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Abstract Background Base editing is a powerful tool for artificial evolution to create allelic diversity and improve agronomic traits. However, the great evolutionary potential for every sgRNA target has been overlooked. And there is currently no high-throughput method for generating and characterizing as many changes in a single target as possible based on large mutant pools to permit rapid gene directed evolution in plants. Results In this study, we establish an efficient germline-specific evolution system to screen beneficial alleles in Arabidopsis which could be applied for crop improvement. This system is based on a strong egg cell-specific cytosine base editor and the large seed production of Arabidopsis, which enables each T1 plant with unedited wild type alleles to produce thousands of independent T2 mutant lines. It has the ability of creating a wide range of mutant lines, including those containing atypical base substitutions, and as well providing a space- and labor-saving way to store and screen the resulting mutant libraries. Using this system, we efficiently generate herbicide-resistant EPSPS, ALS, and HPPD variants that could be used in crop breeding. Conclusions Here, we demonstrate the significant potential of base editing-mediated artificial evolution for each sgRNA target and devised an efficient system for conducting deep evolution to harness this potential.

Abstract Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Abstract The research on the randomness and volatility of wind power (WP) and photovoltaic (PV) output of the integrated energy system (IES) has emerged as a pivotal concern, commonly dealt with by clustering techniques. However, traditional clustering techniques often fall short of capturing the comprehensive characteristics of the original scenery data. This paper presents an enhanced clustering logic to improve WP and PV output correlation scenarios. Utilizing the Frank‐Copula function, the complex relationship between WP and PV is accurately described. The Kendall rank correlation coefficient (Kendall′s tau) is used as a metric to study the correlation between these two renewable energy sources. The original scenes' correlation coefficients are then clustered using the K‐means algorithm, which forms the basis for scene reduction. On the basis, a two‐phase robust optimization method is employed to conduct a planning study for a real IES, with the total cost of the system as the optimal objective. This approach ensures that the planning results are better aligned with the specific local conditions during the operation cycle.

Objective Many important discoveries have been made in shale gas exploration in the Lower Carboniferous Luzhai Formation in the central and northern Guizhong Depression, southern margin of the Xuefengshan Uplift, and commercial test production has achieved successful gas ignition. However, the structure and evolution of the depression in this area have not been clearly defined, which restricts an accurate understanding of the formation conditions for organic-rich mud shale, the distribution of favourable sedimentary facies zones, and shale gas enrichment law. Methods Taking the Rongshui area as an example, this paper studies the main structures and their relationships with shale gas preservation through geological investigation and analysis, 2D-3D seismic section structural interpretation, evolutionary equilibrium section interpretation and other technologies. Results It is believed that there are three main faults and four main NE-NNE synclines in the study area. The preexisting NNE-trending Sanjiang-Rong'an fault is the main factor involved in extensional fault depression and compression-strike-slip transformation. In the study area, the extensional fault depression developed in the Late Devonian, strengthened in the Early Carboniferous and stopped in the late Early Carboniferous. The compression-strike-slip effect of the depression reconstruction developed in the Indochinese and Yanshanian stages, and the local tensioning effect developed in the Alpine stage. The main part of the present fold system was formed in the Indosinian period. Influenced by the increasing thrust of the Sanjiang-Rong'an fault from west to east, the structure pattern of broad and slow synclinal-compound synclinal-faulted folds is distributed. Complex synclines are favourable structural units for shale gas preservation, and the favourable structural styles for shale gas preservation are synclines and anticlines. Conclusion This understanding clearly defines the direction of shale gas exploration and deployment in the next step, and provides a beneficial idea for the structure and evolution of the Liucheng slope in the north-central part of the Guizhong Depression.

Abstract Objectives To compare color Doppler ultrasound and contrast-enhanced ultrasound (CEUS) in evaluating vascular invasion in pancreatic ductal adenocarcinoma (PDAC). Materials and methods This retrospective study included 210 patients with PDAC who were evaluated by color Doppler ultrasound, CEUS, and contrast-enhanced computed tomography (CECT) at our institution between January 2017 and December 2020. Pathologic results were used as the gold standard in patients who underwent surgical and intraoperative exploration. For nonsurgical patients, CECT results were used as the reference standard. The vessels evaluated included those in the peripancreatic arterial system and venous system. The diagnostic performances of color Doppler ultrasound and CEUS for vascular invasion were compared. Results In 51 patients who underwent surgery and intraoperative exploration, color Doppler ultrasound and CEUS differed only in assessing venous system invasion in patients with PDAC of the pancreatic body and tail, with the former being superior to the latter. In 159 nonsurgical patients, there was no difference between CEUS and color Doppler ultrasound in assessing superior mesenteric arteriovenous invasion. CEUS was superior to color Doppler ultrasound in evaluating the celiac artery and its branches, with an accuracy of up to 97.8% for some vessels. Color Doppler ultrasound was ideal for evaluating the splenic and portal veins. Conclusion CEUS is more suitable for the evaluation of peripancreatic arteries than color Doppler. CEUS combined with color Doppler ultrasound can be used as a potential supplement to CECT and is also expected to be used to evaluate vascular invasion of PDAC after chemotherapy. Critical relevance statement Contrast-enhanced US and color Doppler in the assessment of vascular invasion in pancreatic ductal adenocarcinoma have their respective advantages, through standardized ultrasound processes are expected to improve the efficiency of inspection. Key Points Contrast-enhanced US has unique advantages in assessing pancreatic ductal adenocarcinoma invasion of the celiac artery. Doppler imaging is of high value in assessing venous system invasion. Standardization of ultrasound imaging procedures for pancreatic ductal adenocarcinoma is expected to improve efficiency. Graphical Abstract

Abstract Background Psychological resilience has been associated with increased longevity in the oldest old; however, its significance in the broader older adult population has not been thoroughly explored. There is a lack of understanding regarding its relationship with cause-specific mortality in older adults. This study aims to address these gaps by investigating the association between psychological resilience and both overall mortality and cause-specific mortality in individuals aged 65 and older. Methods We enrolled 4,935 participants aged 65 and older in the Chinese Longitudinal Healthy Longevity Survey, with baseline assessments conducted in 2014 and follow-up surveys in 2018. To evaluate the associations between psychological resilience and mortality, we used Cox proportional hazards models. Additionally, we employed restricted cubic spline plots to illustrate the dose-response relationships between these variables. Results During a mean (Standard Deviation) follow-up of 3.2 years (1.2), 1726 participants died. Higher psychological resilience was independently associated with lower all-cause mortality risk (Hazard ratio [HR] 0.74, 95% confidence interval [CI]: 0.67–0.82) and cause-specific mortality from cardiovascular disease (HR 0.74, 95% CI: 0.59–0.93), respiratory diseases (HR 0.63, 95% CI:0.45–0.87), and other causes (HR 0.69, 95% CI: 0.60–0.78), excluding cancer-related mortality. Similar effects were evident when examining the psychological resilience score. The dose-response analysis further indicated a gradual decrease in mortality risk corresponding to higher psychological resilience scores. Interaction analyses revealed that psychological resilience has a more pronounced effect on mortality from other causes among economically independent older adults (P-interaction = 0.02). Conclusions Enhanced psychological resilience is independently associated with reduced all-cause and some cause-specific mortality in older adults. These findings underscore the importance of addressing psychological factors in the promotion of healthy aging and longevity.

Abstract Background Evidence has revealed a connection between cuproptosis and the inhibition of tumor angiogenesis. While the efficacy of a model based on cuproptosis-related genes (CRGs) in predicting the prognosis of peripheral organ tumors has been demonstrated, the impact of CRGs on the prognosis and the immunological landscape of gliomas remains unexplored. Methods We screened CRGs to construct a novel scoring tool and developed a prognostic model for gliomas within the various cohorts. Afterward, a comprehensive exploration of the relationship between the CRG risk signature and the immunological landscape of gliomas was undertaken from multiple perspectives. Results Five genes (NLRP3, ATP7B, SLC31A1, FDX1, and GCSH) were identified to build a CRG scoring system. The nomogram, based on CRG risk and other signatures, demonstrated a superior predictive performance (AUC of 0.89, 0.92, and 0.93 at 1, 2, and 3 years, respectively) in the training cohort. Furthermore, the CRG score was closely associated with various aspects of the immune landscape in gliomas, including immune cell infiltration, tumor mutations, tumor immune dysfunction and exclusion, immune checkpoints, cytotoxic T lymphocyte and immune exhaustion-related markers, as well as cancer signaling pathway biomarkers and cytokines. Conclusion The CRG risk signature may serve as a robust biomarker for predicting the prognosis and the potential viability of immunotherapy responses. Moreover, the key candidate CRGs might be promising targets to explore the underlying biological background and novel therapeutic interventions in gliomas.

Abstract Acellular dermal matrix (ADM) is one of the most promising scaffold materials due to its ability to retain natural extracellular matrix structure. Micronized acellular dermal matrix (mADM) was prepared with no intact cell nuclei and preserved growth factors by High Hydrostatic Pressure (HHP) approach. And mADM-collagen wound dressings were developed with different proportion of type I collagen and recombinant humanized type III collagen. The porous structure of the mADM-collagen wound dressings made them a good candidate for preventing excessive fluid accumulation, while the collagens with gel-like texture combined with mADM powder to form pasty texture wound dressing, which preserving the moisture at the wound site. Moreover, the paste texture of the mADM-collagen wound dressing was easy to reshape to conform any wound shapes and body contours. Furthermore, the resulted mADM-collagen wound dressings showed good biocompatibility by supporting fibroblasts adhesion and proliferation in vitro. Subsequently, a murine model of full-thickness skin wounds was employed to assess its effects on wound healing. Notably, mADM-75% Col-I exhibited superior effects throughout the wound healing process, specifically it promoted neovascularization, skin appendage growth and new skin regeneration. This formulation closely mimicked the collagen ratio found in healthy skin, facilitating the favorable wound repair. These results indicated the superior performance of this mADM-collagen wound dressing providing an optimal environment for wound healing. Graphical Abstract

A nuclear explosion in the rock mass medium can produce strong shock waves, seismic shocks, and other destructive effects, which can cause extreme damage to the underground protection infrastructures. With the increase in nuclear explosion power, underground protection engineering enabled by explosion-proof impact theory and technology ushered in a new challenge. This paper proposes to simulate nuclear explosion tests with on-site chemical explosion tests in the form of multi-hole explosions. First, the mechanism of using multi-hole simultaneous blasting to simulate a nuclear explosion to generate approximate plane waves was analyzed. The plane pressure curve at the vault of the underground protective tunnel under the action of the multi-hole simultaneous blasting was then obtained using the impact test in the rock mass at the site. According to the peak pressure at the vault plane, it was divided into three regions: the stress superposition region, the superposition region after surface reflection, and the approximate plane stress wave zone. A numerical simulation approach was developed using PFC and FLAC to study the peak particle velocity in the surrounding rock of the underground protective cave under the action of multi-hole blasting. The time-history curves of pressure and peak pressure partition obtained by the on-site multi-hole simultaneous blasting test and numerical simulation were compared and analyzed, to verify the correctness and rationality of the formation of an approximate plane wave in the simulated nuclear explosion. This comparison and analysis also provided a theoretical foundation and some research ideas for the ensuing study on the impact of a nuclear explosion.

Abstract To increase the production of biomass and astaxanthin from Haematococcus pluvialis to meet the high market demand for astaxanthin, this study recruited two typical and negligible phytohormones (namely resveratrol and catechol) for the stepwise treatments of H. pluvialis. It was found that the hybrid and sequential treatments of resveratrol (200 μmol) and catechol (100 μmol) had achieved the maximum astaxanthin content at 33.96 mg/L and 42.99 mg/L, respectively. Compared with the hybrid treatment, the physiological data of H. pluvialis using the sequential strategy revealed that the enhanced photosynthetic performance via the Calvin cycle by RuBisCO improved the biomass accumulation during the macrozooid stage; meanwhile, the excessive ROS production had occurred to enhance astaxanthin production with the help of NADPH overproduction during the hematocyst stage. Overall, this study provides improved knowledge of the impacts of phytohormones in improving biomass and astaxanthin of H. pluvialis, which shed valuable insights for advancing microalgae-based biorefinery.

Abstract Background Metastasis renal cell carcinoma (RCC) patients have extremely high mortality rate. A predictive model for RCC micrometastasis based on pathomics could be beneficial for clinicians to make treatment decisions. Methods A total of 895 formalin-fixed and paraffin-embedded whole slide images (WSIs) derived from three cohorts, including Shanghai General Hospital (SGH), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and Cancer Genome Atlas (TCGA) cohorts, and another 588 frozen section WSIs from TCGA dataset were involved in the study. The deep learning-based strategy for predicting lymphatic metastasis was developed based on WSIs through clustering-constrained-attention multiple-instance learning method and verified among the three cohorts. The performance of the model was further verified in frozen-pathological sections. In addition, the model was also tested the prognosis prediction of patients with RCC in multi-source patient cohorts. Results The AUC of the lymphatic metastasis prediction performance was 0.836, 0.865 and 0.812 in TCGA, SGH and CPTAC cohorts, respectively. The performance on frozen section WSIs was with the AUC of 0.801. Patients with high deep learning-based prediction of lymph node metastasis values showed worse prognosis. Conclusions In this study, we developed and verified a deep learning-based strategy for predicting lymphatic metastasis from primary RCC WSIs, which could be applied in frozen-pathological sections and act as a prognostic factor for RCC to distinguished patients with worse survival outcomes.

Abstract Purpose To present the experience of ileal ureter with ileocystoplasty (IUC), and compare the outcomes of IUC in minimally invasive procedures to open procedures. Patients and methods From December 2017 to April 2023, twenty patients underwent IUC in open or minimally invasive (including laparoscopic and robotic) procedures. The baseline characteristics, perioperative data and follow-up outcomes were collected. Success was defined as relief of clinical symptoms, stable postoperative serum creatine and absence of radiographic obstruction. The perioperative and follow-up outcomes of open procedures and minimally invasive procedures were compared. Results The etiology included pelvic irradiation (14/20), urinary tuberculosis (3/20) and surgical injury (3/20). Bilateral ureter strictures were repaired in 15 cases. The surgeries conducted consisted of open procedures in 9 patients and minimally invasive procedures in 11 patients. Compared to open procedures, minimally invasive surgeries had less median estimated blood loss (EBL) (100 ml vs. 300 min, p = 0.010) and shorter postoperative hospitalization (27 d vs. 13 d, p = 0.004). Two patients in the open group experienced grade 3 complications (sigmoid fistula and acute cholecystitis in one patient, and pulmonary embolism in another patient). Over a median follow-up period of 20.1 months, the median bladder functional capacity was 300 ml, with a 100% success rate of IUC. Conclusion IUC is feasible in both open and minimally invasive procedures, with acceptable complications and a high success rate. Minimally invasive procedures can have less EBL and shorter postoperative hospitalization than open procedure. However, prospective studies with larger groups and longer follow-up are needed.

Abstract The secretagogin (SCGN) was originally identified as a secreted calcium-binding protein present in the cytoplasm. Recent studies have found that SCGN has a close relationship with cancer. However, its role in the occurrence, progression, and prognosis of clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we utilized a mutual authentication method based on public databases and clinical samples to determine the role of SCGN in the progression and prognosis of ccRCC. Firstly, we comprehensively analyzed the expression characteristics of SCGN in ccRCC in several public databases. Subsequently, we systematically evaluated SCGN expression on 252 microarrays of ccRCC tissues from different grades. It was found that SCGN was absent in all the normal kidney tissues and significantly overexpressed in ccRCC tumor tissues. In addition, the expression level of SCGN gradually decreased with an increase in tumor grade, and the percentage of SCGN staining positivity over 50% was 86.7% (13/15) and 73.4% (58/79) in Grade1 and Grade2, respectively, while it was only 8.3% (12/144) in Grade3, and the expression of SCGN was completely absent in Grade4 (0/14) and distant metastasis group (0/4). Additionally, the expression of SCGN was strongly correlated with the patient's prognosis, with the higher the expression levels of SCGN being associated with longer overall survival and disease-free survival of patients. In conclusion, our results suggest that reduced expression of SCGN in cancer cells is correlated with the progression and prognosis of ccRCC.

Considering the problem of radar target detection in the sea clutter environment, this paper proposes a deep learning-based marine target detector. The proposed detector increases the differences between the target and clutter by fusing multiple complementary features extracted from different data sources, thereby improving the detection performance for marine targets. Specifically, the detector uses two feature extraction branches to extract multiple levels of fast-time and range features from the range profiles and the range-Doppler (RD) spectrum, respectively. Subsequently, the local-global feature extraction structure is developed to extract the sequence relations from the slow time or Doppler dimension of the features. Furthermore, the feature fusion block is proposed based on adaptive convolution weight learning to efficiently fuse slow-fast time and RD features. Finally, the detection results are obtained through upsampling and nonlinear mapping to the fused multiple levels of features. Experiments on two public radar databases validated the detection performance of the proposed detector.

Abstract Mitochondrial RNA modification (MRM) plays a crucial role in regulating the expression of key mitochondrial genes and promoting tumor metastasis. Despite its significance, comprehensive studies on MRM in lower grade gliomas (LGGs) remain unknown. Single-cell RNA-seq data (GSE89567) was used to evaluate the distribution functional status, and correlation of MRM-related genes in different cell types of LGG microenvironment. We developed an MRM scoring system by selecting potential MRM-related genes using LASSO regression analysis and the Random Survival Forest algorithm, based on multiple bulk RNA-seq datasets from TCGA, CGGA, GSE16011, and E-MTAB-3892. Analysis was performed on prognostic and immunological features, signaling pathways, metabolism, somatic mutations and copy number variations (CNVs), treatment responses, and forecasting of potential small-molecule agents. A total of 35 MRM-related genes were selected from the literature. Differential expression analysis of 1120 normal brain tissues and 529 LGGs revealed that 22 and 10 genes were upregulated and downregulated, respectively. Most genes were associated with prognosis of LGG. METLL8, METLL2A, TRMT112, and METTL2B were extensively expressed in all cell types and different cell cycle of each cell type. Almost all cell types had clusters related to mitochondrial RNA processing, ribosome biogenesis, or oxidative phosphorylation. Cell–cell communication and Pearson correlation analyses indicated that MRM may promoting the development of microenvironment beneficial to malignant progression via modulating NCMA signaling pathway and ICP expression. A total of 11 and 9 MRM-related genes were observed by LASSO and the RSF algorithm, respectively, and finally 6 MRM-related genes were used to establish MRM scoring system (TRMT2B, TRMT11, METTL6, METTL8, TRMT6, and TRUB2). The six MRM-related genes were then validated by qPCR in glioma and normal tissues. MRM score can predict the malignant clinical characteristics, abundance of immune infiltration, gene variation, clinical outcome, the enrichment of signaling pathways and metabolism. In vitro experiments demonstrated that silencing METTL8 significantly curbs glioma cell proliferation and enhances apoptosis. Patients with a high MRM score showed a better response to immunotherapies and small-molecule agents such as arachidonyl trifluoromethyl ketone, MS.275, AH.6809, tacrolimus, and TTNPB. These novel insights into the biological impacts of MRM within the glioma microenvironment underscore its potential as a target for developing precise therapies, including immunotherapeutic approaches.

The addition of growth restricting elements in additive manufacturing of Ti and Ti-based alloys can result in the formation of equiaxed structures. However, an excessive incorporation of these elements frequently impairs the mechanical properties. Obtaining the minimum necessary amount of addition is crucial to achieve the transition from columnar to equiaxed microstructure. This ensures that the desired equiaxed structure is obtained while minimizing any potential negative effects on the material's properties. Here manganese was taken as the potential grain refiner in Ti alloy. Then, evolutions of grain morphologies and microstructures as well as the mechanical properties various of Ti-6Al-4V alloy in laser wire deposition additive manufacturing with the growth restriction factors of 26, 32, 39 were explored respectively. And the average hardness of the deposits were 495 HV, 512 HV, and 530 HV, respectively, showing an increase of approximately 15%, 19% and 23%. When the growth restricting factor value reached 39, the columnar prior β grains underwent a complete transformation into equiaxed grains. Mn elements promoted the decomposition of β→α+Mn2Ti during the multi-pass deposition and the microhardness of the deposits were significantly increased. Additionally, Mn elements were expelled outwards during the β→α transition. Nevertheless, the diffusion rate of Mn elements was low and thereby there was a low growth rate of α phases, thus refining α phases.

Oil tree peony is a unique woody oil crop found exclusively in China. Its seed oil is a highly nutritious edible vegetable oil. However, its seed production varies greatly and is often low. Oil tree peony is a plant that relies on insects for pollination, but inadequate pollination is a common occurrence. In this study, we focused on the Paeonia ostii ‘Fengdan’ species and conducted a five-year study (from 2017 to 2022) in Luoyang, China. Our objective was to assess the extent of pollination deficiency and dependence, as well as quantify the contribution of supplemented bumblebees (Bombus terrestris) to the yield of oil tree peony. We also examined the effect of supplemented bumblebees on the temporal variation in yield through various pollinator survey designs, including supplemented bumblebees (BP), open pollination (OP), pollinator exclusion (EP), self-pollination treatments (SP), and artificial cross-pollination (CP). The results revealed a medium pollination deficit (D = 0.50) at the study sites for three consecutive years from 2020 to 2022, indicating limited pollination for oil tree peony under natural conditions. Importantly, BP significantly compensated for this deficiency (D = 0.22). Over the course of five years, BP increased the yield of oil tree peony by 82.87% on average compared to EP. Furthermore, the yield variation coefficient of EP (CVt=0.20) increased by 100% compared to BP (CVt=0.10). And we also observed significant variability in other yield parameters. Additionally, oil tree peony production was reduced by 44.24% in the absence of flower visitors, and the dependence on BP reached a “high” level. The fatty acid content in the seed oil did not show significant differences across treatments, indicating its stability. Overall, our pollination practices demonstrate that supplementing bee pollination can provide sufficient and stable pollination services, resulting in a higher and more stable yield of oil tree peony seeds.

Abstract Background Studies examining the potential association between cooking oil and frailty risk in older adults have produced conflicting outcomes. Therefore, our objective was to explore the relationship between cooking oil (vegetable and animal fat oils), changes in oil usage, and the risk of frailty in older adults. Methods We included 4,838 participants aged ≥ 65 years without frailty (frailty index

Abstract A dual‐motor servo mechanism is a high‐order and strong‐coupling system with unknown nonlinearity, which brings challenges to controller design to realize high‐performance tracking and synchronization. This article proposes a finite‐time command filtered control strategy to address this problem. In tracking control design, finite‐time command filters are adopted to obtain the derivatives of virtual controllers, and the “explosion of complexity” problem in backstepping is thus solved. An improved compensation system is designed to reduce filtering errors. The tracking control is developed based on the combination of finite‐time control and command filtered approach. Moreover, to deal with unknown nonlinearities and uncertainties, fast finite‐time extended state observers are developed to observe lumped disturbances for the load and motor, respectively. In synchronization control design, two opposite control actions are developed using the speed difference to force two motors to rotate synchronously. The finite‐time convergence of the tracking and synchronization errors is proved. The efficiency of the proposed control strategy is verified via experiments conducted on a dual‐motor servo turntable.

Ultrafine-grained microstructure was successfully obtained in Mg–6Al–3Sn–1Zn (ATZ631) alloy by multi-pass high-speed rolling (HSR) at a rolling speed of 1100 m/min and a rolling temperature of 400 °C. The grain refinement mechanism of ATZ631 alloy during HSR was investigated, which is attributed to mechanically fragmented grains and twinning-induced dynamic recrystallization (TDRX). During the initial stages of rolling, the initial coarse grains are refined by the intersection of twins. With increasing strain, the grain refinement mechanism is the typical dynamic recovery and TDRX. In general, twins are filled with a high density of dislocations and nano-sized precipitates at the dislocations, which can accelerate DRX by increasing the driving force or particle-stimulated nucleation (PSN) within the twins. Subsequently, the coarse grains are refined by forming fine DRXed grains via dislocation entanglement, dislocation rearrangement, and dislocation absorption. As the process proceeds, grain boundaries (GBs) migration is suppressed by the precipitates at the GBs of new DRXed grains. Thus, the growth of the DRXed grains can be inhibited. Finally, ultrafine-grained microstructure with an average size of ∼116 nm is obtained. Moreover, the new grains formed by TDRX exhibit random orientation during this process, indicating that the basal texture gets effectively weakened by increasing the fraction of DRXed grains. These findings bring forward the microstructural evolution during dynamic precipitation and DRX, thus providing a novel notion for improving microstructures and grain refinement in Mg alloys.

Abstract Background Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. Methods In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. Results Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. Conclusion Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

Abstract Integrated switches play a crucial role in the development of reconfigurable optical add-drop multiplexers (ROADMs) that have greater flexibility and compactness, ultimately leading to robust single-chip solutions. Despite decades of research on switches with various structures and platforms, achieving a balance between dense integration, low insertion loss (IL), and polarization-dependent loss (PDL) remains a significant challenge. In this paper, we propose and demonstrate a 32 × 4 optical switch using high-index doped silica glass (HDSG) for ROADM applications. This switch is designed to route any of the 32 inputs to the express ports or drop any channels from 32 inputs to the target 4 drop ports or add any of the 4 ports to any of the 32 express channels. The switch comprises 188 Mach-Zehnder Interferometer (MZI) type switch elements, 88 optical vias for the 44 optical bridges, and 618 waveguide-waveguide crossings with three-dimensional (3D) structures. At 1550 nm, the fiber-to-fiber loss for each express channel is below 2 dB, and across the C and L bands, below 3 dB. For each input channel to all 4 drop/add channels at 1550 nm, the loss is less than 3.5 dB and less than 5 dB across the C and L bands. The PDLs for all express and input channels to the 4 drop/add channels are below 0.3 dB over the C band, and the crosstalk is under −50 dB for both the C and L bands.

Abstract Background The causal relationship between breast cancer (BC) and the oral microbiome remains unclear. In this case–control study, using two‐sample Mendelian randomization (MR), we thoroughly explored the relationship between the oral microbiome and BC in the East Asian population. Methods Genetic summary data related to oral microbiota and BC were collected from genome‐wide association studies involving participants of East Asian descent. MR estimates were generated by conducting various analyses. Sequencing data from a case–control study were used to verify the validity of these findings. Results MR analysis revealed that 30 tongue and 37 salivary bacterial species were significantly associated with BC. Interestingly, in both tongue and salivary microbiomes, we observed the causal effect of six genera, namely, Aggregatibacter, Streptococcus, Prevotella, Haemophilus, Lachnospiraceae, Oribacterium, and Solobacterium, on BC. Our case–control study findings suggest differences in specific bacteria between patients with BC and healthy controls. Moreover, sequencing data confirmed the MR analysis results, demonstrating that compared with the healthy control group, the BC group had a higher relative abundance of Pasteurellaceae and Streptococcaceae but a lower relative abundance of Bacteroidaceae. Conclusions Our MR analysis suggests that the oral microbiome exerts a causative effect on BC risk, supported by the sequencing data of a case–control study. In the future, studies should be undertaken to comprehensively understand the complex interaction mechanisms between the oral microbiota and BC.

Abstract Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients. The role of metformin in reducing cardiovascular events is well‐established, but its effect on coronary artery inflammation in T2DM patients is still unclear. In this study, we evaluated 547 T2DM patients who underwent coronary computed tomography angiography (CCTA) at Wuhan Central Hospital. Using propensity score matching, we compared the attenuation of pericoronary adipose tissue (PCAT), an imaging marker of coronary artery inflammation, between patients treated with and without metformin. Multiple linear regression models were used to analyze the influence of metformin on PCAT attenuation. The results of the propensity‐matched analysis showed that patients on metformin therapy had significantly lower PCAT attenuation, indicating reduced coronary inflammation. Specifically, the PCAT attenuation in the left anterior descending artery (LAD) and right coronary artery (RCA) was lower in the metformin group compared to the non‐metformin group. Metformin use was independently associated with decreased LAD‐PCAT attenuation in the multivariate regression analysis. The association of metformin with PCAT attenuation differed significantly in populations analyzed in subgroups of patients with obesity and chronic kidney disease. In conclusion, our study shows a preliminary signal that metformin therapy may be associated with decreased coronary artery inflammation in T2DM patients, as indicated by PCAT attenuation on CCTA. And this correlation may vary depending on the patient population. This initial finding suggests that PCAT attenuation could be potentially used as an imaging biomarker to monitor the anti‐inflammatory effects of medication.

ABSTRACT Objective: To evaluate objective treatment efficacy and safety, and subjective patient-reported outcomes in patients with complex ureteral strictures (US) undergoing minimally invasive lingual mucosal graft ureteroplasty (LMGU). Materials and Methods: We prospectively enrolled patients underwent robotic or laparoscopic LMGU between May 2020 and July 2022. Clinical success was defined as symptom-free and no radiographic evidence of re-obstruction. Patient-reported outcomes, including health-related quality of life (HRQoL), mental health status and oral health-related quality of life (OHRQoL), were longitudinally evaluated before surgery, 6 and 12 months postoperatively. Results: Overall, 41 consecutive patients were included. All procedures were performed successfully with 32 patients in robotic approach and 9 in laparoscopic. Forty (97.56%) patients achieved clinical success during the median follow-up of 29 (range 15-41) months. Although patients with complex US experienced poor baseline HRQoL, there was a remarkable improvement following LMGU. Specifically, the 6-month and 12-month postoperative scores were significantly improved compared to the baseline (p < 0.05) in most domains. Twenty-eight (68.3%) and 31 (75.6%) patients had anxiety and depression symptoms before surgery, respectively. However, no significant decrease in the incidence of these symptoms was observed postoperatively. Moreover, there was no significant deterioration of OHRQoL at 6 months and 12 months postoperatively when compared to the baseline. Conclusions: LMGU is a safe and efficient procedure for complex ureteral reconstruction that significantly improves patient-reported HRQoL without compromising OHRQoL. Assessing patients’ quality of life enables us to monitor postoperative recovery and progress, which should be considered as one of the criteria for surgical success.

Abstract Background Coronary inflammation plays crucial role in type 2 diabetes mellitus (T2DM) induced cardiovascular complications. Both glucose-lowering drug interventions (GLDIS) and glycemic control (GC) status potentially correlate coronary inflammation, as indicated by changes in pericoronary adipose tissue (PCAT) attenuation, and thus influence cardiovascular risk. This study evaluated the impact of GLDIS and GC status on PCAT attenuation in T2DM patients. Methods This retrospective study collected clinical data and coronary computed tomography angiography (CCTA) images of 1,342 patients, including 547 T2DM patients and 795 non-T2DM patients in two tertiary hospitals. T2DM patients were subgroup based on two criteria: (1) GC status: well: HbA1c 9%; (2) GLDIS and non-GLDIS. PCAT attenuations of the left anterior descending artery (LAD-PCAT), left circumflex artery (LCX-PCAT), and right coronary artery (RCA-PCAT) were measured. Propensity matching (PSM) was used to cross compare PCAT attenuation of non-T2DM and all subgroups of T2DM patients. Linear regressions were conducted to evaluate the impact of GC status and GLDIS on PCAT attenuation in T2DM patients. Results Significant differences were observed in RCA-PCAT and LCX-PCAT between poor GC-T2DM and non-T2DM patients (LCX: − 68.75 ± 7.59 HU vs. – 71.93 ± 7.25 HU, p = 0.008; RCA: − 74.37 ± 8.44 HU vs. − 77.2 ± 7.42 HU, p = 0.026). Higher PCAT attenuation was observed in LAD-PCAT, LCX-PCAT, and RCA-PCAT in non-GLDIS T2DM patients compared with GLDIS T2DM patients (LAD: − 78.11 ± 8.01 HU vs. − 75.04 ± 8.26 HU, p = 0.022; LCX: − 71.10 ± 8.13 HU vs. − 68.31 ± 7.90 HU, p = 0.037; RCA: − 78.17 ± 8.64 HU vs. − 73.35 ± 9.32 HU, p = 0.001). In the linear regression, other than sex and duration of diabetes, both metformin and acarbose were found to be significantly associated with lower LAD-PCAT (metformin: β coefficient = − 2.476, p=0.021; acarbose: β coefficient = − 1.841, p = 0.031). Conclusion Inadequate diabetes management, including poor GC and lack of GLDIS, may be associated with increased coronary artery inflammation in T2DM patients, as indicated by PCAT attenuation on CCTA, leading to increased cardiovascular risk. This finding could help healthcare providers identify T2DM patients with increased cardiovascular risk, develop improved cardiovascular management programs, and reduce subsequent cardiovascular related mortality.

Abstract Despite prolonged surveillance and interventions, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses continue to pose a severe global health burden. Thus, we developed a chimpanzee adenovirus-based combination vaccine, AdC68-HATRBD, with dual specificity against SARS-CoV-2 and influenza virus. When used as a standalone vaccine, intranasal immunization with AdC68-HATRBD induced comprehensive and potent immune responses consisting of immunoglobin (Ig) G, mucosal IgA, neutralizing antibodies, and memory T cells, which protected the mice from BA.5.2 and pandemic H1N1 infections. When used as a heterologous booster, AdC68-HATRBD markedly improved the protective immune response of the licensed SARS-CoV-2 or influenza vaccine. Therefore, whether administered intranasally as a standalone or booster vaccine, this combination vaccine is a valuable strategy to enhance the overall vaccine efficacy by inducing robust systemic and mucosal immune responses, thereby conferring dual lines of immunological defenses for these two viruses.

Abstract Background Oral microbial dysbiosis contributes to the development of oral squamous cell carcinoma (OSCC). Our previous study showed that Prevotella intermedia (P. intermedia) were enriched in the oral mucosal surface, plaque, and saliva of patients with OSCC. Intratumoral microbiome could reshape the immune system and influence the development of various tumors. However, the invasion status of human OSCC tissues by P. intermedia and the pathway through which intratumoral P. intermedia potentiates tumor progression remain unexplored. Methods P. intermedia in human OSCC or normal tissues was detected by FISH. A mouse OSCC cell line SCC7 was adopted to investigate the effects of heat-killed P. intermedia treatment on cell proliferation, invasion, and cytokine release by using CCK-8 assay, transwell invasion assay and ELISA. Moreover, we established a mouse transplanted tumor model by using SCC7 cells, injected heat-killed P. intermedia into tumor tissues, and investigated the effects of heat-killed P. intermedia on tumor growth, invasion, cytokine levels, immune cell infiltrations, and expression levels by using gross observation, H&E staining, ELISA, immunohistochemistry, mRNA sequencing, and transcriptomic analysis. Results Our results indicated that P. intermedia were abundant in OSCC and surrounding muscle tissues. Heat-killed P. intermedia promoted SCC7 cell proliferation, invasion and proinflammatory cytokine secretions, accelerated transplanted tumor growth in mice, exacerbate muscle and perineural invasion of OSCC, elevated the serum levels of IL-17A, IL-6, TNF-α, IFN-γ, and PD-L1, induced Treg cells M2 type macrophages in mouse transplanted tumors. The data of transcriptomic analysis revealed that heat-killed P. intermedia increased the expression levels of inflammatory cytokines and chemokines while reduced the expression levels of some tumor suppressor genes in mouse transplanted tumors. Additionally, IL-17 signaling pathway was upregulated whereas GABAergic system was downregulated by heat-killed P. intermedia treatment. Conclusions Taken together, our results suggest that P. intermedia could inhibit the expression of tumor suppressors, alter the tumor microenvironment, and promote the progression of OSCC.

Abstract Predicting carbon prices is crucial for the growth of China's carbon trading industry. This paper proposes a residual correction model that considers multiple influencing factors. First, the best historical data and main external factors input by the model are determined by using the partial autocorrelation function and Spearman correlation analysis, and the carbon price forecasting index system is constructed. Second, the whale optimization algorithm (WOA) is utilized to determine the optimal parameters of the extreme gradient boosting (XGBoost), and the WOA‐XGBoost model is built to perform preliminary carbon price forecasts and obtain the residual series. Finally, the carbon price residual series undergoes decomposition into multiple components utilizing the complete ensemble empirical mode decomposition for subsequent forecasting and the aggregation of outcomes. Experiments are conducted to predict two carbon trading markets in Hubei and Guangzhou, and a feature importance analysis is performed. The results indicate that the proposed hybrid model consistently outperforms the comparative models in terms of prediction accuracy. Furthermore, it is revealed that historical carbon prices and European Union carbon prices are the key factors influencing the prediction of carbon market prices.

We studied changes in the concentrations of aggregate-cementing agents after different reclamation times and with different fertilization regimes, as well as the formation mechanism of aggregates in reclaimed soil, to provide a theoretical basis for rapid reclamation of soil fertility in the subsidence area of coal mines in Shanxi Province, China. In this study, soil samples of 0–20 cm depth were collected from four fertilization treatments of a long-term experiment started in 2008: no fertilizer (CK), inorganic fertilizer (NPK), chicken manure compost (M), and 50% inorganic fertilizer plus 50% chicken manure compost (MNPK). The concentrations of cementing agents and changes in soil aggregate size distribution and stability were analysed. The results showed that the formation of >2 mm aggregates, the aggregate mean weight diameter (MWD), and the proportion of >0.25 mm water-stable aggregates (WR0.25) increased significantly after 6 and 11 years of reclamation. The concentration of organic cementing agents tended to increase with reclamation time, whereas free iron oxide (Fed) and free aluminium oxide (Ald) concentrations initially increased but then decreased. In general, the MNPK treatment significantly increased the concentrations of organic cementing agents and CaCO3, and CaCO3 increased by 60.4% at 11 years after reclamation. Additionally, CaCO3 had the greatest effect on the stability of aggregates, promoting the formation of >0.25 mm aggregates and accounting for 54.4% of the variance in the proportion and stability of the aggregates. It was concluded that long-term reclamation is beneficial for improving soil structure. The MNPK treatment was the most effective measure for increasing maize grain yield and concentration of organic cementing agents and CaCO3.

The liquid Lead-bismuth eutectic is used as the coolant for Gen-IV reactor concepts. However, due to its strong corrosive and high operating temperature, it is difficult to accurately measure the flow rate in long-term operating conditions. Venturi flowmeter is a simple structured flowmeter, which plays a very important role in the flow measurement of high-temperature liquid metals, especially since the existing flowmeters are difficult to be competent. It has the advantages of easy maintenance and stable operation. Therefore, it is necessary to study the operating conditions of the venturi flowmeter under high-temperature conditions. This work performs a series of simulations of the fluid-solid interaction between the flow liquid metal and venturi flowmeter with COMSOL software, including the dimensional sensitivity analysis of the venturi flowmeter to explore the most suitable structure and parameters for liquid heavy metal, the sensitivity analysis of the geometric parameters of the venturi tube on the varying conditions. It shows that when the contraction angle of the venturi flowmeter is 33°, the diffusion angle is 13°, the diameter of the throat is 8 mm, and the temperature of the lead-bismuth eutectic is 733.15 K, it is most suitable for the measurement in the lead-bismuth circuit.

High-power O-mode radio waves can excite artificial instabilities in the F region, according to experiments conducted at the European Incoherent Scatter Science Association (EISCAT) heating facility. The main instabilities include the parametric decay instability (PDI), oscillating two-stream instability (OTSI), and thermal parametric instability (TPI). The PDI and OTSI not only compete with each other, but also compete with the TPI, leading to a two-stage overshoot phenomenon: a miniovershoot occurs on a millisecond time scale after pump-on, followed by the main overshoot. We gain insight into the miniovershoot via a generalized Zakharov model, whereas the main overshoot can be observed as an enhanced plasma line overshoot phenomenon in incoherent scatter radar spectra. We can also observe that the zero-frequency ion line exists only in the initial heating period after a cold start and that the upshifted and downshifted ion lines behave irregularly in the spectra. The simulation results show that competition between the PDI and OTSI leads to an initial peak, which we named the pre-miniovershoot. The following processes, namely ion density caviton generation, and collapse and cascade in the development of the PDI, contribute to the miniovershoot phenomenon.

Academic debate still exists as to whether and how multi-scale microstructure recovery is linked to creep properties rejuvenation of superalloys. We propose a rejuvenation heat treatment (RHT) for one single-crystal superalloy crept at 1100 °C/120 MPa, by which the degraded phase- and dislocation-microstructure can be recovered to standard heat treatment one. Despite experiencing different plastic deformation, such recovered microstructure leads to nearly a fixed 20% improvement in creep life. Through triple creep-RHT-creep cycle tests, the complete rejuvenation of creep life after special creep time has been validated, while the plastic deformation limit increases, where creep properties recoverability remains.

Achievement of ultra-high yield strength of above 400 MPa for rare-earth-free magnesium (Mg) alloys is quite difficult via traditional thermal-mechanical processing. In this study, Mg–6Al–4Sn–1Zn alloy (ATZ641) sheet with the yield strength of 410 MPa, ultimate tensile strength of 442 MPa, and elongation of 5.1 %, was fabricated by combining extrusion and high-speed rolling (HSR). The results showed significant refinement in the grains of high-speed rolled ATZ641 alloy due to dynamic recrystallization (DRX) effectively promoted by particle-stimulated nucleation (PSN) of pre-existing relatively coarse Mg17Al12 precipitates uniformly distributed along grain boundaries, formed during extrusion prior to HSR. Meanwhile, the Mg17Al12 nano-precipitates with high number density, mainly due to dynamic precipitation during HSR and submicron Mg2Sn precipitates formed during both extrusion and HSR, suppress DRX and thus promote the formation of a certain amount of subgrains via particle pinning. The excellent mechanical properties are mainly attributed to fine-grain strengthening, high density residual dislocations and presence of numerous hybrid particles such as bimodal size (micron and nanometer) Mg17Al12 precipitates and submicron Mg2Sn precipitates as well as a large amount of subgrains. This study offers an important notion for developing rare-earth-free Mg alloys with ultra-high strength.

Cases and studies of protruding early gastric cancer (EGC) combined with spontaneous bleeding are relatively rare. The current study present a female patient aged 70 to 75 years old with hemorrhagic shock caused by spontaneous bleeding from EGC type 0-Isp, which was successfully cured by rapid emergency endoscopic submucosal dissection (ESD).

The benefits of femtosecond laser-assisted in situ keratomileusis (FS-LASIK) for correcting vision, particularly in terms of spherical equivalent (SE) and visual acuity (VA), have gained broad recognition. Nevertheless, it has remained uncertain whether FS-LASIK has a positive impact on contrast sensitivity (CS). In this study, we measured CS on seven participants by the quick contrast sensitivity function (qCSF) and compared CS before and after the surgery at two time points (1 day and 7 days after) by the repeated measures analysis of variance (ANOVA). Then, we clarified the underlying mechanisms using the perceptual template model (PTM). Furthermore, we investigated the relationship among SE, VA, and CS employing the Pearson correlation test. We found that (1) CS exhibited significant improvements on postoperative day 1, with further enhancements observed up to postoperative day 7, (2) CS improvements were dependent on spatial frequency (SF) and external noise, (3) CS improvements were attributed to the reduction of internal noise and the enhancement of the perceptual template, (4) VA and SE demonstrated significant improvement post-surgery, and (5) no significant correlations were observed among SE, VA, and CS, possibly due to limitations in sample size and lighting conditions. These findings contribute to our comprehension of FS-LASIK and provide a great indicator for assessing the outcomes of visual surgery.

Abstract This letter presents a Ka‐band low‐cost microstrip line phase shifter based on liquid crystal (LC) technology. Furthermore, a sum‐difference beamforming antenna array based on the LC phase shifter is designed. The phase shifter is composed of two coaxial connectors, a metal base, an intermediate dielectric layer, a gradient metal sheet and a top glass layer. The simulated results show that a nearly 360° phase shift coverage can be achieved with the effective permittivity of LC varying from 2.5 to 3.5. The sum‐difference beam antenna array is composed of a circulator, a sum‐difference network, a one‐to‐eight power‐division network, eight liquid crystal phase shifters, and a serious fed antenna array. The simulation results show that the antenna array can achieve sum‐difference beam scanning range of ±30°. A prototype of LC phase shifter is fabricated and tested. The results show that the designed LC phase shifter can achieve a 360° phase coverage by applying a direct current (DC) voltage ranging from 0 to 12 V. Compared to traditional phase shifters, the proposed design offers a simple structure at a lower cost. When applied in the design of a sum‐difference beam antenna array, it can reduce the producing cost and enable integrated design.

Ferroptosis is a nonapoptotic form of cell death characterized by iron dependence and lipid peroxidation. Ferroptosis is involved in a range of pathological processes, such as cancer. Many studies have confirmed that ferroptosis plays an essential role in inhibiting cancer cell proliferation. In addition, a series of small-molecule compounds have been developed, including erastin, RSL3, and FIN56, which can be used as ferroptosis inducers. The combination of ferroptosis inducers with anticancer drugs can produce a significant synergistic effect in cancer treatment, and patients treated with these combinations exhibit a better prognosis than patients receiving traditional therapy. Therefore, a thorough understanding of the roles of ferroptosis in cancer is of great significance for the treatment of cancer. This review mainly elaborates the molecular biological characteristics and mechanism of ferroptosis, summarizes the function of ferroptosis in cancer development and treatment,illustrates the application of ferroptosis in patient's prognosis prediction and drug discovery, and discusses the prospects of targeting ferroptosis.

Background: Accurate diagnosis of patients with ulcerative colitis (UC) can reduce their risk of developing colorectal cancer. This study intended to explore whether moxifloxacin, an agent with fluorescence potential, could promote two-photon microscopy (TPM) diagnosis for mice with dextran sodium sulfate (DSS)-induced colitis, which could imitate human UC. Methods: 32 Balb/c mice were randomly divided into 4 groups: control, acute colitis, remission colitis and chronic colitis. Fluorescence parameters, imaging performance, and tissue features of different mouse models were compared under moxifloxacin-assisted TPM and label-free TPM. Results: Excitation wavelength of 720 nm and moxifloxacin labeling time of 2 min was optimal for moxifloxacin-assisted TPM. With moxifloxacin labeling for colonic tissues, excitation power was decreased to 1/10 of that without labeling while fluorescence intensity was increased to 10-fold of that without labeling. Photobleaching was negligible after moxifloxacin labeling and moxifloxacin fluorescence kept stable within 2 h. Compared with the control group, moxifloxacin fluorescence was reduced in the three colitis groups (P < 0.05). Meanwhile, the proportion of enhanced moxifloxacin fluorescence regions was (22.4 ± 1.6)%, (7.7 ± 1.0)%, (13.5 ± 1.7)% and (5.0 ± 1.3)% in the control, acute, remission and chronic groups respectively, with significant reduction in the three colitis groups (P < 0.05). Besides, variant tissue features of experimental colitis models were presented under moxifloxacin-assisted TPM, such as crypt opening, glandular structure, adjacent glandular space and moxifloxacin distribution. Conclusions: With unique biological interaction between moxifloxacin and colonic mucosa, moxifloxacin-assisted TPM imaging is feasible and effective for accurate diagnosis of different stages of experimental colitis.

Abstract Despite the initial efficacy of enzalutamide in castration‐resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, the synergistic induction of copper‐dependent cell death (cuproptosis) in CRPC cells is reported by enzalutamide and copper ionophores (elesclomol/disulfiram). Mechanistically, enzalutamide treatment increases mitochondrial dependence in CRPC cells, rendering them susceptible to cuproptosis, as evidenced by specific reversal with the copper chelator tetrathiomolybdate. This susceptibility is characterized by hallmarks of cuproptosis, including lipoylated protein aggregation and iron‐sulfur cluster protein instability. Interestingly, the mitochondrial matrix reductase, FDX1, specifically correlates with elesclomol sensitivity, suggesting a potential mechanistic divergence between the two copper ionophores. Notably, this synergistic effect extends beyond in vitro models, demonstrating efficacy in 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, enzalutamide significantly enhances copper ionophore‐mediated cytotoxicity in enzalutamide‐resistant cells. Collectively, these findings indicate that enzalutamide and copper ionophores synergistically induce cuproptosis, offering a promising therapeutic avenue for CRPC, potentially including enzalutamide‐resistant cases.

Background: Breast cancer (BC) is a highly common form of cancer that occurs in many parts of the world. However, early -stage BC is curable. Many patients with BC have poor prognostic outcomes owing to ineffective diagnostic and therapeutic tools. The ubiquitination system and associated proteins were found influencing the outcome of individuals with cancer. Therefore, developing a biomarker associated with ubiquitination genes to forecast BC patient outcomes is a feasible strategy. Objective: The primary goal of this work was to develop a novel risk score signature capable of accurately estimate the future outcome of patients with BC by targeting ubiquitinated genes. Methods: Univariate Cox regression analysis was conducted utilizing the E1, E2, and E3 ubiquitination-related genes in the GSE20685 dataset. Genes with p

Background: Previous studies have shown that pyroptosis in hepatocyte is essential for the development of MAFLD. Growing evidence has shown that exosomal miRNAs-mediated communication between inflammatory cells and hepatocyte is an important link in MAFLD. In the present study, we aim to elucidate whether macrophage-derived exosomal miRNAs contribute to the hepatocyte pyroptosis in the pathophysiological process of MAFLD. Methods: The effects of hepatocyte pyroptosis were investigated in an HFD-induced MAFLD mouse model and in the liver tissues from patients with MAFLD using immunohistochemistry, real-time PCR, Western blotting, and luciferase reporter assay, among other techniques. MiR-155 inhibitor tail injections and AAV-FoxO3a-GFP were also administered to respectively inhibit or overexpress its expression in an HFD-induced MAFLD mouse model. Results: Hepatocyte pyroptosis was heightened in the liver tissue of patients with MAFLD or HFD-induced MAFLD mouse. Importantly, treatment with a caspase-1 inhibitor or overexpression of FoxO3a reversed this trend. Our study also demonstrated that miR-155 expression and the number of infiltrated macrophages were increased, and knockdown of miR-155 attenuated hepotocyte pyroptosis and liver fibrosis in HFD-induced mouse. In addition, we demonstrated that macrophage-derived exosomal miR-155 was transferred to hepatocytes, leading to hepatocyte pyroptosis in MAFLD mouse. Furthermore, blockade of exosome secretion improved hepotocyte pyroptosis and liver fibrosis in HFD-induced mouse. On the contrary, macrophage-derived exosomal miR-155 worsened hepotocyte pyroptosis. Moreover, we found that miR-155 promoted hepatocyte pyroptosis in MAFLD by down-regulating FoxO3a. Conclusions: Taken together, our results demonstrated that macrophage-derived exosomal miR-155 promotes hepatocyte pyroptosis and liver fibrosis in MAFLD.

Biological characteristics of pregnant women during early pregnancy make them susceptible to both poor sleep quality and metal/metalloid exposure. However, the effects of metal(loid) exposure on sleep quality in pregnant women remain unknown and unexplored. We aimed to examine the relationship between exposure to a mixture of metal(loid)s and pregnant women’s sleep quality during early pregnancy. We recruited 493 pregnant women in the first trimester from prenatal clinics in Jinan, Shandong Province, China, and collected their spot urine samples. All urine specimens were assessed for eight metal(loid)s: arsenic (As), cadmium (Cd), iron (Fe), zinc (Zn), molybdenum (Mo), lead (Pb), selenium (Se), and mercury (Hg). We used the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Linear regression, logistic regression, generalized additive models (GAMs), quantile g-computation, and Bayesian kernel machine regression (BKMR) were applied to investigate the relationships between metal(loid) exposure and sleep quality. The results from single metal(loid) models, quantile g-computation models, and BKMR models consistently suggested that Fe was positively related to women’s sleep quality. Moreover, in the quantile g-computation models, As was the most critical contributor to the negative effects of the metal(loid) mixture on sleep quality. In addition, we found significant As by Fe interaction for scores of PSQI and habitual sleep efficiency, Pb by Fe interaction for PSQI and sleep latency, and Hg by Fe interaction for PSQI, suggesting the interactive effects of As and Fe, Pb and Fe, Hg and Fe on sleep quality and specific sleep components. Our study provided the first-hand evidence of the effects of metal(loid) exposure on pregnant women’s sleep quality. The underlying mechanisms need to be explored in the future.

Summary: Soft tissues experience strain under mechanical stresses, storing energy as residual stresses and strain energy. However, the specific impact of such strain on cell migration and its molecular mechanisms remains unclear. In this study, we investigated this by using polydimethylsiloxane (PDMS) membranes with varying prestrain levels but constant stiffness to mimic tissue-like conditions. Results showed that higher prestrain levels enhanced 3T3 fibroblast adhesion and reduced filopodia formation. Elevated prestrain also increased integrin and vinculin expression, which was associated with lower cell migration rates. Notably, both 3T3 fibroblasts and primary rat airway smooth muscle cells migrated faster toward higher prestrain areas on substrates with strain gradients. Knockdown of integrin or vinculin inhibited 3T3 cell migration directionality, highlighting their critical role. This research reveals a mechanobiological pathway where strain gradients direct cell migration, providing insight into a common mechanotransduction pathway influencing cellular responses to both stiffness and strain-related mechanical cues.

Microplastics (MPs) and okadaic acid (OA) are known to coexist in marine organisms, potentially impacting humans through food chain. However, the combined toxicity of OA and MPs remains unknown. In this study, mice were orally administered OA at 200 μg/kg bw and MPs at 2 mg/kg bw. The co-exposure group showed a significant increase in malondialdehyde (MDA) content and significant decreases in superoxide dismutase (SOD) activity and glutathione (GSH) level compared to the control, MPs and OA groups (p < 0.05). Additionally, the co-exposure group exhibited significantly higher levels of IL-1β and IL-18 compared to other groups (p < 0.05). These results demonstrated that co-exposure to MPs and OA induces oxidative stress and exacerbates inflammation. Histological and cellular ultrastructure analyses suggested that this combined exposure may enhance gut damage and compromise barrier integrity. Consequently, the concentration of OA in the small intestine of the co-exposure group was significantly higher than that in the OA group. Furthermore, MPs were observed in the lamina propria of the gut in the co-exposure group. Transcriptomic analysis revealed that the co-exposure led to increased expression of certain genes related to the NF-κB/NLRP3 pathway compared to the OA and MPs groups. Overall, this combined exposure may disrupt the intestinal barrier, and promote inflammation through the NF-κB/NLRP3 pathway. These findings provide precious information for the understanding of health risks associated with MPs and phycotoxins.

The microbial fuel cell (MFC), acknowledged as an innovative bioenergy conversion system, has attracted considerable attention in research. An MFC is a device that utilizes microorganisms to directly convert chemical energy present in organic compounds into electrical energy. This bioelectrochemical hybrid system functions not only as a power generation tool but also as an effective instrument for sewage treatment, incorporating nutrient recovery. Its noteworthy advantages encompass energy conservation, sludge reduction, and efficient energy conversion. This paper offers a comprehensive overview of recent cases that involve the synergistic treatment of MFC and traditional sewage treatment technologies. The integration of MFC with conventional sewage treatment processes has demonstrated greater efficiency compared to standalone MFC or traditional sewage treatment methods. This coupled system shows significant promise in converting waste into clean energy, optimizing resource utilization, and addressing the energy crisis. Significantly, the integration of MFC with anaerobic fermentation has attracted considerable attention owing to its distinctive advantages, positioning it as a potential future development trend. The paper concludes by analyzing the multifaceted benefits of this coupling system, providing valuable insights for future research on integrating MFC with other technologies.

The CIE hue angle has significant potential in marine ecology and environment monitoring using remote sensing methods. It is calculated from the remote sensing reflectance (Rrs) of all visible bands, which serves as a comprehensive indicator of seawater radiance information and represents one of the key quantitative parameters for assessing seawater color. In this study, a remote sensing retrieval model of total suspended matter concentration (TSM) was developed using the in situ measured data acquired in the coastal waters of Qinhuangdao from 2013 to 2021. This model, based on the CIE hue angle, achieved performance metrics of R2 = 0.68, MAPE=24.47%, and RMSE=2.72 mg/L, demonstrating better accuracy than traditional empirical models that utilize fewer bands. Based on this model, the monthly and interannual TSM in the coastal waters of Qinhuangdao from 2003 to 2023 were retrieved. Influenced by natural factors, such as the monsoons, the TSM in the coastal waters of Qinhuangdao generally exhibited a trend of first decreasing and then increasing from January to December. Except for certain anomalous years (2007, 2008, 2017, etc.), the overall variation process of TSM from 2003 to 2023 showed an initial increase followed by a decrease, closely related to the pollution reduction management requirements implemented by the Chinese government in different periods. The findings of this paper demonstrate that the coastal waters of Qinhuangdao have become clearer, and the ecological environment has been effectively improved as a result of the Chinese government’s vigorous promotion of ecological civilization construction, adhering to the development concept that ‘lucid waters and lush mountains are invaluable assets’, and by introducing the action plan for the comprehensive treatment of pollution in the Bohai Sea.

ABSTRACT The skin microbiome plays a pivotal role in human health by providing protective and functional benefits. Furthermore, its inherent stability and individual specificity present novel forensic applications. These aspects have sparked considerable research enthusiasm among scholars across various fields. However, the selection of specific 16S rRNA hypervariable regions for skin microbiome studies is not standardized and should be validated through extensive research tailored to different research objectives and targeted bacterial taxa. Notably, third-generation sequencing (TGS) technology leverages the full discriminatory power of the 16S gene and enables more detailed and accurate microbial community analyses. Here, we conducted full-length 16S sequencing of 141 skin microbiota samples from multiple human anatomical sites using the PacBio platform. Based on this data, we generated derived 16S sub-region data through an in silico experiment. Comparisons between the 16S full-length and the derived variable region data revealed that the former can provide superior taxonomic resolution. However, even with full 16S gene sequencing, limitations arise in achieving 100% taxonomic resolution at the species level for skin samples. Additionally, the capability to resolve high-abundance bacteria (TOP30) at the genus level remains generally consistent across different 16S variable regions. Furthermore, the V1-V3 region offers a resolution comparable with that of full-length 16S sequences, in comparison to other hypervariable regions studied. In summary, while acknowledging the benefits of full-length 16S gene analysis, we propose the targeting of specific sub-regions as a practical choice for skin microbial research, especially when balancing the accuracy of taxonomic classification with limited sequencing resources, such as the availability of only short-read sequencing or insufficient DNA.IMPORTANCESkin acts as the primary barrier to human health. Considering the different microenvironments, microbial research should be conducted separately for different skin regions. Third-generation sequencing (TGS) technology can make full use of the discriminatory power of the full-length 16S gene. However, 16S sub-regions are widely used, particularly when faced with limited sequencing resources including the availability of only short-read sequencing and insufficient DNA. Comparing the 16S full-length and the derived variable region data from five different human skin sites, we confirmed the superiority of the V1-V3 region in skin microbiota analysis. We propose the targeting of specific sub-regions as a practical choice for microbial research.

IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.

Oncolytic viruses (OVs) have emerged as a potential strategy for tumor treatment due to their ability to selectively replicate in tumor cells, induce apoptosis, and stimulate immune responses. However, the therapeutic efficacy of single OVs is limited by the complexity and immunosuppressive nature of the tumor microenvironment (TME). To overcome these challenges, engineering OVs has become an important research direction. This review focuses on engineering methods and multi-modal combination therapies for OVs aimed at addressing delivery barriers, viral phagocytosis, and antiviral immunity in tumor therapy. The engineering approaches discussed include enhancing in vivo immune response, improving replication efficiency within the tumor cells, enhancing safety profiles, and improving targeting capabilities. In addition, this review describes the potential mechanisms of OVs combined with radiotherapy, chemotherapy, cell therapy and immune checkpoint inhibitors (ICIs), and summarizes the data of ongoing clinical trials. By continuously optimizing engineering strategies and combination therapy programs, we can achieve improved treatment outcomes and quality of life for cancer patients.