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Abstract Objectives The aim of this study was to identify the synergistic effect and mechanisms of fosfomycin (FM) combined with colistin (COL) against KPC-producing Klebsiella pneumoniae (KPC-Kp). Methods The bactericidal effects, induced drug resistance and cytotoxicity of FM combined with COL were evaluated by time-kill assays and mutation rate test. Time-kill assays and transcriptomics analysis were used to further clarify the mechanism of FM combined with COL. The bacteria were taken from different points in time-kill assays, reactive oxygen species (ROS), nitric oxide and redox related enzymes were detected. The mechanism of synergistic bactericidal action was analyzed by transcriptome. Results The bactericidal effect of FM combined with COL was better than that of monotherapy. The mutation frequency of FM alone at low dose (8 mg/L) was higher than that at high dose (64 mg/L). COL induced resistant isolates resulted in FM and COL resistance, while FM alone or combined with COL only resulted in FM resistance. The survival rate of Thp-1 cells in FM combined with COL against K. pneumoniae was higher than that of monotherapy. The intracellular nitric oxide, activities of total superoxide dismutase and catalase were increased along with the increase of FM concentration against KPC-Kp. FM combined with COL induced ROS accumulation and antioxidant capacity increase. Transcriptome analysis showed FM combined with COL could regulate the levels of soxRS and oxidative phosphorylation, in order to clear ROS and repair damage. In addition, FM combined with COL could result in synergetic bactericidal efficacy by inhibiting ribosomal transcription. Conclusions FM combined with COL mediated synergistic bactericidal effect by regulating ROS accumulation and inhibiting ribosomal protein transcription, resulting in lower resistance and cytotoxicity.

Abstract The prevention and control of human immunodeficiency virus and sexually transmitted infections (HIV/STI) face challenges worldwide, especially in China. Prediction tools, which analyze medical data and information to make future predictions, were once mainly used in HIV/STI research to help make diagnostic or prognostic decisions, has have now extended to the public as a freely accessible tool. This article provides an overview of the different roles of prediction tools in preventing and controlling HIV/STI from the perspectives of individuals, healthcare providers, and policymakers. For individuals, prediction tools serve as a risk assessment solution that assess their risk and consciously improve risk reception or change risky behaviors. For researchers, prediction tools are powerful for assisting in identifying risk factors and predicting patients’ infection risk, which can inform timely and accurate intervention planning in the future. In order to achieve the best performance, current research increasingly underscores the necessity of considering multiple levels of information, such as socio-behavioral data, in developing a robust prediction tool. In addition, it is also crucial to conduct trials in clinical settings to validate the effectiveness of prediction tools. Many studies only use theoretical parameters such as model accuracy to estimate its predictive. If these improvements are made, the application of prediction tools could be a potentially inspiring solution in the prevention and control of HIV/STI, and an opportunity for achieving the World Health Organization’s agenda to end the HIV/STI epidemic by 2030.

The adverse effects of traditional pharmaceutical immunosuppressive regimens have been a major obstacle to successful allograft survival in vascularized composite tissue allotransplantation (VCA) cases. Consequently, there is a pressing need to explore alternative approaches to reduce reliance on conventional immunotherapy. Cell therapy, encompassing immune-cell-based and stem-cell-based regimens, has emerged as a promising avenue of research. Immune cells can be categorized into two main systems: innate immunity and adaptive immunity. Innate immunity comprises tolerogenic dendritic cells, regulatory macrophages, and invariant natural killer T cells, while adaptive immunity includes T regulatory cells and B regulatory cells. Investigations are currently underway to assess the potential of these immune cell populations in inducing immune tolerance. Furthermore, mixed chimerism therapy, involving the transplantation of hematopoietic stem and progenitor cells and mesenchymal stem cells (MSC), shows promise in promoting allograft tolerance. Additionally, extracellular vesicles (EVs) derived from MSCs offer a novel avenue for extending allograft survival. This review provides a comprehensive summary of cutting-edge research on immune cell therapies, mixed chimerism therapies, and MSCs-derived EVs in the context of VCAs. Findings from preclinical and clinical studies demonstrate the tremendous potential of these alternative therapies in optimizing allograft survival in VCAs.

Abstract Background The selection of suitable culture medium is critical for achieving good clinical outcomes in cell therapy. To support the commercial application of stem cell therapy, customized culture media not only need to promote stem cell proliferation, but also need to save costs and meet industrial requirements for inter-batch consistency, efficacy, and biosafety. In this study, we developed a series of serum-free media (SFM) and elucidated the effects between different SFM, as well as between SFM and serum-containing meida (SCM), on human umbilical cord mesenchymal stem cells (hUC-MSCs) phenotype and function. We analyze and emphasize from the perspectives of clinical and commercial application why research on customized culture media is critical for the success of enterprises developing novel cellular therapeutics. Methods We cultured hUC-MSCs with identical cell seeding densities in different formulations of SFM and SCM until passage 10 and examined the changes in cell phenotype and function. We analyzed the results with the commercial application requirments of the cellular therapy industry to assess the potential impact of customized culture media on inter-batch consistency, efficacy, stability, biosafety, and cost-effectiveness of industrial-scale cell production. Results hUC-MSCs cultured in SCM and SFM exhibit consistent cell morphology and surface molecule expression, but hUC-MSCs cultured in SFM demonstrate higher activity, superior proliferative capacity, and greater stability. Furthermore, hUC-MSCs cultured in different SFM exhibit differences in cell activity, proliferative capacity, senescent rate, and S/M ratio of cell cycle, while maintaining a normal karyotype after long-term in vitro cultivation. Moreover, we found that hUC-MSCs cultured in different media exhibit variations in paracrine capacity and in their support of hematopoietic stem cell (HSC) self-renewal. Conclusion Considering the substantial funding and time required for cell-based drug development, our results underscore the importances of comprehensively optimizing the composition of medium for the specific disease prior to conducting clinical trials of cell-based therapies. The criteria for selecting culture medium should be based on the requirements of the target disease for cellular function. In addition, we provide a way to formulate different customized SFM, which is beneficial for the development of cell therapy industry.

Abstract Addressing the significant discrepancy between actual experimental cutting force and its predicted values derived from traditional constitutive model parameter identification methods, a reverse identification research of the Johnson–Cook (J-C) constitutive model for 304 stainless steel was conducted via genetic algorithm. Considering actual cutting zone and the influence of feed motion on the rake (flank) angle, an unequal division shear zone model was established to implement the theoretical calculation for shear zone stress. Through cutting experiments, the spindle speed was negatively correlated with the cutting force at first, and then became positively correlated; The empirical formula (EXP model) for turning force was corrected, revealing that the EXP model was unable to provide optimal predicted values for cutting force. The influence of the J-C constitutive parameter C on the cutting morphology was firstly investigated through simulation analysis, and determined an appropriate value for C, then obtained the precise values for the other four constitutive parameters by genetic algorithm. Moreover, the simulated values of cutting force in JC1 model (obtained from the Split Hopkinson Pressure Bar test) and JCM model (the improved model using genetic algorithm) were obtained by three-dimensional (3-D) simulation via FEM software. The results indicated that, the maximum error between actual experimental cutting force and its simulated values (by JCM model) was 14.8%, with an average error of 6.38%. These results outperformed the JC1 and EXP models, suggesting that the JCM model identified via genetic algorithm was more reliable.

Abstract Face reshaping aims to adjust the shape of a face in a portrait image to make the face aesthetically beautiful, which has many potential applications. Existing methods 1) operate on the pre-defined facial landmarks, leading to artifacts and distortions due to the limited number of landmarks, 2) synthesize new faces based on segmentation masks or sketches, causing generated faces to look dissatisfied due to the losses of skin details and difficulties in dealing with hair and background blurring, and 3) project the positions of the deformed feature points from the 3D face model to the 2D image, making the results unrealistic because of the misalignment between feature points. In this paper, we propose a novel method named face shape transfer (FST) via semantic warping, which can transfer both the overall face and individual components (e.g., eyes, nose, and mouth) of a reference image to the source image. To achieve controllability at the component level, we introduce five encoding networks, which are designed to learn feature embedding specific to different face components. To effectively exploit the features obtained from semantic parsing maps at different scales, we employ a straightforward method of directly connecting all layers within the global dense network. This direct connection facilitates maximum information flow between layers, efficiently utilizing diverse scale semantic parsing information. To avoid deformation artifacts, we introduce a spatial transformer network, allowing the network to handle different types of semantic warping effectively. To facilitate extensive evaluation, we construct a large-scale high-resolution face dataset, which contains 14,000 images with a resolution of 1024 × 1024. Superior performance of our method is demonstrated by qualitative and quantitative experiments on the benchmark dataset.

In this study, three types of three-layer functionally graded materials (FGMs) were designed by mainting the average content of the reinforcement constant and changing the span of the composition. The B4C particle-reinforced Al-matrix FGMs and a homogeneous composite (HC) with the same average composition were prepared using the laser additive manufacturing technique. The FGMs had a higher average secondary-phase content and grain size than the HC. Large (black) and reticulated (white) secondary phases corresponding to B4C phase, T phase, and MgZn2 were observed in the as-deposited FGM samples. The content of the secondary phase in the middle layer was generally low. The bottom layer, which was in direct contact with the substrate, exhibited the smallest grain size. The hardness and wear resistance significantly improved owing to the high B4C content in the top layer. The flexural behaviors of each layer of the FGM in different directions were systematically studied. The plasticity of the single-layer material decreased with increase in the B4C content. When the bottom layer had a high B4C content, the flexural ability significantly reduced. Among all the samples, G2 with 8% B4C particle content in the top layer exhibited the best comprehensive mechanical properties. The hardness value, wear rate of the top layer, maximum bending stress, and maximum bending strain of the FGM were 177.5 HV, 0.367 × 10−3mm3/(N·m), 585.6 MPa, and 7.36%, respectively. This study can provide a reference value for the future design and development of wear-resistant gradient materials for aerospace applications.

Abstract Background Hemoptysis resulting from rupture of the pulmonary artery pseudoaneurysm (PAP) is massive and fatal, while factor contributing to the rupture of pseudoaneurysm remains elusive. This study aimed to elucidate the clinical and radiological features of PAP and identify the risk factors associated with rupture. Methods Patients who developed hemoptysis with PAP were collected from January 2019 to December 2022 retrospectively. Clinical data of the demographic characteristics, radiological findings, treatment strategies, and prognosis were collected. A comparative analysis was performed on the characteristics in the ruptured and non-ruptured cases. Results A total of 58 PAPs were identified in the 50 patients. The most common causes were infection (86%) and cancer (8%). The PAPs were located predominantly in the upper lobes of both lungs, and 57 (99.3%) were distributed in the segmental or subsegmental pulmonary arteries. The median diameter was 6.1(4.3–8.7) mm. A total of 29 PAPs were identified adjacent to pulmonary cavitations, with the median diameter of the cavity being 18.9 (12.4–34.8) mm. Rupture of pseudoaneurysm occurred in 21 cases (42%). Compared to unruptured group, the ruptured group had a significantly higher proportion of massive hemoptysis (57.1% vs. 6.9%, p

Abstract Objectives The aim of this work was to assess dynamic cytokine profiles associated with bloodstream infection (BSI) caused by Klebsiella pneumoniae (Kpn) and investigate the clinical features associated with mortality. Methods A total of 114 patients with positive BSI-Kpn and 12 sepsis individuals without blood positive bacteria culture were followed up. Cytokine profiles were analyzed by multiplex immunoassay on the first, third, seventh and fourteenth day after diagnosis. The test cytokines included arginase, interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-12 (p70), and IL-23. The minimum inhibitory concentration (MIC) of 24 antibiotics were tested for BSI-Kpn. Risk factors associated with the 30-day mortality and 120-day mortality were evaluated using logistic analyses and nomogram. Results There were 55 out of 114 patients with BSI-Kpn were included. All isolates showed high susceptibility rate to novel avibactam combinations. The level of arginase was the highest in carbapenem-resistant Kpn (CRKP) patients. The AUCs of arginase, TNF-α and IL-4 reached 0.726, 0.495, and 0.549, respectively, whereas the AUC for the combination of these three cytokines was 0.805. Notably, 120-day mortality in patients with CRKP was higher than carbapenem-sensitive K. pneumoniae (CSKP). Furthermore, the long-term and high levels of IL-6 and IL-10 were associated with death. Conclusions High expression of arginase is correlated with CRKP. In addition, BSI-CRKP could result in indolent clinic course but poor long-term prognosis. Continuous increase of IL-6 and IL-10 were associated with mortality.

Abstract Functionalized mesoporous materials have become a promising carrier for enzyme immobilization. In this study, Santa Barbara Amorphous 15 (SBA-15) was modified by N-aminoethyl-γ-aminopropyl trimethoxy (R). R-SBA-15 was employed to purify and immobilize recombinant β-glucosidase from Terrabacter ginsenosidimutans (BgpA) in one step for the first time. Optimum pH of the constructed R-SBA-15@BgpA were 7.0, and it has 20 ℃ higher optimal temperature than free enzyme. Relative activity of R-SBA-15@BgpA still retained > 70% at 42 ℃ after 8-h incubation. The investigation on organic reagent resistance revealed that the immobilized enzyme can maintain strong stability in 15% DMSO. In leaching test and evaluation of storage stability, only trace amount of protein was detected in buffer of the immobilized enzyme after storage at 4 ℃ for 33 days, and the immobilized BgpA still maintained > 50% relative activity. It also demonstrated good reusability, with 76.1% relative activity remaining after fourteen successive enzymatic hydrolyses of epimedin A to sagittatoside A. The newly proposed strategy is an effective approach for the purification and immobilization of BgpA concurrently. In addition, R-SBA-15@BgpA was demonstrated to have high efficiency and stability in this application, suggesting its great feasibility and potential to produce bioactive compounds such as secondary glycosides or aglycones from natural products. Graphical Abstract

This study examines the physiological and immunological effects of 0.5 ppm carbaryl exposure on juvenile Asian seabass (Lates calcarifer) over 12 h to 72 h. Notable results include decreased activities of liver enzymes catalase (CAT), lactate dehydrogenase (LDH), and glutathione peroxidase (GSH-PX), while superoxide dismutase (SOD) levels remained stable, with the lowest activities of CAT and GSH-PX observed at 72 h. Serum biochemistry revealed increased alkaline phosphatase (AKP) and acid phosphatase (ACP) at 24 h, with declining aspartate aminotransferase (AST) and a peak in creatinine at 48 h. Histopathological analysis showed carbaryl-induced necrosis in liver and spleen cells, and increased melanomacrophage centers in both organs. Additionally, immune gene expression analysis indicated an upregulation of heat shock proteins and consistent elevation of complement component C3 and interleukin-8 (IL-8). These findings suggest that carbaryl exposure significantly impairs organ function and modulates immune responses in L. calcarifer, underlining the need for further research on protective strategies against pesticide impacts in aquaculture.

Enhancing the thermal shock resistance of Y2O3 ceramic crucibles, coupled with advancements in melting and casting technologies to reduce the adverse influence of interfacial reactions, is essential for producing low-energy consumption, high-quality titanium-aluminum (TiAl) alloys. In this study, the Y2O3 ceramic crucible with good thermal shock resistance was developed through the optimization of particle size distribution and sintering holding time. The interaction mechanisms between Y2O3 ceramics and TiAl alloys under extreme conditions were investigated, and strategies for enhancing the mechanical properties of TiAl alloys through the integration of Y2O3 crucibles with centrifugal casting were discussed. The results indicated that introducing large particles of 1–3 mm under sintering conditions of 2023 K and 6 h effectively enhances the thermal shock resistance of Y2O3 crucible. The interaction between Y2O3 and TiAl alloys primarily involved physical erosion (spalling/dispersion), dissolution of separated particles, and surface modification of interface layer particles (reaction). Physical erosion played an important role in this dynamic interaction, with the extent of erosion intensifying through continuous use of the crucible, while electromagnetic forces ensured the uniform distribution of inclusions within the TiAl alloy matrix. Moreover, the application of centrifugal casting technology substantially refines the grain size and reduces the inclusion count, thereby significantly enhancing the mechanical properties of TiAl alloy.

Abstract Previous studies that focused on univariate correlations between neuroanatomy and cognition in schizophrenia identified some inconsistent findings. Moreover, antipsychotic medication may impact the brain-behavior profiles in affected individuals. It remains unclear whether unmedicated and medicated individuals with schizophrenia would share common neuroanatomy-cognition associations. Therefore, we aimed to investigate multivariate neuroanatomy-cognition relationships in both groups. A sample of 59 drug-naïve individuals with first-episode schizophrenia (FES) and a sample of 115 antipsychotic-treated individuals with schizophrenia were finally included. Multivariate modeling was conducted in the two patient samples between multiple cognitive domains and neuroanatomic features, such as cortical thickness (CT), cortical surface area (CSA), and subcortical volume (SV). We observed distinct multivariate correlational patterns between the two samples of individuals with schizophrenia. In the FES sample, better performance in token motor, symbol coding, and verbal fluency tests was associated with greater thalamic volumes but lower CT in the prefrontal and anterior cingulate cortices. Two significant multivariate correlations were identified in antipsychotic-treated individuals: 1) worse verbal memory performance was related to smaller volumes for the most subcortical structures and smaller CSA mainly in the temporal regions and inferior parietal lobule; 2) a lower symbol coding test score was correlated with smaller CSA in the right parahippocampal gyrus but greater volume in the right caudate. These multivariate patterns were sample-specific and not confounded by imaging quality, illness duration, antipsychotic dose, or psychopathological symptoms. Our findings may help to understand the neurobiological basis of cognitive impairments and the development of cognition-targeted interventions.

Abstract Artificial wrinkles, especially those with responsive erasure/regeneration behaviors have gained extensive interest due to their potential in smart applications. However, current wrinkle modulation methods primarily rely on network rearrangement, causing bottlenecks in in situ wrinkle regeneration. Herein, we report a dually cross-linked network wherein [2]rotaxane cross-link can dissipate stress within the wrinkles through its sliding motion without disrupting the network, and quadruple H-bonding cross-link comparatively highlight the advantages of [2]rotaxane modulation. Acid stimulation dissociates quadruple H-bonding and destructs network, swiftly eliminating the wrinkles. However, the regeneration process necessitates network rearrangement, making in situ recovery unfeasible. By contrast, alkaline stimulation disrupts host–guest recognition, and subsequent intramolecular motion of [2]rotaxane dissipate energy to eliminate wrinkles gradually. The always intact network allows for the in situ recovery of surface microstructures. The responsive behaviors of quadruple H-bonding and mechanical bond are orthogonal, and their combination leads to wrinkles with multiple but accurate responsiveness.

Abstract Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.

Abstract Objectives The aim of this study was to evaluate the characteristics of immunocyte associated with bloodstream infection (BSI) caused by Klebsiella pneumoniae (Kpn). Methods Patients with BSI-Kpn were included from 2015 to 2022 in our hospital. Immunocyte subpopulations of enrolled BSI-Kpn patients were tested on the same day of blood culture using multicolor flow cytometry analysis. Antibiotic susceptibility test was determined by agar dilution or broth dilution method. All included isolates were subjected to whole genome sequencing and comparative genomics analysis. Clinical and genetic data were integrated to investigate the risk factors associated with clinical outcome. Results There were 173 patients with non-duplicate BSI-Kpn, including 81 carbapenem-resistant Kpn (CRKP), 30 extended-spectrum β-lactamases producing Kpn (ESBL-Kpn), 62 none CRKP or ESBL-Kpn (S-Kpn). Among 68 ST11-CRKP isolates, ST11-O2v1:KL64 was the most common serotypes cluster (77.9%, 53/68), followed by ST11-OL101: KL47 (13.2%, 9/68). Compared with CSKP group, subpopulations of immunocyte in patients with CRKP were significantly lower (P

Precisely controlling gene expression is beneficial for optimizing biosynthetic pathways for improving the production. However, promoters in nonconventional yeasts such as Ogataea polymorpha are always limited, which results in incompatible gene modulation. Here, we expanded the promoter library in O. polymorpha based on transcriptional data, among which 13 constitutive promoters had the strengths ranging from 0–55% of PGAP, the commonly used strong constitutive promoter, and 2 were growth phase-dependent promoters. Subsequently, 2 hybrid growth phase-dependent promoters were constructed and characterized, which had 2-fold higher activities. Finally, promoter engineering was applied to precisely regulate cellular metabolism for efficient production of β-elemene. The glyceraldehyde-3-phosphate dehydrogenase gene GAP was downregulated to drive more flux into pentose phosphate pathway (PPP) and then to enhance the supply of acetyl-CoA by using phosphoketolase-phosphotransacetylase (PK-PTA) pathway. Coupled with the phase-dependent expression of synthase module (ERG20∼LsLTC2 fusion), the highest titer of 5.24 g/L with a yield of 0.037 g/(g glucose) was achieved in strain YY150U under fed-batch fermentation in shake flasks. This work characterized and engineered a series of promoters, that can be used to fine-tune genes for constructing efficient yeast cell factories.

ABSTRACT Background For early detection and postoperative monitoring of upper tract urothelial carcinoma (UTUC), the traditional detection method was limited to its invasiveness and insufficient sensitivity. We aim to use urine tumour DNA (utDNA) for detecting minimal residual disease (MRD), early diagnosis and perioperative monitoring in UTUC. Method We previously established a utDNA multidimensional bioinformatic valuation model, named utLIFE, using low‐coverage whole‐genome sequencing and targeted deep sequencing. This prospective cohort enrolled 93 patients diagnosed with UTUC without metastasis. We collected morning urine samples on the day of surgery and the discharge day after the operation for utLIFE testing. In addition, we also enrolled 80 healthy controls to further validate the specificity of the utLIFE model in the study. Results The utLIFE of preoperative samples could discriminate UTUC with high specificity (96.25%, 77/80), and high sensitivity (96.77%, 90/93) regardless of stage and grade. The sensitivity of utLIFE was significantly higher than urine cytology (p

The working temperature is one of the key factors affecting the efficiency and safety performance of automotive power batteries. Current battery pack design primarily focuses on single layout configurations, overlooking the potential impact of mixed arrangements on thermal management performance. This study presents a module-based optimization methodology for comprehensive concept design of Lithium-ion (Li-ion) battery pack. Firstly, the arrangement modules is optimized and performed using particle swarm optimization algorithms considering various arrangement layout (i.e. rectangular, diamond, and staggered arrangements) by taking the intercell spacing and maximum temperature of the modules as design objectives. Secondly, the battery pack configuration design is performed employing a neural network model reflect diverse battery module configurations within the pack, exploring their impact on thermal management performance. The hybrid battery arrangement effectively improves thermal management, and the module spacing helps to enhance heat dissipation. The staggered arrangement has a greater impact on the heat dissipation performance of the battery pack, but the spacing between different modules varies with the position of the modules. When all configuration schemes are staggered modules, the optimal range of the spacing between modules is between 6 and 7 mm. However, the study observes a non-linear relationship between module spacing and the maximum temperature difference within the battery pack. While increasing module spacing initially decreases temperature differences, it eventually reverses, suggesting that spacing alone may not consistently enhance thermal management. Validation with a lithium-ion battery pack case study demonstrates the method’s effectiveness, providing valuable knowledge for future cell and pack designs that employ different battery cell arrangements and diverse cooling strategies.

Promoting the high-quality development of urbanization is a crucial way to achieve sustainable development goals. Water resources are a rigid constraint for such development. However, There is still room for improvement in the research on the spatio-temporal pattern and key driving factors of high-quality urbanization development under the constraint of water resources. Aiming at the problem that the high-quality development of urbanization in the Yellow River Basin (YRB) is facing water resources constraints, this paper discussed the spatial–temporal pattern and key drivers of the high-quality development of urbanization in the YRB under water resource constraints by using the Analytic Hierarchy Process model reformed by entropy technology, multi-objective fuzzy membership function, spatial autocorrelation analysis and obstacle model. The results revealed that, first, we found the High-Quality Urbanization Development Index (UQDI) exhibited steady growth, while both the Water Resources Index (WRI) and the Water Resources Constraint Intensity (WRCI) initially increased and then decreased during the study period. Second, the UQDI displayed a dual-core pattern, with the Shandong Peninsula urban agglomeration and the Central Plains urban agglomeration serving as the cores. WRI exhibited relatively stable spatial distribution, with the southeast region outperforming the northwest. WRCI also demonstrated a relatively stable spatial distribution, resulting in two weak-constraint areas, represented by Shandong and Henan, and a strong-constraint area centered around Ningxia. Third, the UQDI, WRI, and WRCI exhibited spatial interdependence. The spatial interdependence of UQDI and WRI increased, while that of WRCI decreased during the study period. The three indexes also displayed a clear pattern of local clustering in space. Two low-value aggregation areas, namely Shandong and Henan, and a high-value aggregation area located in Ningxia, emerged during the study period. Last, the WRCI was primarily influenced by the fundamental conditions of water resources. The main influencing factors included per capita water resources, mean annual precipitation, total water resources, water resources modulus, and the total amount of foreign investment utilization. In light of the research findings, the paper proposes policy recommendations for promoting high-quality urbanization development in the YRB. This study provides decision-making guidance for countries and regions in arid areas to solve the water resources constraints on the high-quality development of urbanization.

Purpose:. According to the National Comprehensive Cancer Network guidelines, segmental ureterectomy (SU) of upper tract urothelial carcinoma (UTUC) is a considerable option for selected mid- and distal ureteral urothelial carcinoma (UC). As a UTUC endemic area, Taiwan lacks treatment outcome analysis of SU. Materials and methods:. This study retrospectively reviewed the treatment outcomes of SU for clinically localized UTUCs. Patients with biopsy or washing cytology-confirmed UTUCs who underwent open, laparoscopic, or robot-assisted management with curative intent were retrospectively reviewed for the eligibility of analysis. Cox regression was applied for univariable and multivariable analyses. Results:. A total of 161 patients who underwent SU were reviewed and analyzed. The median follow-up period was 44.5 (interquartile range, 21.6–84.9) months. After SU, 56/161 (34.8%) patients were free of UTUCs after the follow-up, 25/161 (15.5%) patients had local recurrence, and 35/161 (21.7%) had lymph node or distant metastasis. Surgical margin involvement was a risk factor associated with worse cancer-specific survival. Higher bladder recurrence and local recurrence rates were observed with concurrent bladder UC. Lymphovascular invasion and previous radical nephroureterectomy (RNU) for UC were related to higher local recurrence rates. Patients with pathological T3/T4 stage and end-stage renal disease tended to have higher metastasis rates. For the management of local recurrence, 19 patients received salvage RNU and 25 patients had adjuvant chemotherapy. However, 26/161 (16.1%) patients died of UTUCs and 2/161 (1.2%) patients died of surgery-related complications. Conclusion:. SU provides acceptable oncological outcomes if the surgeons select candidates carefully. SU is not recommended if the patient has T3 or higher stage or comorbidity of end-stage renal disease. Concurrent bladder UC is a risk factor for worse bladder recurrence-free survival and local recurrence-free survival. Lymphovascular invasion and previous RNU for UC were related to higher local recurrence rates. After SU, periodic follow-up is mandatory because the local recurrence rate is higher than radical surgery.

The proven geological reserves of the Shenfu deep coalbed methane (CBM) field on the eastern margin of the Ordos Basin exceed 100 billion cubic meters. It is of great significance to realizing the efficient development of deep CBM in this region to ensure the national energy supply. However, the complexity of the geological environment which includes high stress, medium-high temperatures, low permeability, strong heterogeneity, and wide developed cleats and natural fractures, makes it challenging for the existed shallow and medium CBM fracturing techniques to be fully applicable to deep CBM resources. As a result, the stimulation scale and parameters for deep coalbed fracturing are still in the trial-and-error stage. In order to explore the stimulation techniques which are compatible with the geological conditions of deep coalbeds, the Shenfu block in the Ordos Basin was taken as the geological background and the large-scale hydraulic fracturing of deep coal seams was conducted as an engineering practice. The authors designed the idea of “Push the limit to the beyond + balanced propagation + effective support”, and proposed the massive hydraulic fracturing techniques based on “multi-stage multi-clusters with moderate-dense cutting + perforation with equal apertures, deep penetration and limited flow + integrated variable viscosity (rock breaking by higher viscous slick water + complex fracture network generating by lower viscous slick water) + high pumping rate with high proppant concentration + pre-acid treatment to reduce the breakdown pressure + graded proppants with multiple sizes to support fractures”. Then, the authors put forward an integrated “Geology-Engineering-AI” workflow to perform post-frac analysis, through double matching and correcting the fracturing pumping pressure and production rate automatically, accurately characterized the stimulated reservoir volume (SRV) and drained rock volume (DRV), and predicted the estimated ultimate recovery (EUR) under different fracturing scales and well types. Finally, by statistically analyzing the gas production characteristics of multiple wells in the Shenfu block and utilizing the random forest method, the primary controlling factors affecting the production capacity of deep CBM were quantitatively analyzed. The results demonstrate that after reservoir stimulation, directional wells can achieve a maximum daily gas production rate exceeding 10 000 m3/d, while horizontal wells can achieve a maximum daily gas production rate exceeding 20 000 m3/d. It indicates that the deep coal beds have good fracturing properties and great development potential. The primary impact factors for peak gas production rate are gas content, coalbed thickness and proppant concentration, while the major impact factors for cumulative gas production include gas content, proppant concentration, and total volume of proppants.

A novel Zr–Ti conversion coating (ZrTiCC) was fabricated on 6016 aluminum alloy. The coating thickness was evaluated, and the corrosion resistance of the coating was investigated through CuSO4 drop experiments to determine the optimum process. Potentiodynamic polarization results revealed the corrosion current density of ZrTiCC (4.821 μA/cm2) was lower than that of bare specimen (12.263 μA/cm2), and the δE of ZrTiCC (0.752V) was significantly lower than bare specimen (0.087 V). Scanning electron microscope and energy dispersive spectrometer was used to characterize the morphology and composition changes of the coating during its growth. The coating was proved to have a double-layer structure, and cracks appeared when the coating thickness continued to increase, which reduced the corrosion resistance. The growth mechanism of the coating was explained in detail. X-ray photoelectron spectroscopy was used to determine the components of the coating, which comprised Al2O3 at the base, with TiO2, AlF3, and ZrF4 at the top and ZrO2 evenly distributed throughout. Bode diagram revealed the impedance modulus of the coating at low frequency was increased to 8.6 × 104 Ω/cm2 after five days immersion in 0.5 M NaCl. The coating's self-sealing behavior and active protection may relate to the formation of SiO2, as well as the dissolution and regeneration of the upper coating (AlF3 and ZrF4) on 6016 aluminum alloy.

Abstract Objectives To explore the diagnostic performance of targeted biopsy (TB) combined with regional systematic biopsy (RSB) in patients with different Prostate Imaging Reporting and Data System (PI-RADS) and histologic zones for prostate lesions. Methods This retrospective study included 1301 patients who underwent multiparametric MRI followed by combined MRI/US fusion-guided TB+systematic biopsy (SB) between January 2019 and October 2022. RSB was defined as the four perilesional SB cores adjacent to an MRI-positive lesion. Cancer detection rates were calculated for TB + SB, TB, SB, and TB + RSB, while the McNemar test was utilized for multiple comparisons among them. Subgroup analyses were performed based on different Pl-RADS and histologic zones. Results Of 1301 included participants (median age, 68 years; interquartile range, 63–74 years), 16,104 total biopsy cores were performed. TB + RSB detected clinically significant prostate cancer in 70.9% (922/1301) of patients, which was significantly higher than TB (67.4%, p

Abstract Alhagi honey (AH) is produced in arid and hot areas of Central Asia, and its polysaccharides (AP) are widely known for their activity in the treatment of intestinal diseases such as diarrhea. However, the therapeutic potential and mechanism of AP in ulcerative colitis (UC) remain unclear. Here, AH polysaccharide‐2 (AP2), a polysaccharide with the highest content in AP, was isolated and evaluated for its effects on dextran sulfate sodium (DSS)‐induced UC in mice. AP2 was found to alleviate UC symptoms and regulate gut microbiota dysbiosis by decreasing Helicobacter levels and increasing Lactobacillus levels. Analysis of PICRUSt2 predicted that AP2 may regulate carbohydrate and amino acid metabolism, and metabolomic analysis confirmed that AP2 promotes the metabolism of tryptophan to produce kynurenic acid (kyna). Moreover, kyna acted as an aryl hydrocarbon receptor (AhR) ligand, which activated AhR to increase the expression of the tight junction proteins claudin‐1 and occludin. Interestingly, AP2 showed similar effects in protecting the intestinal barrier and alleviating colitis as the AhR agonist 6‐formylindolo[3,2‐b]carbazole, and the AhR antagonist CH223191 partially blocked the therapeutic effect of AP2 in UC mice, indicating that the anti‐UC effect of AP2 was AhR dependent. These findings demonstrate that AP2 alleviates UC by regulating the gut microbiota and promoting tryptophan metabolism to generate kyna‐activated AhR. The insights gained from this study could help in the future development of AP2 as a drug candidate or functional food for the treatment of UC.

Abstract Coordination cages have been widely reported to bind a variety of guests, which are useful for chemical separation. Although the use of cages in the solid state benefits the recycling, the flexibility, dynamicity, and metal-ligand bond reversibility of solid-state cages are poor, preventing efficient guest encapsulation. Here we report a type of coordination cage-integrated solid materials that can be swelled into gel in water. The material is prepared through incorporation of an anionic FeII 4L6 cage as the counterion of a cationic poly(ionic liquid) (MOC@PIL). The immobilized cages within MOC@PILs have been found to greatly affect the swelling ability of MOC@PILs and thus the mechanical properties. Importantly, upon swelling, the uptake of water provides an ideal microenvironment within the gels for the immobilized cages to dynamically move and flex that leads to excellent solution-level guest binding performances. This concept has enabled the use of MOC@PILs as efficient adsorbents for the removal of pollutants from water and for the purification of toluene and cyclohexane. Importantly, MOC@PILs can be regenerated through a deswelling strategy along with the recycling of the extracted guests.

Designing compositions for novel alloys requires a fundamental grasp of the role of each alloying element in its properties. This study delves into the influence of alloying elements in Ultra-High Strength Steels on essential high-temperature properties, including thermoelasticity, thermal stress, and strength, utilizing first-principles phonon calculations. These properties are pivotal for steels used in high-temperature applications. Our investigation quantitatively forecasts the impact of alloying elements on elastic properties, providing valuable insights for advanced alloy design in high-temperature environments. The introduction of alloying elements markedly amplifies the elastic modulus of Fe-based alloys. The Ni, Mo, Cr, and C elements significantly enhance the anisotropy of the alloy. While refining elastic modulus and mechanical properties, alloying elements induce thermal stress, posing a potential risk of high-temperature cracking. The quantitative analysis underscores the robust strengthening potential for C, Ni, Mo, and W elements, with interstitial C emerging as pivotal in enhancing mechanical properties. The findings of this study illuminate the diverse roles played by different alloying elements and offer theoretical guidance for the design of advanced Ultra-High Strength Steels.

The generation and evaluation of severely high thermal stress (σ) is known to be responsible for failure of thermal barrier coatings (TBCs) during thermal cycling. It is crucial and challenging to capture fluctuations in σ caused by the phase transition, which has motivated us to develop a high-throughput multiscale evaluation method for σ in TBCs that considers the phase transition of the top ceramic materials by coupling first-principles calculations with finite element simulations. The method quantitatively evaluates and visualizes σ of the real TBC structure under thermal cycling by multifield coupling. Additionally, the thermophysical properties calculated by the first-principles calculations consider the effects of temperature and phase transition, which not only reduces the cost of obtaining data but also has a more physical connotation. In this work, rare earth tantalites (RETaO4) are introduced as ceramic layers, and the results demonstrate that σ undergoes a rapid escalation near the phase transition temperature (Tt), particularly in the TBCs_GdTaO4 system, where it rises from 224 to 435 MPa. This discontinuity in σ may originate from the significant alterations in Young’s modulus (increase by 27%–78%) and thermal conductivity (increase by 53%–146%) near Tt. The TBCs_NdTaO4 and TBCs_SmTaO4 systems exhibit noteworthy temperature drop gradients and minimal σ fluctuations, which are beneficial for extending service lifetime of TBCs. This approach facilitates the prediction of failure mechanisms and provides theoretical guidance for the reverse design of TBC materials to obtain low thermal stress systems.

Renal cancer is one of the most common malignancies of the urinary system, and the number of deaths continues to increase. The standardized management of the diagnosis and treatment of renal cancer is challenging due to the great differences in the diagnosis and treatment of renal cancer in different regions. The Renal Cancer Expert Committee of the National Cancer Quality Control Center (NCQCC) identified a lack of authoritative quality control standards as an opportunity to utilize its multidisciplinary membership to improve the standardized diagnosis and treatment of renal cancer. The Renal Cancer Expert Committee of the NCQCC aims to promote quality control and national standardization, uniformity, and normalization of renal cancer diagnosis and treatment, which ultimately improved the survival rate and quality of life of renal cancer patients. A panel of experts with renal cancer surgery, renal cancer medicine, medical imaging, pathology and radiotherapy were drawn together and determined the quality control standards for the standardized diagnosis and treatment of renal cancer. The Indices includes 20 items that cover all key areas in the diagnosis and treatment of renal cancer, such as standard diagnosis, surgery treatment, systemic treatment, and prognostic evaluation.

ABSTRACT: Mechanically interlocked polymers (MIPs) are promising candidates for the construction of elastomeric materials with desirable mechanical performance on account of their abilities to undergo inherent rotational and translational mechanical movements at the molecular level. However, the investigations on their mechanical properties are lagging far behind their structural fabrication, especially for linear polyrotaxanes in bulk. Herein, we report stretchable poly[2]rotaxane elastomers (PREs) which integrate numerous mechanical bonds in the polymeric backbone to boost macroscopic mechanical properties. Specifically, we have synthesized a hydroxy-functionalized [2]rotaxane that subsequently participates in the condensation polymerization with diisocyanate to form PREs. Benefitting from the peculiar structural and dynamic characteristics of the poly[2]rotaxane, the representative PRE exhibits favorable mechanical performance in terms of stretchability (∼1200%), Young's modulus (24.6 MPa), and toughness (49.5 MJ/m3). Moreover, we present our poly[2]rotaxanes as model systems to understand the relationship between mechanical bonds and macroscopic mechanical properties. It is concluded that the mechanical properties of our PREs are mainly determined by the unique topological architectures which possess a consecutive energy dissipation pathway including the dissociation of host−guest interaction and consequential sliding motion of the wheel along the axle in the [2]rotaxane motif.

Abstract Urine-based testing is promising for noninvasive diagnosis of urothelial carcinoma (UC) but has suboptimal sensitivity for early-stage tumors. Herein, we developed a multitarget urine tumor DNA test, UI-Seek, for UC detection and evaluated its clinical feasibility. The prediction model was developed in a retrospective cohort (n = 382), integrating assays for FGFR3 and TERT mutations and aberrant ONECUT2 and VIM methylation to generate a UC-score. The test performance was validated in a double-blinded, multicenter, prospective trial (n = 947; ChiCTR2300076543) and demonstrated a sensitivity of 91.37% and a specificity of 95.09%. The sensitivity reached 75.81% for low-grade Ta tumors and exceeded 93% in high-grade Ta and higher stages (T1 to T4). Simultaneous identification of both bladder and upper urinary tract tumors was enabled with sensitivities exceeding 90%. No significant confounding effects were observed regarding benign urological diseases or non-UC malignancies. The test showed improved sensitivities over urine cytology, the NMP22 test, and UroVysion FISH alongside comparable specificities. The single-target accuracy was greater than 98% as confirmed by Sanger sequencing. Post-surgery UC-score decreased in 97.7% of subjects. Overall, UI-Seek demonstrated robust performance and considerable potential for the early detection of UC.

Abstract Osteosarcoma (OS) is considered a sex steroid hormone-dependent bone tumor. The development and progression of OS are regulated by 17β-estradiol (E2). However, the detailed mechanisms of E2-modulated OS progression remained to be elucidated. Here, we found that E2-activated mammalian target of rapamycin (mTOR) signaling promoted N6-methyladenosine (m6A) modification through regulating WTAP. Inhibition of mTOR complex 1 (mTORC1) reversed E2-activated WTAP expression. Meanwhile, inhibition of mTORC1 suppressed OS cell proliferation and migration. Deficiency of TSC2 activated mTORC1 signaling and enhanced OS cell proliferation and migration, while abrogated by Rapamycin. Interestingly, mTOMC1 promoted mRNA stability of ubiquitin-specific protease 7 (USP7) through m6A modification. Loss of USP7 suppressed the proliferation, migration, and ASC specks, while promoted apoptosis of OS cells. USP7 interacted with NLRP3 and deubiquitinated NLRP3 through K48-ubiquitination. USP7 was upregulated and positive correlation with NLRP3 in OS patients with high level of E2. Loss of USP7 suppressed the progression of OS via inhibiting NLRP3 inflammasome signaling pathway. Our results demonstrated that E2-activtated mTORC1 promoted USP7 stability, which promoted OS cell proliferation and migration via upregulating NLRP3 expression and enhancing NLRP3 inflammasome signaling pathway. These results discover a novel mechanism of E2 regulating OS progression and provide a promising therapeutic target for OS progression.

Abstract Background Developmental and epileptic encephalopathy-50 (DEE-50) is a rare clinical condition believed to be caused by a mutation in the CAD gene and is associated with a bleak prognosis. CAD-related diseases have a wide range of clinical manifestations and other symptoms that may be easily overlooked. Like other rare diseases, the clinical manifestations and the treatment of DEE-50 necessitate further investigation. Case presentation A 1-year-old male patient presented with developmental delay, seizures, and anaemia at 3 months of age. He further developed refractory status epilepticus (SE), rapid deterioration of cognitive and motor function, and even became comatose at 5 months of age. Whole-exome sequencing of trios (WES-trios) revealed a compound heterozygous variant in the CAD gene, with one locus inherited from his father (c.1252C>T: p.Q418* nonsense mutation) and one from his mother (c.6628G>A: p.G2210S, missense mutation). This compound heterozygous CAD variant was unreported in the Human Gene Mutation Database. After uridine treatment, his cognitive faculties dramatically improved and he remained seizure-free. Forty two cases with CAD gene mutation reported in the literatures were reviewed. Among them, 90% had onset before 3 years of age, with average of 1.6±1.8 years old. The average age of diagnosis was 7.7 ± 10 years. The mortality rate was approximately 9.5%, with all reported deaths occurring in patients without uridine treatment. The clinical entity could be improved dramatically when the patient treated with uridine. Conclusions We present a boy with DEE 50 caused by novel CAD gene mutations and reviewed the clinical features of 42 patients reported previously. DEE 50 has early onset, refractory seizures, even status epilepticus leading to death, with favorable response to treatment with oral uridine. Early uridine treatment is recommended if CAD defect is suspected or genetically diagnosed. This study enhances the knowledge of DEE 50 and expands the spectrum of CAD gene mutations.

Abstract Vortex generators (VGs) have been widely applied to wind turbines thanks to their potential to increase aerodynamic performance. Due to the complex inflow perceived by a rotor and the proneness to flow separation, VGs on wind turbines usually experience highly unsteady flow. While there are models that exist to simulate the steady effects of VGs, we lack a fast and efficient tool to model the unsteady performance of airfoils equipped with VGs. This paper adopts an unsteady double‐wake panel model with viscous–inviscid interaction developed to simulate a vertical axis turbine in dynamic stall, adding the capability of predicting the dynamic aerodynamic performance of VG‐equipped airfoils. The results of a series of steady and unsteady cases of an airfoil with different VG configurations in various pitch motions in free and forced transition are verified against experimental data. Results show that the double wake model offers results with sufficient accuracy compared with experimental data to claim the model's validity in a preliminary evaluation of an airfoil's capability to prevent stall with VGs. A few limitations, including the accuracy in prediction the transition location, separation, and reattachment, have been identified for future development.

The corrosion behavior of bogie steel with two different structures immersed in a sulfur-containing environment for 12 h was studied, including ferrite + pearlite structure (the heating temperature is 1473 K, the final rolling temperature is 1123 K, the final cooling temperature is 873 K, and the cooling rate is controlled at 7–9 K/s) and granular bainite structure (the heating temperature is 1223 K, keep warm for 2 h, cooling in water is 10 min, the cooling rate is greater than 100 K/s). The results show that there is no significant difference in the initial corrosion rate between ferrite + pearlite and granular bainite structures. The former is affected by the micro-region galvanic effect and local residual stress to jointly promote corrosion initiation, while the latter has a uniform distribution of local residual stress on the surface, which is the main factor for corrosion initiation. After the sample is immersed, a dense thin rust layer quickly forms on the surface, blocking O2 in the solution, resulting in the dissolution of the ferrite matrix of the two structures is mainly affected by the reduction of H+ and SO32−/SO42−.

ABSTRACTThe PhiC31 integration system allows for targeted and efficient transgene integration and expression by recognizing pseudo attP sites in mammalian cells and integrating the exogenous genes into the open chromatin regions of active chromatin. In order to investigate the regulatory patterns of efficient gene expression in the open chromatin region of PhiC31 integration, this study utilized Ubiquitous Chromatin Opening Element (UCOE) and activating RNA (saRNA) to modulate the chromatin structure in the promoter region of the PhiC31 integration vector. The study analysed the effects of DNA methylation and nucleosome occupancy changes in the integrated promoter on gene expression levels. The results showed that for the OCT4 promoter with moderate CG density, DNA methylation had a smaller impact on expression compared to changes in nucleosome positioning near the transcription start site, which was crucial for enhancing downstream gene expression. On the other hand, for the SOX2 promoter with high CG density, increased methylation in the CpG island upstream of the transcription start site played a key role in affecting high expression, but the positioning and clustering of nucleosomes also had an important influence. In conclusion, analysing the DNA methylation patterns, nucleosome positioning, and quantity distribution of different promoters can determine whether the PhiC31 integration site possesses the potential to further enhance expression or overcome transgene silencing effects by utilizing chromatin regulatory elements.

Open science movement gains attention since it might enable a second scientific revolution that fundamentally changes research methods and standards across science. However, the discussion topics towards opens science both from the academia and the environments outside the scholarly communication process have not been formally identified. This paper contributes to that end by analyzing 145,716 open-science-related tweets and 3,200 research papers in Scopus from 2011 to 2022. The results show there is increasing interest about open science both on Twitter and from academia. There are similar foci for both the public on Twitter and the academia from Scopus, including cloud computing and COVID-19 pandemic. When the public on Twitter focus on open science events and citizen science, the scholarly research is more concerned about the detailed aspects and novel innovation in research. The findings might interest the policy-maker for offering evidence to facilitate open science policies and practices.

Summary: Background: Masked hypertension is associated with target organ damage (TOD) and adverse health outcomes, but whether antihypertensive treatment improves TOD in patients with masked hypertension is unproven. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial at 15 Chinese hospitals, untreated outpatients aged 30–70 years with an office blood pressure (BP) of

The role of processing bodies (P-bodies) in tumorigenesis and tumor progression is not well understood. Here, we showed that the oncogenes YAP/TAZ promote P-body formation in a series of cancer cell lines. Mechanistically, both transcriptional activation of the P-body-related genes SAMD4A, AJUBA, and WTIP and transcriptional suppression of the tumor suppressor gene PNRC1 are involved in enhancing the effects of YAP/TAZ on P-body formation in colorectal cancer (CRC) cells. By reexpression of PNRC1 or knockdown of P-body core genes (DDX6, DCP1A, and LSM14A), we determined that disruption of P-bodies attenuates cell proliferation, cell migration, and tumor growth induced by overexpression of YAP5SA in CRC. Analysis of a pancancer CRISPR screen database (DepMap) revealed co-dependencies between YAP/TEAD and the P-body core genes and correlations between the mRNA levels of SAMD4A, AJUBA, WTIP, PNRC1, and YAP target genes. Our study suggests that the P-body is a new downstream effector of YAP/TAZ, which implies that reexpression of PNRC1 or disruption of P-bodies is a potential therapeutic strategy for tumors with active YAP.

Lithium–oxygen (Li–O2) batteries with ultra-high theoretical specific energy (3500 Wh kg−1) have attracted significant attention, but the sluggish electrochemical processes of discharge product Li2O2 lead to poor cycling stability. Redox mediators (RMs) as soluble catalysts are widely used to assist with the electrochemical formation/decomposition of Li2O2. However, the shuttle effect of RMs causes severe deterioration of both RMs and Li metal anodes. Herein, for the first time we synthesize a lithiated zeolite-based protective layer on Li anodes to mitigate the shuttle effect of 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) in Li–O2 batteries. The protective layer successfully blocks the migration of TEMPO toward the Li anode owing to the angstrom-level aperture size of lithiated zeolite. Due to the excellent redox-mediator-sieving capability of the protective layer, the cycle life of the Li−O2 batteries is significantly prolonged more than ten times at a current density of 250 mA g−1 and a limited capacity of 500 mA h g−1. This work demonstrates that the lithiated zeolite-based protective layer capable of molecular sieving is a facile and scalable way to mitigate the shuttle effect of RMs in Li–O2 batteries.

The occurrence of excitotoxic damage caused by cerebral ischemia-reperfusion (I/R) injury is closely linked to a decrease in central inhibitory function, in which the concentration of chloride inside the cells ([Cl−]i) plays a crucial role. The outflow and inflow of [Cl−]i are controlled by KCC2 and NKCC1, which are cellular cotransporters for K+/Cl− and Na+/K+/Cl−, respectively. NKCC1/KCC2 is regulated by upstream regulators such as SPAK and OSR1, whose activity is influenced by I/R. Sevoflurane is the most commonly used and controversial general anesthetic. To elucidate the impact of sevoflurane on cerebral ischemia-reperfusion (I/R) injury and its underlying mechanism, we investigated its influence on cognitive function and the mechanism of action utilizing a rat model of I/R. By activating the kinase Spak/OSR1, we discovered that I/R damage enhanced the function of NKCC1 and inhibited the function of KCC2, which triggered an imbalance of [Cl−]i concentration, leading to neurological dysfunction and cognitive dysfunction. At the beginning of reperfusion, administration of 1.3 MAC sevoflurane for 3 h increased activation of Spak/OSR1 kinases on day 7 post-perfusion, resulting in an additional dysregulation of NKCC1 and KCC2 activity, which disappeared on day 14. Administration of Closantel, a Spak/OSR1 kinase inhibitor, to animals treated with sevoflurane reverses the additional stimulation. The research revealed that sevoflurane modified the functioning of NKCC1 and KCC2, resulting in cognitive decline by activating Spak/OSR1 kinase. However, this issue could be resolved by inhibiting Spak/OSR1. The research revealed that sevoflurane transiently alters the function of NKCC1 and KCC2, resulting in exacerbating cognitive decline. However, this can be fixed by suppressing Spak/OSR1.

ObjectiveDespite the fact that China amounts to one-fifth of the world’s population, has a higher proportion of the elderly, and has a higher prevalence of osteoporosis and fracture, limited studies have investigated the association between dietary patterns and bone mineral density (BMD) as well as fracture risk among the elderly Chinese population. We aimed to investigate the association between different dietary patterns and BMD as well as the risk of fractures, and this association may vary between elderly women and men.MethodsBuilding upon the China Osteoporosis Prevalence Study, we included 17,489 subjects aged ≥40 years old randomly sampled across 44 counties/districts of 11 provinces or municipalities in China who completed a food frequency questionnaire. BMD was measured by dual x-ray absorptiometry. Vertebral fracture was defined based on lateral spine radiographs using the semi-quantitative technique of Genant.ResultsA diet rich in “carnivorous”, “vegetarian”, “dairy, fruit, and egg” was significantly associated with higher BMD at total hip (TH), femoral neck (FN), and lumbar spine 1–4 (L1–4). Yet, a diet rich in “beverage and fried food” was associated with a lower BMD at the FN and L1–4. High quartiles of the carnivorous diet were associated with 34%–39% reduced risk of clinical fracture in the past 5 years and vertebral fracture. Stronger associations were observed among women. Sensitivity analysis among postmenopausal women presented even stronger positive associations between carnivorous and vegetarian diets and high BMD, as well as between carnivorous diet and reduced risk of fractures.ConclusionsOur study suggested that a diet rich in meat, vegetables, and dairy, fruit, and eggs might be associated with greater BMD and a lower fracture risk, while beverage and fried foods may be associated with a lower BMD at L1–4, especially among elderly women. These findings are relevant to provide recommendations on dietary nutrition regarding the elderly population at high risk of osteoporosis and fractures, especially postmenopausal women.

ABSTRACT This study aimed to assess the in vitro efficacy of ceftazidime-avibactam (CZA) in combination with various antimicrobial agents against carbapenem-resistant Klebsiella pneumoniae (CRKP). We selected 59 clinical CRKP isolates containing distinct drug resistance mechanisms. The minimum inhibitory concentrations (MICs) of meropenem (MEM), colistin (COL), eravacycline (ERA), amikacin (AK), fosfomycin (FOS), and aztreonam (ATM), both individually and in combination with CZA, were tested using the checkerboard method. The interactions of antimicrobial agent combinations were assessed by fractional inhibitory concentration index (FICI) and susceptible breakpoint index (SBPI). The time-kill curve assay was employed to dynamically evaluate the effects of these drugs alone and in combination format. In the checkerboard assay, the combination of CZA+MEM showed the highest level of synergistic effect against both KPC-producing and carbapenemase-non-producing isolates, with synergy rates of 91.3% and 100%, respectively. Following closely was the combination of FOS+CZA . For metallo-beta-lactamases (MBLs) producing strains, ATM+CZA displayed complete synergy, while the combination of MEM+CZA showed a synergy rate of only 57.14% for NDM-producing strains and 91.67% for IMP-producing strains. In the time-kill assay, MEM+CZA also demonstrated significant synergistic effects against the two KPC-2-producing isolates (Y070 and L70), the two carbapenemase-non-producing isolates (Y083 and L093), and the NDM-1-producing strain L13, with reductions in log10 CFU/mL exceeding 10 compared to the control. Against the IMP-producing strain Y047, ATM+CZA exhibited the highest synergistic effect, resulting in a log10 CFU/mL reduction of 10.43 compared to the control. The combination of CZA and MEM exhibited good synergistic effects against KPC-producing and non-enzyme-producing strains, followed by the FOS+CZA combination. Among MBL-producing strains, ATM+CZA demonstrated the most pronounced synergistic effect. However, the combinations of CZA with ERA, AK, and COL show irrelevant effects against the tested clinical isolates.IMPORTANCEOur study confirmed the efficacy of the combination CZA+MEM against KPC-producing and non-carbapenemase-producing strains. For metalloenzyme-producing strains, CZA+ATM demonstrated the most significant synergy. Additionally, CZA exhibited a notable synergy effect when combined with FOS. These combination therapies present promising new options for the treatment of CRKP infection.

Sakuranetin, a flavonoid phytoalexin in rice, plays a crucial role in defense against pathogen infection. While MYB-type transcription factors are well-known to regulate plant growth, development, secondary metabolism, and adaptation to environmental stresses, the function of rice MYB-related transcription factors in sakuranetin biosynthesis and sakuranetin-mediated defense remains unclear. In this study, we identified and characterized OsMYB1R, a novel single repeat MYB transcription factor that acts as a transcriptional activator in sakuranetin biosynthesis. Protein-DNA binding and activation assays revealed that OsMYB1R directly regulates the gene promoter of OsNOMT, a key enzyme in sakuranetin synthesis. Molecular analyses and infection studies using OsMYB1R-overexpressing (OsMYB1R-OE) and OsMYB1R-knockout (Osmyb1r, generated using CRISPR/Cas9) plants demonstrated that OsMYB1R increases sakuranetin production and decreases Magnaporthe oryzae infection by transcriptionally regulating OsNOMT expression. This finding indicates a positive regulation of sakuranetin biosynthesis and antifungal resistance by the OsMYB1R-OsNOMT crosstalk. Interestingly, the alteration of OsMYB1R expression did not affect yield-related agronomic traits. Our results reveal a novel and positive role of 1R-MYB in secondary metabolite biosynthesis and pathogen defense, suggesting that OsMYB1R is a potential gene for effectively enhancing rice resistance without compromising yield.

Abstract Background The aim of this study was to investigate the pathogenicity of vancomycin-resistant Enterococcus faecalis (VREs) to human colon cells in vitro. Methods Three E. faecalis isolates (2 VREs and E. faecalis ATCC 29212) were cocultured with NCM460, HT-29 and HCT116 cells. Changes in cell morphology and bacterial adhesion were assessed at different time points. Interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGFA) expression were measured via RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. Cell migration and human umbilical vein endothelial cells (HUVECs) tube formation assays were used for angiogenesis studies. The activity of PI3K/AKT/mTOR signaling pathway was measured by Western blotting. Results The growth and adhesion of E. faecalis at a multiplicity of infection (MOI) of 1:1 were greater than those at a MOI of 100:1(p

For the evaluation of the construction effect of engineering projects, this study combines the comprehensive evaluation index system and fuzzy mathematical methods, and improves the calculation process of the fuzzy matrix. A fuzzy mathematical method for the evaluation of river comprehensive improvement project is proposed. The results indicate that the comprehensive evaluation of river improvement benefits needs to start from four directions: engineering benefits, ecological benefits, economic benefits, and social benefits, with target layer weights of 0.2904, 0.4755, 0.0586, and 0.1755, respectively. The expert evaluation results indicate that most evaluation indicators of the project have a rating value greater than 5 points, and some indicators have a rating value of 8 points or above. This indicates that the evaluation samples for comprehensive river improvement in the research area perform well in most indicators and achieve good improvement results. The comprehensive evaluation index belongs to the second category of fuzzy values, and the effect of the river comprehensive improvement project is relatively ideal, which is consistent with the actual evaluation. The results indicate that this method converts qualitative indicators into quantitative indicators, making the evaluation results more comparable and quantifiable, which helps to promote the effective implementation of river regulation work.

Geo-decentralized federated learning (FL) can empower fully distributed model training for future large-scale 6G networks. Without the centralized parameter server, the peer-to-peer model synchronization in geo-decentralized FL would incur excessive communication overhead. Some existing studies optimized synchronization interval for communication efficiency, but may not be applicable to latency-constrained geo-decentralized FL. This paper first proposes the synchronization interval optimization for latency-constrained geo-decentralized FL. The problem is formulated to maximize the model training accuracy within a time window under communication/computation constraints. We mathematically derive the convergence bound by jointly considering data heterogeneity, network topology and communication/computation resources. By minimizing the convergence bound, we optimize the synchronization interval based on the approximated system consistency metric. Extensive experiments on MNIST, Fashion-MNIST and CIFAR10 datasets validate the superiority of the proposed approach by achieving up to 30% higher accuracy than the state-of-the-art benchmarks.

Abstract Digestive tract tumors are heterogeneous and involve the dysregulation of multiple signaling pathways. The Janus kinase-signal transducer and activator of transcription (JAK–STAT) pathway plays a notable role in the oncogenesis of digestive tract tumors. Typically activated by pro-inflammatory cytokines, it regulates important biological processes, such as cell growth, differentiation, apoptosis, immune responses, and inflammation. The aberrant activation of this pathway manifests in different forms, including mutations in JAKs, overexpression of cytokine receptors, and sustained STAT activation, and contributes to promoting the malignant characteristics of cancer cells, including uncontrolled proliferation, resistance to apoptosis, enhanced invasion and metastasis, angiogenesis, acquisition of stem-like properties, and drug resistance. Numerous studies have shown that aberrant activation of the JAK-STAT pathway is closely related to the development and progression of digestive tract tumors, contributing to tumor survival, angiogenesis, changes in the tumor microenvironment, and even immune escape processes. In addition, this signaling pathway also affects the sensitivity of digestive tract tumors to chemotherapy and targeted therapy. Therefore, it is crucial to comprehensively understand the oncogenic mechanisms underlying the JAK-STAT pathway in order to develop effective therapeutic strategies against digestive tract tumors. Currently, several JAK–STAT inhibitors are undergoing clinical and preclinical trials as potential treatments for various human diseases. However, further investigation is required to determine the role of this pathway, as well as the effectiveness and safety of its inhibitors, especially in the context of digestive tract tumors. In this review, we provide an overview of the structure, classic activation, and negative regulation of the JAK-STAT pathway. Furthermore, we discuss the pathogenic mechanisms of JAK-STAT signaling in different digestive tract tumors, with the aim of identifying potential novel therapeutic targets. Video Abstract

Abstract Background The relationship between serum vitamin D status and urinary leakage (UL) among middle-aged females needs to be further studied. The aim of this study was to evaluate the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with UL among American females ages 45 years and over. Methods Seven cycles of the National Health and Nutrition Examination Survey (NHANES) with self-report UL data, were used. A total of 9525 women aged 45 years and older were enrolled in this study. Univariate and multivariate logistic regression models and the smooth curve fitting were utilized to analyze the association between clinical UL and serum 25-hydroxyvitamin D [25(OH)D] concentrations. Results A non-linear relationship between serum 25(OH)D concentrations and clinical ULwas observed. When serum 25(OH)D concentration was higher than the inflection point 63.5 nmol/L, a positive correlation was observed between serum 25(OH)D concentrations and clinical UL ([OR]: 1.007, 95%CI: 1.005–1.009, P