Search

The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N6-methyladenosine (m6A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85—which potently inhibits FTO demethylation in AML cell lines—as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin–proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m6A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m6A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

Abstract Objective There is currently no consensus over whether neoadjuvant immunochemotherapy is more effective in young patients than in elderly patients with IIA–IIIB non-small-cell lung cancer (NSCLC). In this study, we compare the efficacy and safety of neoadjuvant immunochemotherapy in young and elderly patients with IIA–IIIB NSCLC. Methods This retrospective study consecutively included IIA–IIIB NSCLC patients who received 2–4 cycles preoperative immunochemotherapy at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine from 2019 to 2022. The 1:1 propensity score match analysis was conducted to balance the confounding factors between the young patient group (

Abstract Background Video-assisted thoracoscopic surgery (VATS) for a relatively large mediastinal tumor (5.0–10.0 cm) remains controversial. In addition, few studies have focused on comparing different surgical approaches for large mediastinal tumors. Therefore, this study aimed to compare the short-term outcomes between subxiphoid approach VATS, intercostal approach VATS, and traditional sternotomy for large-sized anterior mediastinal tumors. Methods The study consecutively enrolled 159 patients with large-sized anterior mediastinal tumors (5.0–10.0 cm) who received surgery in our hospital between January 2018 and July 2022 (subxiphoid approach VATS: 52 patients, intercostal approach VATS: 70 patients, traditional sternotomy: 37 patients). We analyzed the clinical baseline data, intraoperative and postoperative outcomes, and postoperative complications of all patients. Then the patients were further divided into two groups according to whether there was a peripheral organ (such as pericardium, lung, or left innominate vein) invasion: group A, invasion of the surrounding organ, and group B, no invasion of the surrounding organ. Intraoperative and postoperative outcomes and postoperative complications were also analyzed in group A and group B, respectively. Results In all patients, there were significant differences in blood loss (subxiphoid approach: 33.1 ± 46.0 ml, intercostal approach: 36.9 ± 44.1 ml, sternotomy: 113.0 ± 84.9 ml, P

Introduction: Combination immunotherapy holds promise for improving survival in responsive glioblastoma (GBM) patients. Programmed death-ligand 1 (PD-L1) expression in immune microenvironment (IME) is the most important predictive biomarker for immunotherapy. Due to the heterogeneous distribution of PD-L1, post-operative histopathology fails to accurately capture its expression in residual tumors, making intra-operative diagnosis crucial for GBM treatment strategies. However, the current methods for evaluating the expression of PD-L1 are still time-consuming. Objective: To overcome the PD-L1 heterogeneity and enable rapid, accurate, and label-free imaging of PD-L1 expression level in GBM IME at the tissue level. Methods: We proposed a novel intra-operative diagnostic method, Machine Learning Cascade (MLC)-based Raman histopathology, which uses a coordinate localization system (CLS), hierarchical clustering analysis (HCA), support vector machine (SVM), and similarity analysis (SA). This method enables visualization of PD-L1 expression in glioma cells, CD8+ T cells, macrophages, and normal cells in addition to the tumor/normal boundary. The study quantified PD-L1 expression levels using the tumor proportion, combined positive, and cellular composition scores (TPS, CPS, and CCS, respectively) based on Raman data. Furthermore, the association between Raman spectral features and biomolecules was examined biochemically. Results: The entire process from signal collection to visualization could be completed within 30 min. In an orthotopic glioma mouse model, the MLC-based Raman histopathology demonstrated a high average accuracy (0.990) for identifying different cells and exhibited strong concordance with multiplex immunofluorescence (84.31 %) and traditional pathologists' scoring (R2 ≥ 0.9). Moreover, the peak intensities at 837 and 874 cm−1 showed a positive linear correlation with PD-L1 expression level. Conclusions: This study introduced a new and extendable diagnostic method to achieve rapid and accurate visualization of PD-L1 expression in GBM IMB at the tissular level, leading to great potential in GBM intraoperative diagnosis for guiding surgery and post-operative immunotherapy.

Abstract Background Cardiovascular events secondary to stroke–collectively classified as stroke-heart syndrome–greatly impair the patient’s prognosis, however its underlying mechanism has yet to be determined. To investigate the mechanism of central neuroinflammation and its effects on stroke-heart syndrome, a temperature-ultrasound responsive brain-targeted drug delivery system, DATS/MION-LPE, was synthesized to specifically study neuroinflammation in the mouse middle cerebral artery occlusion (MCAO) model. Results The specific polymer of DATS/MION-LPE can close the nanoparticle pores at 37 °C, restricting drug release in the circulation. After the nanoparticles were targeted to brains, the polymer can be cleaved under external ultrasound irradiation, reopening the nanoparticle pores and allowing drug release, therefore directly managing the neuroinflammation. After a stroke, a significant cerebral inflammation occurred, with elevated IL-1β and pyrin domain-containing 3 (NLRP3) inflammasome. Accordingly, significantly increased histone deacetylase 6 (HDAC6) and decreased sirtuin 1 (SIRT1) were observed. An antagonistic relationship between HDAC6 and SIRT1 was found, which can jointly regulate the cerebral NLRP3 expression. The systemic IL-1β and ATP levels were increased after the stroke, accompanied by a significant heart injury including contractile dysfunction, elevated IL-1β levels, and oxidative stress. Meanwhile, neuroinflammation can trigger sympathetic nervous overexcitation with associated heart damage. DATS/MION-LPE can targetedly effect on ischemic brain, exhibiting cerebral and cardiac protective effects including downregulated cerebral NLRP3 and HDAC6 expressions, upregulated SIRT1 expressions in brain, reduced IL-1β and ATP in circulation, and alleviated cardiac impairment. Conclusion This study introduced the key role of neuroinflammation in stroke-heart syndrome and first investigated the crucial HDAC6/SIRT1-NLRP3 circuit in this process. Heart injury secondary to stroke is mediated by neuroinflammation induced systemic inflammatory responses and sympathoexcitation. DATS/MION-LPE is a unique tool and effective therapeutic agent, which provides new insights into combinational heart and cardiac protection. Graphical Abstract

Abstract The sugar and organic acid content significantly impacts the flavor quality of star fruit, and it undergoes dynamic changes during development. However, the metabolic network and molecular mechanisms governing the formation of sugar and organic acid in star fruit remain unclear. In this study, 23 of 743 components were detected by metabonomic analysis. The highest metabolites contents were organic acids and derivatives. The highest sugar content in the fruit was fructose and glucose, followed by sucrose, which proved that A. carambola is a hexose accumulation type fruit. Genome identification preliminarily screened 141 genes related to glucose metabolism and 67 genes related to acid metabolism. A total of 7,881 unigenes were found in transcriptome data, 6,124 differentially expressed genes were screened, with more up-regulated than down-regulated genes. Transcriptome and metabolome association analysis screened seven core candidate genes related to glucose metabolism and 17 core genes highly related to organic acid pathway, and eight differentially expressed sugar and acid genes were selected for qRT-PCR verification. In addition, 29 bHLHs and eight bZIPs transcription factors were predicted in the glucose metabolism pathway, and 23 MYBs, nine C2H2s transcription factors and one GRAS transcription factor was predicted in the acid metabolism pathway, and transcription factors have both positive and negative regulatory effects on sugar and acid structure genes. This study increased our understanding of A. carambola fruit flavor and provided basic information for further exploring the ornamental and edible values of star fruit.

Abstract Background In patients undergoing breast-conserving therapy without surgical clip implantation, the accuracy of tumor bed identification and the consistency of clinical target volume (CTV) delineation under computed tomography (CT) simulation remain suboptimal. This study aimed to investigate the feasibility of implementing preoperative magnetic resonance (MR) simulation on delineations by assessing interobserver variability (IOV). Methods Preoperative MR and postoperative CT simulations were performed in patients who underwent breast-conserving surgery with no surgical clips implanted. Custom immobilization pads were used to ensure the same supine position. Three radiation oncologists independently delineated the CTV of tumor bed on the images acquired from MR and CT simulation registration and CT simulation alone. Cavity visualization score (CVS) was assigned to each patient based on the clarity of the tumor bed on CT simulation images. IOV was indicated by generalized conformity index (CIgen), denoted as CIgen−CT and CIgen−MR/CT, and the distance between the centroid of mass (dCOM), denoted as dCOMCT and dCOMMR/CT. The variation of IOV in different CVS subgroups was analyzed. Results A total of 10 patients were enrolled in this study. The median and interquartile range (IQR) of maximum pathological diameter of the tumors in all patients were 1.55 (0.80–1.92) cm. No statistical significance was found between the volumes of CTVs on CT simulation and on MR/CT simulation registration images (p = 0.387). CIgen−MR/CT was significantly larger than CIgen−CT (p = 0.005). dCOMMR/CT was significantly smaller than dCOMCT (p = 0.037). The median and IQR of CVS in all patients were 2.34 (2.00–3.08). The difference of CIgen between CIgen−MR/CT and CIgen−CT was larger in the low CVS group (p = 0.016). The difference of dCOM showed a decreasing trend when CVS was lower, although it did not reach statistical significance (p = 0.095). Conclusions For patients who underwent breast-conserving surgery without surgical clip implantation, the use of preoperative MR simulation in delineating the CTV of tumor bed decreased the IOV among observers. The consistency of tumor bed identification was improved especially in cases where the margins of tumor bed were challenging to visualize on CT simulation images. The study findings offer potential benefits in reducing local recurrence and minimizing tissue irritation in the surrounding areas. Future investigation in a larger patient cohort to validate our results is warranted.

Abstract Bacterial therapy for colorectal cancer (CRC) represents a burgeoning frontier. The probiotic Limosilactobacillus fermentum GR-3, derived from traditional food “Jiangshui”, exhibited superior antioxidant capacity by producing indole derivatives ICA and IPA. In an AOM/DSS-induced CRC mouse model, GR-3 treatment alleviated weight loss, colon shortening, rectal bleeding and intestinal barrier disruption by reducing oxidative stress and inflammation. GR-3 colonization in distant colon induced apoptosis and reduced tumor incidence by 51.2%, outperforming the control strain and vitamin C. The beneficial effect of GR-3 on CRC was associated with gut microbiome modulation, increasing SCFA producer Lachnospiraceae NK4A136 group and suppressing pro-inflammatory strain Bacteroides. Metagenomic and metabolic analyses revealed that GR-3 intervention upregulated antioxidant genes (xseA, ALDH) and butyrate synthesis gene (bcd), while increasing beneficial metabolites (SCFAs, ICA, IPA, VB12 and VD3) and reducing harmful secondary bile acids. Overall, GR-3 emerges as a promising candidate in CRC therapy, offering effective gut microbiome remediation.

Abstract Per- and poly-fluoroalkyl substances (PFAS) have gained widespread attention due to their adverse effects on health and environment. Developing efficient technology to capture PFAS from contaminated sources remains a great challenge. In this study, we introduce a type of reusable polymeric sorbent (PFPE-IEX + ) for rapid, efficient, and selective removal of multiple PFAS impurities from various contaminated water sources. The resin achieves >98% removal efficiency ([PFPE-IEX + ] = 0.5–5 mg mL−1, [PFAS]0 = 1–10 ppb in potable water and landfill leachate) and >500 mg g−1 sorption capacity for the 11 types of examined PFAS. We achieve efficient PFAS removal without breakthrough and subsequent resin regeneration and demonstrate good PFAS recovery in a proof-of-concept cartridge setup. The outcomes of this study offer valuable guidance to the design of platforms for efficient and selective PFAS capture from contaminated water, such as drinking water and landfill leachate.

Abstract Objectives This retrospective study evaluated the individual benefits of tislelizumab and surgery, as well as their synergistic effect on progression-free survival (PFS) and overall survival (OS) of stage II-III non-small cell lung cancer (NSCLC) patients. Methods From September 2019 to June 2022, all participants with potentially resectable NSCLC who received chemotherapy (C) or tislelizumab plus chemotherapy (T) were included in the study. Participants were categorized into four groups based on surgery or not (S or NS) and the utilization of tislelizumab (T or C). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan–Meier method and log-rank test, as well as Cox proportional hazards models. Results Compared to C, T was associated with significantly higher objective response rate (64.54% vs. 34.78%, p = 0.003), higher pathological complete response rate (40.00% vs. 14.06%, p = 0.007), and higher major pathological response rate (60.00% vs. 20.31%, p

Introduction: Despite radiotherapy being one of the major treatments for triple-negative breast cancer (TNBC), new molecular targets for its treatment are still required due to radioresistance. CDK2 plays a critical role in TNBC. However, the mechanism by which CDK2 promotes TNBC radioresistance remains to be clearly elucidated. Objectives: We aimed to elucidate the relationship between CDK2 and TRIM32 and the regulation mechanism in TNBC. Methods: We performed immunohistochemical staining to detect nuclear TRIM32, CDK2 and STAT3 on TNBC tissues. Western blot assays and PCR were used to detect the protein and mRNA level changes. CRISPR/Cas9 used to knock out CDK2. shRNA-knockdown and transfection assays also used to knock out target genes. GST pull-down analysis, immunoprecipitation (IP) assay and in vitro isomerization analysis also used. Tumorigenesis studies also used to verify the results in vitro. Results: Herein, tripartite motif-containing protein 32 (TRIM32) is revealed as a substrate of CDK2. Radiotherapy promotes the binding of CDK2 and TRIM32, thus leading to increased CDK2-dependent phosphorylation of TRIM32 at serines 328 and 339. This causes the recruitment of PIN1, involved in cis–trans isomerization of TRIM32, resulting in importin α3 binding to TRIM32 and contributing to its nuclear translocation. Nuclear TRIM32 inhibits TC45-dephosphorylated STAT3, Leading to increased transcription of STAT3 and radioresistance in TNBC. These results were validated by clinical prognosis confirmed by the correlative expressions of the critical components of the CDK2/TRIM32/STAT3 signaling pathway. Conclusions: Our findings demonstrate that regulating the CDK2/TRIM32/STAT3 pathway is a promising strategy for reducing radioresistance in TNBC.

Abstract Bacterial pathogens carrying multidrug resistance (MDR) plasmids are a major threat to human health. The acquisition of antibiotic resistance genes (ARGs) in plasmids is often facilitated by mobile genetic elements that copy or translocate ARGs between DNA molecules. The agglomeration of mobile elements in plasmids generates resistance islands comprising multiple ARGs. However, whether the emergence of resistance islands is restricted to specific MDR plasmid lineages remains understudied. Here we show that the agglomeration of ARGs in resistance islands is biased towards specific large plasmid lineages. Analyzing 6784 plasmids in 2441 Escherichia, Salmonella, and Klebsiella isolates, we quantify that 84% of the ARGs in MDR plasmids are found in resistance islands. We furthermore observe rapid evolution of ARG combinations in resistance islands. Most regions identified as resistance islands are shared among closely related plasmids but rarely among distantly related plasmids. Our results suggest the presence of barriers for the dissemination of ARGs between plasmid lineages, which are related to plasmid genetic properties, host range and the plasmid evolutionary history. The agglomeration of ARGs in plasmids is attributed to the workings of mobile genetic elements that operate within the framework of existing plasmid lineages.

The rapid spread of mobile tigecycline resistance presents a significant public health threat, particularly with the increasing prevalence of tet(X4)-positive Enterobacterales across various species. This study aimed to investigate the epidemic features and transmission dynamics of tet(X4)-positive Klebsiella pneumoniae (K. pneumoniae) through the analysis of 206 raw meats, including pork (n = 182), beef (n = 16), duck (n = 5), and chicken (n = 3). These samples were collected from schools, markets, and restaurants in Chengdu City, China. A total of 25 isolates were obtained from 13 administrative regions. All isolates exhibited resistance to tetracycline, tigecycline, ampicillin, chloramphenicol, and florfenicol. Over half of the isolates also demonstrated resistance to streptomycin (80 %), sulfamethoxazole/trimethoprim (72 %), ciprofloxacin (64 %), and ampicillin/sulbactam (56 %). Among these strains, 14 distinct sequence types (STs) were identified, revealing evidence of inter-regional clonal spread, notably among 9 K. pneumoniae ST3393. Phylogenetic analysis revealed the presence of two K. pneumoniae ST5 closely resembling hypervirulent K. pneumoniae from Jiangsu. Importantly, 12 isolates were capable of transferring tigecycline resistance to Escherichia coli J53. Further plasmid analysis showed that the tet(X4)-harboring plasmids in K. pneumoniae could be classified into four types, primarily belonging to the IncFIA(HI1)/HI1A/HI1B hybrid plasmid (n = 16) and IncFII plasmid (n = 7), which significantly contributed to the cross-species dissemination of tet(X4). In summary, this study highlights the prevalence of MDR tet(X4)-positive K. pneumoniae in Chengdu, driven predominantly by clonal expansion and plasmid-mediated horizontal gene transfer. These findings emphasize the importance of continuous surveillance of tet(X4)-positive K. pneumoniae in raw meat and the implementation of effective measures to control their spread.

Abstract The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to diverticulitis. Additionally, we observed that microbial composition modulated the protective association between a prudent fiber-rich diet and diverticulitis. Our findings offer insights into the perturbations in inflammation-related microbial and metabolic signatures associated with diverticulitis, supporting the potential of microbial-based diagnostics and therapeutic targets.

Abstract Precise identification of glioblastoma (GBM) microinfiltration, which is essential for achieving complete resection, remains an enormous challenge in clinical practice. Here, the study demonstrates that Raman spectroscopy effectively identifies GBM microinfiltration with cellular resolution in clinical specimens. The spectral differences between infiltrative lesions and normal brain tissues are attributed to phospholipids, nucleic acids, amino acids, and unsaturated fatty acids. These biochemical metabolites identified by Raman spectroscopy are further confirmed by spatial metabolomics. Based on differential spectra, Raman imaging resolves important morphological information relevant to GBM lesions in a label‐free manner. The area under the receiver operating characteristic curve (AUC) for Raman spectroscopy combined with machine learning in detecting infiltrative lesions exceeds 95%. Most importantly, the cancer cell threshold identified by Raman spectroscopy is as low as 3 human GBM cells per 0.01 mm2. Raman spectroscopy enables the detection of previously undetectable diffusely infiltrative cancer cells, which holds potential value in guiding complete tumor resection in GBM patients.

Gene therapy has emerged as a highly promising strategy for the clinical treatment of large segmental bone defects and non-union fractures, which is a common clinical need. Meanwhile, many preclinical data have demonstrated that gene and cell therapies combined with optimal scaffold biomaterials could be used to solve these tough issues. Bone tissue engineering, an interdisciplinary field combining cells, biomaterials, and molecules with stimulatory capability, provides promising alternatives to enhance bone regeneration. To deliver and localize growth factors and associated intracellular signaling components into the defect site, gene therapy strategies combined with bioengineering could achieve a uniform distribution and sustained release to ensure mesenchymal stem cell osteogenesis. In this review, we will describe the process and cell molecular changes during normal fracture healing, followed by the advantages and disadvantages of various gene therapy vectors combined with bone tissue engineering. The growth factors and other bioactive peptides in bone regeneration will be particularly discussed. Finally, gene-activated biomaterials for bone regeneration will be illustrated through a description of characteristics and synthetic methods.

ObjectiveExpanding on previous investigations, this study aims to elucidate the role of lipid metabolism disorders in the development of intracranial atherosclerotic stenosis (ICAS) and the determination of stroke risk. The primary objective is to explore the connections between lipid parameters and acute ischemic stroke (AIS), while also examining the potential mediating influence of fasting glucose levels.MethodsRetrospectively, we collected data from symptomatic ICAS patients at the First Affiliated Hospital of Soochow University, including their baseline information such as medical histories and admission blood biochemical parameters. Stenotic conditions were evaluated using magnetic resonance imaging, computed tomography angiography, or digital subtraction angiography. The associations between lipid parameters and AIS risks were investigated via multivariate logistic regression analysis.ResultsA total of 1103 patients with symptomatic ICAS were recruited, among whom 441 (40.0%) suffered new ischemic events during hospitalization. After adjusting for confounding factors, the RCS curves exhibited a dose-response relationship between the atherogenic index of plasma (AIP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and AIS. Further multivariate analysis revealed significant associations between these parameters and AIS. Furthermore, mediation analysis indicated that fasting blood glucose (FBG) acted as a mediator in the association between lipid parameters (AIP, TC, and TG) and AIS.ConclusionHigher lipid parameters in ICAS patients, particularly AIP, TC, and TG, were associated with an increased AIS risk. Additionally, FBG may mediate stroke risk in ICAS patients, highlighting the need for further exploration of underlying mechanisms.

Purpose: An emergency rescue situation is an inevitable challenge in medical work, requiring collaborative efforts from healthcare professionals. Due to a lack of practical experience, novice nurses may encounter difficulties in successfully managing emergency resuscitation events. This study aimed to analyse the authentic psychological experiences of novice nurses participating in emergency resuscitation events by exploring applicable coping methods and management strategies. Methods: This study utilized a hermeneutic phenomenological qualitative research method. We employed purposive sampling to select 27 Novice nurses from West China Hospital of Sichuan University for face-to-face semistructured interviews. Data collection for this study was conducted from November 2023 to January 2024. The interviews were fully audio-recorded and transcribed verbatim. The data were coded, categorized and summarized with the help of Nvivo 20.0 software based on the interpretation of phenomenological research methods. Thematic analysis was performed to deeply analyse and extract corresponding themes. The COREQ criteria were used to guide the reporting of this study. Results: The authentic psychological experiences of novice nurses participating in emergency rescue events mainly include six aspects: lack of rescue knowledge reserves and related abilities, psychological and emotional changes, psychological stress after the rescue, rational arrangement of manpower, team cooperation, and postevent reflection and learning. Their authentic psychological experiences directly affect whether novice nurses can effectively respond to emergency rescue events. Conclusions: This study suggested enhancing novice nurses' knowledge, improving their resuscitation skills, and improving their psychological well-being during resuscitation events. It advocates for organized staffing, effective teamwork, and robust support systems to empower novice nurses and improve their overall capabilities in emergencies. These findings offer valuable insights for future research in this area.

IntroductionGlobally, rodents and shrew populations constitute crucial elements of diverse environments and animal communities. It is imperative to study their population dynamics to mitigate any potential negative impact on humans, as they can be involved in the transmission of critical zoonotic agents, such as Blastocystis. Therefore, this study aimed to identify the prevalence and genetic composition of Blastocystis in wild rodents and shrews residing in the Zhejiang provinces of China.MethodsA total of 652 wild rodents and and shrews were captured from three different regions in Zhejiang Province from April 1st to October 31, 2023. The DNA was isolated by collecting fresh feces from the intestines of each rodent or and shrew. Rodent and shrew species were examined by vertebrate cytochrome b (cytb) analysis and PCR amplification. Blastocystis was also found in all fecal samples using PCR analysis and sequencing of the partial small subunit of ribosomal RNA (SSU rRNA) gene.ResultsAmong all the samples, 6.6% (43/652) showed a positive result for Blastocystis. In the results, 6 species of rodent and shrew were identified with Blastocystis, including Apodemus agrarius (n = 36) (2.8%), Niviventer confucianus (n = 75) (17.3%), Rattus losea (n = 18) (5.6%), R. norvegicus (n = 155) (2.6%), R. tanezumi (n = 86) (3.5%), and Suncus murinus (n = 282) (7.4%). The existence of 6 Blastocystis subtypes, ST4 (n = 33), ST1 (4), ST7 (n = 3), ST2 (n = 1), ST3 (n = 1), and ST5 (n = 1), were confirmed by sequence analysis.DiscussionBased on the molecular data obtained, the wild rodents and shrews under investigation were found to be concurrently infected with zoonotic subtypes of Blastocystis, including ST1 to ST5 and ST7. This suggests that these animals could potentially pose a zoonotic threat to humans and other animals susceptible to Blastocystis infection.

BackgroundPrevious studies suggest a link between diet-derived circulating antioxidants and epilepsy, but the causal relationship is unclear. This study aims to investigate the causal effect of these antioxidants on epilepsy.MethodsTo assess the causal link between dietary antioxidants and epilepsy risk, we conducted a two-sample Mendelian randomization (MR) analysis. This involved examining antioxidants such as zinc, selenium, α- and γ-tocopherol, vitamin A (retinol), vitamin C (ascorbate), and vitamin E (α-tocopherol). We utilized instrumental variables (IVs) which were genetic variations highly associated with these commonly used antioxidants. Exposure data were sourced from a comprehensive genome-wide association study (GWAS). We aggregated data from the International League Against Epilepsy (ILAE) Consortium sample, which included various types of epilepsy, as an outcome variable. Finally, we applied the inverse variance weighting method and conducted sensitivity analyses for further validation.ResultsBased on the primary MR estimates and subsequent sensitivity analyses, the inverse variance weighting (IVW) method revealed that a genetically predicted increase in zinc per standard deviation was positively associated with three types of epilepsy. This includes all types of epilepsy (OR = 1.06, 95% CI: 1.02–1.11, p = 0.008), generalized epilepsy (OR = 1.13, 95% CI: 1.01–1.25, p = 0.030), and focal epilepsy (documented hippocampal sclerosis) (OR = 1.01, 95% CI: 1.00–1.02, p = 0.025). However, there is no evidence indicating that other antioxidants obtained from the diet affect the increase of epilepsy either positively or negatively.ConclusionOur research indicates that the risk of developing epilepsy may be directly linked to the genetic prediction of zinc, whereas no such association was found for other antioxidants.

BackgroundThe association between dietary zinc intake and epilepsy remains unclear. This study aimed to investigate the relationship between zinc intake from the diet and epilepsy, employing Mendelian randomization (MR) to explore potential causal links between zinc and epilepsy.MethodsThe cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2018. Among the 4,434 participants included, 1.5% (67/4,434) reported having epilepsy. Restricted cubic spline models and logistic regression models were employed to examine the relationships between dietary zinc intakes and epilepsy. Subsequently, a 2-sample Mendelian randomization (MR) analysis was conducted using the inverse variance weighted (IVW) approach as the primary analysis.ResultsIn the restricted cubic spline (RCS) analysis, the relationship between dietary zinc consumption and epilepsy displayed an L-shaped curve (nonlinear, p = 0.049). After multivariate adjustments, the adjusted odds ratios for epilepsy in T2 (5.0–11.0 mg/day) and T3 (≥11.0 mg/day) were 0.49 (95% confidence interval [CI]: 0.26–0.92, p = 0.026) and 0.60 (95% CI: 0.31–1.17, p = 0.132), respectively, compared to the lowest dietary zinc consumption tertile (T1, ≤5.0 mg/day). The IVW method indicated that genetically predicted zinc intake per standard-deviation increase was inversely associated with three types of epilepsy, including all types of epilepsy (OR = 1.06, 95% CI: 1.02–1.11, p = 0.008), generalized epilepsy (OR = 1.13, 95% CI: 1.01–1.25, p = 0.030), and focal epilepsy (documented hippocampal sclerosis) (OR = 1.01, 95% CI: 1.00–1.02, p = 0.025).ConclusionOur findings suggest that a daily zinc intake ranging from 5.0 to 11.0 mg is associated with the lowest risk of epilepsy. Furthermore, Mendelian randomization (MR) studies provide additional support for the existence of a causal relationship between zinc and epilepsy.

Abstract Background The caffeoyl-CoA-O methyltransferase (CCoAOMT) family plays a crucial role in the oxidative methylation of phenolic substances and is involved in various plant processes, including growth, development, and stress response. However, there is a limited understanding of the interactions among CCoAOMT protein members in tea plants. Results In this study, we identified 10 members of the CsCCoAOMT family in the genome of Camellia sinensis (cultivar ‘HuangDan’), characterized by conserved gene structures and motifs. These CsCCoAOMT members were located on six different chromosomes (1, 2, 3, 4, 6, and 14). Based on phylogenetic analysis, CsCCoAOMT can be divided into two groups: I and II. Notably, the CsCCoAOMT members of group Ia are likely to be candidate genes involved in lignin biosynthesis. Moreover, through the yeast two-hybrid (Y2H) assay, we established protein interaction networks for the CsCCoAOMT family, revealing 9 pairs of members with interaction relationships. Conclusions We identified the CCoAOMT gene family in Camellia sinensis and conducted a comprehensive analysis of their classifications, phylogenetic and synteny relationships, gene structures, protein interactions, tissue-specific expression patterns, and responses to various stresses. Our findings shed light on the evolution and composition of CsCCoAOMT. Notably, the observed interaction among CCoAOMT proteins suggests the potential formation of the O-methyltransferase (OMT) complex during the methylation modification process, expanding our understanding of the functional roles of this gene family in diverse biological processes.

The Well Mitan-1 has achieved a major breakthrough in the exploration of Ordovician subsalt natural gas in the mid-eastern Ordos Basin, demonstrating a high-yield industrial gas flow in fourth member of the Majiagou Formation of Ordovician (O1m4). Despite this success, there are ongoing disputes regarding the origin of the natural gas found in Well Mitan-1. Measured results show that the natural gas in Well Mitan-1 is mainly composed of alkane gas (95.18 %). The gas drying coefficient (C1/C1-5) is measured at 0.947, and the H2S content is 3.49 %, with a small amount of N2 and CO2 in the non-hydrocarbon gas. The carbon isotopic compositions of methane, ethane, and propane in the natural gas are −45.5 ‰, −26.4 ‰, and −24.3 ‰, respectively. Based on the regional geological background, the characteristics of potential source rocks and the geochemical characteristics of natural gas, it is considered that the natural gas in Well Mitan-1 is self-generated and self-accumulated oil-associated gas in Ordovician subsalt carbonate rocks. However, certain geochemical anomalies, such as the lighter methane carbon isotope value (δ13C1) and coal-type gas characteristics in ethane carbon isotope (δ13C2), raise questions. Further insights from thermal simulation experiments on hydrocarbon generation and the analysis of residual gas in rocks suggest a close relationship between the special geochemical characteristics of Well Mitan-1 and the presence of gypsum rocks. The ubiquitous gypsum rock serves a dual purpose: acting as an effective caprock, facilitating the retention of early-generated natural gas, and promoting the generation of heavy hydrocarbon gases (C2+) and H2S. The relatively low H2S content (less than 5 %) and higher C2+ content indicate that thermochemical sulfate reduction (TSR), if present, is not strong enough to significantly impact methane. The δ13C2 is identified as a potentially sensitive parameter for identifying TSR.

Abstract Mosquitoes are the deadliest animal in the word, transmitting a variety of insect-borne infectious diseases, such as malaria, dengue fever, yellow fever, and Zika, causing more deaths than any other vector-borne pathogen. Moreover, in the absence of effective drugs and vaccines to prevent and treat insect-borne diseases, mosquito control is particularly important as the primary measure. In recent decades, due to the gradual increase in mosquito resistance, increasing attention has fallen on the mechanisms and effects associated with pathogen infection. This review provides an overview of mosquito innate immune mechanisms in terms of physical and physiological barriers, pattern recognition receptors, signalling pathways, and cellular and humoral immunity, as well as the antipathogenic effects of mosquito symbiotic bacteria. This review contributes to an in-depth understanding of the interaction process between mosquitoes and pathogens and provides a theoretical basis for biological defence strategies against mosquito-borne infectious diseases. Graphical Abstract

Abstract Colorectal cancer (CRC) is a common malignancy worldwide. Angiogenesis and metastasis are the critical hallmarks of malignant tumor. Runt-related transcription factor 1 (RUNX1), an efficient transcription factor, facilitates CRC proliferation, metastasis and chemotherapy resistance. We aimed to investigate the RUNX1 mediated crosstalk between tumor cells and M2 polarized tumor associated macrophages (TAMs) in CRC, as well as its relationship with neoplastic angiogenesis. We found that RUNX1 recruited macrophages and induced M2 polarized TAMs in CRC by promoting the production of chemokine 2 (CCL2) and the activation of Hedgehog pathway. In addition, we found that the M2 macrophage-specific generated cytokine, platelet-derived growth factor (PDGF)-BB, promoted vessel formation both in vitro and vivo. PDGF-BB was also found to enhance the expression of RUNX1 in CRC cell lines, and promote its migration and invasion in vitro. A positive feedback loop of RUNX1 and PDGF-BB was thus formed. In conclusion, our data suggest that RUNX1 promotes CRC angiogenesis by regulating M2 macrophages during the complex crosstalk between tumor cells and TAMs. This observation provides a potential combined therapy strategy targeting RUNX1 and TAMs-related PDGF-BB in CRC.

Abstract Probiotics hold promise as a potential therapy for colorectal cancer (CRC), but encounter obstacles related to tumor specificity, drug penetration, and dosage adjustability. In this study, genetic circuits based on the E. coli Nissle 1917 (EcN) chassis were developed to sense indicators of tumor microenvironment and control the expression of therapeutic payloads. Integration of XOR gate amplify gene switch into EcN biosensors resulted in a 1.8-2.3-fold increase in signal output, as confirmed by mathematical model fitting. Co-culturing programmable EcNs with CRC cells demonstrated a significant reduction in cellular viability ranging from 30% to 50%. This approach was further validated in a mouse subcutaneous tumor model, revealing 47%-52% inhibition of tumor growth upon administration of therapeutic strains. Additionally, in a mouse tumorigenesis model induced by AOM and DSS, the use of synthetic bacterial consortium (SynCon) equipped with multiple sensing modules led to approximately 1.2-fold increased colon length and 2.4-fold decreased polyp count. Gut microbiota analysis suggested that SynCon maintained the abundance of butyrate-producing bacteria Lactobacillaceae NK4A136, whereas reducing the level of gut inflammation-related bacteria Bacteroides. Taken together, engineered EcNs confer the advantage of specific recognition of CRC, while SynCon serves to augment the synergistic effect of this approach.

Abstract To comprehensively understand the characteristics of the GH3 gene family in tea plants (Camellia sinensis), we identified 17 CsGH3 genes and analyzed their physicochemical properties, phylogenetic relationships, gene structures, promoters, and expression patterns in different tissues. The study showed that the 17 CsGH3 genes are distributed on 9 chromosomes, and based on evolutionary analysis, the CsGH3 members were divided into three subgroups. Gene duplication analysis revealed that segmental duplications have a significant impact on the amplification of CsGH3 genes. In addition, we identified and classified cis-elements in the CsGH3 gene promoters and detected elements related to plant hormone responses and non-biotic stress responses. Through expression pattern analysis, we observed tissue-specific expression of CsGH3.3 and CsGH3.10 in flower buds and roots. Moreover, based on predictive analysis of upstream regulatory transcription factors of CsGH3, we identified the potential transcriptional regulatory role of gibberellin response factor CsDELLA in CsGH3.14 and CsGH3.15. In this study, we found that CsGH3 genes are involved in a wide range of activities, such as growth and development, stress response, and transcription. This is the first report on CsGH3 genes and their potential roles in tea plants. In conclusion, these results provide a theoretical basis for elucidating the role of GH3 genes in the development of perennial woody plants and offer new insights into the synergistic effects of multiple hormones on plant growth and development in tea plants.

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.

Abstract Based on previous findings, collateral circulation in the brain is vital in mitigating cerebral ischemia's effects and influencing stroke risk. This retrospective study examined collateral circulation, admission ischemic stroke status, and long‐term recurrence in patients with multiple craniocervical artery stenoses. Consecutive symptomatic internal carotid artery (ICA) stenosis patients from the First Affiliated Hospital of Soochow University were recruited. Baseline data including medical histories and neurological function at admission were collected. Imaging techniques assessed collateral compensative capacity. Multivariate logistic regression analysis was used to investigate the association between collateral circulation and case status. A total of 559 patients with symptomatic ICA stenosis were included, among whom 153 (27.4%) had concurrent moderate to severe vertebro‐basilar artery (VBA) stenosis. Dizziness, weakness/numbness, and slurring of speech were the primary symptoms in all patients. Over 36 months, 71 (12.7%) patients experienced a recurrence of acute ischemic stroke (AIS). In multivariate analysis, collateral circulation was found to be negatively associated with AIS (regional leptomeningeal collateral [rLMC] scores: OR: 0.798, 95% CI: 0.743–0.857, p

BackgroundA useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI.MethodsUsing two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women).ResultsInitial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE.ConclusionsIn contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Abstract For the treatment of patients with oral squamous cell carcinoma (OSCC), the imaging of cervical lymph nodes and the evaluation of metastastic progression are of great significance. In recent years, the development of new non-radioactive lymph node tracers has been an area of intense research. Here, we report the synthesis, good biocompatibility, and in vivo evaluation of a new small molecule near-infrared (NIR) fluorescence probe by the conjugation of Lapatinib to S0456 (LP-S). We show that like Lapatinib, LP-S binds to the epidermal growth factor receptor (EGFR) resulting in high quality fluorescence imaging of metastatic lymph nodes in OSCC mouse models. After local injection of LP-S into the tumor, the lymphatic drainage pathway and lymph nodes can be clearly identified by NIR fluorescence imaging. Further, the LP-S probe shows higher contrast and longer retention in metastatic lymph nodes, allowing them to be differentiated from normal lymph nodes, and affording a new choice for fluorescence-guided surgery. Graphical abstract Scheme. Chemical synthesis and application of EGFR targeting probe LP-S for imaging of metastatic lymph nodes (mLNs) in OSCC

Abstract Background Stabilization and increased activity of hypoxia-inducible factor 1-α (HIF-1α) can directly increase cancellous bone formation and play an essential role in bone modeling and remodeling. However, whether an increased HIF-1α expression in adipose-derived stem cells (ADSCs) increases osteogenic capacity and promotes bone regeneration is not known. Results In this study, ADSCs transfected with small interfering RNA and HIF-1α overexpression plasmid were established to investigate the proliferation, migration, adhesion, and osteogenic capacity of ADSCs and the angiogenic ability of human umbilical vein endothelial cells (HUVECs). Overexpression of HIF-1α could promote the biological functions of ADSCs, and the angiogenic ability of HUVECs. Western blotting showed that the protein levels of osteogenesis-related factors were increased when HIF-1α was overexpressed. Furthermore, the influence of upregulation of HIF-1α in ADSC sheets on osseointegration was evaluated using a Sprague–Dawley (SD) rats implant model, in which the bone mass and osteoid mineralization speed were evaluated by radiological and histological analysis. The overexpression of HIF-1α in ADSCs enhanced bone remodeling and osseointegration around titanium implants. However, transfecting the small interfering RNA (siRNA) of HIF-1α in ADSCs attenuated their osteogenic and angiogenic capacity. Finally, it was confirmed in vitro that HIF-1α promotes osteogenic differentiation and the biological functions in ADSCs via the VEGF/AKT/mTOR pathway. Conclusions This study demonstrates that HIF-1α has a critical ability to promote osteogenic differentiation in ADSCs by coupling osteogenesis and angiogenesis via the VEGF/AKT/mTOR signaling pathway, which in turn increases osteointegration and bone formation around titanium implants. Graphical Abstract

BackgroundPrevious research has yielded conflicting results on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics.MethodsWe used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy.ResultsThe analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types (OR = 1.17, 95% CI:1.03 to 1.32, p = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, p = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, p = 0.02). The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 (OR = 1.06, 95% CI: 1.02 to 1.09, p = 0.002). For other relationships, there was no reliable supporting data available.ConclusionThe drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.

Bisphenol A (BPA), an environmental endocrine disruptor (EDC), has been implicated in impairing intestinal and male reproductive dysfunction. The efficacy of gut microbiota modulation for BPA-exposed testicular dysfunction has yet to be verified through research. Therefore, this study explored the potential of mixed probiotics in restoring spermatogenesis damage through the gut-testis axis under BPA exposure. We selected two probiotics strains (Lactobacillus rhamnosus and Lactobacillus plantarum) with BPA removal properties in vitro and the BPA-exposed male mice model was established. The probiotics mixture effectively reduced BPA residue in the gut, serum, and testis in mice. Through 16 S rDNA-seq and metabolomics sequencing, we uncovered that vitamin D metabolism and bile acid levels in the gut was abolished under BPA exposure. This perturbation was linked to an increased abundance of Faecalibaculum and decreased abundance of Lachnospiraceae_NK4A136_group and Ligilactobacillus. The probiotics mixture restored this balance, enhancing intestinal barrier function and reducing oxidative stress. This improvement was accompanied by a restored balance of short-chain fatty acids (SCFAs). Remarkably, the probiotics ameliorated testicular dysfunction by repairing structures of seminiferous tubules and reversing arrested spermiogenesis. Further, the probiotics mixture enhanced testosterone-driven increases in spermatogonial stem cells and all stages of sperm cells. Testicular transcriptome profiling linked these improvements to fatty acid degradation and peroxisome pathways. These findings suggest a significant interplay between spermatogenesis and gut microbiota, demonstrating that probiotic intake could be a viable strategy for combating male subfertility issues caused by BPA exposure.

Usually, it is difficult to achieve satisfactory fire retardancy of epoxy resin (EP) at low addition by adding inorganic nano-fillers alone. Herein, sepiolite nanofibers loaded with layered double metal hydroxide (a-SEP@LDH) and phosphorus/nitrogen-containing flame retardant nanosheets (PAMA) were prepared via hydrothermal method, respectively. The UL-94 V-0 rating and an limiting oxygen index (LOI) value of 31.6% were achieved for EP by loading 1 wt% a-SEP@LDH and 2 wt% PAMA. Compared to adding sole a-SEP@LDH, the thermal stability of EP/a-SEP@LDH/PAMA3 was improved significantly, the total heat release (THR) and peak heat release rate (pHRR) decreased by 10.2 and 28.8%, respectively. Additionally, the total CO2 production decreased by 12.5% and the char residue yield increased to 19.9 wt%. Moreover, the tensile strength and impact strength of the EP composites were remarkably improved owing to the incorporation of PAMA. To sum up, this work provides an environmentally benign, low-cost and efficient way for EP to achieve outstanding fire retardance, thermal stability and high mechanical properties at a low addition.

n-Type silicon (n-Si), with surface easily oxidized and passivated in an aqueous electrolyte, has suffered from sluggish oxygen evolution reaction (OER) kinetics for photoelectrochemical (PEC) water splitting. Herein, a trimetallic Ni0.9Fe0.05Co0.05 protective layer is successfully electrodeposited on a p+n-Si substrate by underpotential deposition. The prepared Ni0.9Fe0.05Co0.05/p+n-Si photoanode exhibits excellent stability and activity for PEC water oxidation, with a low onset potential of 0.938 V versus a reversible hydrogen electrode (RHE) and a remarkable photocurrent density of about 33.1 mA∙cm−2 at 1.23 V versus RHE, which significantly outperforms the Ni/p+n-Si photoanode as a reference. It is revealed that the incorporation of Fe into the Ni layer creates a large band bending at the Ni0.9Fe0.05Co0.05/p+n-Si interface, promoting interfacial charge separation. Moreover, the incorporation of Co produces abundant Ni3+ and oxygen vacancies (Ov) that act as active sites to accelerate the OER kinetics, synergistically contributing to a major enhancement of PEC water oxidation activity. Encouragingly, by connecting the Ni0.9Fe0.05Co0.05/p+n-Si photoanode to an inexpensive Si solar cell, an integrated photovoltaic/PEC (PV/PEC) device achieved a solar-to-hydrogen conversion efficiency of as high as 12.0% without bias. This work provides a facile approach to design efficient and stable n-Si-based photoanodes with a deep understanding of the structure–activity relationship, which exhibits great potential for the integration of low-cost PV/PEC devices for unassisted solar-driven water splitting.

Abstract Background The gut microbiome regulates host energy balance and adiposity-related metabolic consequences, but it remains unknown how the gut microbiome modulates body weight response to physical activity (PA). Methods Nested in the Health Professionals Follow-up Study, a subcohort of 307 healthy men (mean[SD] age, 70[4] years) provided stool and blood samples in 2012–2013. Data from cohort long-term follow-ups and from the accelerometer, doubly labeled water, and plasma biomarker measurements during the time of stool collection were used to assess long-term and short-term associations of PA with adiposity. The gut microbiome was profiled by shotgun metagenomics and metatranscriptomics. A subcohort of 209 healthy women from the Nurses’ Health Study II was used for validation. Results The microbial species Alistipes putredinis was found to modify the association between PA and body weight. Specifically, in individuals with higher abundance of A. putredinis, each 15-MET-hour/week increment in long-term PA was associated with 2.26 kg (95% CI, 1.53–2.98 kg) less weight gain from age 21 to the time of stool collection, whereas those with lower abundance of A. putredinis only had 1.01 kg (95% CI, 0.41–1.61 kg) less weight gain (p interaction = 0.019). Consistent modification associated with A. putredinis was observed for short-term PA in relation to BMI, fat mass%, plasma HbA1c, and 6-month weight change. This modification effect might be partly attributable to four metabolic pathways encoded by A. putredinis, including folate transformation, fatty acid β-oxidation, gluconeogenesis, and stearate biosynthesis. Conclusions A greater abundance of A. putredinis may strengthen the beneficial association of PA with body weight change, suggesting the potential of gut microbial intervention to improve the efficacy of PA in body weight management. Video Abstract

To address the drawback that subcarrier activation pattern (SAP) of the orthogonal frequency division multiplexing with index modulation (OFDM-IM) cannot match the binary numbers which affects the system performance, the orthogonal frequency division multiplexing with subcarrier supply index modulation (OFDM-SSIM) transmission scheme was proposed.The index utilization of the system was improved and the spectral efficiency (SE) of the system was enhanced by adding the supply index.Also, as the subcarrier activation pattern of the proposed scheme match the binary numbers, low complexity log-likelihood ratio (LLR) detection was made easy to adopt and bit error rate (BER) performance was maintained good.Theoretical analysis and simulation results show that the proposed scheme effectively improves the SE and BER performance over classical OFDM-IM scheme in additive white Gaussian noise (AWGN) channels and Rayleigh fading channels.

Abstract Owing to its difficulty in degrading and ease of accumulation in the body, perfluorooctanoic acid (PFOA) has a detrimental effect on reproduction. This study aimed to examine the effect of PFOA concentration in follicular fluid during ovulation stimulation on embryo quality and the impact of PFOA exposure on the metabolic components of follicular fluid. This was a single-center prospective study that included 25 patients with diminished ovarian reserve (DOR), 25 with normal ovarian reserve (NOR), and 25 with polycystic ovary syndrome (PCOS). Follicular fluid samples were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry. We demonstrated that the PFOA levels of follicular fluid in the DOR group were higher than those in the NOR group and PCOS group (P

Chemotherapy is one of the most commonly treatments of advanced colorectal cancer (CRC). However, the drug resistant following chemotherapeutic treatment is a significant challenge in the clinical management of CRC. Therefore, understanding the resistance mechanisms and developing new strategies for enhancing the sensitivity are urgently needed to improve CRC outcome. Connexins contribute to the formation of gap junctions among neighboring cells and then advance gap junctional intercellular communication (GJIC) for transportation of ions and small molecules. Although the drug resistance resulted from GJIC dysfunctional by aberrant expression of connexins is relatively well understood, the underlying mechanisms of mechanical stiffness mediated by connexin responsible for chemoresistance are largely unknown in CRC. Here, we demonstrated that connexin 43 (CX43) expression was downregulated in CRC and that loss of CX43 expression was positively correlated with metastasis and poor prognosis of CRC patients. The CX43 overexpressing suppressed CRC progression and increased the sensitivity to 5-fluorouracil (5-FU) via enhanced GJIC in vitro and in vivo. Moreover, we also highlight that the downregulation of CX43 in CRC increases the stemness of cells via reducing the cell stiffness, thus promoting the drug resistance. Our results further suggest that both effects, that is changes in the mechanical stiffness of the cell and GJIC mediated by CX43 deregulated, are closely related to drug resistance in CRC, which indicating CX43 as a target against cancer growth and chemoresistance in CRC.

Abstract Fostering human–wildlife coexistence necessitates a thorough and nuanced grasp of local attitudes toward wildlife. Attitudes can vary substantially based on the sociodemographic backgrounds of individuals within a society. This study examines Tibetan attitudes toward large carnivores, emphasizing the importance of contextualization in discerning the effects of sociodemographic factors on attitudes. We began by analyzing existing research on Tibetan attitudes toward wildlife in China, identifying previously studied sociodemographic variables. We then executed an online survey to evaluate the affective, behavioral, cognitive, and overall attitudes of ethnic Tibetans in China toward snow leopards (Panthera uncia), gray wolves (Canis lupus), and brown bears (Ursus arctos). Our findings show that while factors such as gender, age, religious identity, and level of education shape these attitudes, their influence differs depending on the specific attitude component and the target animal under examination. Therefore, making broad generalizations about sociodemographic differences in attitudes can be misleading. It is imperative for attitude research to clearly define the attitude component (what type of attitude), object (attitude toward what), and circumstance (attitude in which situation) being studied. Conducting ethnographic fieldwork in collaboration with local cultural experts can deepen our understanding of local perspectives and the ways sociodemographic factors influence attitudes. Such insights are pivotal for developing conservation strategies attuned to local sociocultural contexts.

ABSTRACTThe role of diet and the gut microbiome in the etiopathogenesis of irritable bowel syndrome (IBS) is not fully understood. Therefore, we investigated the interplay between dietary risk factors and gut microbiota in IBS subtypes using a food frequency questionnaire and stool metagenome data from 969 participants aged 18–65 years in the ZOE PREDICT 1 study, an intervention study designed to predict postprandial metabolic responses. We identified individuals with IBS subtype according to the Rome III criteria based on predominant bowel habits during symptom onset: diarrhea (i.e. looser), constipation (i.e. harder), and mixed. Participants with IBS-D (n = 59) consumed more healthy plant-based foods (e.g. whole grains, leafy vegetables) and fiber, while those with IBS-C (n = 49) tended to consume more unhealthy plant-based foods (e.g. refined grains, fruit juice) than participants without IBS (n = 797). Microbial diversity was nominally lower in patients with IBS-D than in participants without IBS or with IBS-C. Using multivariable-adjusted linear regression, we identified specific microbiota variations in IBS subtypes, including slight increases in pro-inflammatory taxa in IBS-C (e.g. Escherichia coli) and loss of strict anaerobes in IBS-D (e.g. Faecalibacterium prausnitzii). Our analysis also revealed intriguing evidence of interactions between diet and Faecalibacterium prausnitzii. The positive associations between fiber and iron intake and IBS-diarrhea were stronger among individuals with a higher relative abundance of Faecalibacterium prausnitzii, potentially driven by carbohydrate metabolic pathways, including the superpathway of β-D-glucuronide and D-glucuronate degradation. In conclusion, our findings suggest subtype-specific variations in dietary habits, gut microbial composition and function, and diet-microbiota interactions in IBS, providing insights into potential microbiome-informed dietary interventions.

Background Gastric cancer (GC) stem cells play an important role in GC progression. Circular RNAs (circRNAs) act as microRNA (miRNA) sponges and inhibit the biological function of miRNAs in GC cytoplasm. MiRNAs also participate in GC progress. circ_0051246 was shown to be associated with miR-375 after analyzing GC microarray data GSE78091 and GSE83521. The oncoprotein Yes-associated protein 1 (YAP1) is targeted by miR-375 and can be inactivated via the Hippo tumor suppressor pathway. Due to insufficient research on circ_0051246, this study aimed to investigate its relationship with miR-375 and YAP1 in cancer stem cells (CSCs). Methods SGC-7901 CSCs were used to establish knockdown/overexpression models of circ_0051246, miR-375, and YAP1. Malignant phenotypes of CSCs were assessed using Cell Counting Kit 8, colony/sphere formation, 5-Ethynyl-2′-deoxyuridine assay, flow cytometry, Transwell, and wound healing assays. To detect the interactions between circ_0051246, miR-375, and YAP1 in CSCs, a dual-luciferase reporter assay and fluorescence in situ hybridization were performed. In addition, 24 BALB/c nude mice were used to establish orthotopic xenograft tumor models. Four groups of mice were injected with CSCs (1 × 106 cells/100 µL) with circ_0051246 knockdown, miR-375 overexpression, or their respective control cells, and tumor progression and gene expression were observed by hematoxylin-eosin staining, immunohistochemistry. Western blot and quantitative real-time PCR were utilized to examine protein and gene expression, respectively. Results Circ_0051246 silencing reduced viability, promoted apoptosis, and inhibited proliferation, migration and invasion of CSCs. The functional effects of miR-375 mimics were comparable to those of circ_0051246 knockdown; however, the opposite was observed after miR-375 inhibitors treatment of CSCs. Furthermore, circ_0051246-overexpression antagonized the miR-375 mimics’ effects on CSCs. Additionally, YAP1 overexpression promoted CSC features, such as self-renewal, migration, and invasion, inhibited apoptosis and E-cadherin levels, and upregulated the expression of N-cadherin, vimentin, YAP1, neurogenic locus notch homolog protein 1, and jagged canonical notch ligand 1. Conversely, YAP1-silenced produced the opposite effect. Moreover, miR-375 treatment antagonized the malignant effects of YAP1 overexpression in CSCs. Importantly, circ_0051246 knockdown and miR-375 activation suppressed CSC tumorigenicity in vivo. Conclusion This study highlights the promotion of circ_0051246-miR-375-YAP1 axis activation in GC progression and provides a scientific basis for research on the molecular mechanism of CSCs.

Globally, Enterocytozoon bieneusi has been detected in humans and various animal hosts. Wild rats and shrews have the potential to act as carriers of E. bieneusi, facilitating the parasite’s transmission to humans and domestic animals. We aimed to investigate the prevalence of E. bieneusi in 652 wild rats and shrews from Zhejiang Province, China, by amplifying the internal transcribed spacer (ITS) region of rDNA through polymerase chain reaction (PCR). To determine animal species, we amplified the Cytochrome b (Cyt-b) gene in their fecal DNA using PCR. Furthermore, we determined the genotype of E. bieneusi by amplifying the ITS region of rDNA through PCR. Genetic traits and zoonotic potential were evaluated using similarity and phylogenetic analyses. Suncus murinus (n = 282) and five rat species, Rattus losea (n = 18), Apodemus agrarius (n = 36), Rattus tanezumi (n = 86), Rattus norvegicus (n = 155), and Niviventer niviventer (n = 75), were identified. The average infection rate of E. bieneusi was 14.1% (92/652) with 18.1% (51/282) in S. murinus and 11.1% (41/370) in rats (27.8% in R. losea, 22.2% in A. agrarius, 10.5% in R. tanezumi, 8.4% in R. norvegicus, and 8.0% in N. niviventer). Thirty-three genotypes were identified, including 16 known genotypes. The most commonly known genotypes were HNR-VI (n = 47) and Peru11 (n = 6). Type IV, KIN-1, SHW7, and HNPL-II were each found in two samples, while Macaque4, CH5, K, Henan-III, Henan-V, HNP-II, HNPL-I, HNPL-III, HNHZ-II, and HNHZ-III were each found in one sample. Additionally, 17 novel genotypes were discovered: WZR-VIII (n = 5), WZR-I to WZR-VII, WZR-IX to WZR-XII, and WZSH-I to WZSH-V (n = 1 each). Those 33 genotypes were divided into three groups: Group 1 (n = 25), Group 2 (n = 3), and Group 13 (n = 5). The initial report underscores the extensive occurrence and notable genetic diversity of E. bieneusi in wild rats and shrews from Zhejiang province, China. These results suggest that these animals play a pivotal role in the transmission of E. bieneusi. Furthermore, animals carrying the zoonotic genotypes of E. bieneusi pose a serious threat to residents.

Abstract Background ACEs hurt subsequent physical and mental health outcomes. However, still little has been known about the rate of ACEs among rural Chinese emerging adults and the different buffering effects of the three types of social support on different kinds of ACEs. This study described the rate of ACEs among Chinese rural emerging adults, examined the relationship between ACEs and deviant behaviors, and tested the moderating effect of three different sources of perceived social support on this relationship. We hope these results will be helpful in further interventions. Methods We used the second wave of a longitudinal survey that included ACEs variables in 2018. A total of 1031 emerging adults aged 18 to 25 participated in the current study. Results we found that (1) the rate of abuse, neglect, and household dysfunction was 10.0, 30.0, and 24.9%, respectively among Chinese rural emerging adults; (2) abuse and household dysfunction experience were significantly and positively associated with deviant behaviors; (3) friend support moderated the relationship between three types of ACEs and deviant behaviors. Other support moderated the relationship between abuse/household dysfunction and deviant behaviors. Conclusions ACEs could increase the risk of deviant behaviors. Perceived friend support could reduce the negative effect of three types of ACEs. Other support could reduce the negative impact of abuse and household dysfunction. These results suggest that reducing ACEs to make children’s family environments safer and enhancing social support for emerging adults from rural areas are beneficial, which could prevent or reduce their deviant behaviors.

Abstract Despite of suitable band structures for harvesting solar light and driving water redox reactions, polymeric carbon nitride (PCN) has suffered from poor charge transfer ability and sluggish surface reaction kinetics, which limit its photocatalytic activity for water splitting. Herein, atomically dispersed Zn-coordinated three-dimensional (3D) sponge-like PCN (Zn-PCN) is synthesized through a novel intermediate coordination strategy. Advanced characterizations and theoretical calculations well evidence that Zn single atoms are coordinated and stabilized on PCN in the form of Zn-N6 configuration featured with an electron-deficient state. Such an electronic configuration has been demonstrated contributive to promoted electron excitation, accelerated charge separation and transfer as well as reduced water redox barriers. Further benefited from the abundant surface active sites derived from the 3D porous structure, Zn-PCN realizes visible-light photocatalysis for overall water splitting with H2 and O2 simultaneously evolved at a stoichiometric ratio of 2:1. This work brings new insights into the design of novel single-atom photocatalysts by deepening the understanding of electronic configurations and reactive sites favorable to excellent photocatalysis for water splitting and related solar energy conversion reactions.

Introduction: Preclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI. Methods and Materials: Pre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure. Results: Among 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences. Conclusions: Prior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation.

Abstract Background Dietary magnesium deficiency, which is common in modern diet, has been associated with osteoarthritis (OA) susceptibility. Despite this clinical association, no study has addressed if dietary magnesium deficiency accelerates OA development, especially at molecular level. This study aimed to explore aggravating effects of dietary magnesium deficiency on cartilage damage in an injury-induced murine OA model and to determine the underlying mechanism. Methods Twelve-week-old C57BL/6J mice subject to injury-induced OA modeling were randomized into different diet groups in which the mice were fed a diet with daily recommended magnesium content (500 mg/kg) or diets with low magnesium content (100 or 300 mg/kg). Articular cartilage damage was evaluated using the OARSI score. To determine molecular mechanisms in vitro, mouse chondrocytes were treated with media of low magnesium conditions at 0.1 and 0.4 mM, compared with normal magnesium condition at 0.7 mM as control. Anabolic and catabolic factors, autophagy markers, β-catenin, Wnt ligands, and a magnesium channel transient receptor potential cation channel subfamily member 7 (TRPM7) were analyzed by quantitative real-time PCR and immunoblotting. Autolysosomes were detected by DALGreen staining via fluorescence microscopy and autophagosomes were evaluated by transmission electron microscopy. Autophagy markers, β-catenin, and TRPM7 were assessed in vivo in the mouse cartilage, comparing between dietary magnesium deficiency and normal diet, by immunohistochemistry. Results Dietary magnesium deficiency aggravated injury-induced cartilage damage, indicated by significant higher OARSI scores. Autophagy markers LC3-II and Beclin-1 were decreased both in low magnesium diet-fed mice and low magnesium-treated chondrocytes. The number of autolysosomes and autophagosomes was also reduced under low magnesium conditions. Moreover, magnesium deficiency induced decreased anabolic and increased catabolic effect of chondrocytes which could be restored by autophagy activator rapamycin. In addition, reduced autophagy under low magnesium conditions is mediated by activated Wnt/β-catenin signaling. The expression of TRPM7 also decreased in low magnesium diet-fed mice, indicating that downstream changes could be regulated through this channel. Conclusions Dietary magnesium deficiency contributes to OA development, which is mediated by reduced autophagy through Wnt/β-catenin signaling activation. These findings indicated potential benefits of adequate dietary magnesium for OA patients or those individuals at high risk of OA.

Rechargeable zinc-iodine (ZnI _2 ) batteries have gained popularity within the realm of aqueous batteries due to their inherent advantages, including natural abundance, intrinsic safety, and high theoretical capacity. However, challenges persist in their practical applications, notably battery swelling and vulnerability in aqueous electrolytes, primarily linked to the hydrogen evolution reaction and zinc dendrite growth. To address these challenges, this study presents an innovative approach by designing a solid-state ZnI _2 battery featuring a solid perfluoropolyether based polymer electrolyte. The results demonstrate the formation of a solid electrolyte interphase layer on zinc, promoting horizontal zinc growth, mitigating dendrite penetration, and enhancing battery cycle life. Moreover, the solid electrolyte hinders the iodine ion shuttle effect, reducing zinc foil corrosion. Symmetric batteries employing this electrolyte demonstrate excellent cycle performance, maintaining stability for approximately 5000 h at room temperature, while solid-state ZnI _2 batteries exhibit over 7000 cycles with a capacity retention exceeding 72.2%. This work offers a promising pathway to achieving reliable energy storage in solid-state ZnI _2 batteries and introduces innovative concepts for flexible and wearable zinc batteries.

Abstract Background C-reactive protein (CRP) is an important biomarker of inflammation and plays a pivotal role in predicting the clinical prognosis of cardiovascular and cerebrovascular diseases. However, the mechanism of inflammation influencing the outcome of patients with ischemic stroke are unknown. Aims We aim to investigate the association between hsCRP and mRS in 194 eligible patients by therapy-stratified analyses. Methods The modification effects of antiplatelet therapy on the association between mRS and different exposure variables were analyzed. The retained variables were analyzed in the receiver operating characteristic (ROC) curve to discriminate patients with poor outcome. Results hsCRP was positively correlated with mRS in therapy-stratified analyses. There was a statistical modification effect of antiplatelet therapy on the association of hsCRP and mRS (P for interaction = 0.0101). The discriminative effect of poor outcome was further verified by ROC curve analyses (AUCwith from 0.758 to 0.872, AUCwithout from 0.709 to 0.713). Conclusions hsCRP is correlated with the clinical outcome of patients treated with IVrt-PA, and may be a better predictor of post-thrombolytic functional outcome in patients with previous antiplatelet therapy than in non-used patients.