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In order to improve the comprehensive utilization value of the skin of the frog (Rana nigromaculata), the extraction process of antioxidant peptides of the skin of the frog (Rana nigromaculata) was studied in this experiment and its activity was evaluated. Ultrafiltration was used to separate the protease hydrolysis solution of the skin of the frog (Rana nigromaculata) to obtain small molecule peptides with different molecular weight. The antioxidant properties of frog (Rana nigromaculata) skin small molecule peptides were evaluated in Caenorhabditis elegans model as well as in vitro. Taking the yield of highly active small molecule peptides as the index, the response surface method was utilized to optimize the four parameters containing enzyme addition, ultra-high pressure, the action time, and liquid-to-material ratio to determine the best extraction process for small molecule peptides. Results showed that 1~2000 Da small molecule peptides possessed the optimal antioxidant effect compared to other peptides in the same molecular weight range, the scavenging capacity of DPPH free radicals and ABTS+ free radicals reached 76.93% and 59.23%, respectively. The antioxidant capacity of Caenorhabditis elegans was significantly improved. Besides, on the basis of neutral protease hydrolysis, the optimum technology parameters for secondary enzymatic hydrolysis were alkaline protease dosage 10210 U/g, ultra-high pressure pressure 315 MPa, pressure action time 9.3 min, liquid-material ratio 16 times, and the yield of small molecule peptides with 1~2000 Da was 25.26% under above condition. Ultra-high pressure assisted two-enzyme hydrolysis significantly increased the yield of small-molecule peptides from the skin of the frog (Rana nigromaculata). The results of this research provide a reference for the high-value utilization of by-products of the frog (Rana nigromaculata).

Abstract Background Salvia miltiorrhiza is a highly valuable medicinal plant and its cultivation is constrained by limited suitable land. Long-term continuous cropping practices alleviate limitations in planting area as well as causes the decline in plant yield and quality. Endophytic microorganisms colonize inside plant roots and are known to play important roles in improving the performance of model plants (such as Arabidopsis thaliana) and food crops (such as wheat, soybean, rice and maize). However, the understanding of how medicinal plants with different growth status (i.e., healthy and disease) shape the assembly of root-endophytic microorganisms and the functional importance of these microorganisms in improving plant performance remains largely unknown. Results Here, we investigated the assembly of root-endophytic microorganisms in medicinal plants with different growth status and its links with plant performance improvement. We found that medicinal plants with different growth status had distinct root-endophytic bacterial communities. Healthy plant roots recruited some potentially beneficial bacteria partners, particularly Pseudomonas into the endosphere. We further investigated the functional importance of these potentially beneficial bacteria on plant performance in subsequent greenhouse and field experiments. We found that root-endophytic Pseudomonas effectively increased medicinal plant seedling growth, crop yield, and the content of effective medicinal components. Conclusions Taken together, we demonstrate that healthy medicinal plants can form a distinct root-endophytic bacterial community, leading to an increase in plant growth-promoting endophytic bacteria (PGPEB) that contribute to the improvement of crop growth and quality. Our research provides valuable insights into the significant role of PGPEB in enhancing crop growth and improving medicinal plants quality for human health development in the future.

Introduction: Advanced maternal age is associated with reduced implantation and pregnancy rates, yet the underlying mechanisms remain poorly understood, and research models are limited. Objectives: Here, we aim to elucidate the impacts of senescence on implantation ability by employing blastoids to construct a novel research model. Methods: We used a novel three-dimensional system with totipotent blastomere-like cells (TBLCs) to construct TBL-blastoids and established senescence-related embryo models derived from oxidative stress-induced TBLCs. Results: Morphological and transcriptomic analyses revealed that TBL-blastoids exhibited characteristic blastocyst morphology, cell lineages, and a higher consistency in developmental rate. TBL-blastoids demonstrated the ability to develop into postimplantation structures in vitro and successfully implanted into mouse uteri, inducing decidualization and forming embryonic tissues. Importantly, senescence impaired the implantation potential of TBL-blastoids, effectively mimicking the impaired implantation ability and reduced pregnancy rates associated with advanced age. Furthermore, analysis of differentially expressed genes (DEGs) in human homologous deciduae revealed enrichment in multiple fertility-related diseases and other complications of pregnancy. The genes implicated in these diseases and the common DEGs identified in the lineage-like cells of the two types of TBL-blastoids and deciduae may represent potential targets for addressing impaired implantation potential. Conclusion: These results unveiled that TBL blastoids are an improved model for investigating implantation and early postimplantation, offering valuable insights into pregnancy-related disorders in women with advanced age and potential targets for therapeutic interventions.

Abstract Reproductive hormones associated with the hypothalamic-pituitary-gonadal (HPG) axis are closely linked to bone homeostasis. In this study, we demonstrate that Gonadotropin inhibitory hormone (GnIH, one of the key reproductive hormones upstream of the HPG axis) plays an indispensable role in regulating bone homeostasis and maintaining bone mass. We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density (BMD) in mice primarily by enhancement of osteoclast activation in vivo and in vitro. Mechanistically, GnIH/Gpr147 inhibits osteoclastogenesis by the PI3K/AKT, MAPK, NF-κB and Nfatc1 signaling pathways. Furthermore, GnIH treatment was able to alleviate bone loss in aging, ovariectomy (OVX) or LPS-induced mice. Moreover, the therapy using green light promotes the release of GnIH and rescues OVX-induced bone loss. In humans, serum GnIH increases and bone resorption markers decrease after green light exposure. Therefore, our study elucidates that GnIH plays an important role in maintaining bone homeostasis via modulating osteoclast differentiation and demonstrates the potential of GnIH therapy or green light therapy in preventing osteoporosis.

Abstract Background This study aimed to investigate deoxyribonucleic acid (DNA) copy number variations (CNVs) in children with neurodevelopmental disorders and their association with craniofacial abnormalities. Methods A total of 1,457 children who visited the Child Health Department of our hospital for unexplained Neurodevelopmental disorders (NDDs) between November 2019 and December 2022 were enrolled. Peripheral venous blood samples (2 mL) were collected from the children and their parents for whole-exome sequencing. Positive results were verified through Sanger sequencing for locus and pedigree validation. Simultaneously, a specific sign-scoring scale was created to evaluate characteristics related to the developments of eyes, nose, ears, eyebrows, head, mouth, face, trunk, limbs, and reproductive, urinary, and cardiovascular systems. Results A total of 536 children (36.78%, 536/1,457) were found to have genetic variations, with 379 (70.71%, 379/536) exhibiting pathogenic monogenic mutations. Furthermore, 157 children (29.29%, 157/536) harbored DNA copy number variants, encompassing microdeletions (68.15%, 107/157) and microduplications (31.85%, 50/157). Regarding the pathogenicity of CNVs, 91 (57.96%, 91/157) were identified as pathogenic, 28 (17.83%, 28/157) as variants of uncertain clinical significance (VOUS), and 38 (24.20%, 38/157) as benign according to the American College of Medical Genetics and Genomics (ACMG).Using a specific sign-scoring scale, the proportion of pathogenic CNVs in children graded 1 point or higher (64%, 58/91) was significantly higher than that of non-pathogenic CNVs (43%, 29/66) (P

Abstract Background The molecular genetic diagnosis of congenital adrenal hyperplasia (CAH) is very challenging due to the high homology between the CYP21A2 gene and its pseudogene CYP21A1P. Methodology This study aims to assess the clinical efficacy of targeted long-read sequencing (T-LRS) by comparing it with a control method based on the combined assay (NGS, Multiplex ligation-dependent probe amplification and Sanger sequencing) and to introduce T-LRS as a first-tier diagnostic test for suspected CAH patients to improve the precise diagnosis of CAH. Results A large cohort of 562 participants including 322 probands and 240 family members was enrolled for the perspective (96 probands) and prospective study (226 probands). The comparison analysis of T-LRS and control method have been performed. In the perspective study, 96 probands were identified using both the control method and T-LRS. Concordant results were detected in 85.42% (82/96) of probands. T-LRS performed more precise diagnosis in 14.58% (14/96) of probands. Among these, a novel 4141 kb deletion involving CYP21A2 and TNXB was established. A new diagnosis was improved by T-LRS. The duplications were also precisely identified to clarify the misdiagnosis by MLPA. In the prospective study, Variants were identified not only in CYP21A2 but also in HSD3B2 and CYP11B1 in 226 probands. Expand to 322 probands, the actual frequency of duplication haplotype (1.55%) could be calculated due to the accurate genotyping. Moreover, 75.47% of alleles with SNVs/indels, 22.20% of alleles with deletion chimeras. Conclusion T-LRS has higher resolution and reduced cost than control method with accurate diagnosis. The clinical utility of L-LRS could help to provide precision therapy to CAH patients, advance the life-long management of this complex disease and promote our understanding of CAH.

Background: In endoscopic nasobiliary drainage (ENBD), it is complicated to reposition the catheter from the mouth to nostril. We developed a new technique using an 1-mL syringe tube combined with guide-wire when repositioning an ENBD tube from mouth to nose. The aim of this study was to verify its utility. Methods: A single-center, prospective, randomized, controlled study was conducted between January 2021 and December 2022. Compared to traditional guide-wire technique, the new technique added a 1-mL syringe tube readily available in clinical work. The primary outcome was the ENBD repositioning time.The secondary outcomes included number of ENBD repositioning operations and technical success rate. Results: A total of 253 patients who underwent ENBD during the study period. Among them, 241 patients were enrolled in this study. The procedure time was significantly shorter in the new technique group than in the conventional group (60.7 vs. 98.7, p

Abstract Enhancing the sensitivity of radiotherapy (RT) towards renal cell carcinoma (RCC) remains a challenge because RCC is a radioresistant tumor. In this work, we design and report asymmetrically Polyethylene Glycol (PEG)ylated and amphipathic heptamethine indocyanine dyes for efficient radiosensitization of RCC treatment. They were synthesized by modifying different lengths of PEG chains as hydrophilic moieties on one N-alkyl chain of a mitochondria-targeting heptamethine indocyanine dye (IR-808), and a radiosensitizer 2-nitroimidazole (NM) as a hydrophobic moiety on another N-alkyl chain. The PEG modification significantly improved water solubility, decreased the intermolecular π–π large aggregates, thereby enhanced renal excretion. The asymmetrical and amphipathic modification enhanced the preferential accumulation in renal tumors through self-assembly into small-size nanoparticles in aqueous environment. Radiosensitization was further improved by preferential accumulation in renal tumor cells and their mitochondria as mitochondria play a crucial role in rapid cancer cell growth, metastasis, and RT resistance. Additionally, the modification also increased the abilities of fluorescence emission and photostability, which is meaningful for imaging-guided precise RCC RT. Therefore, our findings may present a theranostic radiosensitizer for renal tumor-targeted imaging and radiosensitization. Graphical Abstract

Abstract Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SCL7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SCL7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SCL7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SCL7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SCL7A11 expression levels were negatively associated with lung cancer patients’ survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.

Abstract Background Parkinson’s disease (PD) is a progressive neurodegenerative disease associated with functional and structural alterations beyond the nigrostriatal dopamine projection. However, the structural-functional (SC-FC) coupling changes in combination with subcortical regions at the network level are rarely investigated in PD. Methods SC-FC coupling networks were systematically constructed using the structural connectivity obtained by diffusion tensor imaging and the functional connectivity obtained by resting-state functional magnetic resonance imaging in 53 PD and 72 age- and sex-matched healthy controls (HCs). Then, we explored how SC-FC coupling varied within and between several well-defined functional domains. Results Results showed that the SC-FC coupling in patients with PD was globally reduced in comparison with HCs. Specifically, regional SC-FC decoupled in the inferior parietal lobule, occipitotemporal cortex, motor cortex, and higher-order association cortex in patients with PD. Moreover, PD showed intranetwork SC-FC decoupling in the visual network (VIS), limbic and higher-order association networks. Furthermore, internetwork decoupling mainly linked to the VIS, the somatomotor network (SOM), the dorsal attention network, and the default mode network, was observed, increased internetwork coupling was found between the subcortical network and the SOM in PD (all p

Abstract Background Several therapeutic drugs have been authorized for the treatment of patients with Coronavirus disease 2019 (COVID-19). However, further research on the mechanisms of action, efficacy, and target populations of these novel therapeutic drugs are necessary. This study included mild, moderate, severe, and critical COVID-19 patients to evaluate azvudine’s effectiveness across different severity levels. Methods We conducted a retrospective cohort study of patients with COVID-19 admitted to our hospital from December 1, 2022, to March 31, 2023. Patients were divided into retrospective cohorts receiving azvudine antiviral therapy and standard treatment, and were followed-up for up to 28 days. Results Prior to data processing, azvudine treatment was associated with reduced mortality rates at 7 days (1.09/1000 persons vs. 5.06/1000 persons, P

Abstract Artemisia argyi Lévl. et Vant. (A. argyi) leaf possesses various health promoting functions contributed by its main bioactive flavonoids. In this study, the anti-aging effect and mechanism of Artemisia argyi leaf extract (AALE) were identified using Caenorhabditis elegans (C. elegans) as a model. The results showed that the AALE promoted the lifespan and stress resistance of C. elegans. It was found that the AALE boosted the expression of oxidative stress-related proteins by regulating the insulin/ IGF-1 signaling (IIS) pathway, which then activated the transcription factors DAF-16/FOXO. The results of RNA-sequence analysis indicated that the changes of genes in nematodes treated with AALE were associated with the responses against oxidative stress, cell maturation, and immune reaction, and stress. The positive results suggest that Artemisia argyi leaf could have the robust benefits for improving healthy aging as well as preventing aging-related diseases in the human body.

A MoS2 concentration gradient coating of an osteoarticular-like structure with efficient strain transfer efficiency was prepared on titanium alloy via multiple plasma electrolytic oxidation. This structure facilitates efficient strain transfer by dissipating compressive and shear strains via dislocation annihilation and MoS2 interlayer sliding, thereby preserving a strain gradient. Leveraging this mechanism, the coefficient of friction was reduced by 50.2% compared to graphene coatings, while the frictional stabilization time was extended by 160% about Single MoS2/TiO2. This study elucidates the dislocation behavior and the mechanisms of strain transfer during friction within this structure.

Daphnetin, a coumarin derivative isolated from Daphne odorifera, has anti-tumor effects. The MAPK, STAT3, and NF-κB signaling pathways are closely related to the pathogenesis of lung cancer. To investigate the effect of daphnetin on anti-lung adenocarcinoma A549 cells and its mechanism. The anti-tumor effects of daphnetin on the proliferation, clone formation, migration, and invasion of A549 lung adenocarcinoma cells were investigated. The results showed that daphnetin inhibited the proliferation, colony formation, migration, and invasion of A549 cells through the MAPK/STAT3/NF-KB pathway, and mainly inhibited the clonal formation and migration of A549 cells through the JNK pathway. These results provide a new research direction and theoretical basis for the use of daphnetin in the inhibition of lung adenocarcinoma.

Abstract Objective Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by hormonal imbalances and insulin resistance (IR). Among the metabolic abnormalities associated with PCOS, obesity is often present concurrently. Nevertheless, the correlation between obesity, sex hormone levels, and blood lipid profiles in PCOS patients with IR remains uncertain. Methods This is a cross-sectional study including a total of 206 Chinese women diagnosed with PCOS, enrolled between March 2016 and December 2021. The participants’ anthropometric measurements, such as weight, height, waist circumference, and hip circumference, were recorded. Additionally, fasting blood samples were collected to measure various parameters, including fasting glucose, insulin levels, lipid profiles, and sex hormone levels. Results Our findings highlight that obesity exhibited a significant correlation with lower levels of sex hormone binding globulin (SHBG) and elevated levels of free androgen index (FAI), fasting insulin, and HOMA-IR in PCOS patients diagnosed with IR. However, no significant association between obesity and blood lipid profiles was observed within this particular group of women. Conclusion This study suggests that among PCOS patients with IR, lower levels of SHBG and higher levels of FAI are associated with obesity. These findings indicate that SHBG and FAI may have the potential to serve as a biomarker for the initial identification and prognosis of IR in PCOS patients. Trial registration Retrospectively registered on 25/04/2020 at ClinicalTrials.gov Identifer: NCT04264832.

To simultaneously detect 13 illegally added chemical drugs, a high performance liquid chromatography (HPLC) analytical method applicable to health food products for improving sexual function and prostate function was established. The samples were processed by vortex shaking for 1 min, followed by methanol extraction for 10 min under the ultrasonic condition. Then, the sample was separated on an Agilent 5 HC-C18 (2) column (250 mm×4.6 mm, 5 µm) with a gradient separation using methanol-phosphate-triethylamine buffer as the mobile phase. The detection wavelengths were of 218 nm and 245 nm, the column temperature was 30 ℃, and the sample size was 10 µL. Results showed that the correlation coefficients (r) in the linear range were all greater than 0.999, the detection limits were 0.76～4.61 mg/kg, the average recoveries were 92.4%~100.7%, and the relative standard deviations were 0.44%~1.06%. The method was applied to the rapid screening of 65 batches of health foods for improving sexual and prostate function, and results indicated that paroxetine hydrochloride was detected in 2 batches of samples (15.26 mg/tablet, 6.34 mg/pellet, respectively) and yohimbine hydrochloride was detected in 1 batch of samples (10.12 mg/pellet). In summary, the method is easy to conduct and characterized with high sensitivity and reliability, which is suitable for daily supervision and inspection of illegal added drugs in health foods for improving sexual and prostate function.

Abstract The harmonic problems caused by non‐linear factors of the grid connected inverter (GCI) system are more complicated, including both non‐characteristic harmonics emitted by the dead‐time and the changes in harmonic impedance characteristics. Harmonics interact with the changing impedance, and even cause harmonic amplification and resonance. The harmonic deterioration of the multiple GCIs system is serious. To analyse the mechanism and way of harmonic deterioration in grid‐connected system caused by nonlinear factors, the active impedance models of single inverter and multiple GCIs system including dead‐time effect and digital control delay are established first. In view of this, the influence mechanism of non‐linear factors on system stability is explored. The improved modal analysis method is used to traverse the network series parallel resonance caused by nonlinear factors. The results show that both the dead‐time effect and digital control delay reduce phase margin of the system, resulting in the resonant frequency shift and the resonant peak increase. When the harmonic excitation source interacts with the complex network under the influence of nonlinear factors, it will lead to further deterioration of harmonics. Finally, based on the MATLAB and RT‐LAB hardware‐in‐the‐loop simulation platforms, a multiple GCIs system model is built to verify the correctness of the established active impedance model and harmonic deterioration analysis.

Abstract. Tuberculosis (TB) is a prominent infectious disease globally that imposes a substantial health burden. Genital TB (GTB), an extrapulmonary manifestation, leads to complications such as tubal adhesions, blockage, and diminished ovarian function, culminating in infertility, and is recognized as a prevalent cause of infertility in nations with high-burden TB. In regions with low TB rates, infertility and active TB during pregnancy have been reported to be most common among female immigrants from countries with high-burden TB. In the context of TB, pregnant women often exhibit exacerbated symptoms after in vitro fertilization-embryo transfer (IVF-ET), heightening the risk of dissemination. Miliary pulmonary TB and tuberculous meningitis pose a serious threat to maternal and fetal health. This article integrates recent epidemiological data and clinical research findings, delineating the impact of TB on infertility and assisted reproduction and particularly focusing on the diagnosis and treatment of GTB, underscored by the imperative of TB screening before IVF-ET. Our objective is to increase awareness among respiratory and reproductive health professionals, promoting multidisciplinary management to enhance clinical vigilance. This approach seeks to provide patients with judicious reproductive plans and scientifically rigorous pregnancy management, thereby mitigating adverse pregnancy outcomes related to TB activity.

Abstract Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.

Abstract Background Spiroplasma eriocheiris has been proved to be a pathogen causing tremor disease of Eriocheir sinensis, it is also infectious to other aquatic crustaceans, resulting in a serious threat on the sustainable development of the aquaculture industry. S. eriocheiris is a helical-shaped microbe without a cell wall, and its motility is related to the cytoskeleton protein MreB which belongs to the actin superfamily and has five MreB homologs. Results In this study, we purified MreB3, MreB4 and MreB5, and successfully prepared monoclonal antibodies. After S. eriocheiris treated with actin stabilizator Phalloidin and inhibitors A22, we found that Phalloidin and A22 affect the S. eriocheiris morphology by altering MreB expression. We confirmed that the ability of S. eriocheiris to invade E. sinensis was increased after treatment with Phalloidin, including that the morphology of E. sinensis blood lymphocytes was deteriorated, blood lymphocytes viability was decreased, peroxidase activity and cell necrosis were increased. On the contrary, the pathogenicity of S. eriocheiris decreased after treatment with A22. Conclusions Our findings suggest that the MreB protein in S. eriocheiris plays a crucial role in its morphology and pathogenicity, providing new insights into potential strategies for the prevention and control of S. eriocheiris infections.

Abstract Background Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. Methods We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. Results We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Conclusions Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.

Abstract Background Fertilization practices control bacterial wilt-causing Ralstonia solanacearum by shaping the soil microbiome. This microbiome is the start of food webs, in which nematodes act as major microbiome predators. However, the multitrophic links between nematodes and the performance of R. solanacearum and plant health, and how these links are affected by fertilization practices, remain unknown. Results Here, we performed a field experiment under no-, chemical-, and bio-organic-fertilization regimes to investigate the potential role of nematodes in suppressing tomato bacterial wilt. We found that bio-organic fertilizers changed nematode community composition and increased abundances of bacterivorous nematodes (e.g., Protorhabditis spp.). We also observed that pathogen-antagonistic bacteria, such as Bacillus spp., positively correlated with abundances of bacterivorous nematodes. In subsequent laboratory and greenhouse experiments, we demonstrated that bacterivorous nematodes preferentially preyed on non-pathogen-antagonistic bacteria over Bacillus. These changes increased the performance of pathogen-antagonistic bacteria that subsequently suppressed R. solanacearum. Conclusions Overall, bacterivorous nematodes can reduce the abundance of plant pathogens, which might provide a novel protection strategy to promote plant health. Video Abstract

Abstract Background Soil nutrient status and soil-borne diseases are pivotal factors impacting modern intensive agricultural production. The interplay among plants, soil microbiome, and nutrient regimes in agroecosystems is essential for developing effective disease management. However, the influence of nutrient availability on soil-borne disease suppression and associated plant-microbe interactions remains to be fully explored. T his study aims to elucidate the mechanistic understanding of nutrient impacts on disease suppression, using phosphorous as a target nutrient. Results A 6-year field trial involving monocropping of tomatoes with varied fertilizer manipulations demonstrated that phosphorus availability is a key factor driving the control of bacterial wilt disease caused by Ralstonia solanacearum. Subsequent greenhouse experiments were then conducted to delve into the underlying mechanisms of this phenomenon by varying phosphorus availability for tomatoes challenged with the pathogen. Results showed that the alleviation of phosphorus stress promoted the disease-suppressive capacity of the rhizosphere microbiome, but not that of the bulk soil microbiome. This appears to be an extension of the plant trade-off between investment in disease defense mechanisms versus phosphorus acquisition. Adequate phosphorus levels were associated with elevated secretion of root metabolites such as L-tryptophan, methoxyindoleacetic acid, O-phosphorylethanolamine, or mangiferin, increasing the relative density of microbial biocontrol populations such as Chryseobacterium in the rhizosphere. On the other hand, phosphorus deficiency triggered an alternate defense strategy, via root metabolites like blumenol A or quercetin to form symbiosis with arbuscular mycorrhizal fungi, which facilitated phosphorus acquisition as well. Conclusion Overall, our study shows how phosphorus availability can influence the disease suppression capability of the soil microbiome through plant-microbial interactions. These findings highlight the importance of optimizing nutrient regimes to enhance disease suppression, facilitating targeted crop management and boosting agricultural productivity. Video Abstract

The exploration of the first member of Permian Maokou Formation (Maokou 1) in the Weiyuan area of southern Sichuan Basin has been limited. Previous analyses of cast thin sections and argon ion electron microscopy based on earlier drilling data suggested that talc pores were the primary reservoir spaces, with talc formation significantly contributing to the reservoir. However, the latest drilling data shows substantial differences in the types of reservoir spaces and the genesis of the Maokou 1 marlstone reservoirs compared to earlier understanding. It is necessary to further clarify the main controlling factors for the development of these reservoirs in the Maokou 1 member. Through core observation, thin section identification, physical property analysis, nitrogen adsorption, argon ion polishing scanning electron microscopy, and quantitative pore characterization, the primary reservoir spaces and types of the Maokou 1 marlstone were analyzed from both qualitative and quantitative perspectives. The main controlling factors for the development of these reservoirs were identified by combining total organic carbon (TOC) content determination, rare earth element analysis, and whole rock X-ray diffraction. High-quality reservoirs in the Maokou 1 member of the Weiyuan area are developed in marlstone, characterized by low porosity and permeability fractures and pore-type reservoirs, predominantly Type Ⅲ with some Type Ⅱ reservoirs. The main reservoir spaces include corroded pores, organic matter pores, and talc pores and fractures, with pore development closely related to TOC content. Talc formation, dolomitization, and silicification did not significantly contribute to secondary reservoir spaces, and their contribution to porosity is minimal. The development of marlstone reservoirs is jointly controlled by early dissolution, sedimentary facies, and organic matter abundance. Early dissolution is the key to the formation of corroded pores and fractures, while high primary productivity and high organic matter settling rate of the inner gentle slope shallow water environment provided the material basis for the formation of organic matter pores. This understanding provides theoretical support for the exploration of similar oil and gas reservoirs in the basin.

Background: A Delphi consensus was conducted to formulate an expert opinion on the definition of in-vitro fertilization (IVF) success, to provide a reference basis for clinical practice. Methods: Chinese experts in assisted reproductive technology (ART) were surveyed using the Delphi method. Based on the literature related to IVF success, eight experts developed a framework of statements and items. A questionnaire was then distributed to 23 experts to canvas their opinions on these statements. If consensus was not achieved, the statement was revised and revoted upon until a consensus was reached. Results: Consensus was reached for 19 statements related to the definition of IVF success, the most relevant of which are summarized as follows: (1) Goal of IVF treatment ([Formula: see text] statement): to attain a healthy live birth in the shortest possible time and with the lowest possible risks; (2) Definition of IVF success ([Formula: see text] statements): effectiveness, safety, and efficiency of IVF treatment should be included in the definition of success, with the cumulative live birth rate per ovarian stimulation cycle within 2 years being a performance indicator (PI) of success, and IVF success should be measured from a patient-centered perspective, including the patient’s burden and satisfaction. (3) Assurance of IVF success ([Formula: see text] statements): to provide evidence-based treatment and avoid the introduction of IVF add-ons into routine clinical practice without any clear evidence of benefit, optimize treatment quality by establishing and monitoring key PIs, and improving quality control systems. (4) Hurdles of IVF success ([Formula: see text] statements): cycle cancellation before oocyte pickup and treatment discontinuation after failed cycles are hurdles of success to IVF. Conclusions: Based on the Delphi method, the expert opinion on the definition of IVF success has been formed, which could complement guidelines and may help improve treatment outcomes.

ObjectiveTo investigate the association between insulin resistance, measured by the triglyceride-glucose (TyG) index, and clinical outcomes in patients with acute ischemic stroke who underwent intravenous thrombolysis with alteplase.MethodsThis retrospective study included 165 patients with acute ischemic stroke treated with intravenous alteplase. Insulin resistance was evaluated using the TyG index, and its relationship with the modified Rankin Scale (mRS) scores was analyzed. The analysis was conducted using R software (version R 4.1.3) to evaluate the correlation between the TyG index and functional outcomes at 14, 30, and 90 days post-stroke.ResultsThe study found that each unit increase in the TyG index significantly raised the risk of poor functional outcomes at 14 days (OR 9.86; 95% CI: 3.32–32.21; P < 0.001), 30 days (OR 5.82; 95% CI: 2.08–17.45; P = 0.001), and 90 days (OR 9.79; 95% CI: 3.33–31.66; P < 0.001) following a stroke. Higher TyG index values were associated with worse neurological outcomes. Although male gender, older age, and smoking were also linked to poorer outcomes, these associations did not reach statistical significance.ConclusionThe findings suggest that a higher TyG index, indicating greater insulin resistance, is associated with worse neurological outcomes in stroke patients. Early intervention targeting insulin resistance may improve clinical outcomes in ischemic stroke patients, and further research is needed to explore additional factors affecting neurological recovery.

Glioblastoma (GBM) is the most prevalent primary malignant brain tumor, characterized by a high mortality rate and a poor prognosis. The blood-brain barrier (BBB) and the blood-tumor barrier (BTB) present significant obstacles to the efficacy of tumor-targeted pharmacotherapy, thereby impeding the therapeutic potential of numerous candidate drugs. Targeting delivery of adequate doses of drug across the BBB to treat GBM has become a prominent research area in recent years. This emphasis has driven the exploration and evaluation of diverse technologies for GBM pharmacotherapy, with some already undergoing clinical trials. This review provides a thorough overview of recent advancements and challenges in targeted drug delivery for GBM treatment. It specifically emphasizes systemic drug administration strategies to assess their potential and limitations in GBM treatment. Furthermore, this review highlights promising future research directions in the development of intelligent drug delivery systems aimed at overcoming current challenges and enhancing therapeutic efficacy against GBM. These advancements not only support foundational research on targeted drug delivery systems for GBM but also offer methodological approaches for future clinical applications.

Summary: Background: To date, comprehensive data on the distribution of chronic kidney disease (CKD), the most prevalent comorbidity in diabetes, among Chinese adults with diabetes is lacking. Additionally, research gaps exist in understanding the association between CKD and cardiovascular health (CVH), an integrated indicator of lifestyle and metabolic control, within a nationwide sample of Chinese adults with diabetes. Methods: A nationally community-based cross-sectional survey was conducted in 2018–2020. 58,560 residents diagnosed with diabetes aged 18–74 years nationwide were invited to participate, and 52,000 participants with complete CKD data were included in this study. CKD was identified by the presence of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) and/or decreased estimated glomerular filtration rate (eGFR,

To address the challenge of low accuracy of the range image recovery of Geiger-mode avalanche photodiode (GM-APD) LiDAR in low signal-to-background ratios (SBRs), this paper proposes a non-local regularization-based fractional-order total variational compressive sensing (CS) algorithm for recovering GM-APD LiDAR images. First, the kurtosis factor peak method was utilized to obtain the target range image at low SBRs. Subsequently, a non-local regularization-based fractional-order total variational CS model for GM-APD LiDAR image recovery is proposed, leveraging the sparse and constrained isometric properties of CS as well as the memorability of fractional-order calculus. This model aims to compress and sample high-dimensional range images while performing a sparse representation. Finally, an augmented Lagrange algorithm was employed to precisely recover the target range image. The results of the experiments demonstrate that the proposed method can enhance the degree of target recovery by a minimum of 4.29% and increase the peak signal-to-noise ratio by at least 9.29% under conditions of a 60% sampling rate, identical SBR, and statistical frame number.

ABSTRACT Background Coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is a major concern due to its astonishing prevalence and high fatality rate, especially among elderly people. Patients suffering from COVID‐19 may exhibit immunosuppression in the initial stage of infection, while a cytokine storm can occur when the disease progresses to a severe stage. This inopportune immune rhythm not only makes patients more susceptible to the virus but also leads to numerous complications resulting from the excessive production of inflammatory factors. A20, which is widely accepted as a pivotal regulator of inflammation, has been shown to be implicated in the processes of antiviral responses and immunosuppression. Thus, A20 may participate in regulating the pathological processes of COVID‐19. Methods This narrative literature review summarizes recent evidence on the mechanisms of A20 in regulating the pathological processes of COVID‐19. We also downloaded single‐cell RNA‐seq data sets from healthy individuals and patients with varying severities of COVID‐19 from the NCBI GEO database to further dissect A20's regulatory mechanisms of these intricate cytokine pathways that are closely associated with SARS‐CoV‐2 infection. Results A20 might be one of the most critical anti‐infectious and anti‐inflammatory factors involved in the pathogenesis of COVID‐19. It effectively suppresses the immune damage and inflammatory storm caused by viral infection. Conclusions Understanding the relationship between A20‐regulated signaling pathways and pathological processes of COVID‐19 can provide insight into potential targets for intervention. Precise regulation of A20 to induce antiviral activity and an anti‐inflammatory response could mediate the pathogenesis of COVID‐19 and could become an effective treatment.

IntroductionThis study investigates how anxiety, depression, and sleep disorders impact heart rate variability (HRV) in the elderly, exploring the clinical implications of HRV changes.MethodsWe examined 355 patients (163 men, 192 women) at Xijing Hospital from July 2021 to December 2022 during health check-ups. Demographics were recorded, and emotional status was assessed using the Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Scale (HAMD). The Pittsburgh Sleep Quality Scale (PSQI) evaluated sleep quality. Patients were categorized into groups A-G based on the presence of emotional states and sleep disorders. HRV indices—SDNN, SDANN, RMSSD, PNN50, LF/HF, LF, and HF—were analyzed using ANOVA and multivariate logistic regression.ResultsNo statistically significant differences were observed in demographic, clinical, and lifestyle factors across the eight groups. Variables assessed included age, sex, body mass index (BMI), fasting blood glucose, glycated hemoglobin (HbA1c), blood lipids, blood pressure, heart rate, and histories of smoking and alcohol consumption. Additionally, the presence of hypertension, diabetes, coronary heart disease, marital status, income, and education level were evaluated, with all showing equivalence (P > 0.05). Significant differences in HRV indices were observed across groups, particularly in group G (patients with anxiety, depression and sleep disorders), which showed decreased HRV parameters except LF/HF, and group H (control group), which showed increased parameters, also except LF/HF (P < 0.01). Anxiety was an independent risk factor for reduced SDNN, SDANN, and LF (P ≤ 0.01), and increased LF/HF ratio (P < 0.01). Depression was linked to decreased SDNN, RMSSD, PNN50, and HF (P < 0.05). Sleep disorders independently predicted reduced PNN50 and SDANN (P < 0.01).ConclusionHRV indices of individuals with varying emotional states and sleep disorders exhibited varying degrees of decrease. Anxiety, depression, and sleep disorders presented a superimposed effect on HRV. SDNN, SDANN, RMSSD, PNN50, HF and LF of HRV are of great reference value in the diagnosis of emotional and sleep disorders. For elderly patients experiencing cognitive impairment, HRV is anticipated to serve as a convenient and effective tool for assessing mood and sleep disorders.

Intestinal barrier damage causes an imbalance in the intestinal flora and microbial environment, promoting a variety of gastrointestinal diseases. This study aimed to explore the mechanism by which adipose-derived stem cells (ADSCs) repair intestinal barrier damage. The human colon adenocarcinoma cell line Caco-2 and rats were treated with lipopolysaccharide (LPS) to establish in vitro and in vivo models, respectively, of intestinal barrier damage. The expression of inflammatory cytokines (TNF-α, HMGB1, IL-1β and IL-6), antioxidant enzymes (iNOS, SOD and CAT), and oxidative products (MDA and 8-iso-PGF2α) was detected using ELISA kits and related reagent kits. Apoptosis-related proteins (Bcl-2, Bax, Caspase-3 and Caspase-9), tight junction proteins (ZO-1, Occludin, E-cadherin, and Claudin-1) and p38 MAPK pathway-associated protein were detected by Western blotting. In addition, cell viability and apoptosis was determined by a CCK-8 kit and flow cytometry, respectively. Cell permeability was assayed by the transepithelial electrical resistance value and FITC-dextran concentration. The homing effect of ADSCs was detected by fluorescence labeling, and intestinal barrier tissue was observed by HE staining. After ADSC treatment, the level of phosphorylated p38 MAPK protein decreased, the expression of inflammatory factors, oxidative stress and cell apoptosis decreased, the expression of tight junction proteins increased, and cell permeability decreased in Caco-2 cells stimulated with LPS. In rats, ADSCs are directionally recruited to damaged intestinal tissue. ADSCs significantly decreased the levels of D-lactate, diamine oxidase (DAO) and FITC-dextran induced by LPS. ADSCs promoted tight junction proteins and inhibited oxidative stress in intestinal tissue. These effects were reversed after the use of a p38 MAPK activator. ADSCs can be directionally recruited to intestinal tissue, upregulate tight junction proteins, and reduce apoptosis and oxidative stress by inhibiting the p38MAPK signaling pathway. This study provides novel insights into the treatment of intestinal injury.

IntroductionRiptortus pedestris is a destructive pest that threatens multiple leguminous crops in China. The intestinal microbiota plays a crucial role in the growth and reproduction of host insects. However, the composition and function of the gut microbiota at different developmental stages remain unclear.MethodsHere, metagenomic sequencing was performed to clarify the gut microbial diversity and function in 2nd-, 3rd-, 4th-, and 5th- instar nymphs (2 N–5 N) and female adults (FAs) of R. pedestris and the effects of vital gut bacteria on development was detected. The gut bacteria have the stage specificity, indicating their function in the development of R. pedestris.ResultsEnterococcus and Caballerronia were the predominant bacteria present during the development of the 2 N–FAs. In addition, the microbial abundances in the 3 N and 4 N guts were significantly greater than those in the others guts. Furthermore, 5 N harbored the abundant microbiota Burkholderia-Paraburkholderia-Caballeronia. The metabolic pathways were significantly enriched from 2 N to FAs. Carbohydrate metabolism, including glycoside hydrolases (GHs) and glycosyl transferases (GTs), occurs throughout the entire developmental stage. Many antibiotic resistance genes (ARGs) were detected from 2 N to FAs. The bacteria from Pseudomonadota and Bacillota presented a broad spectrum of antibiotic resistance. Excitingly, Burkholderia bacteria eliminated by antibiotic treatment were unable to molt normally, and their lifespan was shortened in nymphs, indicating that the gut microbiota had a significant effect on nymph development.ConclusionIn summary, our results, for the first time, systematically illustrate the abundance and function across the gut microbiota from the different developmental stages of R. pedestris and demonstrate that the genera Burkholderia are crucial during the development of R. pedestris. This study provides the basis for stinkbug management strategies that focus on the pivotal gut microbiota.

BackgroundWith the rising global burden of chronic diseases, traditional health management models are encountering significant challenges. The integration of artificial intelligence (AI) into chronic disease management has enhanced patient care efficiency, optimized treatment strategies, and reduced healthcare costs, providing innovative solutions in this field. However, current research remains fragmented and lacks systematic, comprehensive analysis.ObjectiveThis study conducts a bibliometric analysis of AI applications in chronic disease health management, aiming to identify research trends, highlight key areas, and provide valuable insights into the current state of the field. Hoping our findings will serve as a useful reference for guiding further research and fostering the effective application of AI in healthcare.MethodsThe Web of Science Core Collection database was utilized as the source. All relevant publications from inception to August 2024 were retrieved. The external characteristics of the publications were summarized using HistCite. Keyword co-occurrences among countries, authors, and institutions were analyzed with Vosviewer, while CiteSpace was employed to assess keyword frequencies and trends.ResultsA total of 341 publications were retrieved, originating from 775 institutions across 55 countries, and published in 175 journals by 2,128 authors. A notable surge in publications occurred between 2013 and 2024, accounting for 95.31% (325/341) of the total output. The United States and the Journal of Medical Internet Research were the leading contributors in this field. Our analysis of the 341 publications revealed four primary research clusters: diagnosis, care, telemedicine, and technology. Recent trends indicate that mobile health technologies and machine learning have emerged as key focal points in the application of artificial intelligence in the field of chronic disease management.ConclusionDespite significant advancements in the application of AI in chronic disease management, several critical challenges persist. These include improving research quality, fostering greater international and inter-institutional collaboration, standardizing data-sharing practices, and addressing ethical and legal concerns. Future research should prioritize strengthening global partnerships to facilitate cross-disciplinary and cross-regional knowledge exchange, optimizing AI technologies for more precise and effective chronic disease management, and ensuring their seamless integration into clinical practice.

ObjectivesSepsis-associated acute kidney injury (SA-AKI) commonly occurs in critically ill patients and is closely associated with adverse outcomes. A comprehensive analysis of the current research landscape in SA-AKI can help uncover trends and key issues in this field. This study aims to provide a scientific basis for research directions and critical issues through bibliometric analysis.MethodsWe searched all articles on SA-AKI indexed in the SCI-Expanded of WoSCC up to May 7, 2024, and conducted bibliometric and visual analyses using bibliometric software CiteSpace and VOSviewer.ResultsOver the past 20 years, there has been a steady increase in literature related to renal repair following AKI. China and the United States contribute over 60% of the publications, driving research in this field. The University of Pittsburgh is the most active academic institution, producing the highest number of publications. J. A. Kellum is both the most prolific and the most cited author in this area. “Shock” and “American Journal of Physiology-Renal Physiology” are the most popular journals, publishing the highest number of articles. Recent high-frequency keywords in this field include “septic AKI,” “mitochondrial dysfunction,” “inflammasome,” “ferroptosis,” and “macrophage.” The terms “mitochondrial dysfunction,” “inflammasome,” “ferroptosis,” and “macrophage” represent current research hotspots and potential targets in this area.ConclusionThis is the first comprehensive bibliometric study to summarize the trends and advancements in SA-AKI research in recent years. These findings identify current research frontiers and hot topics, providing valuable insights for scholars studying SA-AKI.

Uranium poisoning, particularly from exposure to Depleted Uranium (DU), occurs when uranyl ions enter the bloodstream and bind primarily to transferrin, osteopontin, and albumin before entering cells via corresponding receptors on renal tubular membranes, leading to cellular damage. Uranium poisoning remains a significant clinical challenge, with no ideal treatment currently available. In this study, we investigate the therapeutic potential of human umbilical cord-derived mesenchymal stem cell exosomes (MSC-EXs) in mice exposed to DU. Our results showed that MSC-EXs could ameliorate renal damage and enhance kidney and bone marrow morphology but also effectively promote uranium excretion while reducing internal retention. Notably, the protective effects of MSC-EXs exceed those of MSCs and are comparable to those of sodium bicarbonate, as confirmed by various analytical techniques. Proteomic studies have shown that MSC-EXs reduce uranyl ion deposition in renal tubule cells through competitive binding with transferrin, osteopontin, and albumin. They also enhance oxidative stress resistance via modulation of glutathione metabolism, Cysteine and Methionine metabolism signaling pathways. This regulation leads to a reduction in mitochondrial ROS production, alleviates lipid peroxidation, and consequently decreases cellular apoptosis and ferroptosis. This study identifies MSC-EXs as a novel therapeutic strategy against depleted uranium poisoning, presenting potential advancements in treatment methodologies.

Maintaining grassland stock and improving its ecosystem services (ES) are critical yet challenging for ecological and economic sustainability. However, the diversity and spatial heterogeneity of global grasslands pose significant challenges to studying the spatio-temporal coupling characteristics of grassland area and ES changes, especially in the karst desertification control (KDC) regions. This study quantified the grassland area, grassland ES, and the elasticity of grassland ES in response to changes in grassland area within the KDC region of South China. The Moran index was applied to analyze spatio-temporal evolution characteristics, and a quantile regression model was used to explored the segmentation effects of influencing factors. Results showed that: (1) During 2000–2020, despite a 4.36 % decrease in grassland area (399,205 hm2) within the KDC region of South China, the comprehensive index of grassland ES increased from 0.99 to 1.03. Furthermore, counties where the elasticity index of grassland ES exceeded 1 constituted 73.52 %, indicating a general improvement in ES supply capacity. (2) Factors influencing grassland ES in the KDC region demonstrated clear segmentation effects, with the intensity and direction of the same factors varying significantly across different thresholds. The significance of socio-economic factors has been increasing steadily. (3) Within the framework of the UN Decade on Ecosystem Restoration 2021–2030, differentiated ecological engineering measures should be tailored based on the specific constraints of grassland ES in the KDC region. Our research results open a new perspective for the study of the impact mechanism of grassland ES. It can enrich the understanding of grassland ES and offer valuable insights to guide future initiatives for ecosystem restoration and sustainable development in ecologically fragile, particularly karst, areas.

Abstract A simple wideband magneto‐electric (ME) dipole antenna is presented in this letter. In particular, two pairs of L‐shaped slots with different sizes are successively etched out of the pair of horizontal patches of electric dipole, which can enlarge the bandwidth of ME dipole antenna without increasing the antenna size. Two new resonant frequency points are generated respectively at the lower and upper frequency region. To improve the impedance matching characteristics, two vertical rectangular patches are loaded in the middle of the horizontal portion of the Г‐shaped feed structure. A prototype is fabricated and measured, and an overlapped bandwidth of 101.3% (from 1.36 to 4.15 GHz) in terms of VSWR ≤ 2 is achieved, which can simultaneously cover the n50 (1.432–1.517 GHz), n51 (1.427–1.432 GHz), n78 (3.300–3.800 GHz) and 52.5% of n77 (3.8–4.4 GHz) bands of sub‐6G. It should be highlighted that other excellent properties of ME dipole antenna, such as stable radiation pattern, high gain, and low cross‐polarization level (CRPL), are maintained, which makes the proposed ME dipole antenna a good candidate for sub‐6G applications.

Summary: We previously described that the KDM5B histone H3 lysine 4 demethylase is an oncogene in estrogen-receptor-positive breast cancer. Here, we report that KDM5A is amplified and overexpressed in basal breast tumors, and KDM5 inhibition (KDM5i) suppresses the growth of KDM5-amplified breast cancer cell lines. Using CRISPR knockout screens in a basal breast cancer cell line with or without KDM5i, we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitizes cells to KDM5i, whereas deletion of RHO-GTPases leads to resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed co-localization of ZBTB7A and KDM5A/B at promoters with high histone H3K4me3 and dependence of KDM5A chromatin binding on ZBTB7A. ZBTB7A knockout altered the transcriptional response to KDM5i at NF-κB targets and mitochondrion-related pathways. High expression of ZBTB7A in triple-negative breast cancer is significantly associated with poor response to neoadjuvant chemotherapy. Our work furthers the understanding of KDM5-mediated gene regulation and identifies mediators of sensitivity to KDM5i.

Summary: Background: Polycystic ovary syndrome (PCOS) is a common endocrinopathy with significant reproductive, metabolic, and psychological complications. Consensus on PCOS clinical research priorities across end-users is fundamental and necessitates a robust co-development of a clinical research roadmap to guide international research efforts. Methods: A multistage process included: i) international surveys of women and healthcare providers to identify research priorities and unmet needs; ii) interrogation of systematic reviews conducted for the International PCOS Guideline to identify research gaps; iii) International PCOS Guideline Network consensus generated clinical research roadmap; and iv) international peer review for external validation. Findings: A codesigned survey engaging 1278 women with PCOS and 1474 healthcare providers found general concordance on research priorities. International PCOS Guideline development processes identified gaps in the literature and coproduced over 150 research priorities throughout the women’s life course, affirmed in international peer review. Key themes included: 1) Optimizing PCOS diagnosis; understanding natural history across diverse populations and life stages; detecting and preventing complications, and integrating and interrogating large data assets; 2) developing evidence-based resources, exploring optimal modes for information provision and models of care; 3) exploring effective lifestyle and weight management strategies; minimising weight stigma; 4) exploring intervention effects (including treatment efficacy, safety, cost-effectiveness, and long-term follow-up) on diverse features of PCOS across subgroups; and 5) optimising preconception care and fertility treatments in PCOS. Interpretation: This rigorously coproduced International PCOS Guideline clinical research roadmap addresses stakeholder priorities to guide future clinical research in this common yet neglected condition. The roadmap complements the established PCOS Core Outcome Set to enhance research quality, and tackles evidence-practice gaps to improve health outcomes for women with PCOS throughout their life course. Funding: The survey, International PCOS Guideline Network and 2018 and 2023 International PCOS Guidelines were funded by the Australian National Health and Medical Research Council (NHMRC) Centres of Research excellence in PCOS (APP1078444) and in Women’s Health in Reproductive life (APP1171592). Guideline partners, American Society for Reproductive Medicine (ASRM), Endocrine Society, European Society of Human Reproduction and Embryology (ESHRE), and European Society of Endocrinology (ESE), provided additional funding and assisted in guideline development. HT and AM are NHMRC Research Fellows. LM was funded by a Heart Foundation Future Leader and Veski Fellowship and CTT by the NHMRC Centres of Research excellence in Women’s Health in Reproductive life. All disclosures of interest were declared before commencing GDG involvement and updated before all major milestones and are available alongside the PCOS Guideline (https://www.monash.edu/__data/assets/pdf_file/0009/3371292/Register-of-disclosures-of-interest.pdf).

To solve poor engineering performance of copper-tungsten alloys operated at high temperatures, 3D network tungsten frameworks were prepared using a selective laser melting (SLM) process, and then copper was melted and diffused into these tungsten network structures to form copper matrix composites with different copper contents (i.e. Cu-10vol%W and Cu-30vol%W). Their mechanical/electrical properties and arc ablation performance were characterized. Results showed the obtained CuW composites were dense with good interfacial bonding, and the connected Cu phases formed a heat conduction channel and improved electrical and thermal conductivities of the composites. Electrical conductivities of Cu-30W and Cu-10W composites were 44.7% and 80.3% IACS, and their thermal conductivities at 25°C were 247.5 and 375.4 W/(m·K), respectively. The W-skeleton grid structure in the composites showed enhanced effects on impact toughness and anti-friction/wear resistance. Tensile strengths of Cu-30W and Cu-10W composites measured at 300°C were 95 MPa and 135 MPa, and their impact toughness values were 11.25 and 15.25 J/cm2, respectively. For the arc ablation performance, the copper phase of CuW composite was identified as the key influencing phase, whereas the W skeleton effectively hindered the spread of arc spots, inhibited quick melting of copper phases, and played effective support and protection functions.

The rapid advancement in intelligent bionics has elevated electronic skin to a pivotal component in bionic robots, enabling swift responses to diverse external stimuli. Combining wearable touch sensors with IoT technology lays the groundwork for achieving the versatile functionality of electronic skin. However, most current touch sensors rely on capacitive layer deformations induced by pressure, leading to changes in capacitance values. Unfortunately, sensors of this kind often face limitations in practical applications due to their uniform sensing capabilities. This study presents a novel approach by incorporating graphitic carbon nitride (GCN) into polydimethylsiloxane (PDMS) at a low concentration. Surprisingly, this blend of materials with higher dielectric constants yields composite films with lower dielectric constants, contrary to expectations. Unlike traditional capacitive sensors, our non-contact touch sensors exploit electric field interference between the object and the sensor’s edge, with enhanced effects from the low dielectric constant GCN/PDMS film. Consequently, we have fabricated touch sensor grids using an array configuration of dispensing printing techniques, facilitating fast response and ultra-low-limit contact detection with finger-to-device distances ranging from 5 to 100 mm. These sensors exhibit excellent resolution in recognizing 3D object shapes and accurately detecting positional motion. Moreover, they enable real-time monitoring of array data with signal transmission over a 4G network. In summary, our proposed approach for fabricating low dielectric constant thin films, as employed in non-contact touch sensors, opens new avenues for advancing electronic skin technology.

ABSTRACTThe air quality in China has changed due to the implementation of clean air actions since 2013. Evaluating the spatial pattern of PM2.5 and the effectiveness of reducing anthropogenic emissions in urban and nonurban areas is crucial. Therefore, the China Long-term Air Pollutant dataset for PM2.5 (CLAP_PM2.5) was generated from 2010 to 2022 with a daily 0.1° resolution using the random forest model and integrating multiple data sources, including extensive in-situ PM2.5 measurements, visibility, satellite retrievals, surface and upper-level meteorological data and other ancillary data. The CLAP_PM2.5 dataset is more reliable and accurate than other public datasets. Analysis of CLAP_PM2.5 from 2010 to 2022 reveals the decrease in positive urban-nonurban PM2.5 differences and higher decreasing rates of PM2.5 in most city clusters in eastern China. Furthermore, separating meteorological and emission contributions to the PM2.5 variability by a meteorological normalization approach indicates that meteorological contribution gradually changed from unfavorable to PM2.5 reduction during 2013–2017 to favorable to decline enhancement during 2018–2022, and in urban regions, meteorological contribution is higher than that in nonurban areas. Overall, the reduction in deweathered PM2.5 concentrations highlights China's significant achievements in terms of comprehensive clean air actions.

Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 μM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.

ABSTRACTHelicobacter pylori (H. pylori) causes a diversity of gastric diseases. The host immune response evoked by H. pylori infection is complicated and can influence the development and progression of diseases. We have reported that the Group 2 innate lymphocytes (ILC2) were promoted and took part in building type-2 immunity in H. pylori infection-related gastric diseases. Therefore, in the present study, we aim to clarify how H. pylori infection induces the activation of ILC2. It was found that macrophages were necessary for activating ILC2 in H. pylori infection. Mechanistically, H. pylori infection up-regulated the expression of indoleamine 2,3-dioxygenase (IDO) in macrophages to induce M2 polarization, and the latter secreted the alarmin cytokine Thymic Stromal Lymphopoietin (TSLP) to arouse ILC2.

Background Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age. It is frequently comorbid with obesity and negative emotions. Currently, there are few reports on the relationship between obesity and negative emotions in patients with PCOS. Here we performed both basic and clinical studies to study the relationship between obesity and negative emotions in PCOS.Methods We performed a cross-sectional study including 608 patients with PCOS and 184 healthy participants to assess the mental health status of people with different body mass indices (BMI). Self-rated anxiety, depression, and perceived stress scales were used for subjective mood evaluations. Rat PCOS models fed 45 and 60% high-fat diets were used to confirm the results of the clinical study. Elevated plus maze and open field tests were used to assess anxiety- and depression-like behaviors in rats.Results We observed overweight/obesity, increased depression, anxiety, and perceived stress in women with PCOS, and found that anxiety and depression were negatively correlated with BMI in patients with severe obesity and PCOS. Similar results were confirmed in the animal study; the elevated plus maze test and open field test demonstrated that only 60% of high fat diet-induced obesity partly reversed anxiety- and depression-like behaviors in PCOS rats. A high-fat diet also modulated rat hypothalamic and hippocampal luteinizing hormone and testosterone levels.Conclusion These results reveal a potential relationship between obesity and negative emotions in PCOS and prompt further investigation. The interactions between various symptoms of PCOS may be targeted to improve the overall well-being of patients.

Delirium in critical ill patients is a complex and common neurological syndrome in the intensive care unit (ICU) that is caused by a range of structural or functional abnormalities. ICU Delirium is associated with reduced compliance, prolonged hospital stays, greater use or delayed withdrawal of sedatives, higher rates and durations of mechanical ventilation, and higher rates of mortality. The aetiology and pathogenesis of ICU delirium are unclear, and the lack of better prediction, prevention, and treatment measures leads to a non-standardized control of delirium. By searching the relevant literature, we aim in this narrative review to describe progress in the pathogenesis, predictive biomarkers, diagnosis, and treatment of ICU delirium.

Background Glioblastoma (GBM) is an aggressive primary brain tumor with a high recurrence rate and poor prognosis. Necroptosis, a pathological hallmark of GBM, is poorly understood in terms of its role in prognosis, tumor microenvironment (TME) alteration, and immunotherapy.Methods & Results We assessed the expression of 55 necroptosis-related genes in GBM and normal brain tissues. We identified necroptosis-stratified clusters using Uni-Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression to establish the 10-gene Glioblastoma Necroptosis Index (GNI). GNI demonstrated significant prognostic efficacy in the TCGA dataset (n = 160) and internal validation dataset (n = 345) and in external validation cohorts (n = 591). The GNI-high subgroup displayed a mesenchymal phenotype, lacking the IDH1 mutation, and MGMT methylation. This subgroup was characterized by significant enrichment in inflammatory and humoral immune pathways with prominent cell adhesion molecules (CD44 and ICAM1), inflammatory cytokines (TGFB1, IL1B, and IL10), and chemokines (CX3CL1, CXCL9, and CCL5). The TME in this subgroup showed elevated infiltration of M0 macrophages, neutrophils, mast cells, and regulatory T cells. GNI-related genes appeared to limit macrophage polarization, as confirmed by immunohistochemistry and flow cytometry. The top 30% high-risk score subset exhibited increased CD8 T cell infiltration and enhanced cytolytic activity. GNI showed promise in predicting responses to immunotherapy and targeted treatment.Conclusions Our study highlights the role of necroptosis-related genes in glioblastoma (GBM) and their effects on the tumor microenvironment and patient prognosis. TheGNI demonstrates potential as a prognostic marker and provides insights into immune characteristics and treatment responsiveness.