammatory cytokines in HaCaT cells. Modular pharmacology analysis pinpointed Th17 differentiation as the pivotal mechanism behind CA's therapeutic effect on AD. In vitro, CA fostered the differentiation of naïve T cells into Tregs while inhibiting their differentiation into Th17 cells. Furthermore, CA augmented the proliferation of human iTregs. In vivo, CA alleviated skin manifestations and decreased the levels of inflammatory mediators (IL-4, IL-5, IL-13, TSLP, and NF-κB related cytokines) in AD-like mouse models. Simultaneously, it regulated Treg/Th17 balance through suppressing IL-17A and RORγt expressions and bolstering FOXP3 expression., Conclusions: The study provides insights into the mechanistic pathways through which CA exerts its anti-inflammatory effects, particularly through promoting Treg cell differentiation and inhibiting Th17 cell differentiation. Furthermore, CA emerges as an alternative or adjunctive treatment strategy for managing AD., Competing Interests: Declaration of competing interest Bin Li (binli@shsmu.edu.cn) is a cofounder of Biotheus Inc. and chairman of its scientific advisory board. The other 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 oncogenesis and development of glioblastoma multiforme have been linked to glycosylation modifications, which are common post-translational protein modifications. Abnormal glycosyltransferase development leads to irregular glycosylation patterns, which hold clinical significance for GB prognosis. By utilizing both single-cell and bulk data, we developed a scoring system to assess glycosylation levels in GB. Moreover, a glycosylation-based signature was created to predict GB outcomes and therapy responsiveness. The study led to the development of an glyco-model incorporating nine key genes. This risk assessment tool effectively stratified GB patients into two distinct groups. Extensive validation through ROC analysis, RMST, and Kaplan-Meier (KM) survival analysis emphasized the model's robust predictive capabilities. Additionally, a nomogram was constructed to predict survival rates at specific time intervals. The research revealed substantial disparities in immune cell infiltration between low-risk and high-risk groups, characterized by differences in immune cell abundance and elevated immune scores. Notably, the glyco-model predicted diverse responses to immune checkpoint inhibitors and drug therapies, with high-risk groups exhibiting a preference for immune checkpoint inhibitors and demonstrated superior responses to drug treatments. Furthermore, the study identified two potential drug targets and utilized Connectivity Map analysis to pinpoint promising therapeutic agents. Clofarabine and YM155 were identified as potent candidates for the treatment of high-risk GB. Our well-crafted glyco-model effectively discriminates patients by calculating the risk score, accurately predicting GB outcomes, and significantly enhancing prognostic assessment while identifying novel immunotherapeutic and chemotherapeutic strategies for GB treatment., 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 Jin, Chen and Zhao.)

Actinomycetes have long been recognized as important sources of clinical antibiotics. However, the exploration of rare actinomycetes, despite their potential for producing bioactive molecules, has remained relatively limited compared to the extensively studied Streptomyces genus. The extensive investigation of Streptomyces species and their natural products has led to a diminished probability of discovering novel bioactive compounds from this group. Consequently, our research focus has shifted towards less explored actinomycetes, beyond Streptomyces , with particular emphasis on Kitasatospora setae ( K. setae ). The genome of K. setae was annotated and analyzed through whole-genome sequencing using multiple bio-informatics tools, revealing an 8.6 Mbp genome with a 74.42% G + C content. AntiSMASH analysis identified 40 putative biosynthetic gene clusters (BGCs), approximately half of which were recessive and unknown. Additionally, metabolomic mining utilizing mass spectrometry demonstrated the potential for this rare actinomycete to generate numerous bioactive compounds such as glycosides and macrolides, with bafilomycin being the major compound produced. Collectively, genomics- and metabolomics-based techniques confirmed K. setae 's potential as a bioactive secondary metabolite producer that is worthy of further exploration.

Classical trigeminal neuralgia (CTN) refers to episodic pain that is strictly confined to the trigeminal distribution area, and the thalamus is an important component of the trigeminal sensory pathway. Probabilistic tracking imaging algorithm was used to identify specific connections between the thalamus and the cortex, in order to identify structural changes in the thalamus of patients with CTN and perform thalamic segmentation. A total of 32 patients with CTN and 32 healthy controls underwent DTI-MRI scanning (3.0 T). Differences in fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) between the groups were studied. Correlation analysis was performed with clinical course and pain level. Compared to the healthy controls, patients in the CTN group had significantly reduced FA, increased AD, RD and MD in somatosensory subregion of the bilateral thalamus, increased RD in frontal subregion, increased RD and MD in motor subregion. Correlation analysis showed that patient history was positively correlated with pain grading, and that medical history was positively correlated with significantly reduced FA in somatosensory subregion, negatively correlated with increased RD and MD in motor subregion. We used DTI-based probabilistic fiber tracking to discover altered structural connectivity between the thalamus and cerebral cortex in patients with CTN and to obtain a thalamic segmentation atlas, which will help to further understand the pathophysiology of CTN and serve as a future reference for thalamic deep brain stimulation electrode implantation for the treatment of intractable pain., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The removal of toxic heavy metal ions from wastewater is of great significance in the protection of the environment and human health. Poly(gamma-glutamic acid) (PGA) is a non-toxic, biodegradable, and highly water-soluble polymer possessing carboxyl and imino functional groups. Herein, water-insoluble PGA-based hydrogels were prepared, characterized, and investigated as heavy metal adsorbents. The prepared hydrogels were recyclable and exhibited good adsorption effects on heavy metal ions including Cu 2+ , Cr 6+ , and Zn 2+ . The effects of adsorption parameters including temperature, solution pH, initial concentration of metal ions, and contact time on the adsorption capacity of the hydrogel for Cu 2+ were investigated. The adsorption was a spontaneous and exothermic process. The process followed the pseudo-first-order kinetic model and Langmuir isotherm model, implying a physical and monolayer adsorption. The adsorption mechanisms investigation exhibited that Cu 2+ adsorbed on the hydrogel via electrostatic interactions with anionic carboxylate groups of PGA in addition to the coordination interactions with the -NH groups. Importantly, the PGA hydrogel exhibited good reusability and the adsorption capability for Cu 2+ remained high after five consecutive cycles. The properties of PGA hydrogel make it a potential candidate material for heavy metal ion removal in wastewater treatment., Competing Interests: The authors declare no conflicts of interest.

Background: Chronic obstructive pulmonary disease (COPD) is closely associated with frailty, and prevention of acute exacerbations is important for disease management. Moreover, COPD patients with frailty experience a higher risk of acute exacerbations. However, the frailty instruments that can better predict acute exacerbations remain unclear., Purpose: (1) To explore the factors influencing frailty and acute exacerbations in stable COPD patients, and (2) quantify the ability of multidimensional frailty instruments to predict acute exacerbations within 1 year., Patients and Methods: In this retrospective longitudinal study, stable COPD patients were recruited from the outpatient department of Sichuan Provincial People's Hospital from July 2022 to June 2023. COPD patients reviewed their frailty one year ago and their acute exacerbations within one year using face-to-face interviews with a self-developed frailty questionnaire. Frailty status was assessed using the Frailty Index (FI), frailty questionnaire (FRAIL), and Clinical Frailty Scale (CFS). One-way logistic regression was used to explore the factors influencing frailty and acute exacerbations. Multivariate logistic regression was used to establish a prediction model for acute exacerbations, and the accuracy of the three frailty instruments was compared by measuring the area under the receiver operating characteristic curve (AUC)., Results: A total of 120 individuals were included. Frailty incidence estimates using FI, FRAIL, and CFS were 23.3%, 11.7%, and 15.8%, respectively. The three frailty instruments showed consistency in COPD assessments ( P <0.05). After adjusting for covariates, frailty reflected by the FI and CFS score remained an independent risk factor for acute exacerbations. The CFS score was the best predictor of acute exacerbations (AUC, 0.764 (0.663-0.866); sensitivity, 57.9%; specificity, 80.0%). Moreover, the combination of CFS plus FRAIL scores was a better predictor of acute exacerbations (AUC, 0.792 (0.693-0.891); sensitivity, 86.3%; specificity, 60.0%)., Conclusion: Multidimensional frailty assessments could improve the identification of COPD patients at high risk of acute exacerbations and facilitate targeted interventions to reduce acute exacerbations in these patients., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Wei et al.)