Search

Objectives: Bone and joint infections (BJI) pose formidable challenges in orthopaedics due to antibiotic resistance and the complexities of biofilm, complicating treatment. This comprehensive exploration addresses the intricate challenges posed by BJI and highlights the significant role of phage therapy as a non-antibiotic strategy. Methods: BJI, which encompass prosthetic joint infections, osteomyelitis, and purulent arthritis, are exacerbated by biofilm formation on bone and implant surfaces, hindering treatment efficacy. Gram-negative bacterial infections, characterized by elevated antibiotic resistance, further contribute to the clinical challenge. Amidst this therapeutic challenge, phage therapy emerges as a potential strategy, showing unique characteristics such as strict host specificity and biofilm disruption capabilities. Results: The review unveils the dynamics of phages, including their origins, lifecycle outcomes, and genomic characteristics. Animal studies, in vitro investigations, and clinical research provide compelling evidence of the efficacy of phages in treating Staphylococcus aureus infections, particularly in osteomyelitis cases. Phage lysins exhibit biofilm-disrupting capabilities, offering a meaningful method for addressing BJI. Recent statistical analyses reveal high clinical relief rates and a favourable safety profile for phage therapy. Conclusions: Despite its promise, phage therapy encounters limitations, including a narrow host range and potential immunogenicity. The comprehensive analysis navigates these challenges and charts the future of phage therapy, emphasizing standardization, pharmacokinetics, and global collaboration. Anticipated strides in phage engineering and combination therapy hold promise for combating antibiotic-resistant BJI.

Background In this study, effective antigens of mRNA vaccine were excavated from the perspective of ICD, and ICD subtypes of PRAD were further distinguished to establish an ICD landscape, thereby determining suitable vaccine recipients.Research design and methods TCGA and MSKCC databases were applied to acquire RNA-seq data and corresponding clinical data of 554 and 131 patients, respectively. GEPIA was employed to measure prognostic indices. Then, a comparison of genetic alterations was performed utilizing cBioPortal, and correlation of identified ICD antigens with immune infiltrating cells was analyzed employing TIMER. Moreover, ICD subtypes were identified by means of consensus cluster, and ICD landscape of PRAD was depicted utilizing graph learning-based dimensional reduction.Results In total, 4 PRAD antigens were identified in PRAD, including FUS, LMNB2, RNPC3, and ZNF700, which had association with adverse prognosis and infiltration of APCs. PRAD patients were classified as two ICD subtypes based on their differences in molecular, cellular, and clinical features. Furthermore, ICD modulators and immune checkpoints were also differentially expressed between two ICD subtype tumors. Finally, the ICD landscape of PRAD showed substantial heterogeneity among individual patients.Conclusions In summary, the research may provide a theoretical foundation for developing mRNA vaccine against PRAD as well as determining appropriate vaccine recipients.

Numerical models have risen to prominence as indispensable tools for the in-depth study of the water cycle and these extreme hydrological phenomena， gaining widespread application across the globe.To delve into the spatiotemporal evolution patterns of global terrestrial water circulation against the backdrop of climate change and to decipher the intricate feedback mechanisms among atmospheric， land， and hydrological systems， the exploration of coupled atmospheric-land-hydrological models has emerged as a pivotal area of focus in the international research landscape dedicated to atmospheric and hydrological studies.This paper embarks on its journey by meticulously reviewing and delineating the evolution of coupled models， shedding light on the distinct advantages of the Weather Research and Forecasting Model Hydrological （WRF-Hydro） modeling system.It methodically dissects the primary sensitivity parameters of the WRF-Hydro model， while extensively covering its applications in analyzing surface runoff， soil moisture， the energy-water cycle， and the intertwined atmospheric and hydrological processes.The discourse culminates in a forward-looking exploration of the future directions in the development of the WRF-Hydro coupled model.Emphasizing strategic advancements， the paper advocates for a concerted effort towards the creation of robust scale conversion schemes， the refinement of parameterization methods， and the execution of high-resolution simulations.These simulations are crucial for accurately mapping the spatial and temporal dynamics of atmospheric and hydrological variables within basins， thereby significantly enhancing the model's capacity to intricately depict the interactions among atmospheric conditions， land surface phenomena， and hydrological processes.This comprehensive approach underlines the imperative to deepen our understanding and improve our modeling capabilities， aiming at a more effective prediction and management of the impacts arising from climate change and extreme hydrometeorological events.

Purpose: To evaluate the effect of anterior-segment structure on vault and position after implantable collamer lens (ICL) implantation using ultrasound biomicroscopy. Methods: The retrospective case-control study included insufficient vault eyes (750 µm). The preoperative biometric parameters of the anterior-segment structure and basic data between the three groups were analyzed using one-way analysis of variance. Results: There were significant differences (P < 0.05) between the three groups in maximum ciliary body thickness (CBTmax), iris-zonule distance (IZD), and trabecular-ciliary angle (TCA). The vault gradually decreased as CBTmax decreased and TCA increased. In the pairwise comparison, the CBTmax comparison between the insufficient vault (750 µm) group was statistically significant (P = 0.024, 95% CI: −0.17–0.017 µm); the TCA comparison between the insufficient vault (750 µm) group was statistically significant (P = 0.005, 95% CI: 1.78°–12.15°); The IZD comparison between the insufficient vault (750 µm) group was statistically significant (P = 0.037, 95% CI: 0.0027–0.1119 µm). The analysis of 284 ICL haptics locations showed that there were 16.67%, 32.69%, and 70.83% haptics located in the ciliary sulcus in three groups, respectively. Conclusion: The vault and ICL haptics position are related to anterior-segment structure. A thinner and posteriorly positioned ciliary body would increase the risk of low vault and fewer ICL haptics located in the ciliary sulcus after ICL implantation. This provides guidance for the selection of the ICL size and placement position before surgery.

The pyrolysis behavior of biomass is critical for industrial process design, yet the complexity of pyrolysis models makes this task challenging. This paper introduces an innovative hybrid model to quantify the pyrolysis potential of pine needles, predicting the entire process of their pyrolysis behavior. Through experimental analyses and kinetic parameter calculations of pine needle pyrolysis, the study employs a kinetic model with a chemical reaction mechanism. Additionally, it introduces an improved dung beetle optimization algorithm to accurately capture the primary trends in pine needle pyrolysis. The developed artificial neural network model incorporates meta-heuristic algorithms to address process error factors. Validation is based on experimental data from TG at three different heating rates. The results demonstrate that the hybrid model exhibits strong predictive performance compared to the standalone model, with coefficients of determination (R²) of 0.9999 and 0.999 for predicting the conversion degree and conversion rate of untrained data, respectively. Additionally, the standard errors of prediction (SEP) are 0.249% and 0.449% for predicting the conversion degree and conversion rate of untrained data, respectively.

Colletotrichum species can function as plant pathogens, saprobes or endophytes on a wide variety of plant hosts and are considered amongst the ten most significant genera of plant pathogens globally. China contributes almost half the walnut production in the world. However, Colletotrichum species occurring on walnut remain largely unresolved in China. To explore the Colletotrichum species found on walnut in China, 470 walnut fruit or leaf samples with anthracnose were collected from 14 main walnut-producing regions across seven provinces. A total of 165 Colletotrichum strains were isolated from these samples. The Colletotrichum isolates were identified, based on morphological characteristics and sequence analyses of ACT, CHS-1, GAPDH, ITS and TUB2. Twelve species, including 11 known Colletotrichum species (C. boninense, C. citrulli, C. fioriniae, C. fructicola, C. godetiae, C. juglandicola, C. karsti, C. mengyinense, C. pandanicola, C. peakense and C. siamense) and a novel species (C. chinensis sp. nov.) were identified. The species distribution revealed regional prevalence as follows: C. mengyinense was the most dominant species in Gansu, C. mengyinense and C. siamense in Shandong, C. chinensis in Beijing, C. pandanicola in Shaanxi and C. godetiae in Yunnan. Colletotrichum siamense was the sole species isolated in Sichuan and Xinjiang Provinces. Koch’s postulates were fulfilled, demonstrating that all 12 species cause anthracnose on walnut. This is the first report of C. boninense, C. citrulli and C. karsti as pathogens of walnut anthracnose worldwide.

Abstract Background The National Chest Pain Center Program (NCPCP) is a nationwide, quality enhancement program aimed at raising the standard of care for patients experiencing acute chest pain in China. The benefits of chest pain center (CPC) accreditation on acute coronary syndrome have been demonstrated. However, there is no evidence to indicate whether CPC accreditation improves outcomes for patients with acute aortic dissection (AAD). Methods We conducted a retrospective observational study of patients with AAD from 1671 hospitals in China, using data from the NCPCP spanning the period from January 1, 2016 to December 31, 2022. The patients were divided into 2 groups: pre-accreditation and post-accreditation admissions. The outcomes examined included in-hospital mortality, misdiagnosis, and Stanford type A AAD surgery. Multivariate logistic regression was employed to explore the relationship between CPC accreditation and in-hospital outcomes. Furthermore, we stratified the hospitals based on their geographical location (Eastern/Central/Western regions) or administrative status (provincial/non-provincial capital areas) to assess the impact of CPC accreditation on AAD patients across various regions. Results The analysis encompassed a total of 40,848 patients diagnosed with AAD. The post-accreditation group exhibited significantly lower rates of in-hospital mortality and misdiagnosis (12.1% vs. 16.3%, P

Abstract Purpose Bone metastases occur in 50-70% of patients with breast cancer (BC) and result in high mortality. Platelet distribution width (PDW), a commonly used parameter of activated platelets, has been associated with a poor prognosis in BC. We aim to investigate the prognostic role of PDW for bone metastasis in BC patients. Methods 515 patients who received BC surgery in the Harbin Medical University Cancer Hospital from July 1, 2016, to December 31, 2017, were reviewed. Patients’ characteristics and platelet indices upon enrollment in this study were collected. The Kaplan-Meier method was used to estimate the 5-year bone metastasis incidence. The univariate and multivariate Cox regression analyses were utilized to identify risk factors associated with bone metastasis. Results The patients with bone metastases exhibited lower PDW levels than the patients without bone metastases. Moreover, decreased PDW was significantly correlated with histologic type, multifocal disease, and lymph node status. In addition, the patients with reduced PDW levels were more likely to develop bone metastasis. Multivariate analysis showed that PDW was an independent predictor for bone metastasis. Conclusion PDW is an independent predictor of bone metastasis in BC. Further research is warranted.

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

Abstract Multiplexed imaging technologies have made it possible to interrogate complex tissue microenvironments at sub-cellular resolution within their native spatial context. However, proper quantification of this complexity requires the ability to easily and accurately segment cells into their sub-cellular compartments. Within the supervised learning paradigm, deep learning-based segmentation methods demonstrating human level performance have emerged. However, limited work has been done in developing such generalist methods within the unsupervised context. Here we present an easy-to-use unsupervised segmentation (UNSEG) method that achieves deep learning level performance without requiring any training data via leveraging a Bayesian-like framework, and nucleus and cell membrane markers. We show that UNSEG is internally consistent and better at generalizing to the complexity of tissue morphology than current deep learning methods, allowing it to unambiguously identify the cytoplasmic compartment of a cell, and localize molecules to their correct sub-cellular compartment. We also introduce a perturbed watershed algorithm for stably and automatically segmenting a cluster of cell nuclei into individual nuclei that increases the accuracy of classical watershed. Finally, we demonstrate the efficacy of UNSEG on a high-quality annotated gastrointestinal tissue dataset we have generated, on publicly available datasets, and in a range of practical scenarios.

Abstract Background Treatment strategy against immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) frequently requires other immunosuppressive agents. Tofacitinib is a rapidly acting JAK-STAT inhibitor with proven efficacy in multiple autoimmune diseases. We aimed to evaluate the efficacy and safety of tofacitinib in the management of irAEs in cancer patients. Methods Cancer patients who received ICIs and were treated with tofacitinib for the management of irAEs at 6 institutions were retrospectively included in this study. Demographic and clinical characteristics were obtained from electronic medical records. Longitudinal assessment of cardiac troponin T (cTnT) with clinical assessment was utilized to evaluate the benefit of tofacitinib treatment in patients with ICI myocarditis. Overall survival (OS) was also assessed. Results Fifty-three patients were included in this study. The median time from irAE onset to tofacitinib therapy was 17 (range, 2–186) days and the median duration of tofacitinib treatment was 52.5 (range, 3–277) days. Enrolled patients were subdivided into 3 groups based on clinical severity and steroid responsiveness including 11 life-threatening cases, 30 steroid-resistant cases, and 12 cases with steroid taper failure. Clinical remission rate in each group was 54.5%, 96.7%, and 100%, respectively (P

Abstract Plants possess the ability to induce programmed cell death (PCD) in response to abiotic and biotic stresses; nevertheless, the evidence on PCD initiation during pear scald development and the involvement of the scald trigger 6-methyl-5-hepten-2-one (MHO) in this process is rudimentary. Pyrus bretschneideri Rehd. cv. ‘Dangshansuli’ pear was used to validate such hypothesis. The results showed that superficial scald occurred after 120-d chilling exposure, which accompanied by typical PCD-associated morphological alterations, such as plasmolysis, cell shrinkage, cytosolic and nuclear condensation, vacuolar collapse, tonoplast disruption, subcellular organelle swelling, and DNA fragmentation. These symptoms were aggravated after MHO fumigation but alleviated by diphenylamine (DPA) dipping. Through transcriptome assay, 24 out of 146 PCD-related genes, which were transcribed during cold storage, were identified as the key candidate members responsible for these cellular biological alternations upon scald development. Among these, PbrCNGC1, PbrGnai1, PbrACD6, and PbrSOBIR1 were implicated in the MHO signaling pathway. Additionally, PbrWRKY2, 34 and 39 could bind to the W-box element in the promoter of PbrGnai1 or PbrSOBIR1 and activate their transcription, as confirmed by dual-luciferase, yeast one-hybrid, and transient overexpression assays. Hence, our study confirms the PCD initiation during scald development and explores the critical role of MHO in this process.

Abstract Perineural invasion (PNI) is a new approach of cervical cancer invasion and metastasis, involving the cross-talk between tumor and nerve. However, the initiating signals and cellular interaction mechanisms of PNI remain largely elusive. The nerve-sparing radical hysterectomy (NSRH) proposed to improve postoperative quality of life is only applicable to cervical cancer patients without PNI. Therefore, it is important to elucidate the underlying mechanisms initiating PNI, and suggest the effective biomarkers to predict PNI before NSRH surgery. Here, we found that PNI is the characteristic of advanced cervical cancer, and Schwann cells were the antecedent cells that initiating PNI. Further, neuropeptide neuromedin B (NMB) produced by cervical cancer cells was determined to induce PNI by reprogramming Schwann cells, including driving their morphological and transcriptional changes, promoting their proliferation and migration, and initiating PNI by secreting CCL2 and directing axon regeneration. Mechanistically, cervical cancer cells-produced NMB activated its receptor NMBR in Schwann cells, and opened the T-type calcium channels to stimulate Ca2+ influx through PKA signaling, which could be blocked by the inhibitor. Clinically, combined examination of serum NMB and CCL2 levels was suggested to effectively predict PNI in cervical cancer patients. Our data demonstrate that cervical cancer-produced NMB initiates the reprograming of Schwann cells, which then direct axon regeneration, thus causing PNI onset. The elevated serum NMB and CCL2 levels may be useful for the decision-making to nerve sparing during hysterectomy surgery of cervical cancer patients.

Abstract Background The current clinical management of carotid atherosclerosis is based on the control of risk factors and medicine. However, the risk of adverse events associated with the medicine resulting in concerns and low medication compliance makes it necessary to seek a safer alternative therapy. This study assessed the effectiveness and safety of acupuncture as a treatment for carotid atherosclerosis. Methods In this randomized controlled trial, patients with carotid atherosclerotic plaques were included and randomly assigned (1:1) to receive real acupuncture or sham acupuncture for 12 weeks. The follow-up period was 12 weeks. The primary outcome included carotid intima-media thickness (cIMT), plaque score (PS), plaque volume (PV) and grey-scale median (GSM). Secondary outcome was pulse wave velocity (PWV). Adverse events results were recorded as safety outcomes. Results From January 2021 to February 2022, 60 eligible patients were included. 55 patients (91.7%) completed the intervention and the 12-week follow-up and there was no statistical difference in demographics between the groups. At the end of treatment, the real acupuncture group had significantly reduced PS (P = 0.002), PV (P = 0.000), and improved GSM (P = 0.044). There was no significant difference in the reduction in cIMT (Left cIMT: P = 0.338, Right cIMT: P = 0.204) and PWV between the groups (the left BS: P = 0.429; the left ES: P = 0.701; the right BS: P = 0.211; the right ES: P = 0.083). Three mild adverse reactions occurred during the study. Conclusion This study found that acupuncture had a certain effect on reducing the thickness and volume of carotid plaque and improving the stability of plaque with minor side effects. These findings suggest that acupuncture may be a potential alternative therapy for carotid atherosclerosis. Trial registration This trial has been registered at ClinicalTrials.gov (ChiCTR2100041762). Submitted 30 December 2020, Registered 4 January 2021 Prospectively registered.

Abstract Abnormalities in ether lipid metabolism as well as the formation of neutrophil extracellular traps have recently been recognized as detrimental factors affecting tumorigenesis and progression. However, the role of abnormal ether lipid metabolism in colorectal cancer (CRC) evolution has not been reported. Here we show that the lipid metabolism-related gene enoyl-CoA δ-isomerase 2 (ECI2) plays a tumor-suppressor role in CRC and is negatively associated with poor prognosis in CRC patients. We mechanistically demonstrate that ECI2 reduces ether lipid-mediated Interleukin 8 (IL-8) expression leading to decreased neutrophil recruitment and neutrophil extracellular traps formation for colorectal cancer suppression. In particular, ECI2 inhibits ether lipid production in CRC cells by inhibiting the peroxisomal localization of alkylglycerone phosphate synthase (AGPS), the rate-limiting enzyme for ether lipid synthesis. These findings not only deepen our understanding of the role of metabolic reprogramming and neutrophil interactions in the progression of CRC, but also provide ideas for identifying potential diagnostic markers and therapeutic targets for CRC.

Highlights A novel cascade strategy is proposed to construct Pd-NiCo2O4 electrocatalyst. First time discovery that Ni incorporation together with Pd loading is able to balance the competitive adsorption of OH– and 5-hydroxymethylfurfural. Pd–NiCo2O4 promotes both the indirect and direct synergistic oxidation process. Pd–NiCo2O4 catalyst exhibits extraordinary current density and excellent Faradaic Efficiency at a low potential.

Abstract Pyroptosis, a lytic form of cell death mediated by the gasdermin family, is characterized by cell swelling and membrane rupture. Inducing pyroptosis in cancer cells can enhance antitumor immune responses and is a promising strategy for cancer therapy. However, excessive pyroptosis may trigger the development of inflammatory diseases due to immoderate and continuous inflammatory reactions. Nanomaterials and nanobiotechnology, renowned for their unique advantages and diverse structures, have garnered increasing attention owing to their potential to induce pyroptosis in diseases such as cancer. A nano-delivery system for drug-induced pyroptosis in cancer cells can overcome the limitations of small molecules. Furthermore, nanomedicines can directly induce and manipulate pyroptosis. This review summarizes and discusses the latest advancements in nanoparticle-based treatments with pyroptosis among inflammatory diseases and cancer, focusing on their functions and mechanisms and providing valuable insights into selecting nanodrugs for pyroptosis. However, the clinical application of these strategies still faces challenges owing to a limited understanding of nanobiological interactions. Finally, future perspectives on the emerging field of pyroptotic nanomaterials are presented. Graphical abstract

Abstract Background Insulin resistance is linked to an increased risk of frailty, yet the comprehensive relationship between the triglyceride glucose-body mass index (TyG-BMI), which reflects weight, and frailty, remains unclear. This relationship is investigated in this study. Methods Data from 9135 participants in the China Health and Retirement Longitudinal Study (2011–2020) were analysed. Baseline TyG-BMI, changes in the TyG-BMI and cumulative TyG-BMI between baseline and 2015, along with the frailty index (FI) over nine years, were calculated. Participants were grouped into different categories based on TyG-BMI changes using K-means clustering. FI trajectories were assessed using a group-based trajectory model. Logistic and Cox regression models were used to analyse the associations between the TyG-BMI and FI trajectory and frail incidence. Nonlinear relationships were explored using restricted cubic splines, and a linear mixed-effects model was used to evaluate FI development speed. Weighted quantile regression was used to identify the primary contributing factors. Results Four classes of changes in the TyG-BMI and two FI trajectories were identified. Individuals in the third (OR = 1.25, 95% CI: 1.10–1.42) and fourth (OR = 1.83, 95% CI: 1.61–2.09) quartiles of baseline TyG-BMI, those with consistently second to highest (OR = 1.49, 95% CI: 1.32–1.70) and the highest (OR = 2.17, 95% CI: 1.84–2.56) TyG-BMI changes, and those in the third (OR = 1.20, 95% CI: 1.05–1.36) and fourth (OR = 1.94, 95% CI: 1.70–2.22) quartiles of the cumulative TyG-BMI had greater odds of experiencing a rapid FI trajectory. Higher frail risk was noted in those in the fourth quartile of baseline TyG-BMI (HR = 1.42, 95% CI: 1.28–1.58), with consistently second to highest (HR = 1.23, 95% CI: 1.12–1.34) and the highest TyG-BMI changes (HR = 1.58, 95% CI: 1.42–1.77), and those in the third (HR = 1.10, 95% CI: 1.00-1.21) and fourth quartile of cumulative TyG-BMI (HR = 1.46, 95% CI: 1.33–1.60). Participants with persistently second-lowest to the highest TyG-BMI changes (β = 0.15, 0.38 and 0.76 respectively) and those experiencing the third to fourth cumulative TyG-BMI (β = 0.25 and 0.56, respectively) demonstrated accelerated FI progression. A U-shaped association was observed between TyG-BMI levels and both rapid FI trajectory and higher frail risk, with BMI being the primary factor. Conclusion A higher TyG-BMI is associated with the rapid development of FI trajectory and a greater frail risk. However, excessively low TyG-BMI levels also appear to contribute to frail development. Maintaining a healthy TyG-BMI, especially a healthy BMI, may help prevent or delay the frail onset.

Abstract Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4’s potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab’s efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.

Abstract Superconducting quantum bits (qubits) rely on ultra-thin, amorphous oxide tunneling barriers that can have significant inhomogeneities and defects as grown. This can result in relatively large uncertainties and deleterious effects in the circuits, limiting the scalability. Finding a robust solution to the junction reproducibility problem has been a long-standing goal in the field. Here, we demonstrate a transformational technique for controllably tuning the electrical properties of aluminum-oxide tunnel junctions. This is accomplished using a low-voltage, alternating-bias applied individually to the tunnel junctions, with which resistance tuning by more than 70% can be achieved. The data indicates an improvement of coherence and reduction of two-level system defects. Transmission electron microscopy shows that the treated junctions are predominantly amorphous, albeit with a more uniform distribution of alumina coordination across the barrier. This technique is expected to be useful for other devices based on ionic amorphous materials.

Abstract Background To investigate the cross-sectional and longitudinal associations between depressive symptoms and the prevalence of frailty and its components in a nationally representative sample of middle-aged and older Chinese adults. Method The China Health and Retirement Longitudinal Study (CHARLS) provided data on 2581 (after inclusion and exclusion criteria) adults aged ≥ 45 years. Every two years, face-to-face, computer-aided personal interviews (CAPI), and structured questionnaires were used to follow up with the respondents. The Chinese version of the Center for Epidemiologic Studies-Depression Scale (CES-D) was used to evaluate depressive symptoms, and the Fried criteria were used to measure frailty. The odds ratio (OR) and 95% confidence interval (CI) for the association of exposure (depressive symptoms at baseline) with the onset of the outcome (frailty and its components) in the individuals at baseline were analyzed by binary logistic regression. Results At baseline, 11.62% of participants had frailty, and 57.92% had depressive symptoms. In the cross-sectional analysis, depressive symptoms (OR = 5.222, 95%CI 3.665–7.442) were associated with frailty. In the longitudinal analysis, after adjusting for the full set of covariates among participants free of baseline frailty, depressive symptoms were significantly associated with incident frailty during the short term (OR = 2.193, 95%CI 1.324–3.631) and the long term (OR = 1.926, 95%CI 1.021–3.632). Meanwhile, depressive symptoms were associated with an increased risk of weakness (OR = 1.990, 95%CI 1.250–3.166), slowness (OR = 1.395, 95%CI 1.044–1.865), and exhaustion (OR = 2.827, 95%CI 2.150–3.719) onset during the short-term. Depressive symptoms were associated with an increased risk of exhaustion (OR = 2.869, 95%CI 2.004–4.109) onset during the long-term. Conclusion Among middle-aged and older adults, depressive symptoms could predict frailty during 2 years of follow-up and 4 years of follow-up. When considering potential confounding factors, depressive symptoms were considered a predictor of weakness, slowness, and exhaustion. Interventions aimed at preventing depressive symptoms may be beneficial in reducing frailty and its components.

Abstract This study aims to address the issue of high energy consumption in the hydrocyclone separation process. By introducing a novel slotted overflow pipe structure and utilizing experimental and response surface optimization methods, the optimal parameters were determined. The research results indicate that the number of slots, slot angles, and positioning dimensions significantly influence the performance of the hydrocyclone separator. The optimal combination was found to be three layers of slots, a positioning dimension of 5.3 mm, and a slot angle of 58°. In a Φ100mm hydrocyclone separator, validated through multiple experiments, the separation efficiency increased by 0.26% and the pressure drop reduced by 24.88% under a flow rate of 900 ml/s. CFD simulation verified the reduction in internal flow field velocity and pressure drop due to the slotted structure. Therefore, this study provides an effective reference for designing efficient and low-energy hydrocyclone separators.

Abstract There is a relative scarcity of large-scale population studies investigating the relationship between the insulin resistance index of homeostasis model assessment (HOMA-IR) and vascular damage. Therefore, we assessed the association between HOMA-IR and vascular damage in adults aged 18 years and older in China. A total of 17,985 research subjects were included. Vascular damage markers and relevant laboratory tests were measured. HOMA-IR was calculated as (fasting insulin * fasting blood glucose)/22.5. Vascular damage included arteriosclerosis (ba-PWV > 1800 cm/s), peripheral artery disease (ABI 30 mg/g). The relationship between HOMA-IR and vascular damage was analyzed using the RCS. The restricted cubic spline (RCS) analysis suggested that HOMA-IR was nonlinearly associated with arteriosclerosis (P for no-liner

Abstract Nanocrystalline metallic materials have the merit of high strength but usually suffer from poor ductility and rapid grain coarsening, limiting their practical application. Here, we introduce a core-shell nanostructure in a multicomponent alloy to address these challenges simultaneously, achieving a high tensile strength of 2.65 GPa, a large uniform elongation of 17%, and a high thermal stability of 1173 K. Our strategy relies on an ordered superlattice structure that excels in dislocation accumulation, encased by a ≈3 nm disordered face-centered-cubic nanolayer acting as dislocation sources. The ordered superlattice with high anti-phase boundary energy retards dislocation motions, promoting their interaction and storage within the nanograins. The disordered interfacial nanolayer promotes dislocation emission and effectively accommodates the plastic strain at grain boundaries, preventing intergranular cracking. Consequently, the order-disorder core-shell nanostructure exhibits enhanced work-hardening capability and large ductility. Moreover, such core-shell nanostructure exhibits high coarsening resistance at elevated temperatures, enabling it high thermal stability. Such a design strategy holds promise for developing high-performance materials.

Abstract Background Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI. Results Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI. Conclusions Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.

Abstract Background Limited data exists on the efficacy of immune checkpoint inhibitor (ICI) combinations in non-small-cell lung cancer (NSCLC) with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET. This study retrospectively assessed ICI-combination therapy outcomes in this molecular subset of NSCLC. Methods We retrospectively analyzed patients with advanced NSCLC confirmed with driver alterations in genes including ERBB2, BRAF, RET or MET, and received ICI combined with chemotherapy (ICI + chemo) and/or targeted therapy (ICI + chemo/TT) as first-line (1L) or second- or third-line (≥ 2L) treatment at Hunan Cancer Hospital between January 2018 and May 2024. Results Of the 181 patients included in the study, 131 patients received 1L-ICI + chemo (ERBB2, n = 64; BRAF, n = 34; RET, n = 23; and MET, n = 10), and 50 patients received ≥ 2L-ICI + chemo/TT (ERBB2, n = 16; BRAF, n = 7; RET, n = 14; MET, n = 13). The full cohort had an overall response rate (ORR) of 45.9% and disease control rate of 84.0%. Among patients who received 1L-ICI + chemo, ORR ranged between 51.6% and 60.0%, with the median progression-free survival (mPFS) and overall survival (mOS) of 8.2 and 21.0 months for those with ERBB2-altered tumors, 10.0 and 15.0 months for BRAF-altered tumors, 12.1 months and OS not reached for RET-altered tumors, and 6.2 and 28.0 months for MET-altered tumors, respectively. Additionally, ORR ranged between 14.3% and 30.8% for ≥ 2L-ICI + chemo/TT; mPFS and mOS were 5.4 and 16.2 months for patients with ERBB2-altered tumors, 2.7 and 5.0 months for BRAF-altered tumors, 6.2 and 14.3 months for RET-altered tumors, and 5.7 and 11.5 months for MET-altered tumors, respectively. Conclusion ICI-based combination therapies, regardless of treatment line, were effective in treating patients with advanced NSCLC harboring driver alterations in ERBB2, BRAF, RET, or MET. This suggests their potential as alternative treatment options in this patient population.

Abstract Background Chronic stress induces cognitive deficits. There is a well-established connection between the enteric and central nervous systems through the microbiota-gut-brain (MGB) axis. However, the effects of the gut microbiota on cognitive deficits remain unclear. The present study aimed to elucidate the microbiota composition in cognitive deficits and explore its potential in predicting chronic stress-induced cognitive deficits. Methods Mice were randomly divided into control and chronic restraint stress (CRS) groups. The mice subjected to CRS were further divided into cognitive deficit (CRS-CD) and non-cognitive deficit (CRS-NCD) groups using hierarchical cluster analysis of novel object recognition test results. The composition and diversity of the gut microbiota were analyzed. Results After being subjected to chronic restraint distress, the CRS-CD mice travelled shorter movement distances (p = 0.034 vs. CRS-NCD; p

The colonic mucosal barrier is an important component of the intestinal barrier, and its integrity is crucial for maintaining digestive tract homeostasis and normal metabolism in the body. This study aimed to elucidate the mechanisms by which malvidin-3-O-galactoside (M3G) might ameliorate colonic mucosal barrier function, from the perspective of physical barrier function and immune barrier function. Male C57BL/6J mice were given dextran sulfate sodium (DSS) to establish a mice model for colitis and then administrated with or without M3G for one week. The results showed that M3G supplementation significantly improved the disease activity index (DAI) score and colon tissue injury in mice with DSS-induced colitis. M3G improved the colonic physical barrier function by modulating the expression of mucin2 (MUC2), claudin-1, occludin, zona occludens 1 (ZO-1), and intestinal fatty acid binding protein (iFABP) in the colonic mucosa. Additionally, M3G also relieved the colonic immune barrier of mice by increasing the level of secretory immunoglobulin A (SIgA) in colon tissue and the percentages of CD4+T (CD3+CD4+) and CD8+T (CD3+CD8+) cells in colon lamina propria monocytes in mice. Furthermore, M3G down-regulated Notch signaling pathway-related proteins such as Notch1, notch intracellular domain (NICD), delta-like ligand 4 (DLL4), delta-like ligand 1 (DLL1), and hairy/enhancer of split 1 (Hes1) of colon tissue. The present results demonstrated that M3G can improve colonic mucosal barrier function by inhibiting the Notch signaling pathway.

Objective To investigate the long-term efficacy of amygdala-hippocampus deep brain stimulation (AH - DBS) in treating refractory medial temporal lobe epilepsy (mTLE) and its impact on cognitive function. Methods Seven patients with refractory mTLE who were treated at The First Medical Center of Chinese PLA General Hospital from January 2014 to December 2018 were enrolled in this study. All 7 patients underwent AH -DBS. Seizure types, seizure frequency, and antiepileptic seizure medicine (ASM) usage were compared before and after surgery. Cognitive function was assessed using Wechsler Adult Intelligence Scale - Revised (WAIS - R). Post - operative stimulation parameters and surgery - related complications were recorded. Results Of the 7 patients, 4 patients received bilateral AH-DBS, 2 patients received left AH - DBS, and one patient received left AH - DBS combined with right anterior temporal lobectomy. There were 6 patients underwent the occipital approach, and one patient underwent the frontal approach. Only one patient experienced poor healing of the scalp incision, which healed after local skin grafting. The mean follow-up period was (73.00 ± 8.98) months. During the follow-up period, there were reductions in complex partial seizure (CPS) frequency [1.00 (0.00, 31.00) times per month vs. 2.00 (1.50, 60.00) times per month; Z = - 2.207, P = 0.027], secondary generalized tonic - clonic seizure (SGTCS) frequency [0.00 (0.00, 1.00) times per month vs. 2.00 (1.00, 3.00) times per month; Z = - 2.428, P = 0.015], and the total seizure frequency [1.00 (0.50, 31.00) times per month vs. 5.00 (2.50, 64.00) times per month; Z = - 2.366, P = 0.018]. However, there were no significant differences in the number of ASM types [1.00 (1.00, 2.00) types vs. 1.00 (1.00, 3.00) types; Z = - 1.633, P = 0.102] or WAIS-R [(85.50 ± 7.09) scores vs. (89.00 ± 9.47) scores; t = - 1.761, P = 0.078] before and after surgery. Conclusions As a novel anti - epileptic treatment method, AH-DBS can reduce the frequency of refractory mTLE without serious adverse events and has no significant impact on cognitive function.

Objective To study the effect of Salidroside(Sal) on platelet activation and aggregation and the interaction between human platelets and MDA-MB-468 cells of breast cancer. Methods Human platelets were collected, platelet suspension was prepared, and platelets were treated with different concentrations of Sal. The effects of Sal on platelet activation and aggregation were detected by thromboelastogram(TEG) and flow cytometry. Breast cancer MDA-MB-468 cells were cultured in vitro, and human platelets were treated with different concentrations of Sal, and then activated by thrombin. The effects of Sal on the interaction between platelets and MDA-MB-468 cells were analyzed by adhesion test and scratch test. Results TEG detection: The ADP inhibition rate in the blank control group was (10.97±12.69)%, and the ADP inhibition rate in all Sal intervention groups was higher than that in the blank control group (P

Objective: To explore the correlation between genotypes of Orientia (O.) tsutsugamushi and clinical characteristics of scrub typhus patients. Methods: Clinical data of patients with scrub typhus admitted to different types of medical institutions in Guangzhou from September 2012 to December 2016 were collected using medical records. Demographic data, clinical manifestations, as well as hematological and biochemical indicators of patients infected with different genotypes were analyzed and compared. Results: A total of 192 patients were included in this study, including 121 patients with Karp genotype of O. tsutsugamushi infection (63.0%), 36 patients with Gilliam genotype (19.0%), 23 patients with Kato genotype (12.0%), and 12 patients with TA763 genotype (6.0%) infection. The median value of albumin in patients with Karp genotype infection was significantly lower than that of Gilliam-infected patients (P=0.032). Patients with Karp genotype infection had a significantly longer hospital stay (9 days) than those with Gilliam genotype (7 days) (P=0.009) and Kato genotype infection (6 days) (P=0.005). Karp-infected patients also represented for the largest number of patients with complicated organ involvement (88/133, 66.2%). Furthermore, Karp-infected patients had higher risk of developing multiple organ dysfunction syndrome (18.2%) and requiring intensive care unit treatment (15.9%). Besides, patients with Gilliam genotype (8 days) and TA763 genotype infection (7.5 days) had shorter fever duration than those with Karp genotype (9 days) and Kato genotype (9 days) infection, respectively. Conclusions: Genotypes of Orientia tsutsugamushi were associated with varying clinical manifestations, organ involvement, and treatment outcomes, suggesting that genotypes ranged in virulence.

Abstract Voltage-sensing phosphatases (VSPs) dephosphorylate phosphoinositide (PIP) signaling lipids in response to membrane depolarization. VSPs possess an S4-containing voltage sensor domain (VSD), resembling that of voltage-gated cation channels, and a lipid phosphatase domain (PD). The mechanism by which voltage turns on enzyme activity is unclear. Structural analysis and modeling suggest several sites of VSD-PD interaction that could couple voltage sensing to catalysis. Voltage clamp fluorometry reveals voltage-driven rearrangements in three sites implicated earlier in enzyme activation—the VSD-PD linker, gating loop and R loop—as well as the N-terminal domain, which has not yet been explored. N-terminus mutations perturb both rearrangements in the other segments and enzyme activity. Our results provide a model for a dynamic assembly by which S4 controls the catalytic site.

Abstract Aim Recent imaging studies have found significant abnormalities in the brain’s functional or structural connectivity among patients with high myopia (HM), indicating a heightened risk of cognitive impairment and other behavioral changes. However, there is a lack of research on the topological characteristics and connectivity changes of the functional networks in HM patients. In this study, we employed graph theoretical analysis to investigate the topological structure and regional connectivity of the brain function network in HM patients. Methods We conducted rs-fMRI scans on 82 individuals with HM and 59 healthy controls (HC), ensuring that the two groups were matched for age and education level. Through graph theoretical analysis, we studied the topological structure of whole-brain functional networks among participants, exploring the topological properties and differences between the two groups. Results In the range of 0.05 to 0.50 of sparsity, both groups demonstrated a small-world architecture of the brain network. Compared to the control group, HM patients showed significantly lower values of normalized clustering coefficient (γ) (P = 0.0101) and small-worldness (σ) (P = 0.0168). Additionally, the HM group showed lower nodal centrality in the right Amygdala (P

Abstract Aortic valve replacement (AVR) is a critical procedure for patients with aortic valve diseases. This study compares the effectiveness of three minimally-invasive surgical approaches for AVR: totally thoracoscopic (TT), right anterior mini-thoracotomy, and upper mini-sternotomy. We analyzed retrospective data from 130 patients who underwent one of these surgeries, focusing on various factors such as duration of hospital stay, operation time, times for cardiopulmonary bypass and aortic cross-clamping, postoperative complications, levels of cardiac biomarkers, pain intensity using the Visual Analog Scale, and mid-term survival rates. Results show that while the TT method had the longest operation times, it also had the shortest hospital stays and faster pain reduction post-surgery. Although the TT group initially showed higher cardiac biomarker levels after surgery, these levels normalized by the third day, similar to the other groups. There were no significant differences in mid-term survival and major adverse cardiac and cerebrovascular event (MACCE) rates among the groups. These findings suggest that the TT method, despite longer surgical times, offers a quicker initial recovery, making it a viable option for AVR.

Abstract The endothelial glycocalyx is damaged in postcardiac arrest syndrome (PCAS), but the prognostic value is unknown. We aimed to observe the expression and prognostic value of glycocalyx shedding products, including syndecan-1 (SDC-1), hyaluronan (HA), and heparan sulfate (HS) in PCAS. Data on clinical and 28-day outcomes of seventy-one consecutive patients with out-of-hospital cardiac arrest (OHCA) after the return of spontaneous circulation (ROSC) were collected. SDC-1, HA, and HS were measured on days 0, 1, and 3 after ROSC. Thirty healthy individuals were controls. Glycocalyx shedding was observed in human umbilical vein endothelial cells (HUVECs) stimulated during hypoxia and reoxygenation in vitro. Within 4 h of ROSC, SDC-1 and HA levels, significantly increased. In the 28-day non-survivors, HA levels showed a gradual upward trend, SDC-1 remained at a high level, and HS levels first increased, then decreased. Kaplan–Meier curves and binary logistic regression analysis showed the prognostic value of SDC-1 levels on days 0, 1, and 3, HA levels on days 1 and 3, and HS levels on day 1. Only HS levels on day 1 showed a prognostic value for 28-day neurological outcomes. SDC-1 and HA levels were positively correlated with the no-flow time. In vitro, HUVECs showed shedding of SDC-1 and HS during a prolonged duration of hypoxia. After ROSC, SDC-1, HA, and HS levels may predict the 28-day survival after PCAS, and HS levels are associated with functional outcomes.

Abstract Background The association between the triglyceride-glucose (TyG) index and clinical outcomes in patients with both coronary artery disease (CAD) and psoriasis is unclear. This study investigated the association between the TyG index and major adverse cardiovascular events (MACE) in patients with both CAD and psoriasis. Methods This retrospective cohort study included patients diagnosed with both CAD and psoriasis who underwent coronary angiography at the Fuwai Hospital, Beijing, China, between January 2017 and May 2022. The study endpoint was the occurrence of MACE or end of follow-up time. Multivariate Cox proportional analysis and restricted cubic splines (RCS) were used to determine the association between the TyG index and MACE. Receiver operating characteristic (ROC) curves were used to determine the optimal threshold value of the TyG index for predicting MACE. Results This study enrolled 293 patients with both CAD and psoriasis, including 258 (88.1%) males with a mean age of 58.89 ± 9.61 years. Patients were divided into four groups based on the TyG quartiles: Q1 (N = 74), Q2 (N = 73), Q3 (N = 73), and Q4 (N = 73). After adjusting for the potential confounders, the TyG index was independently associated with MACE, both as a continuous variable (HR = 1.53, 95% CI = 1.03–2.28, P = 0.035) and as a categorical variable (Q1: reference; Q2: HR = 1.85, 95% CI = 0.88–3.87, P = 0.105; Q3: HR = 2.39, 95% CI = 1.14-5.00, P = 0.021; Q4: HR = 2.19, 95% CI = 1.001–4.81, P = 0.0497; P for trend = 0.039). RCS analysis showed an linear association between the TyG index and MACE (P-overall = 0.027, P-non-linear = 0.589). ROC curve analysis showed that the TyG index of ≥ 8.73 was the optimal threshold value (area under the ROC curve = 0.60, 95% CI 0.53–0.67). TyG index ≥ 8.73 was significantly associated with MACE (HR = 2.10, 95% CI = 1.32–3.34, P = 0.002). After adjustment for confounders, the TyG index showed independent association with MACE (HR = 2.00, 95% CI = 1.17–3.42, P = 0.011). Conclusions The TyG index showed a positive linear correlation with MACE in patients with both CAD and psoriasis. The TyG index of ≥ 8.73 might be the optimal threshold for predicting MACE. Graphical Abstract

Aiming to address the problems of high cost, large size and complex structure of the traditional back-to-back three-level converter, this paper proposes a new dual-port three-level converter topology. This new topology reduces the number of switching devices and optimizes the system size through device multiplexing. Firstly, the operating principle of the proposed converter topology is analyzed in detail, outlining the six effective switching states, current flow paths, and corresponding dual-port output levels of the single leg, while also discussing and the voltage stresses of each switching device. Secondly, a level-shifting pulse width modulation for the proposed converter topology is investigated and designed, and the effect of modulating wave overlap is avoided by adding DC offsets. Thirdly, the key problems of the modulation scheme under both the common frequency and different frequency operation modes, such as the modulation regime range and phase angle difference constraints are analyzed. The principles for selecting DC offsets and constraint range of two-port modulation system in each operating mode are introduced. Finally, the different operating modes are verified using the DSP-FPGA-Typhoon HIL 402 experimental platform. The experimental results show that level-shifting pulse width modulation with DC offsets makes the output power quality of the converter better and the harmonic content lower on the premise of achieving stable output of voltage and current for the proposed converter topology.

Abstract Bladder cancer remains a significant health challenge due to its high recurrence and progression rates. This study aims to evaluate the role of POLR3G in the development and progression of bladder cancer and the potential of POLR3G to serve as a novel therapeutic target. We constructed a bladder cancer model in Wistar rats by administering N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), which successfully induced a transition from normal mucosa to hyperplasia and ultimately to urothelial carcinoma. We observed a progressive upregulation of POLR3G expression during the bladder cancer development and progression. To investigate the functional role of POLR3G, we performed functional experiments in bladder cancer cell lines. The results demonstrated that knocking down POLR3G significantly inhibited cell proliferation, migration, and invasion. We further conducted RNA sequencing on POLR3G-knockdown bladder cancer cells, and Metascape was employed to perform the functional enrichment analysis of the differentially expressed genes (DEGs). Enrichment analysis revealed the enrichment of DEGs in the RNA polymerase and apoptotic cleavage of cellular proteins pathways, as well as their involvement in the Wnt and MAPK signaling pathways. The downregulation of Wnt pathway-related proteins such as Wnt5a/b, DVL2, LRP-6, and phosphorylated LRP-6 upon POLR3G knockdown was further confirmed by Western blotting, indicating that POLR3G might influence bladder cancer behavior through the Wnt signaling pathway. Our findings suggest that POLR3G plays a crucial role in bladder cancer progression and could serve as a potential therapeutic target. Future studies should focus on the detailed mechanisms by which POLR3G regulates these signaling pathways and its potential as a biomarker for early detection and prognosis of bladder cancer.

Abstract Background Autophagy regulation plays vital roles in many cancers. We aimed to investigate the expression, prognostic value, and immune infiltration of autophagy-related genes in hepatocellular carcinoma (HCC) by bioinformatics analysis. Method Human autophagy-related differentially expressed genes (DEGs) between adjacent and HCC tissues were identified. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We also evaluated immune infiltration and the response to tumor-sensitive drugs. Finally, we verified the expression of these proteins in clinical samples by immunohistochemistry (IHC), RNA isolation and real-time reverse transcription polymerase chain reaction (RT‒PCR). Results A total of 57 autophagy-related DEGs were identified. The HUB genes (BIRC5, CDKN2A, SPP1, and IGF1) were related to the diagnosis and prognosis of HCC. The HUB genes were significantly enriched in immune-related pathways. Furthermore, correlation analysis revealed that HUB gene expression was associated with immune infiltration. We identified 35 tumor-sensitive drugs targeting the HUB genes. Finally, by IHC, we discovered that the protein of CDKN2A, BIRC5, and SPP1 were upregulated in HCC tissues, while IGF1 was downregulated in HCC tissues compared with the levels in paracarcinoma tissues; by RT‒PCR, we discovered that the mRNA of CDKN2A, BIRC5, and SPP1 were upregulated in HCC tissues, while the mRNA of IGF1 was downregulated in HCC tissues compared with the levels in paracarcinoma tissues. Conclusion We screened and validated four autophagy-related genes associated with immune infiltration and prognosis in patients with HCC.

Abstract In recent studies, erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, has exhibited notable anticancer properties. Ferroptosis, a novel form of programmed cell death, holds potential as a strategy to overcome Temozolomide (TMZ) resistance in glioma by inducing ferroptosis in TMZ-resistant glioma cells. Here, utilizing various phenotyping experiments, including cell counting kit-8 (CCK-8) assays, EdU assays, transwell assays, neurosphere formation assays and extreme limiting dilution (ELDA) assays, we demonstrated that erianin exerts its anticancer activity on both TMZ sensitive and TMZ-resistant glioma stem cells (GSCs). Furthermore, we made an exciting discovery that erianin enhances TMZ sensitivity in TMZ-resistant GSCs. Subsequently, we demonstrated that erianin induced ferroptosis in TMZ-resistant GSCs and enhances TMZ sensitivity through inducing ferroptosis, which was confirmed by intracellular measurements of ROS, GSH, and MDA, as well as through the use of BODIPY (581/591) C11 and transmission electron microscopy. Conversely, the ferroptosis inhibitor ferrostatin-1 (Fer-1) blocked the effects of erianin. The underlying mechanism of ferroptosis induced by erianin was further explored through co-immunoprecipitation (Co-IP) assays, ubiquitination assays, protein stability assessments, chromatin immunoprecipitation (ChIP) assays and luciferase reporter gene assays. We found that erianin specifically targets REST, inhibiting its transcriptional repression function without altering its expression levels. Consequently, this suppression of REST’s role leads to an upregulation of LRSAM1 expression. In turn, LRSAM1 ubiquitinates and degrades SLC40A1, a protein that inhibits ferroptosis by exporting ferrous ions. By downregulating SLC40A1, erianin ultimately induces ferroptosis in TMZ-resistant GSCs. Taken together, our research demonstrates that the natural product erianin inhibits the malignant phenotype of GSCs and increases the sensitivity of TMZ in TMZ-resistant GSCs by inducing ferroptosis. These findings suggest erianin as a prospective compound for the treatment of TMZ-resistant glioma.

Sleep is crucial for wellness, and emerging research reveals a profound connection to gut microbiota. This review explores the bidirectional relationship between gut microbiota and sleep, exploring the mechanisms involved and the therapeutic opportunities it presents. The gut–brain axis serves as a conduit for the crosstalk between gut microbiota and the central nervous system, with dysbiosis in the microbiota impairing sleep quality and vice versa. Diet, circadian rhythms, and immune modulation all play a part. Specific gut bacteria, like Lactobacillus and Bifidobacterium, enhance sleep through serotonin and gamma-aminobutyric acid production, exemplifying direct microbiome influence. Conversely, sleep deprivation reduces beneficial bacteria, exacerbating dysbiosis. Probiotics, prebiotics, postbiotics, and fecal transplants show therapeutic potential, backed by animal and human research, yet require further study on safety and long-term effects. Unraveling this intricate link paves the way for tailored sleep therapies, utilizing microbiome manipulation to improve sleep and health. Accelerated research is essential to fully tap into this promising field for sleep disorder management.

Abstract As an important pest on winter wheat, Rhopalosiphum padi (L.) causes damage to the wheat yield by sucking plant nutrients, transmitting plant viruses and producing mildew. R. padi has been reported to develop resistance to pyrethroids and neonicotinoids. To explore potential alternative approaches for R. padi control, the activity of 10 botanical insecticides was evaluated. Results suggested that the toxicity of rotenone and pyrethrins to R. padi were the highest and near to the commonly used chemical insecticides. When exposed to the low-lethal concentrations (LC10, LC30) of rotenone or pyrethrins for 24 h, the lifespan and fecundity of adults in F0 generation decreased significantly compared to control. The negative effect could also be observed in the F1 generation, including the decreased average offspring, longevity of adult, and prolonged nymph period. The population parameters in F1 generation of R. padi were also inhibited by exposing to the low-lethal concentrations of rotenone or pyrethrins, including the decreased net reproductive rate, intrinsic rate of natural increase, finite rate of population increase, and gross reproduction rate. Co-toxocity factor results showed that mixtures of rotenone and thiamethoxam, pyrethrins and thiamethoxam showed synergistic effect. Our work suggested that rotenone and pyrethrins showed negative effect on the population growth under low-lethal concentrations. They are suitable for R. padi control as foliar spraying without causing population resurgence.

Abstract Road defect detection is critical step for road maintenance periodic inspection. Current methodologies exhibit drawbacks such as low detection accuracy, slow detection speed, and the inability to support edge deployment and real-time detection. To solve this issue, we introduce an improved YOLOv8 road defect detection model. Firstly, we designed the EMA Faster Block structure using partial convolution to replace the Bottleneck structure in the YOLOv8 C2f module, and the enhanced C2f module was labeled as C2f-Faster-EMA. Secondly, we improved the model speed by introducing SimSPPF instead of SPPF. Finally, for the head, Detect-Dyhead, chosen to replace the original head, significantly improves the representation ability of heads without introducing any GFLOPs. Experimental results on the road defect detection dataset show that the improved model in this paper outperforms the original YOLOv8, with a 5.8% increase in average accuracy (mAP@0.5), and notable reductions of 22.33% in model size, 23.03% in parameter size, and 21.68% in computational complexity.

Abstract To evaluate the genetic etiology of fetal dextrocardia, associated ultrasound anomalies, and perinatal outcomes, we investigated the utility of whole exome sequencing (WES) for prenatal diagnosis of dextrocardia. Fetuses with dextrocardia were prospectively collected between January 2016 and December 2022. Trio-WES was performed on fetuses with dextrocardia, following normal karyotyping and/or chromosomal microarray analysis (CMA) results. A total of 29 fetuses with dextrocardia were collected, including 27 (93.1%) diagnosed with situs inversus totalis and 2 (6.9%) with situs inversus partialis. Cardiac malformations were present in nine cases, extra-cardiac anomalies were found in seven cases, and both cardiac and extra-cardiac malformations were identified in one case. The fetal karyotypes and CMA results of 29 cases were normal. Of the 29 cases with dextrocardia, 15 underwent WES, and the other 14 cases refused. Of the 15 cases that underwent WES, clinically relevant variants were identified in 5/15 (33.3%) cases, including the diagnostic variants DNAH5, DNAH11, LRRC56, PEX10, and ZIC3, which were verified by Sanger sequencing. Of the 10 cases with non-diagnostic results via WES, eight (80%) chose to continue the pregnancies. Of the 29 fetuses with dextrocardia, 10 were terminated during pregnancy, and 19 were live born. Fetal dextrocardia is often accompanied by cardiac and extra-cardiac anomalies, and fetal dextrocardia accompanied by situs inversus is associated with a high risk of primary ciliary dyskinesia. Trio-WES is recommended following normal karyotyping and CMA results because it can improve the diagnostic utility of genetic variants of fetal dextrocardia, accurately predict fetal prognosis, and guide perinatal management and the reproductive decisions of affected families.

Abstract Background Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. Methods This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. Results We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. Conclusion This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

Abstract Ischemic stroke is a complex, high-mortality disease with multifactorial etiology and pathogenesis. Currently, drug therapy is mainly used treat ischemic stroke in clinic, but there are still some limitations, such as limited blood-brain barrier (BBB) penetration efficiency, a narrow treatment time window and drug side effects. Recent studies have pointed out that drug delivery systems based on polymeric nanocarriers can effectively improve the insufficient treatment for ischemic stroke. They can provide neuronal protection by extending the plasma half-life of drugs, enhancing the drug’s permeability to penetrate the BBB, and targeting specific structures and cells. In this review, we classified polymeric nanocarriers used for delivering ischemic stroke drugs and introduced their preparation methods. We also evaluated the feasibility and effectiveness and discussed the existing limitations and prospects of polymeric nanocarriers for ischemic stroke treatment. We hoped that this review could provide a theoretical basis for the future development of nanomedicine delivery systems for the treatment of ischemic stroke. Graphical Abstract

Abstract Background Multiple vaccinations have received approval for the prevention of the coronavirus illness. Nevertheless, the sluggish vaccination rate is mostly attributed to the general population’s limited understanding and unwillingness to accept the use of vaccinations. Thus, it is important to investigate the Rwandan population’s knowledge, attitudes, and perceptions toward COVID-19 vaccines. Methods A cross-sectional survey was conducted among 370 participants from 11th to 17th February 2023. Demographic information was gathered, and knowledge, attitudes, and perceptions of COVID-19 vaccinations were assessed. A binary logistic regression analysis was undertaken to determine the parameters that determine the perception of COVID-19 vaccinations. Results This study included 370 participants. Among them, 85% had good knowledge about COVID-19 vaccines, and 84% had a positive attitude towards them. Additionally, the study had a diverse group, with half of the participants being female and nearly half falling between the ages of 30 and 39. Several key findings emerged through logistic regression analysis. Those aged 30–39 had 1.39 times higher odds of positive perception than 18–28 (OR = 1.39, 95% CI = 1.08–3.24). Participants with a university education were twice as likely to have a positive perception compared to those without an education level (OR = 2.43, 95% CI = 1.30–6.20). Additionally, single individuals were three times more likely to have a positive perception than their married counterparts (OR = 3.39, 95% CI = 1.28–9.09). Vaccinated individuals had twice the odds of positive perception than non-vaccinated individuals (OR = 2.89, 95% CI = 1.01–8.89). Those receiving information from government health institutions were three times more likely to have a positive perception than those who received the information from friends (OR = 3.19, 95% CI = 1.02–12.7). Moreover, employed participants were four times more likely to have a positive perception non-employed individuals (OR = 4.21, 95% CI = 1.48–13.6). Besides, gender and COVID-19 diagnosis did not significantly correlate with positive COVID-19 vaccine perception. Conclusion The results indicate that the general public in Rwanda has good knowledge, positive attitudes, and a positive perception toward the COVID-19 vaccination, however, some of the participants had some misconceptions towards COVID-19. The findings of this study will be valuable for policymakers and healthcare authorities working to improve vaccination rates.