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Abstract Backgrounds Cancer antigen 125 (CA125) is widely used for screening ovarian cancer (OC), yet its effectiveness remains debated. Potential factors may include ineffective cut-off value for CA125 in screening, as well as a lack of consideration for CA125 trajectories and trajectory-specific progression. Methods Based on data from multiple rounds of CA125 tests and transvaginal ultrasound (TVU) examinations conducted on 28,456 women in the PLCO Trial, time-dependent receiver-operating-characteristic curves (ROCs) and area-under-the-curves (tdAUCs) analyses were employed to identify the optimal CA125 cut-off values for OC screening. Participants were categorized into four CA125 trajectories: stable negative CA125 (CA125SN), loss of positive CA125 (CA125LP), stable positive CA125 (CA125SP), and gain of positive CA125 (CA125GP). The associations between different CA125 trajectories, trajectory-specific progression indicators, and OC risk were explored. The effectiveness of risk-stratified CA125 screening, incorporating CA125 trajectories, trajectory-specific progression, and TVU, was evaluated using hazard ratio and 95% confidence intervals [HR (95%CIs)], with adjustments for potential confounders. Results After a median follow-up of 14.8 years for OC incidence and 23.8 years for OC mortality, 250 OC cases and 218 OC deaths were identified. The tdAUC for 10-year OC incidence with CA125 was 0.663, with an optimal cut-off value of 13.00 U/ml. Trajectory analyses showed that both CA125SP and CA125GP were significantly associated with increased risks of OC incidence [HRs (95%CIs): 2.00(1.47–2.73) and 3.06(2.25–4.16)] and mortality [HRs (95%CIs):1.58(1.13–2.21) and 2.60(1.87–3.62)] compared to CA125SN. Trajectory-specific progression analyses identified relative velocity as the optimal progression indicators for both CA125SP and CA125GP (tdAUCs: 0.712 and 0.767), with optimal cut-off values of 9% and 32% per year, respectively. Positive progression was associated with significantly increased risks of OC incidence [HRs (95%CI): 7.26(4.00-13.17) and 3.83(1.96–7.51) CA125GP and CA125SP] and mortality [HRs (95%CI): 8.03(4.15–15.56) and 6.04(2.78–13.14)] compared to negative progression. Optimized risk-stratified CA125 screening, which integrated CA125 trajectories, trajectory-specific progression, and TVU, reduced missed OC by 3.6% and improved accuracy compared to traditional screening methods. Conclusions Incorporating CA125 trajectories and trajectory-specific progression into screening protocols enhances the identification of the population at high-risk of OC. An optimized screening strategy, which includes these factors along with TVU, is recommended to improve the effectiveness of OC screening.

Abstract Objectives To examine the correlation between healthy lifestyle patterns, their change trajectories, and the risk of multimorbidity in adults. Methods Based on two representative national cohorts, the English Longitudinal Study of Aging (ELSA) and the Health and Retirement Study (HRS) including adults aged 50 years and over. We employed Cox regression, lifestyle change trajectories, and restricted mean survival times to explore the relationship between lifestyle (assessed by SCORE2, LE’8, and HLS scores) and multimorbidity. We also conducted mediation analysis to investigate the underlying mechanisms. Results A healthy lifestyle (higher LE’8, higher HLS, or lower SCORE2) can reduce the risk of multimorbidity. 2-10% lower multimorbidity risk per one-point increase in LE’8 and HLS. The hazard ratio of multimorbidity for improvements in unhealthy lifestyles or deterioration in healthy lifestyles compared to always healthy lifestyles ranged from 1.598 to 5.602. Besides, for LE’8 and HLS, participants with higher scores had a slower decrease in survival probability in ELSA. Triglyceride, C-reaction protein, fibrinogen, and cystatin C partly mediate the association between lifestyle and multimorbidity. Conclusions Keeping a healthy lifestyle over time can help reduce the risk of multimorbidity.

Background: Allergic asthma is largely dominated by Th2 lymphocytes. Micropeptides in Th2 cells and asthma remain unmasked. Here, we aimed to demonstrate a micropeptide, T-cell regulatory micropeptide (TREMP), in Th2 cell differentiation in asthma. Methods: TREMP translated from lincR-PPP2R5C was validated using Western blotting and mass spectrometry. TREMP knockout mice were generated using CRISPR/Cas9. Coimmunoprecipitation revealed that TREMP targeted pyrroline-5-carboxylate reductase 1 (PYCR1), which was further explored in vitro and in vivo. The levels of TREMP and PYCR1 in Th2 cells from clinical samples were determined by flow cytometry. Results: TREMP, encoded by lincR-PPP2R5C, was in the mitochondrion. The lentivirus encoding TREMP promoted Th2 cell differentiation. In contrast, Th2 differentiation was suppressed in TREMP−/− CD4+ T cells. In the HDM-induced model of allergic airway inflammation, TREMP was increased in pulmonary tissues. Allergic airway inflammation was relieved in TREMP−/− mice treated with HDM. Mechanistically, TREMP interacted with PYCR1, which regulated Th2 differentiation via glycolysis. Glycolysis was decreased in Th2 cells from TREMP−/− mice and PYCR1−/− mice. Similar to TREMP−/− mice, allergic airway inflammation was mitigated in HDM-challenged PYCR1−/− mice. Moreover, we measured TREMP and PYCR1 in asthma patients. And we found that, compared with those in healthy controls, the levels of TREMP and PYCR1 in Th2 cells were significantly increased in asthmatic patients. Conclusions: The micropeptide TREMP encoded by lincR-PPP2R5C promoted Th2 differentiation in allergic airway inflammation by interacting with PYCR1 and enhancing glycolysis. Our findings highlight the importance of neglected micropeptides from noncoding RNAs in allergic diseases.

Abstract This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses.

Abstract Background Placenta previa accreta (PPA) is a severe obstetric condition that can cause massive postpartum hemorrhage and transfusion. Cesarean hysterectomy is necessary in some severe cases of PPA to stop the life-threatening bleeding, but cesarean hysterectomy can be associated with significant surgical blood loss and major complications. The current study is conducted to investigate the potential risk factors of excessive blood loss during cesarean hysterectomy in women with PPA. Methods This is a retrospective study including singleton pregnancies after 28 weeks of gestation in women with placenta previa and pathologically confirmed placenta accreta spectrum who received hysterectomy during cesarean sections. A total of 199 women from January 2012 to August 2023 were included in this study and were divided into Group 1 (estimated surgical blood loss (EBL) ≤ 3500 mL, n = 103) and Group 2 (EBL > 3500 mL, n = 96). The primary outcome was defined as an EBL over 3500 mL. Baseline characteristics and surgical outcomes were compared between the two groups. A multivariate logistic regression model was applied to find potential risk factors of the primary outcome. Results Massive surgical blood loss was prevalent in our study group, with a median EBL of 3500 mL. The multivariate logistic analysis showed that emergency surgery (OR 2.18, 95% CI 1.08–4.41, p = 0.029), cervical invasion of the placenta (OR 2.70, 95% CI 1.43–5.10, p = 0.002), and intraoperative bladder injury (OR 5.18, 95% CI 2.02–13.28, p = 0.001) were all associated with the primary outcome. Bilateral internal iliac arteries balloon occlusion (OR 0.57, 95% CI 0.34–0.97) and abdominal aortic balloon occlusion (OR 0.33, 95% CI 0.19–0.56) were negatively associated with the primary outcome. Conclusions Emergency surgery, cervical invasion of the placenta, and intraoperative bladder injury were potential risk factors for additional EBL during cesarean hysterectomy in women with PPA. Future prospective studies are needed to confirm the effect of intra-arterial balloon occlusion in cesarean hysterectomy of PPA.

Abstract Objectives To assess the efficacy of the Chinese herbal medication Shugan Hewei formula (SHF) combined with rabeprazole in patients with refractory gastroesophageal reflux disease (rGERD). Method A total of 264 participants were randomly assigned to the treatment group (n = 132) receiving SHF granules (20 mg) combined with rabeprazole (10 mg) and the control group (n = 132) receiving placebo SHF granules (20 mg) combined with rabeprazole (20 mg). Both groups undergo 8 weeks of treatment and 2 weeks of follow-up. Results The treatment group showed higher total clinical symptom efficacy and lower total symptom scores compared to the control group. The treatment group was superior to the control group in reducing rGERD major symptom scores, including heartburn, retrosternal pain, regurgitation and belching, and acid regurgitation. Additionally, treatment group (Z = 8.169, P

Abstract The MuralDH dataset is an invaluable digital resource developed for the conservation and restoration of Dunhuang murals, which are critical components of global cultural heritage facing threats from degradation. This dataset comprises over 5000 high-resolution images tailored to 512 × 512 pixels, emphasizing the preservation of mural integrity and detail. It includes 1000 images with pixel-level damage annotations for segmentation research and 500 images specially processed for super-resolution studies, catering to a wide range of digital restoration needs. While the primary focus of this work is the dataset itself, we also introduce a supportive digital restoration framework. This framework, which encompasses damage segmentation, inpainting, and super-resolution techniques, serves as a secondary validation of MuralDH’s utility and versatility. Through MuralDH, technology revives ancient art, embodying the essence of interdisciplinary innovation. By facilitating advanced research in computer vision and artificial intelligence, MuralDH aims to revolutionize the digital preservation practices for murals and other cultural artifacts, demonstrating the critical role of interdisciplinary collaboration in safeguarding our cultural legacy.

Abstract Background Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. Methods Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. Results We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. Conclusions Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Background: Preterm premature rupture of membranes (PPROM) contributes to over one-third of preterm births, and PPROM infants are more susceptible to infections. However, the risk factors remain poorly understood. We here aim to investigate the association of duration of premature rupture of membranes (PROM) and environmental microbiota with the gut microbiota and infection in PPROM infants. Methods: Forty-six premature infants were recruited from two hospitals, and infant fecal and environmental samples were collected. 16 s rRNA sequencing was performed to analyze the fecal and environmental microbiome. Human inflammatory cytokines in cord vein plasma were measured. Results: The gut microbiota composition of PPROM infants was different from that of non-PPROM infants, and the microbiome phenotypes were predicted to be associated with a higher risk of infection, further evidenced by the significantly increased levels of IL-6 and IL-8 in cord vein plasma of PPROM infants. The diversity of the gut microbiota in PPROM infants increased significantly as the duration of PROM excessed 12 h, and Pseudomonas contributed significantly to the dynamic changes. The Pseudomonas species in the gut of PPROM infants were highly homologous to those detected in the ward environment, suggesting that prolonged PROM is associated with horizontal transmission of environmental pathogens, leading to a higher risk of infection. Conclusions: This study highlights that the duration of PROM is associated with the accumulation of environmental pathogens in the gut of PPROM infants, which is a risk factor for nosocomial infections. Improving environmental hygiene could be effective in optimizing the clinical care of PPROM infants.

Enterocytozoon hepatopenaei (EHP) is a specialized intracellular parasitic microsporidian species that infects the hepatopancreas of shrimp and causes hepatopancreatic microsporidiosis (HPM). It was discovered in stunted Penaeus monodon in Thailand in 2004. It is a fungal pathogen that can infect various crustacean hosts. It affects farmed shrimp in Southeast Asia and South America, including Thailand, Vietnam, China, Indonesia, India, Malaysia, South Korea and Venezuela. An E. hepatopenaei infection does not cause death in shrimp, but can lead to necrosis and rupture of the hepatopancreatic epithelial cells. This results in reduced digestive and absorptive functions of the hepatopancreatic gland and impaired nutrient storage functions. Therefore, an EHP infection usually leads to shrimp growth retardation or stagnation that greatly reduces shrimp production and seriously affects the high-quality development of shrimp farming. E. hepatopenaei infections were detected in farmed shrimp in coastal provinces of China since 2013 and their high infection rate causes serious economic losses to the cultured shrimp industry. It is difficult to confirm EHP infections solely based on the symptoms of diseased shrimp in the field owing to the extremely small size of EHP and the lack of obvious symptoms in the early stages of EHP infection. Furthermore, the early stages of infection are difficult to accurately detect by light microscopy and histopathological sections. Pathological changes of EHP infection are only observed in the middle and later stages by histopathological sections. In addition, tissue section preparation is time-consuming and complex. This makes it unsuitable as a practical technical method to detect EHP. In contrast, molecular biology methods have become a common laboratory method to detect EHP. This study collected 936 shrimp samples from coastal areas in China from 2021 to 2022, detected EHP positive samples by TaqMan quantitative polymerase chain reaction (qPCR), and analyzed the morphology by histopathology. This study aims to clarify the prevalence of EHP in major shrimp farming species in coastal provinces and cities in China from 2021 to 2022, and to clarify the hazard risk of EHP in cultured shrimp.TaqMan qPCR assays showed that the positive detection rate of EHP in shrimp samples from coastal areas was 10.67% (54/506) in 2021. There was a decreasing trend compared with the national aquatic animal disease surveillance plan from 2017 to 2020. However, the positive rate of EHP in shrimp samples from coastal areas reached 13.72% (59/430) in 2022. There was an increase in the EHP positive detection rate compared with the national surveillance data from 2019 to 2020. The detection results of EHP in samples collected from different regions showed that the positive rate of EHP was high in samples collected from Liaoning (10%) and Shandong (18.80%) in 2021, and in samples collected from Liaoning (14.63%), Hebei (29.17%), Tianjin (28.57%), and Shandong (16.88%) in 2022. The results of samples collected from different shrimp varieties showed that EHP was mainly detected in P. vannamei in 2021 and 2022, with positive rates of 14.10% (54/383) and 16.71% (58/347), respectively. Among them, one sample of Exopalaemon carinicauda was positive for EHP, while no EHP positive sample was detected in Macrobrachium rosenbergii, Protocrayfish cruzi, Penaeus monodon, Marsupenaeus japonicus, and Penaeus chinensis. This study collected and analyzed 506 and 430 shrimp samples from coastal provinces and cities in China in 2021 and 2022, respectively by TaqMan qPCR. These detection results are more reliable than those of previous studies owing to the large sample size and the high specificity and sensitivity of the detection method. The results provided an important reference for a comprehensive understanding of the epidemic situation of EHP in major cultured shrimp in coastal areas of China from 2021 to 2022. Histopathological examination of EHP-positive P. vannamei revealed that scattered or clustered EHP spores and EHP protoplasts were observed in hepatopancreatic epithelial cells.The epidemiological survey and molecular epidemiological analysis of shrimp farmed in coastal provinces, municipalities, and some inland provinces of China in 2021 to 2022 showed that the prevalence rate of EHP is generally decreasing compared to previous years. This indicated that remarkable achievements were made to prevent and control EHP in China's shrimp farming industry in recent years. However, EHP is widely prevalent in farmed shrimp in coastal provinces in Northern China. Therefore, measures such as strict EHP quarantine of brood stock and seedlings and the promotion of non-EHP seedlings should be taken to further reduce the epidemic range and risk of EHP and promote the green and high-quality development of the shrimp culture industry in China.

Abstract Background Multivariate synchronization index (MSI) has been successfully applied for frequency detection in steady state visual evoked potential (SSVEP) based brain–computer interface (BCI) systems. However, the standard MSI algorithm and its variants cannot simultaneously take full advantage of the time-local structure and the harmonic components in SSVEP signals, which are both crucial for frequency detection performance. To overcome the limitation, we propose a novel filter bank temporally local MSI (FBTMSI) algorithm to further improve SSVEP frequency detection accuracy. The method explicitly utilizes the temporal information of signal for covariance matrix estimation and employs filter bank decomposition to exploits SSVEP-related harmonic components. Results We employed the cross-validation strategy on the public Benchmark dataset to optimize the parameters and evaluate the performance of the FBTMSI algorithm. Experimental results show that FBTMSI outperforms the standard MSI, temporally local MSI (TMSI) and filter bank driven MSI (FBMSI) algorithms across multiple experimental settings. In the case of data length of one second, the average accuracy of FBTMSI is 9.85% and 3.15% higher than that of the FBMSI and the TMSI, respectively. Conclusions The promising results demonstrate the effectiveness of the FBTMSI algorithm for frequency recognition and show its potential in SSVEP-based BCI applications.

In this study, the high-temperature evolution of eutectic carbides in a medium-alloy steel was investigated as well as their precipitation mechanism. Results revealed that MC and M6C eutectic carbides in the steel appeared during the final solidification due to the segregation of Mo and V and the melt undercooling. These eutectic carbides consist of blocky shapes with varying orientations, and rod-like shapes with the same orientation. Further investigation was confirmed that the carbides (MC and M6C) exhibited an intergrowth behavior. The cooling rate had a direct influence on the secondary dendrite arm spacing (SDAS), which decreased from 180 to 130 μm as the rate ranged from 0.6 to 21.9 °C/min. After holding for 0, 25, 50, and 80 h, respectively, the volume percentage of eutectic carbides exhibited a significant decreasing trend from 2 to 0.2%. Additionaly, the carbides exhibited irregular morphology after holding for 0–50 h, respectively, and which was transformed into the rod-like shape with a small size distributed along the grain boundaries after holding for 80 h. This phenomenon was attributed to the mutual diffusion between Mo, V, and other alloying elements in the carbides and Fe element in the steel matrix.

Abstract Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3–36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9–7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.

Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse fetal outcomes, yet its influence on offspring growth remains unclear. Our study dynamically tracks growth rates in children from ICP and healthy mothers and investigates the link between maternal liver function and developmental abnormalities in offspring. Method Our case‒control study involved 97 women with ICP and 152 with uncomplicated pregnancies nested in a cohort of their offspring, including 50 from the ICP group and 87 from the uncomplicated pregnancy group. We collected pediatric growth and development data, with a maximum follow-up duration of 36 months. Stratified analyses of children's height, weight, and head circumference were conducted, and Spearman's rank correlation was applied to examine the relationships between maternal serological markers and pediatric growth metrics. Result Maternal liver and renal functions, along with serum lipid profiles, significantly differed between the ICP and normal groups. In the ICP group, the offspring showed elevated alanine aminotransferase (ALT), direct bilirubin (DBIT), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (APOB) levels. Notably, the length-for-age z score (LAZ), weight-for-age z score (WAZ), and head circumference-for-age z score (HCZ) were lower in ICP offspring compared with those from normal pregnancies within the 1- to 12-month age range (P

Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.

ABSTRACT Phage-antibiotic synergy (PAS) represents a superior treatment strategy for pathogen infections with less probability of resistance development. Here, we aim to understand the molecular mechanism by which PAS suppresses resistance in terms of population evolution. A novel hypervirulent Klebsiella pneumoniae (KP) phage H5 was genetically and structurally characterized. The combination of H5 and ceftazidime (CAZ) showed a robust synergistic effect in suppressing resistance emergence. Single-cell Raman analysis showed that the phage-CAZ combination suppressed bacterial metabolic activities, contrasting with the upregulation observed with phage alone. The altered population evolutionary trajectory was found to be responsible for the contrasting metabolic activities under different selective pressures, resulting in pleiotropic effects. A pre-existing wcaJ point mutation (wcaJG949A) was exclusively selected by H5, conferring a fitness advantage and up-regulated activity of carbohydrate metabolism, but also causing a trade-off between phage resistance and collateral sensitivity to CAZ. The wcaJ point mutation was counter-selected by H5-CAZ, inducing various mutations in galU that imposed evolutionary disadvantages with higher fitness costs, and suppressed carbohydrate metabolic activity. H5 and H5-CAZ treatments resulted in opposite effects on the transcriptional activity of the phosphotransferase system and the ascorbate and aldarate metabolism pathway, suggesting potential targets for phage resistance suppression. Our study reveals a novel mechanism of resistance suppression by PAS, highlighting how the complexity of bacterial adaptation to selective pressures drives treatment outcomes.IMPORTANCEPhage-antibiotic synergy (PAS) has been recently proposed as a superior strategy for the treatment of multidrug-resistant pathogens to effectively reduce bacterial load and slow down both phage and antibiotic resistance. However, the underlying mechanisms of resistance suppression by PAS have been poorly and rarely been studied. In this study, we tried to understand how PAS suppresses the emergence of resistance using a hypervirulent Klebsiella pneumoniae (KP) strain and a novel phage H5 in combination with ceftazidime (CAZ) as a model. Our study reveals a novel mechanism by which PAS drives altered evolutionary trajectory of bacterial populations, leading to suppressed emergence of resistance. The findings advance our understanding of how PAS suppresses the emergence of resistance, and are imperative for optimizing the efficacy of phage-antibiotic therapy to further improve clinical outcomes.

Background Histone deacetylase (HDAC), a kind of protease that regulates gene expression by modifying protein acetylation levels, is usually aberrantly activated in tumors. The approved pan-HDAC inhibitors (HDACi) have exhibited clinical benefits for hematopoietic malignancies. Recently, HDACis have emerged as enhancers of antitumor immunity. However, the effect of HDACs on the tumor immune microenvironment of lung adenocarcinoma (LUAD) and the underlying mechanism is largely unknown.Methods C57BL/6J and BALB/c nude mice with subcutaneous tumors were used for in vivo therapeutic effects and mechanistic investigations. Flow cytometry was used to measure the toxicity and exhaustion of human CD8+T cells after co-culturing with tumor cells and to determine the immunophenotype of tumor-infiltrating CD8+T cells. A series of experimental techniques, including RNA sequencing, quantitative PCR, western blot, ELISA, mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation and immunohistochemistry, were used to explore the underlying molecular mechanism.Results The pan-HDACi vorinostat (SAHA) promoted CD8+T cell infiltration and effector function in LUAD through suppressing FGL1, a newly identified major ligand of LAG-3. Mechanistically, SAHA inhibited the activity of HDAC1, an essential deacetylase of JAK1. This increased the acetylation level of JAK1 at lysine 1109, thus promoting its proteasomal degradation and subsequently reducing STAT3-driven FGL1 transcription. The combination regimen of SAHA and anti-LAG-3 therapy was further explored in an immunocompetent LUAD mouse model. Compared with those receiving control or single agent treatments, mice receiving combination therapy exhibited a lower tumor burden and superior CD8+T-cell-killing activity.Conclusions Our results revealed a novel mechanism by which the HDACi SAHA potentiates CD8+T-cell-mediated antitumor activity through the HDAC1/JAK1/FGL1 axis, providing a rationale for the combined use of HDACis and immunotherapy.

Abstract Herein, hierarchically structured microgrid frameworks of Co3O4 and carbon composite deposited on reduced graphene oxide (Co3O4@C/rGO) are demonstrated through the three‐dimensioinal (3D) printing method, where the porous structure is controllable and the height and width are scalable, for dendrite‐free Na metal deposition. The sodiophilicity, facile Na metal deposition kinetics, and NaF‐rich solid electrolyte interphase (SEI) formation of cubic Co3O4 phase are confirmed by combined spectroscopic and computational analyses. Moreover, the uniform and reversible Na plating/stripping process on 3D‐printed Co3O4@C/rGO host is monitored in real time using in situ transmission electron and optical microscopies. In symmetric cells, the 3D printed Co3O4@C/rGO electrode achieves a long‐term stability over 3950 at 1 mA cm−2 and 1 mAh cm−2 with a superior Coulombic efficiency (CE) of 99.87% as well as 120 h even at 20 mA cm−2 and 20 mAh cm−2, far exceeding the previously reported carbon‐based hosts for Na metal anodes. Consequently, the full cells of 3D‐printed Na@Co3O4@C/rGO anode with 3D‐printed Na3V2(PO4)3@C‐rGO cathode (≈15.7 mg cm−2) deliver the high specific capacity of 97.97 mAh g−1 after 500 cycles with a high CE of 99.89% at 0.5 C, demonstrating the real operation of flexible Na metal batteries.

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the “last patient in” date. Methods: Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23–0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08–0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Objective: To construct an interpretation structure model of adverse experiences of cardiac surgery patients in intensive care unit, so as to provide a reference for optimizing the experience of critical patients step by step. Methods: Literature review, semi-structured interviews, questionnaires and Delphi method were used to summarize and analyze the influencing factors of intensive care experience in cardiac surgery. The explanatory structural model was used to divide the influencing factors into levels and construct the explanatory structural model of adverse experience of cardiac surgery patients in intensive care. Results: A hierarchical structure model containing 34 elements and 15 levels was constructed, which were divided into Surface level, middle level and root level. Conclusion: The intensive care experience of patients in cardiac surgery department is mainly affected by 34 factors. There are direct or indirect correlations between the influencing factors, and different levels have different effects.

BackgroundLipofibromatosis-like neural tumors (LPF-NT), which have only recently been established, are intermediate soft tissue tumors with neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene alterations and are typically misdiagnosed as dermatofibrosarcoma protuberans, low-grade malignant peripheral nerve sheath tumors, or spindle cell lipoma due to their histopathological and immunohistochemical expression of CD34 and S-100.Case presentationThe patient was admitted to our hospital with a painless back mass that had appeared more than 4 years prior to admission. Physical examination revealed a subcutaneous mass on the back, approximately 1.5 cm in diameter and protruding into the skin, with clear boundaries and no tenderness. The tumor was surgically resected. The postoperative pathological results suggested a spindle cell soft tissue tumor, and dermatofibrosarcoma protuberan was initially considered. After consultation at a provincial hospital, the patient was diagnosed with a cutaneous lipofibromatosis-like neural tumor of the back. A second extended resection was then performed. Intraoperative rapid freezing examination revealed negative incision margins.ConclusionHistological and immunohistochemical detections aid in the differential diagnosis of LPF-NTs. Complete surgical resection is the preferred treatment for LPF-NTs.

GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gαi/q and their ability to bind GDP-bound (inactive form) Gαi/q. As a result, SNX25 recruits these RGS proteins to endosomes, leading to the termination of endosomal Gαi/q signaling. Furthermore, we have found that the SNX25/RGS complex also exerts a negative regulatory effect on Gαi/q signaling from the plasma membrane. This is achieved by recruiting Gαi/q to endosomes and preventing its activation on the plasma membrane. Our findings shed light on the previously unknown role of redox-modulated SNX25 in inhibiting Gαi/q signaling, thereby uncovering a novel mechanism for terminating Gαi/q signaling from endosomes. Importantly, this study expands our understanding of the regulation of GPCR-Gαi/q signaling beyond the plasma membrane.

Abstract Background The worldwide occurrence of triplet pregnancy is estimated to be 0.093%, with a natural incidence of approximately 1 in 8000. This study aims to analyze the neonatal health status and birth weight discordance (BWD) of triplets based on chorionicity from birth until discharge. Methods This was a retrospective study. We reviewed a total of 136 triplet pregnancies at our tertiary hospital between January 1, 2001, and December 31, 2021. Maternal and neonatal outcomes, inter-triplet BWD, neonatal morbidity, and mortality were analyzed. Results Among all cases, the rates of intrauterine death, neonatal death, and perinatal death were 10.29, 13.07, and 24.26%, respectively. Thirty-seven of the cases resulted in fetal loss, including 13 with fetal anomalies. The maternal complications and neonatal outcomes of the 99 triplet pregnancies without fetal loss were compared across different chorionicities, including a dichorionic (DC) group (41 cases), trichorionic (TC) group (37 cases), and monochorionic (MC) group (21 cases). Neonatal hypoproteinemia (P 25% increased the risk of neonatal anemia (AOR = 10.135) and need for blood transfusion after birth (AOR = 7.127). TC pregnancy, MCDA or MCTA, and BWD > 25% increased neonatal hypoproteinemia, with AORs of 4.629, 5.123, and 5.343, respectively. Conclusions The BWD differed significantly according to chorionicity. Additionally, TC pregnancies reduced the risk of neonatal anemia and need for blood transfusion, but increased the risk of neonatal hypoproteinemia. In contrast, the BWD between the largest and smallest triplets increased the risk of neonatal anemia and the need for blood transfusion. TC pregnancy, MCDA or MCTA, and BWD > 25% increased the risks of neonatal hypoproteinemia. However, due to the limited number of triplet pregnancies, further exploration of the underlying mechanism is warranted.

Abstract Background Metals have been linked to a diverse spectrum of age-related diseases; however, the effects of metal exposure on health span remains largely unknown. This cohort study aims to determine the association between plasma metal and health span in elder adults aged ≥ 90 years. Methods The plasma concentrations of seven metals were measured at baseline in 300 elder adults. The end of the health span (EHS) was identified as the occurrence of one of eight major morbidities or mortality events. We used Cox regression to assess hazard ratios (HR). The combined effects of multiple metal mixtures were estimated using grouped-weighted quantile sum (GWQS), quantile g-computation (Q-gcomp), and Bayesian kernel machine regression (BKMR) methods. Results The estimated HR for EHS with an inter-quartile range (IQR) increment for selenium (Se) was 0.826 (95% confidence interval [CI]: 0.737–0.926); magnesium (Mg), 0.806 (95% CI: 0.691–0.941); iron (Fe), 0.756 (95% CI: 0.623–0.917), and copper (Cu), 0.856 (95% CI: 0.750–0.976). The P for trend of Se, Mg, and Fe were all

Graphitic carbon nitride (g-C3N4) is emerging as a promising visible-light photocatalyst while the low crystallinity with sluggish charge separation/migration dynamics significantly restricts its practical applications. Currently, synthesizing highly crystalline g-C3N4 with sufficient surface activities still remains challenging. Herein, different from using alkali molten salts which is commonly reported, we propose an approach for synthesis of highly crystalline g-C3N4 with FeCl3/KCl rock/molten mixed salts. The rock salt can serve as the structure-directing template while molten salt provides the required liquid medium for re-condensation. Intriguingly, the synthesized photocatalyst showed further enhanced crystallinity and improved surface area along with high π→π∗ excitation compared with crystalline C3N4 prepared from conventional molten-salt methods. These catalytically advantageous features lead to its superior photocatalytic and piezocatalytic activities with a high reactivity for overall water splitting that is not commonly reported for C3N4. This work provides an effective strategy for structural optimization of organic semiconductor based materials and may inspire new ideas for the design of advanced photocatalysts.

Atmospheric inversion plays an important role in meteorological research and air quality research.This study used ERA5 hourly temperature profile data from 2011 to 2020 to evaluate the low-level atmospheric inversion features of six regions， including Northwest China， North China， Northeast China， Southwest China， East China， and South China.In terms of daily variation， the temperature inversion frequency and intensity mostly peak at 07:00 （Beijing time， the same as after）， the frequency and intensity of the inversion can reach 70% and 2 ℃， respectively， and the thickness of the inversion peaks mostly between 11:00 and 18:00.From the perspective of monthly variation， the temperature inversion characteristics of the sites all reach the maximum value in January to February and December， and the minimum value in June to August.The temperature inversion frequency of some sites in January can reach 90%， the temperature inversion intensity can reach more than 3 ℃， and the overall temperature inversion thickness is mostly concentrated between 200 and 400 m.When looking at annual variation， the majority of stations' temperature inversion characteristics show little change， and the annual variations in temperature inversion frequency， intensity， and thickness are about 10%， 0.4 ℃， and 60 m， respectively.While the temperature inversion features of the stations in East and South China do not clearly indicate an upward or downward trend， the stations in northeast China exhibit a general downward tendency.Ground radiative cooling， weather， and climate are the key factors that affect how temperature inversion features vary over time.Due to the effect of warm air brought by the circulation over the ocean， the coastal regions in northeast China， East China， and South China are more vulnerable to the creation of temperature inversions from the standpoint of geographical distribution.In comparison to Northwest China （23.4%）， Southwest China （13.4%）， and North China （21.84%）， the regional average temperature inversion frequency was greater in each of those three regions （44.5%， 48.7%， and 48.65%， respectively）.The temperature inversion intensity and thickness are the highest in northwest China， East China and coastal areas of South China.The temperature inversion intensity and temperature inversion thickness are above 1.5 ℃ and 300 m as a whole.The humid and cloudy environment in Southwest China is not conducive to the formation of temperature inversion layer， and the temperature inversion intensity and temperature inversion thickness are the smallest.For the subsequent analysis of the vertical buildup and diffusion of air pollutants in various locations of China， this work can serve as a scientific reference.

Abstract Background The present study was performed to assess the association between the neutrophil-to-apolipoprotein A1 ratio (NAR) and outcomes in patients with acute decompensated heart failure (ADHF) at different glucose metabolism states. Methods We recruited 1233 patients with ADHF who were admitted to Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University from December 2014 to October 2019. The endpoints were defined as composites of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke and exacerbation of chronic heart failure. The restricted cubic spline was used to determine the best cutoff of NAR, and patients were divided into low and high NAR groups. Kaplan-Meier plots and multivariable Cox proportional hazard models were used to investigate the association between NAR and the risk of adverse outcomes. Results During the five-year follow-up period, the composite outcome occurred in 692 participants (56.1%). After adjusting for potential confounding factors, a higher NAR was associated with a higher incidence of composite outcomes in the total cohort (Model 1: HR = 1.42, 95% CI = 1.22–1.65, P0.05). Conclusions The NAR has predictive value for adverse outcomes of ADHF with DM, which implies that the NAR could be a potential indicator for the management of ADHF.

Abstract Gastric cancer (GC) is a common malignant tumor worldwide, especially in East Asia, with high incidence and mortality rate. Epigenetic modifications have been reported to participate in the progression of gastric cancer, among which m6A is the most abundant and important chemical modification in RNAs. Fat mass and obesity-associated protein (FTO) is the first identified RNA demethylase but little is known about its role in gastric cancer. In our study, data from TCGA and clinical samples showed that FTO was highly expressed in gastric cancer tissues. Kaplan–Meier plotter suggested that patients with the high level of FTO had a poor prognosis. In vitro and in vivo experiments confirmed the role of FTO in promoting gastric cancer cell proliferation. Mechanistically, we found that FTO bound to circFAM192A at the specific site and removed the m6A modification in circFAM192A, protecting it from degradation. CircFAM192A subsequently interacted with the leucine transporter solute carrier family 7 member 5 (SLC7A5) and enhancing its stability. As a result, an increased amount of SLC7A5 was on the membrane, which facilitated leucine uptake and activated the mTOR signaling pathway. Therefore, our study demonstrated that FTO promoted gastric cancer proliferation through the circFAM192A/SLC7A5 axis in the m6A-dependent manner. Our study shed new light on the role of FTO in gastric cancer progression.

Abstract In the future, novel and highly pathogenic viruses may re-emerge, leading to a surge in healthcare demand. It is essential for urban epidemic control to investigate different cities’ spatiotemporal spread characteristics and medical carrying capacity during the early stages of COVID-19. This study employed textual analysis, mathematical statistics, and spatial analysis methods to examine the situation in six highly affected Chinese cities. The findings reveal that these cities experienced three phases during the initial outbreak of COVID-19: “unknown-origin incubation”, “Wuhan-related outbreak”, and “local exposure outbreak”. Cities with a high number of confirmed cases exhibited a multicore pattern, while those with fewer cases displayed a single-core pattern. The cores were distributed hierarchically in the central built-up areas of cities’ economic, political, or transportation centers. The radii of these cores shrank as the central built-up area’s level decreased, indicating a hierarchical decay and a core–edge structure. It suggests that decentralized built environments (non-clustered economies and populations) are less likely to facilitate large-scale epidemic clusters. Additionally, the deployment of designated hospitals in these cities was consistent with the spatial distribution of the epidemic; however, their carrying capacity requires urgent improvement. Ultimately, the essence of prevention and control is the governance of human activities and the efficient management of limited resources about individuals, places, and materials through leveraging IT and GIS technologies to address supply–demand contradictions.

Abstract Background We designed and synthesized a novel bisphosphonate radiopharmaceutical (68 Ga- or 177Lu-labeled DOTA-ibandronate [68 Ga/177Lu-DOTA-IBA]) for the targeted diagnosis and treatment of bone metastases. The biodistribution and internal dosimetry of a single therapeutic dose of 177Lu-DOTA-IBA were evaluated using a series of single-photon emission computerized tomography (SPECT) images and blood samples. Five patients with multiple bone metastases were included in this prospective study. After receiving 1110 MBq 177Lu-DOTA-IBA, patients underwent whole-body planar, SPECT/CT imaging and venous blood sampling over 7 days. Dosimetric evaluation was performed for the main organs and tumor lesions. Safety was assessed using blood biomarkers. Results 177Lu-DOTA-IBA showed fast uptake, high retention in bone lesions, and rapid clearance from the bloodstream in all patients. In this cohort, the average absorbed doses (ADs) in the bone tumor lesions, kidneys, liver, spleen, red marrow, bladder-wall, and osteogenic cells were 5.740, 0.114, 0.095, 0.121, 0.095, and 0.333 Gy/GBq, respectively. Although no patient reached the predetermined dose thresholds, the red marrow will be the dose-limiting organ. There were no adverse reactions recorded after the administration of 1110 MBq 177Lu-DOTA-IBA. Conclusion Dosimetric results show that the ADs for critical organs and total body are within the safety limit and with high bone retention. It is a promising radiopharmaceutical alternative for the targeted treatment of bone metastases, controlling its progression, and improving the survival and quality of life of patients with advanced bone metastasis.

Abstract This study aimed to investigate the effects of ammonia addition on ethylene counter-flow diffusion flames with different diluents on the fuel or oxidizer side, using kinetic analyses. A special emphasis was put on assessing the coupled chemical effects of NH3 and CO2 on C2H4 combustion chemistry. The chemical effects could be evaluated by comparing fictitious inert NH3 or CO2 with normal active NH3 or CO2. The results revealed that the addition of NH3 decreased the mole fractions and production rates of key soot precursors, such as acetylene, propynyl, and benzene. When CO2 was used as the dilution gas, the coupled chemical effects of NH3 and CO2 were affected by the chemical effects of CO2 to varying degrees. With the oxidizer-side CO2 addition, the coupled chemical effects of NH3 and CO2 reduced the mole fractions of H, O, OH radicals, acetylene, propynyl, and benzene, while the effects differed from the fuel-side CO2 addition. The coupled chemical effects of NH3 and CO2 also promoted the formation of aldehyde contaminants, such as acetaldehyde, to some extent, particularly with CO2 addition on the oxidizer side.

Abstract Background The increasing prevalence of gestational diabetes mellitus (GDM) is a major challenge, particularly in rural areas of China where control rates are suboptimal. This study aimed to evaluate the effectiveness of a GDM subsidy program in promoting GDM screening and management in these underserved regions. Methods This multicenter, randomized controlled trial (RCT) was conducted in obstetric clinics of six rural hospitals located in three provinces in China. Eligible participants were pregnant women in 24–28 weeks’ gestation, without overt diabetes, with a singleton pregnancy, access to a telephone, and provided informed consent. Participants were randomly assigned in a 1:1 ratio to either the intervention or control groups using an internet-based, computer-generated randomization system. The intervention group received subsidized care for GDM, which included screening, blood glucose retesting, and lifestyle management, with financial assistance provided to health care providers. In contrast, the control group received usual care. The primary outcomes of this study were the combined maternal and neonatal complications associated with GDM, as defined by the occurrence of at least one pre-defined complication in either the mother or newborn. The secondary outcomes included the GDM screening rate, rates of glucose retesting for pregnant women diagnosed with GDM, dietary patterns, physical activity levels, gestational weight gain, and antenatal visit frequency for exploratory purposes. Primary and secondary outcomes were obtained for all participants with and without GDM. Binary outcomes were analyzed by the generalized linear model with a link of logistic, and odds ratios (OR) with 95% confidence intervals (CIs) were reported. Count outcomes were analyzed by Poisson regression, and incidence rate ratios with 95% CIs were reported. Results A total of 3294 pregnant women were randomly assigned to either the intervention group (n = 1649) or the control group (n = 1645) between 15 September 2018 and 30 September 2019. The proportion of pregnant women in the intervention group who suffered from combined maternal and/or neonatal complications was lower than in the control group with adjusted OR = 0.86 (0.80 to 0.94, P = 0.001), and a more significant difference was observed in the GDM subgroup (adjusted OR = 0.66, 95% CI 0.47 to 0.95, P = 0.025). No predefined safety or adverse events of ketosis or ketoacidosis associated with GDM management were detected in this study. Both the intervention and control groups had high GDM screening rates (intervention: 97.2% [1602/1649]; control: 94.5% [1555/1645], P

Abstract Transparent immunodeficient animal models not only enhance in vivo imaging investigations of visceral organ development but also facilitate in vivo tracking of transplanted tumor cells. However, at present, transparent and immunodeficient animal models are confined to zebrafish, presenting substantial challenges for real-time, in vivo imaging studies addressing specific biological inquiries. Here, we employed a mitf −/−/prkdc −/−/il2rg −/− triple-knockout strategy to establish a colorless and immunodeficient amphibian model of Xenopus tropicalis. By disrupting the mitf gene, we observed the loss of melanophores, xanthophores, and granular glands in Xenopus tropicalis. Through the endogenous mitf promoter to drive BRAFV600E expression, we confirmed mitf expression in melanophores, xanthophores and granular glands. Moreover, the reconstruction of the disrupted site effectively reinstated melanophores, xanthophores, and granular glands, further highlighting the crucial role of mitf as a regulator in their development. By crossing mitf −/− frogs with prkdc −/−/il2rg −/− frogs, we generated a mitf −/−/prkdc −/−/il2rg −/− Xenopus tropicalis line, providing a colorless and immunodeficient amphibian model. Utilizing this model, we successfully observed intravital metastases of allotransplanted xanthophoromas and migrations of allotransplanted melanomas. Overall, colorless and immunodeficient Xenopus tropicalis holds great promise as a valuable platform for tumorous and developmental biology research.

Abstract Background Respiratory diseases are a major health burden, and educational inequalities may influence disease prevalence. We aim to evaluate the causal link between educational attainment and respiratory disease, and to determine the mediating influence of several known modifiable risk factors. Methods We conducted a two-step, two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS) and single nucleotide polymorphisms (SNPs) as instrumental variables for educational attainment and respiratory diseases. Additionally, we performed a multivariable MR analysis to estimate the direct causal effect of each exposure variable included in the analysis on the outcome, conditional on the other exposure variables included in the model. The mediating roles of body mass index (BMI), physical activity, and smoking were also assessed. Findings MR analyses provide evidence of genetically predicted educational attainment on the risk of FEV1 (β = 0.10, 95% CI 0.06, 0.14), FVC (β = 0.12, 95% CI 0.07, 0.16), FEV1/FVC (β = − 0.005, 95% CI − 0.05, 0.04), lung cancer (OR = 0.54, 95% CI 0.45, 0.65) and asthma (OR = 0.86, 95% CI 0.78, 0.94). Multivariable MR dicated the effect of educational attainment on FEV1 (β = 0.10, 95% CI 0.04, 0.16), FVC (β = 0.07, 95% CI 0.01, 0.12), FEV1/FVC (β = 0.07, 95% CI 0.01, 0.01), lung cancer (OR = 0.55, 95% CI 0.42, 0.71) and asthma (OR = 0.88, 95% CI 0.78, 0.99) persisted after adjusting BMI and cigarettes per day. Of the 23 potential risk factors, BMI, smoking may partially mediate the relationship between education and lung disease. Conclusion High levels of educational attainment have a potential causal protective effect on respiratory diseases. Reducing smoking and adiposity may be a target for the prevention of respiratory diseases attributable to low educational attainment.

Anode-free lithium metal batteries (AFLMBs) are expected to achieve high energy density without Li anode. However, their capacities are fading quickly due to the lack of excessive Li resources from the anode side (N/P=0). Previously, cathode pre-lithiation to supplement excess Li in NCM811 was proven feasible to extend the battery lifespan of AFLMB, but deep lithiation suffers from crystal structure damage, resulting in short cycle life. Here, we proposed a hybrid Li-rich cathode by pre-lithiation of spinel structure material LiMn2O4 instead of Li-rich NCM compositing with NCM811, providing a new way to extend the lifespan of AFLMBs. During the first charge process, Li2Mn2O4, as a pre-lithiation reagent, releases excess Li to form a lithium layer on the anode and revert to LiMn2O4, maintaining stable electrochemical reversibility in the following cycles. The anode-free lithium metal pouch cell employing a Li-rich hybrid cathode achieves a high energy density of nearly 400 Wh kg−1 with 80 % capacity retention after 50 cycles.

Abstract For the porous‐membrane‐based osmotic energy generator, the potential synergistic enhancement mechanism of various key parameters is still controversial, especially because optimizing the trade‐off between permeability and selectivity is still a challenge. Here, to construct a permeability and selectivity synergistically enhanced osmotic energy generator, the two‐dimensional porous membranes with tunable charge density are prepared by inserting sulfonated polyether sulfone into graphene oxide. Influences of charge density and pore size on the ion transport are explored, and the ionic behaviors in the channel are calculated by numerical simulations. The mechanism of ion transport in the process is studied in depth, and the fundamental principles of energy conversion are revealed. The results demonstrate that charge density and pore size should be matched to construct the optimal ion channel. This collaborative enhancement strategy of permeability and selectivity has significantly improved the output power in osmotic energy generation; compared to the pure graphene oxide membrane, the composite membrane presents almost 20 times improvement.

Summary: Memory B cells (MBCs) are essential for humoral immunological memory and can emerge during both the pre-germinal center (GC) and GC phases. However, the transcription regulators governing MBC development remain poorly understood. Here, we report that the transcription regulator Notch2 is highly expressed in MBCs and their precursors at the pre-GC stage and required for MBC development without influencing the fate of GC and plasma cells. Mechanistically, Notch2 signaling promotes the expression of complement receptor CD21 and augments B cell receptor (BCR) signaling. Reciprocally, BCR activation up-regulates Notch2 surface expression in activated B cells via a translation-dependent mechanism. Intriguingly, Notch2 is dispensable for GC-derived MBC formation. In summary, our findings establish Notch2 as a pivotal transcription regulator orchestrating MBC development through the reciprocal enforcement of BCR signaling during the pre-GC phase and suggest that the generation of GC-independent and -dependent MBCs is governed by distinct transcriptional mechanisms.

BackgroundNon-specific Orbital Inflammation (NSOI) is a chronic idiopathic condition marked by extensive polymorphic lymphoid infiltration in the orbital area. The integration of metabolic and immune pathways suggests potential therapeutic roles for C-peptide and G protein-coupled receptor 146 (GPR146) in diabetes and its sequelae. However, the specific mechanisms through which GPR146 modulates immune responses remain poorly understood. Furthermore, the utility of GPR146 as a diagnostic or prognostic marker for NSOI has not been conclusively demonstrated.MethodsWe adopted a comprehensive analytical strategy, merging differentially expressed genes (DEGs) from the Gene Expression Omnibus (GEO) datasets GSE58331 and GSE105149 with immune-related genes from the ImmPort database. Our methodology combined LASSO regression and support vector machine-recursive feature elimination (SVM-RFE) for feature selection, followed by Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) to explore gene sets co-expressed with GPR146, identifying a significant enrichment in immune-related pathways. The tumor microenvironment’s immune composition was quantified using the CIBERSORT algorithm and the ESTIMATE method, which confirmed a positive correlation between GPR146 expression and immune cell infiltration. Validation of GPR146 expression was performed using the GSE58331 dataset.ResultsAnalysis identified 113 DEGs associated with GPR146, with a significant subset showing distinct expression patterns. Using LASSO and SVM-RFE, we pinpointed 15 key hub genes. Functionally, these genes and GPR146 were predominantly linked to receptor ligand activity, immune receptor activity, and cytokine-mediated signaling. Specific immune cells, such as memory B cells, M2 macrophages, resting mast cells, monocytes, activated NK cells, plasma cells, and CD8+ T cells, were positively associated with GPR146 expression. In contrast, M0 macrophages, naive B cells, M1 macrophages, activated mast cells, activated memory CD4+ T cells, naive CD4+ T cells, and gamma delta T cells showed inverse correlations. Notably, our findings underscore the potential diagnostic relevance of GPR146 in distinguishing NSOI.ConclusionOur study elucidates the immunological signatures associated with GPR146 in the context of NSOI, highlighting its prognostic and diagnostic potential. These insights pave the way for GPR146 to be a novel biomarker for monitoring the progression of NSOI, providing a foundation for future therapeutic strategies targeting immune-metabolic pathways.

Preterm infants face a high risk of various complications, and their gut microbiota plays a pivotal role in health. Delivery modes have been reported to affect the development of gut microbiota in term infants, but its impact on preterm infants remains unclear. Here, we collected fecal samples from 30 preterm infants at five-time points within the first four weeks of life. Employing 16 S rRNA sequencing, principal coordinates analysis, the analysis of similarities, and the Wilcoxon rank-sum test, we examined the top dominant phyla and genera, the temporal changes in specific taxa abundance, and their relationship with delivery modes, such as Escherichia-Shigella and Enterococcus based on vaginal delivery and Pluralibacter related to cesarean section. Moreover, we identified particular bacteria, such as Taonella, Patulibacter, and others, whose proportions fluctuated among preterm infants born via different delivery modes at varying time points, as well as the microbiota types and functions. These results indicated the influence of delivery mode on the composition and function of the preterm infant gut microbiota. Importantly, these effects are time-dependent during the early stages of life. These insights shed light on the pivotal role of delivery mode in shaping the gut microbiota of preterm infants and have significant clinical implications for their care and management.

Abstract Post-COVID-19 syndrome may be associated with the abnormal immune status. Compared with the unexposed age-matched elder group, PD-1 in the CD8+ T cells from recovered COVID-19 patients was significantly lower. IFN-γ in the plasma of COVID-19 convalescent patients was increased, which inhibited PD-1 expression in CD8+ T cells from COVID-19 convalescent patients. scRNA-seq bioinformatics analysis revealed that AKT/GSK3β may regulate the INF-γ/PD-1 axis in CD8+ T cells from COVID-19 convalescent patients. In parallel, an IFN-γ neutralizing antibody reduced AKT and increased GSK3β in PBMCs. An AKT agonist (SC79) significantly decreased p-GSK3β. Moreover, AKT decreased PD-1 on CD8+ T cells, and GSK3β increased PD-1 on CD8+ T cells according to flow cytometry analysis. Collectively, we demonstrated that recovered COVID-19 patients may develop long COVID. Increased IFN-γ in the plasma of recovered Wuhan COVID-19 patients contributed to PD-1 downregulation on CD8+ T cells by regulating the AKT/GSK3β signaling pathway.

Objective To investigate the prevalence of Hepatitis E virus (HEV) among blood donors in Wuhan urban agglomeration, aimed at providing data support for the development of HEV screening strategies for blood donors. Methods A total of 3 329 blood samples were collected from four centralized testing areas (Ezhou, Tianmen, Xiantao and Qianjiang) and screened at Wuhan Blood Center from January to December 2021. Among them, 2 737 were eligible blood samples with normal ALT (ALT normal group) and 592 were with elevated ALT (ALT elevated group). Enzyme linked immunosorbent assay (ELISA) was used to detect anti-HEV IgG, anti-HEV IgM and HEV-Ag, and Real-time PCR was used to perform single HEV RNA detection on blood samples with elevated ALT and normal ALT anti-HEV IgM+ blood samples. A two-sided Pearson’s chi-squared test or Fisher's exact test was used to evaluate the differences in the positive rates of anti-HEV IgG and anti-HEV IgM in different regions and ALT groups. Results The overall positive rates of anti-HEV IgG, anti-HEV IgM, and HEV-Ag in 3 329 blood samples from four regions were 21.63%, 1.29%, and 0%, respectively. There was a significant difference in the positive rates of anti-HEV IgG among blood donors in different regions (P

Abstract Purpose More than 90% of patients with diabetes worldwide are type 2 diabetes (T2D), which is caused by insulin resistance or impaired producing insulin by pancreatic β cells. T2D and its complications, mainly large cardiovascular (LCV) and kidney (Ne) complications, are the major cause of death in diabetes patients. Recently, the dysregulation of peripheral T cell immune homeostasis was found in most T2D patients. However, the characteristics of T-cell receptors (TCR) remain largely unexplored in T2D patients. Patients and methods Here we investigated the TCR repertoire using high-throughput sequencing in peripheral blood collected from T2D patient with (8 LCV and 7 Ne) or without complications. Results Our analysis of TCR repertoires in peripheral blood samples showed that TCR profiles in T2D patients with complications tended to be single and specific compared to controls, according to the characteristics of TCR repertoire in V-J combination number, diversity, principal component analysis (PCA) and differential genes. And we identified some differentially expressed V-J gene segments and amino acid clonotypes, which had the potential to contribute to distinguishing T2D patient with or without complications. As the progression of the disease, we found that the profiling of TCR repertoire was also differential between T2D patients with LVD and Ne complications base on this pilot analysis. Conclusion This study demonstrated the protentional unique property of TCR repertoire in peripheral blood of T2D patient with and without complications, or T2D patients with LVD and Ne complications, which provided the possibility for future improvements in immune-related diagnosis and therapy for T2D complications.

Abstract Asthma represents a significant global challenge that affects individuals across all age groups and imposes substantial social and economic burden. Due to heterogeneity of the disease, not all patients obtain benefit with current treatments. The objective of this study was to explore the impact of MD2 on the progression of asthma using L6H21, a novel MD2 inhibitor, to identify potential targets and drug candidates for asthma treatment. To establish an asthma-related murine model and evaluate the effects of L6H21, ovalbumin (OVA) was used to sensitize and challenge mice. Pathological changes were examined with various staining techniques, such as H&E staining, glycogen staining, and Masson staining. Inflammatory cell infiltration and excessive cytokine secretion were evaluated by analyzing BALF cell count, RT-PCR, and ELISA. The TLR4/MD2 complex formation, as well as the activation of the MAPK and NF-кB pathways, was examined using western blot and co-IP. Treatment with L6H21 demonstrated alleviation of increased airway resistance, lung tissue injury, inflammatory cell infiltration and excessive cytokine secretion triggered by OVA. In addition, it also ameliorated mucus production and collagen deposition. In the L6H21 treatment group, inhibition of MAPK and NF-кB activation was observed, along with the disruption of TLR4/MD2 complex formation, in contrast to the model group. Thus, L6H21 effectively reduced the formation of the MD2 and TLR4 complex induced by OVA in a dose-dependent manner. This reduction resulted in the attenuation of MAPKs/NF-κB activation, enhanced suppression of inflammatory factor secretion, reduced excessive recruitment of inflammatory cells, and ultimately mitigated airway damage. MD2 emerges as a crucial target for asthma treatment, and L6H21, as an MD2 inhibitor, shows promise as a potential drug candidate for the treatment of asthma.

AbstractContext Da-Cheng-Qi Decoction (DCQD) has a significant effect on Severe Acute Pancreatitis-Associated Acute Lung Injury (SAP-ALI).Objective To explore the mechanism of DCQD in the treatment of SAP-ALI based on intestinal barrier function and intestinal lymphatic pathway.Materials and methods Forty-five Sprague-Dawley rats were divided into three groups: sham operation, model, and DCQD. The SAP model was induced by a retrograde infusion of 5.0% sodium taurocholate solution (1 mg/kg) at a constant rate of 12 mL/h using an infusion pump into the bile-pancreatic duct. Sham operation and model group were given 0.9% normal saline, while DCQD group was given DCQD (5.99 g/kg/d) by gavage 1 h before operation and 1, 11 and 23 h after operation. The levels of HMGB1, RAGE, TNF-α, IL-6, ICAM-1, d-LA, DAO in blood and MPO in lung were detected using ELISA. The expression of HMGB1, RAGE, NF-κB p65 in mesenteric lymph nodes and lung were determined.Results Compared with SAP group, DCQD significantly reduced the histopathological scoring of pancreatic tissue (SAP, 2.80 ± 0.42; DCQD, 2.58 ± 0.52), intestine (SAP, 3.30 ± 0.68; DCQD, 2.50 ± 0.80) and lung (SAP, 3.30 ± 0.68; DCQD, 2.42 ± 0.52). DCQD reduced serum HMGB1 level (SAP, 134.09 ± 19.79; DCQD, 88.05 ± 9.19), RAGE level (SAP, 5.05 ± 1.44; DCQD, 2.13 ± 0.54). WB and RT-PCR showed HMGB1-RAGE pathway was inhibited by DCQD (p

Arable land loss has become a critical issue in China because of rapid urbanization, industrial expansion, and unsustainable agricultural practices. While previous studies have explored the factors contributing to this loss, they often fall short in addressing the challenges of spatial heterogeneity and large-scale dataset analysis. This research introduces an innovative approach to geographically weighted regression (GWR) for assessing arable land loss in China, effectively addressing these challenges. Focusing on Chongqing, Guizhou, and Yunnan Provinces over the past two decades, it examines spatial autocorrelation with R-squared values exceeding 0.6 and residuals. Eight factors, including environmental elements (rain, evaporation, slope, digital elevation model) and human activities (distance to city, distance to roads, population, GDP), were analyzed. By visualizing and analyzing R² spatial patterns, the results reveal a clear spatial agglomeration distribution, primarily in urban areas with industries, highly urbanized cities, and flat terrains near rivers, influenced by GDP, population, rain, and slope. The novelty of this study is that it significantly enhances GWR computational capabilities for handling extensive datasets by utilizing Compute Unified Device Architecture (CUDA) on a high-performance GPU cloud server. Simultaneously, it conducts comprehensive analyses of the GWR model’s local results through visualization and spatial autocorrelation tools, enhancing the interpretability of the GWR model. Through spatial clustering analysis of local results, this study enables targeted exploration of factors influencing arable land changes in various temporal and spatial dimensions while also evaluating the reliability of the model results.

The southern catfish (Silurus meridionalis) is an economically important carnivorous freshwater fish in China. In this study, we compared the properties of skin collagen from southern catfish fed with raw food (RF) and cooked food (CF). The skin collagen yield in the RF group (8.66 ± 0.11%) was significantly higher than that of the CF group (8.00 ± 0.27%). SDS-PAGE, circular dichroism spectroscopy, and FTIR analyses revealed that the collagen extracted from southern catfish skin in both groups was type I collagen, with a unique triple helix structure and high purity. The thermal denaturation temperature of collagen in the RF group (35.20 ± 0.11 °C) was significantly higher than that of the CF group (34.51 ± 0.25 °C). The DPPH free radical scavenging rates were 68.30 ± 2.41% in the RF collagen and 61.78 ± 3.91% in the CF collagen, which was higher than that found in most fish collagen. Both the RF and CF groups had high ability to form fibrils in vitro. Under the same conditions, the CF group exhibited faster fibril formation and a thicker fibril diameter (p < 0.05). In addition, the RF group exhibited significantly higher expression of col1a1 compared to the CF group. These results indicated that feeding southern catfish raw food contributed to collagen production, and the collagen from these fish may have potential in biomaterial applications.

Accurate load prediction is a prerequisite for the design, operation, scheduling, and management of energy systems. In the context of the development of smart grids, the extensive integration of highly volatile distributed energy generation into the power system has brought new challenges to the accuracy, reliability, real-time performance, and intelligence of short-term load forecasting. Therefore, this article proposes a novel short-term power load composite prediction model based on AM–CNN–Bi–LSTM. First, CNN is used to extract relevant feature quantities of power load coupling characteristics. Then, AM is used to evaluate the importance of the feature data, highlighting the features that have a greater impact on the prediction results. Finally, the Bi-LSTM network captures bidirectional temporal information from multiple time steps for prediction. Taking one year of measured data as an example, the error comparison of the prediction results of the composite prediction model overlay shows that compared with other models, the composite prediction model has improved prediction accuracy, feature extraction, generalization ability, and other aspects. The research results improve the accuracy of short-term power load forecasting while providing effective model references for decision-making in power system optimization scheduling, safe operation, and reasonable pricing.

ABSTRACTHospital sewage serves as a crucial reservoir for antibiotic resistance genes. As colistin and carbapenems are the last-resort antibiotics, the emergence of their resistance genes has become a significant concern in clinical settings. In this study, we found that two novel mcr alleles (mcr-3.43 and mcr-7.2) with two carbapenemase genes (blaNDM-1 and blaKPC-2) were encoded in a single Aeromonas caviae strain isolated from hospital sewage. Our phylogenetic analysis revealed that the mcr-3.43 gene clustered with mcr-3.17 (with 95.55% amino acid identity), while the mcr-7.2 gene clustered with mcr-7.1 (with 68.68% amino acid identity). BLAST search against GenBank showed that mcr-7.2 was exclusively detected in Aeromonas spp. Mobile genetic elements were not found in the genetic context of mcr-7.2, suggesting that the dissemination of mcr-7.2 in Aeromonas spp. may be dependent on vertical transfer or recombination. The blaNDM-1 was adjacent to a recombinase gene and flanked by two IS91 elements, indicating a potential mobilization mechanism mediated by recombination and/or ISs. The blaKPC-2 gene was located on an IncU plasmid and adjacent to an ISKpn6. In summary, our study provides evidence for Aeromonas spp. as one of the potential reservoirs of colistin and carbapenem resistance genes.IMPORTANCEThe study discovered two novel mcr genes (mcr-3.43 and mcr-7.2) and two carbapenemase genes (blaNDM-1 and blaKPC-2) in a single Aeromonas caviae strain retrieved from hospital sewage. Using phylogenetic analysis and comparative data evaluation, the study revealed the genetic relatedness and dissemination potential of the detected resistance genes. With the exclusive discovery that mcr-7.2 is only present in Aeromonas spp. and the lack of mobile genetic elements in its genetic context, there is a strong indication of limited dissemination. The identification of these four resistance genes in a single strain of Aeromonas provided valuable insights into their potential presence in this genus. This study revealed that hospital sewage functions as a significant reservoir for antibiotic resistance genes, including colistin and carbapenem resistance genes.

Under the guidance of the 'dual carbon' goals and 'rural revitalization' strategy, the development of microgrids primarily based on wind, solar, and biogas energy is rapidly advancing in rural areas. A critical and challenging area of current research is how to optimally configure the capacity of these microgrids of varying sizes, taking into account the availability of resources in the system's environment and specific climatic conditions, to maximize economic benefits. Based on this, the article constructs a model of a hybrid AC/DC microgrid system powered by wind, solar, and biogas energy. It undertakes multi-objective optimization to achieve the highest utilization of renewable energy, the most economical cost, and the minimum carbon emissions while ensuring the reliability of the system's power supply. The study explores the economically and technically optimal configuration of this microgrid energy system under certain climatic conditions. The results indicate that the optimal configuration for a rural microgrid powered by wind, solar, and biogas energy should include a 2.6 kW biogas generator, 30.00 kW solar panels, 5.24 kW wind turbines, a 2.6 kW battery storage system, and a 10.00 kW bidirectional inverter. This configuration results in the lowest total net cost of the system, achieving optimal outcomes in terms of total net cost, cost per kilowatt-hour, and supply reliability.