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Abstract Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Inflammation can initiate osteolysis, which is the breakdown of bone by fully developed osteoclasts. The compound Oleandrin is recognized for its effects against inflammation and tumors. Our objective was to examine the effects of Oleandrin on osteoclastogenesis and osteolysis, both in vitro and in vivo. In vitro, the impact of Oleandrin on osteoclastogenesis was assessed using CCK-8 assays, TRAP staining, and bone resorption assays. Additionally, a mouse model of osteolysis caused by LPS injection into the calvaria was used to conduct an in vivo investigation, examining bone histomorphology, histology, and immunohistochemistry. In vitro, concentrations of 5 nM and 10 nM of Oleandrin were found to be non-cytotoxic based on the results obtained. In vitro, Oleandrin hindered the osteoclastogenesis and bone resorption induced by RANKL. Oleandrin successfully inhibited the phosphorylation of NF-κB p65 and PI3K p85 in osteolytic tissue, thereby suppressing LPS-induced inflammatory osteolysis in mice calvaria during the in vivo study. Furthermore, the Oleandrin-treated group exhibited a noteworthy decrease in the expression level of NFATc1, which is a crucial controller of osteoclastogenesis. To sum up, our discoveries indicate that Oleandrin could hinder osteoclastogenesis and bone resorption, thereby having the ability to suppress inflammation-induced osteolysis. The underlying mechanism involves the NF-κB/PI3K pathway and inhibition of NFATc1 activation. Therefore, the findings suggest that Oleandrin holds potential as a therapeutic remedy for osteolytic ailments.

Urolithiasis is a heat-specific disease. Exploring heat-related urolithiasis susceptibility subtypes, economic burden, and modifying factors could assist governments in targeting interventions to reduce the heat-related health risks of urolithiasis morbidity. We collected data on 23,492 patients with upper urinary tract stones (main subtypes of urolithiasis) from 2013 to 2017 in Nanjing, China. We adopted generalized additive quasi-Poisson models to examine the associations between daily mean temperatures and morbidity of upper urinary tract stones, while generalized additive Gaussian models were used to explore the relationships between temperatures and log-transformed medical costs. We examined the modification effects of disease subtypes (kidney and ureteral calculus), sex, and age through stratified analyses and the modification effects of other meteorological factors by introducing interaction terms in the models. We found that short-term summer heat exposure has a statistically significant effect on ureteral calculus morbidity but not on kidney calculus morbidity. For ureter calculus, a 1 °C temperature increase was associated with a 4.36% (95% confidence interval [CI]: 1.94%, 6.83%) increase in daily hospitalization and a 5.44% (95% CI: 2.71%, 8.25%) increase in daily medical costs. The attributable fraction associated with heat (greater than the median value of daily mean temperature, 26.8 °C) was 7.85% (95% empirical confidence interval [eCI]: 3.64%, 11.44%) for hospitalization and 9.36% (95% eCI: 4.91%, 13.14%) for medical costs. The effects of heat on ureter calculus morbidity were significantly higher among the males and those with high sunshine duration than females and those with low sunshine duration. Short-term summer heat exposure was associated with increased morbidity and medical costs of ureteral calculus. Relevant government organizations should take effective intervention measures, including community health education, to reduce the health hazards and economic losses caused by heat.

Abstract Osteoporosis (OP) is a disorder of bone remodeling caused by an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, inhibiting excessive osteoclast activity is one of the promising strategies for treating OP. A major transient receptor potential cation channel, known as transient receptor potential ankyrin 1 (TRPA1), was found to alleviate joint pain and cartilage degeneration in osteoarthritis. However, little research has focused on TRPA1 function in OP. As a result, this study aimed to explore the TRPA1 characteristics and its potential therapeutic function during osteoclastogenesis. The TRPA1 expression gradually increased in the osteoclast differentiation process; however, its suppression with small interfering RNA and an inhibitor (HC030031) significantly controlled the osteoclast count and the expression of osteoclast characteristic genes. Its suppression also inhibited endoplasmic reticulum (ER) stress-related pancreatic ER kinase (PERK) pathways. An ER stress inhibitor (thapsigargin) reversed the down-regulated levels of ER stress and osteoclast differentiation by suppressing TRPA1. Transcriptome sequencing results demonstrated that TRPA1 negatively regulated reactive oxygen species (ROS) and significantly increased the expression of an antioxidant gene, SRXN1. The osteoclast differentiation and the levels of ER stress were enhanced with SRXN1 inhibition. Finally, TRPA1 knockdown targeting macrophages by adeno-associated virus-9 could relieve osteoclast differentiation and osteopenia in ovariectomized mice. In summary, silencing TRPA1 restrained osteoclast differentiation through ROS-mediated down-regulation of ER stress via inhibiting PERK pathways. The study also indicated that TRPA1 might become a prospective treatment target for OP.

Osteosarcoma, which primarily affects children and adolescents, is a highly malignant bone tumor with high rates of disability and mortality. Therefore, the exploration of biological markers related to its occurrence, development, and prognosis is crucial. Genome-wide association studies have revealed the vital role of genetic polymorphisms in the pathogenesis of osteosarcoma. This study aims to provide new insights into reliable biomarkers of osteosarcoma through the analysis of the functional single-nucleotide polymorphisms of tumor-related genes.

Abstract Freeze–thaw cycles are frequently overlooked as a pivotal factor contributing to leakage and structural failures in clayey soil-impermeable barriers used in landfills or tailings repositories in regions subject to seasonal freezing. This investigation explores the recovery and residual strength properties of Jilin ball clay undergoing six freeze–thaw cycles, and assesses the pore structure characteristics through a series of nuclear magnetic resonance (NMR) tests. The results indicate that normal stress has a greater impact on peak recovery strength than dry density and rest periods. Cohesion increases earlier and more significantly during rest periods compared to internal friction angle. Although the pore diameter remains consistent within the micropores during the freeze–thaw cycles, the soil’s structural integrity undergoes notable changes. The concluding analysis provides valuable insights for the construction and management of impermeable barriers in landfills or tailings repositories within seasonally frozen areas.

Abstract The exploitable heap layouts are used to determine the exploitability of heap vulnerabilities in general-purpose applications. Prior studies have focused on using fuzzing-based methods to generate more exploitable heap layouts. However, the exploitable heap layout cannot fully demonstrate the exploitability of a vulnerability, as it is uncertain whether the attacker can control the data covered by the overflow. In this paper, we propose the Heap Overflow Exploitability Evaluator (Hoee), a new approach to automatically reveal the exploitability of heap buffer overflow vulnerabilities by evaluating proof-of-concepts (PoCs) generated by fuzzers. Hoee leverages several techniques to collect dynamic information at runtime and recover heap object layouts in a fine-grained manner. The overflow context is carefully analyzed to determine whether the sensitive pointer is corrupted, tainted, or critically used. We evaluate Hoee on 34 real-world CVE vulnerabilities from 16 general-purpose programs. The results demonstrate that Hoee accurately identifies the key factors for developing exploits in vulnerable contexts and correctly recognizes the behavior of overflow.

Abstract Jellyfish exhibit innovative swimming patterns that contribute to exploring the origins of animal locomotion. However, the genetic and cellular basis of these patterns remains unclear. Herein, we generated chromosome-level genome assemblies of two jellyfish species, Turritopsis rubra and Aurelia coerulea, which exhibit straight and free-swimming patterns, respectively. We observe positive selection of numerous genes involved in statolith formation, hair cell ciliogenesis, ciliary motility, and motor neuron function. The lineage-specific absence of otolith morphogenesis- and ciliary movement-related genes in T. rubra may be associated with homeostatic structural statocyst loss and straight swimming pattern. Notably, single-cell transcriptomic analyses covering key developmental stages reveal the enrichment of diapause-related genes in the cyst during reverse development, suggesting that the sustained diapause state favours the development of new polyps under favourable conditions. This study highlights the complex relationship between genetics, locomotion patterns and survival strategies in jellyfish, thereby providing valuable insights into the evolutionary lineages of movement and adaptation in the animal kingdom.

Abstract Background Spinal cord injury (SCI) is characterized by extensive demyelination and inflammatory responses. Facilitating the clearance of lipid droplets (LDs) within microglia contributes to creating a microenvironment that favors neural recovery and provides essential materials for subsequent remyelination. Therefore, investigating MicroRNAs (miRNAs) that regulate lipid homeostasis after SCI and elucidating their potential mechanisms in promoting LDs clearance in microglia have become focal points of SCI research. Methods We established a subacute C5 hemicontusion SCI model in mice and performed transcriptomic sequencing on the injury epicenter to identify differentially expressed genes and associated pathways. Confocal imaging was employed to observe LDs accumulation. Multi-omics analyses were conducted to identify differentially expressed mRNA and miRNA post-SCI. Pathway enrichment analysis and protein-protein interaction network construction were performed using bioinformatics methods, revealing miR-223-Abca1 as a crucial miRNA-mRNA pair in lipid metabolism regulation. BV2 microglia cell lines overexpressing miR-223 were engineered, and immunofluorescence staining, western blot, and other techniques were employed to assess LDs accumulation, relevant targets, and inflammatory factor expression, confirming its role in regulating lipid homeostasis in microglia. Results Histopathological results of our hemicontusion SCI model confirmed LDs aggregation at the injury epicenter, predominantly within microglia. Our transcriptomic analysis during the subacute phase of SCI in mice implicated ATP-binding cassette transporter A1 (Abca1) as a pivotal gene in lipid homeostasis, cholesterol efflux and microglial activation. Integrative mRNA-miRNA multi-omics analysis highlighted the crucial role of miR-223 in the neuroinflammation process following SCI, potentially through the regulation of lipid metabolism via Abca1. In vitro experiments using BV2 cells overexpressing miR-223 demonstrated that elevated levels of miR-223 enhance ABCA1 expression in myelin debris and LPS-induced BV2 cells. This promotes myelin debris degradation and LDs clearance, and induces a shift toward an anti-inflammatory M2 phenotype. Conclusions In summary, our study unveils the critical regulatory role of miR-223 in lipid homeostasis following SCI. The mechanism by which this occurs involves the upregulation of ABCA1 expression, which facilitates LDs clearance and myelin debris degradation, consequently alleviating the lipid burden, and inhibiting inflammatory polarization of microglia. These findings suggest that strategies to enhance miR-223 expression and target ABCA1, thereby augmenting LDs clearance, may emerge as appealing new clinical targets for SCI treatment.

In this paper, nano-Ti-2Fe-0.1B alloys with different grain sizes were processed by high pressure torsion (HPT) deformation. The study examined the microstructural evolution of the Ti–2Fe-0.1B alloy during HPT and evaluated its mechanical properties through microhardness and tensile tests. The results of the microstructural observations revealed that the grain size of the Ti–2Fe-0.1B alloy progressively decreased from 3.14 μm in the as-annealed state to approximately 20 nm after 10 turns. In the initial state, the alloy consists of α-phase and β-phases, with a volume ratio of approximately 5:1. During the HPT process, transformations of α-phase and β-phase to ω-phase were observed. The primary reason for this is that the shear forces applied during the HPT process facilitated the phase transformation of the α-phase. Additionally, the presence of Fe element in the alloy altered the lattice compatibility between the grains of β-phase and ω-phase, thereby promoting the phase transformation of the β-phase, with the accumulated turns of HPT process, the fraction of ω-phase increased in the beginning gradually, then decreased, which reached to the maximum 80.8% in the 5 turns. This is higher than that of pure titanium and Ti–Fe alloys under the same conditions, because the proportion of the ω-phase increases with the increase in Fe content. Studies of mechanical properties demonstrated that HPT can substantially enhance the hardness of Ti–2Fe-0.1B alloys to as high as 483 HV, and the tensile strength of the Ti–2Fe-0.1B alloy was observed to increase from 725 MPa to 1568 MPa after 5 turns, which is much higher than Ti–6Al–4V subjected to the identical processing conditions. It can be ascribed to the exist of mass ω-phase as well as finer grain size in nanocrystalline Ti–2Fe-0.1B alloy.

Current methodologies for cleaning wind power anomaly data exhibit limited capabilities in identifying abnormal data within extensive datasets and struggle to accommodate the considerable variability and intricacy of wind farm data. Consequently, a method for cleaning wind power anomaly data by combining image processing with community detection algorithms (CWPAD-IPCDA) is proposed. To precisely identify and initially clean anomalous data, wind power curve (WPC) images are converted into graph structures, which employ the Louvain community recognition algorithm and graph- theoretic methods for community detection and segmentation. Furthermore, the mathematical morphology operation (MMO) determines the main part of the initially cleaned wind power curve images and maps them back to the normal wind power points to complete the final cleaning. The CWPAD-IPCDA method was applied to clean datasets from 25 wind turbines (WTs) in two wind farms in northwest China to validate its feasibility. A comparison was conducted using density-based spatial clustering of applications with noise (DBSCAN) algorithm, an improved isolation forest algorithm, and an image-based (IB) algorithm. The experimental results demonstrate that the CWPAD-IPCDA method surpasses the other three algorithms, achieving an approximately 7.23% higher average data cleaning rate. The mean value of the sum of the squared errors (SSE) of the dataset after cleaning is approximately 6.887 lower than that of the other algorithms. Moreover, the mean of overall accuracy, as measured by the F1-score, exceeds that of the other methods by approximately 10.49%; this indicates that the CWPAD-IPCDA method is more conducive to improving the accuracy and reliability of wind power curve modeling and wind farm power forecasting.

Abstract Background Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigated the involvement of microRNAs (miRNAs) in lipophagy during demyelinating diseases, assessed their capacity to modulate LDAM subtypes, and elucidated the potential underlying mechanisms involved. Methods C57BL/6 mice were used for in vivo experiments. Two weeks post demyelination induction at cervical level 4 (C4), histological assessments and confocal imaging were performed to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. miRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. The role of miR-223 in lipophagy under these conditions was specifically explored. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral infection, validated the bioinformatics findings. Immunofluorescence staining was used to measure LD accumulation, autophagy levels, target gene expression, and inflammatory mediator levels to elucidate the mechanisms of action of miR-223 in LDAM. Results Oil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy revealed increased numbers of autophagic vacuoles at the injury site. Multi-omics analysis revealed miR-223 as a crucial regulatory gene in lipophagy during demyelination. It was identified that cathepsin B (CTSB) targets miR-223 in autophagy to integrate miRNA, mRNA, and autophagy gene databases. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased the expression of the inflammatory mediator IL-1β. Conclusion These findings indicate that miR-223 plays a pivotal role in lipophagy under demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens the understanding of the molecular mechanisms of lipophagy and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases.

Background: Epidemiological reports indicate a potential association between androgenic alopecia (AGA) and increased prostate cancer (PC) prevalence, but conflicting reports also exist. This study aims to elucidate the causality of AGA on PC risk using Mendelian randomization (MR) analysis. Materials and methods: Two-sample MR analyses utilized public genome-wide association studies summary data for single-nucleotide polymorphisms associated with AGA. Four statistical methods were used: inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode, with IVW as the preliminary estimation method. Additionally, sensitivity analyses were conducted to address pleiotropic bias. Results: Genetically proxied AGA did not demonstrate a causal effect on PC risk (IVW P > 0.05). Consistently, complementary methods yielded results aligned with IVW. Conclusions: Our MR analysis indicates no causal relationship between genetically predicted AGA and PC risk, suggesting that observed associations in epidemiological studies may not be causal.

Despite the existence of many interventions to mitigate or adapt to the health effects of climate change, their effectiveness remains unclear. Here, we introduce the Comprehensive Evaluation Framework for Intervention on Health Effects of Ambient Temperature to evaluate study designs and effects of intervention studies. The framework comprises three types of interventions: proactive, indirect, and direct, and four categories of indicators: classification, methods, scope, and effects. We trialed the framework by an evaluation of existing intervention studies. The evaluation revealed that each intervention has its own applicable characteristics in terms of effectiveness, feasibility, and generalizability scores. We expanded the framework's potential by offering a list of intervention recommendations in different scenarios. Future applications are then explored to establish models of the relationship between study designs and intervention effects, facilitating effective interventions to address the health effects of ambient temperature under climate change.

Abstract Electron microscopy (EM) revolutionized the way to visualize cellular ultrastructure. Volume EM (vEM) has further broadened its three-dimensional nanoscale imaging capacity. However, intrinsic trade-offs between imaging speed and quality of EM restrict the attainable imaging area and volume. Isotropic imaging with vEM for large biological volumes remains unachievable. Here, we developed EMDiffuse, a suite of algorithms designed to enhance EM and vEM capabilities, leveraging the cutting-edge image generation diffusion model. EMDiffuse generates realistic predictions with high resolution ultrastructural details and exhibits robust transferability by taking only one pair of images of 3 megapixels to fine-tune in denoising and super-resolution tasks. EMDiffuse also demonstrated proficiency in the isotropic vEM reconstruction task, generating isotropic volume even in the absence of isotropic training data. We demonstrated the robustness of EMDiffuse by generating isotropic volumes from seven public datasets obtained from different vEM techniques and instruments. The generated isotropic volume enables accurate three-dimensional nanoscale ultrastructure analysis. EMDiffuse also features self-assessment functionalities on predictions’ reliability. We envision EMDiffuse to pave the way for investigations of the intricate subcellular nanoscale ultrastructure within large volumes of biological systems.

Abstract Engineering natural microbiomes for biotechnological applications remains challenging, as metabolic interactions within microbiomes are largely unknown, and practical principles and tools for microbiome engineering are still lacking. Here, we present a combinatory top-down and bottom-up framework to engineer natural microbiomes for the construction of function-enhanced synthetic microbiomes. We show that application of herbicide and herbicide-degrader inoculation drives a convergent succession of different natural microbiomes toward functional microbiomes (e.g., enhanced bioremediation of herbicide-contaminated soils). We develop a metabolic modeling pipeline, SuperCC, that can be used to document metabolic interactions within microbiomes and to simulate the performances of different microbiomes. Using SuperCC, we construct bioremediation-enhanced synthetic microbiomes based on 18 keystone species identified from natural microbiomes. Our results highlight the importance of metabolic interactions in shaping microbiome functions and provide practical guidance for engineering natural microbiomes.

Coherent precipitation, a common strengthening approach, is typically subjected to spatial non-uniformity due to microscopic segregation, leading to multi-scale stress heterogeneity. Such heterogeneity remains poorly characterized because unavailable local strain-free lattice parameters invalidate traditional diffraction-based stress measurement techniques. To overcome these limitations, we demonstrate a submicron-resolved synchrotron X-ray diffraction method to map coherency stress distribution based on the γ/γ′ lattice misfits in Ni-based superalloys. Assisted by finite element analysis, sub-dendritic stresses are deduced from heterogeneous coherency stresses, confirmed by the diffraction experiments. The methodology offers a comprehensive framework to assess stress heterogeneity at multi-scales for all coherent precipitation strengthened alloys.Impact statementThis study marks the first successful quantification of stress heterogeneity at multi-scales in alloys strengthened by non-uniform coherent precipitation, even in absence of strain-free lattice constants.

Vitamin B6 plays a crucial role in cellular metabolism and stress response, making it an essential component for growth in all known organisms. However, achieving efficient biosynthesis of vitamin B6 faces the challenge of maintaining a balanced distribution of metabolic flux between growth and production. In this study, our focus is on addressing this challenge through the engineering of phosphoserine aminotransferase (SerC) to resolve its redundancy and promiscuity. The enzyme SerC was semi-designed and screened based on sequences and predicted kcat values, respectively. Mutants and heterologous proteins showing potential were then fine-tuned to optimize the production of vitamin B6. The resulting strain enhances the production of vitamin B6, indicating that different fluxes are distributed to the biosynthesis pathway of serine and vitamin B6. This study presents a promising strategy to address the challenge posed by multifunctional enzymes, with significant implications for enhancing biochemical production through engineering processes.

This paper provided an effective method to further improve the mechanical properties of the AZ80+0.4%Ce magnesium alloy wheel spoke. The effect of high strength and ductility was obtained with a yield strength of 295.36 MPa, an elongation of 10%, by the combination of pre-deformation (7% deformation) and two-stage aging treatment (120 °C/9 h + 175 °C/24 h). The evolution of the microstructure and properties of the alloy was explored under the coupling conditions of different pre-deformation degrees and multi-stage aging. The results show that, pre-deformation introduced a large number of (101¯2) tensile twinning and dislocations, which greatly promoted the probability of continuous precipitates (CPs) appearing. On the contrary, the discontinuous precipitates (DPs) were limited by the vertical and horizontal twin structure. As a result, the pre-nucleation method of two-stage aging increased the proportion of CPs by 34%-38%. Owing to the DPs was effectively suppressed, the alloy's yield strength has been greatly improved. Besides, under multi-stage aging, the twin boundaries induce protruding nucleation to form static recrystallization by hindering the migration of dislocations, and the matrix swallows the twins, then the texture gradually tilts from the two poles to the basal plane. As an important supplement, the grain refinement and oblique texture promoted the improvement of the yield strength of the component.

Abstract The mechanism of hypoxia in chemoresistance of pancreatic ductal adenocarcinoma (PDAC) remains elusive. In this study, we revealed the essential role of miR-485-3p in PDAC, particularly its impact on cancer stemness and gemcitabine resistance under hypoxic conditions. We found substantial downregulation of miR-485-3p in PDAC tissues, with lower expression correlating to poor patient outcomes. Mechanistically, miR-485-3p influenced stemness characteristics, as evidenced by reduced tumor-sphere formation and increased sensitivity to gemcitabine upon overexpression. Moreover, we identified SOX9 and SLC7A11 as two targets of miR-485-3p, which play a vital role in stemness and ferroptosis. Under the hypoxic condition, DNMT3B expression was upregulated, leading to hypermethylation of the miR-485-3p promoter region. The reduced miR-485-3p expression promoted stemness and chemoresistance of PDAC. In conclusion, our findings elucidate the intricate interplay of hypoxia, epigenetic modifications, and ferroptosis in PDAC and shed light on potential avenues for targeted interventions that modulate cancer stemness and chemosensitivity, offering prospects for improved therapeutic strategies for PDAC.

Abstract Background The patterns of blood pressure (BP) change throughout the pregnancy were related to adverse birth outcomes. However, little is known about the long-term effect of BP change patterns on child neurodevelopment. This study aimed to explore the relationship between the BP trajectory and BP variability during pregnancy and early childhood neurodevelopment. Method A total of 2797 mother-newborn pairs were derived from the Wuhan Healthy Baby Cohort Study. BP was measured during each antenatal visit, and Mental and Psychomotor Development Indexes (MDI and PDI) were assessed using the Bayley Scales of Infant Development (BSID) when the children were 2 years old. Delayed neurodevelopment was defined as scores of PDI or MDI less than − 1SD relative to the mean score of the study population. A group-based multi-trajectory model was adopted to identify multi-trajectories of systolic blood pressure (SBP) and diastolic blood pressure (DBP). Visit-to-visit BP variability was assessed by the coefficient of variation (CV), standard deviation (SD), and average real variability (ARV). Generalized linear models and multivariate logistic regressions were used to assess the associations of BP trajectories and variability with BSID scores and delayed neurodevelopment, respectively. Results Five distinct trajectories for SBP and DBP were identified, namely, “Low-increasing,” “Low-stable,” “Moderate-decreasing,” “Moderate-increasing,” and “High-stable” groups. Compared with the “Low-stable” group, the children whose mothers’ BP fell into the other four groups had lower PDI scores, and mothers in the “Low-increasing,” “Moderate-increasing,” and “Moderate-decreasing” groups had 43% (OR: 1.43, 95% CI: 1.01, 2.03), 48% (OR: 1.48, 95% CI: 1.05, 2.08) and 45% (OR:1.45, 95% CI: 1.03, 2.04) higher risk of having offspring with delayed psychomotor neurodevelopment, respectively. High DBP variability was associated with lower BSID scores, and delayed psychomotor neurodevelopment (OR = 1.46, 95% CI: 1.10, 1.92 for DBP-SD; OR = 1.53, 95% CI: 1.16, 2.02 for DBP-CV). Conclusion Our findings suggest that BP change patterns assessed by multi-trajectory and visit-to-visit variability were associated with lower BSID scores and delayed neurodevelopment. Health professionals should be aware of the influence of BP level and its oscillations during pregnancy on the risk of delayed neurodevelopment.

Abstract Cervical cancer is a significant global health issue, its prevalence and prognosis highlighting the importance of early screening for effective prevention. This research aimed to create and validate an artificial intelligence cervical cancer screening (AICCS) system for grading cervical cytology. The AICCS system was trained and validated using various datasets, including retrospective, prospective, and randomized observational trial data, involving a total of 16,056 participants. It utilized two artificial intelligence (AI) models: one for detecting cells at the patch-level and another for classifying whole-slide image (WSIs). The AICCS consistently showed high accuracy in predicting cytology grades across different datasets. In the prospective assessment, it achieved an area under curve (AUC) of 0.947, a sensitivity of 0.946, a specificity of 0.890, and an accuracy of 0.892. Remarkably, the randomized observational trial revealed that the AICCS-assisted cytopathologists had a significantly higher AUC, specificity, and accuracy than cytopathologists alone, with a notable 13.3% enhancement in sensitivity. Thus, AICCS holds promise as an additional tool for accurate and efficient cervical cancer screening.

Abstract Background The animal sperm shows high diversity in morphology, components, and motility. In the lepidopteran model insect, the silkworm Bombyx mori, two types of sperm, including nucleate fertile eupyrene sperm and anucleate unfertile apyrene sperm, are generated. Apyrene sperm assists fertilization by facilitating the migration of eupyrene spermatozoa from the bursa copulatrix to the spermatheca. During spermatogenesis, eupyrene sperm bundles extrude the cytoplasm by peristaltic squeezing, while the nuclei of the apyrene sperm bundles are discarded with the same process, forming matured sperm. Results In this study, we describe that a mechanoreceptor BmPiezo, the sole Piezo ortholog in B. mori, plays key roles in larval feeding behavior and, more importantly, is essential for eupyrene spermatogenesis and male fertility. CRISPR/Cas9-mediated loss of BmPiezo function decreases larval appetite and subsequent body size and weight. Immunofluorescence analyses reveal that BmPiezo is intensely localized in the inflatable point of eupyrene sperm bundle induced by peristaltic squeezing. BmPiezo is also enriched in the middle region of apyrene sperm bundle before peristaltic squeezing. Cytological analyses of dimorphic sperm reveal developmental arrest of eupyrene sperm bundles in BmPiezo mutants, while the apyrene spermatogenesis is not affected. RNA-seq analysis and q-RT-PCR analyses demonstrate that eupyrene spermatogenic arrest is associated with the dysregulation of the actin cytoskeleton. Moreover, we show that the deformed eupyrene sperm bundles fail to migrate from the testes, resulting in male infertility due to the absence of eupyrene sperm in the bursa copulatrix and spermatheca. Conclusions In conclusion, our studies thus uncover a new role for Piezo in regulating spermatogenesis and male fertility in insects.

Abstract Background Pulmonary fibromatosis (PF) is a specific variant of fibromatosis, which is rarely reported occurring in the lung. PF with HIPK2-YAP1 fusion was a novel entity. Case presentation In this report, a 66-year-old male with PF had been smoking over 40 years. Multiple cords and small nodules in both lungs had been detected in a health examination two years earlier at our hospital. But approximately twofold enlarged in the lingual segment of the upper lobe in the left lung were disclosed in this year. Immunohistochemical analysis demonstrated that the vimentin and β-Catenin were positive in the largest nodule. After underwent a DNA/RNA panel next-generation sequencing (NGS), missense mutations and HIPK2-YAP1 fusion were found in this sample. Ultimately, the case diagnosis as PF with HIPK2-YAP1 fusion after multidisciplinary treatment. Currently, the patient is doing well and recurrence-free at 14 months post-surgery. Conclusions It’s difficult for patients with complex morphology to make accurate diagnosis solely based on morphology and immunohistochemistry. But molecular detection is an effective method for further determining pathological subtypes.

Abstract Background Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone. Methods A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children’s Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher’s exact test, and survival was analyzed by the Kaplan–Meier method. Results DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P

Abstract Background Patients with immunocompromise were suspected to encounter a high risk for severe coronavirus disease 2019 (COVID-19) infection on early period; however, data is lacking nowadays and immune response remain unclear. Methods In this retrospective study, internet questionnaire survey and medical records were acquired in pediatric hematology oncology patients. Clinical severity, immunological characteristics, and outcomes were analyzed from December 1, 2022 to January 31, 2023 at the 3rd year of pandemic in China. Results A total of 306 patients were included, with 21 patients (6.9%) asymptomatic, 262 (85.6%) mild severity, 17 (5.6%) moderate severity, 5 (1.6%) severe severity, and 1 (0.3%) critical severity. Seventy-eight (25.5%) patients were on intensive chemotherapy, and 32.0% children were on maintenance chemotherapy. Delays in cancer therapy occurred in 86.7% patients. Univariable analysis revealed active chemotherapy (P

Abstract Objective Placenta accreta spectrum disorder (PAS) is a serious obstetric complication associated with significant maternal morbidity and mortality. Prophylactic balloon occlusion (PBO), as an intravascular interventional therapies, has emerged as a potential management strategy for controlling massive hemorrhage in patients with PAS. However, current evidence about the clinical application of PBO in PAS patients are still controversial. This study aimed to evaluate the effectiveness and safety of PBO in the management of PAS. Methods A retrospective cohort study including PAS patients underwent cesarean delivery was conducted in a tertiary hospital from January 2015 to March 2022. Included PAS patients were further divided into balloon and control groups by whether PBO was performed. Groups were compared for demographic characteristics, intraoperative and postoperative parameters, maternal and neonatal outcomes, PBO-related complication and follow up outcomes. Additionally, multivariate-logistic regression analysis was performed to determine the definitive associations between PBO and risk of massive hemorrhage and hysterectomy. Results A total of 285 PAS patients met the inclusion criteria were included, of which 57 PAS patients underwent PBO (PBO group) and 228 women performed cesarean section (CS) without PBO (control group). Irrespective of the differences of baseline characteristics between the two groups, PBO intervention did not reduce the blood loss, hysterectomy rate and postoperative hospital stay, but it prolonged the operation time and increased the cost of hospitalization (All P 0.05). In particular, patients undergoing PBO were more likely to develop the venous thrombosis postoperatively (P = 0.001). However, multivariate logistic regression analysis showed that PBO significantly decreased the risk of massive hemorrhage (OR 0.289, 95%CI:0.109–0.766, P = 0.013). The grade of PAS and MRI with S2 invasion were the significant risk factors affecting massive hemorrhage(OR:6.232 and OR:5.380, P

Abstract Background It is challenging to identify residual or recurrent fistulas from the surgical region, while MR imaging is feasible. The aim was to use dynamic contrast-enhanced MR imaging (DCE-MRI) technology to distinguish between active anal fistula and postoperative healing (granulation) tissue. Methods Thirty-six patients following idiopathic anal fistula underwent DCE-MRI. Subjects were divided into Group I (active fistula) and Group IV (postoperative healing tissue), with the latter divided into Group II (≤ 75 days) and Group III (> 75 days) according to the 75-day interval from surgery to postoperative MRI reexamination. MRI classification and quantitative analysis were performed. Correlation between postoperative time intervals and parameters was analyzed. The difference of parameters between the four groups was analyzed, and diagnostic efficiency was tested by receiver operating characteristic curve. Results Wash-in rate (WI) and peak enhancement intensity (PEI) were significantly higher in Group I than in Group II (p = 0.003, p = 0.040), while wash-out rate (WO), time to peak (TTP), and normalized signal intensity (NSI) were opposite (p = 0.031, p = 0.007, p = 0.010). Area under curves for discriminating active fistula from healing tissue within 75 days were 0.810 in WI, 0.708 in PEI, 0.719 in WO, 0.783 in TTP, 0.779 in NSI. All MRI parameters were significantly different between Group I and Group IV, but not between Group II and Group III, and not related to time intervals. Conclusion In early postoperative period, DCE-MRI can be used to identify active anal fistula in the surgical area. Trial registration Chinese Clinical Trial Registry: ChiCTR2000033072.

Abstract Background Diminished ovarian reserve (DOR) is one of the obstacles affecting the reproductive outcomes of patients receiving assisted reproductive therapy. The purpose of this study was to investigate whether dual trigger, including gonadotropin‐releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG), can improve pregnancy outcomes in patients with DOR undergoing in vitro fertilization (IVF) cycles using mild stimulation protocols. Methods A total of 734 patients with DOR were included in this retrospective study. Patients were divided into a recombinant hCG trigger group and a dual trigger group (hCG combined with GnRHa) according to the different trigger drugs used. The main outcome measures included the number of oocytes retrieved, the fertilization rate, the number of transferable embryos, the implantation rate, the clinical pregnancy rate, the miscarriage rate, the live birth rate (LBR), and the cumulative live birth rate (CLBR). Generalized linear model and logistic regression analyses were performed for confounding factors. Results There were 337 cycles with a single hCG trigger and 397 cycles with dual trigger. The dual trigger group demonstrated significantly higher numbers of retrieved oocytes [3.60 vs. 2.39, adjusted β = 0.538 (0.221–0.855)], fertilized oocytes [2.55 vs. 1.94, adjusted β = 0.277 (0.031–0.523)] and transferable embryos [1.22 vs. 0.95, adjusted β = 0.162 (-0.005–0.329)] than did the hCG trigger group, whereas no significant difference in the fertilization rate was observed between the two groups. Moreover, the embryo transfer cancellation rate (35.5% vs. 43.9%) was obviously lower in the dual trigger group. Among the fresh embryo transfer cycles, the implantation rate, clinical pregnancy rate, miscarriage rate and live birth rate were similar between the two groups. After controlling for potential confounding variables, the trigger method was identified as an independent factor affecting the number of oocytes retrieved but had no significant impact on the CLBR. Conclusions Dual triggering of final oocyte maturation with hCG combined with GnRHa can significantly increase the number of oocytes retrieved in patients with DOR but has no improvement effect on the implantation rate, clinical pregnancy rate or LBR of fresh cycles or on the CLBR.

The global renewable energy portfolio is experiencing a growing proportion of shipboard photovoltaic (PV) energy. Grid-connected system has become the development trend of photovoltaic power generation technology in marine applications because of its high energy utilization efficiency. However, in the grid-connected process, harmonic pollution is easily caused by time-varying marine environment disturbance, which affects the quality of grid-connected power. The current recurrent neural network Levenberg-Marquardt backpropagation (CRNN-LM-BP) method, a control methodology, is introduced in this paper to ensure the robustness, stability, and consistency of the system. In addition, the inductance-capacitance-inductance (LCL) filter is optimized using particle swarm optimization (PSO) to minimize the presence of high frequency harmonics. The system that has been developed possesses the ability to improve the accuracy of steady-state control, operate with high efficiency and effectiveness, and maintain a total harmonic distortion of 1.73 %. Concurrently, streamlining the Jacobian matrix in the LM algorithm expedites convergence. It enables the system to improve its dynamic response, minimize excess, and quickly return to a stable condition when faced with load variations, a wide range of filter parameter adjustments, and voltage fluctuations. The suggested method’s effectiveness and applicability are evaluated by comparing it to the traditional proportional-resonant control, CRNN-BP control, using Matlab/Simulink and the real-time simulator OPAL-RT5700..

High-resolution Digital Elevation Models (DEMs) are essential for precise geographic analysis. However, obtaining high-resolution DEMs in regions with dense vegetation, complex terrain, or satellite imagery voids presents substantial challenges. This study introduces a deep learning approach using three-dimensional (3D) terrain features combined with Conditional Generative Adversarial Networks (CGANs) to reconstruct DEMs. The 3D terrain features, such as valley and ridge lines, exhibit topographic relief patterns and provide constraints for CGANs to reconstruct DEMs. Experiments conducted in the Loess Plateau of Shaanxi confirmed the performance of the proposed method, demonstrating marked improvements in the accuracy of DEM reconstruction compared to models based on two-dimensional (2D) terrain features. The elevation accuracy of the reconstructed DEMs by the proposed method is 5.30 m, which is higher than that of the 2D terrain features method (18.90 m) by 71.96 %. Meanwhile, the proposed method shows a 15.78 % and 17.64 % improvement in elevation accuracy and slope accuracy, respectively, when reconstructing a 5 m high-resolution DEM from a 30 m low-resolution DEM. The proposed method can be flexibly used for reconstructing, repairing, and filling voids in DEM data.

Atomic-level manufacturing is fundamentally concerned with the precise removal, addition, and migration of material at the atomic and close-to-atomic scale (ACS). Tip-based electrochemical deposition, a quintessential ACS electrochemical additive manufacturing technique, offers promising prospects for achieving bottom-up fabrication of metallic micro/nano structures. However, the complex physicochemical reactions involved in electrodes lead to a limited understanding of the mechanisms underlying atomic electrodeposition and structural evolution. For the first time, this study proposes electric double-layer controlled electrochemical kinetics and investigates the effect of direct current (DC) and pulse current (PC) on nickel atomic electrodeposition using molecular dynamics (MD) simulations. The findings reveal that compared to DC electrodeposition, PC electrodeposition results in more orderly deposition morphology, improved surface smoothness, reduced dislocation density, and lower crystal distortion, with these effects being particularly pronounced under low pulse duty ratio conditions. In addition, the pulse frequency significantly influences the morphology and structure of the deposit. The high pulse frequency yields smoother surfaces with local protrusions, while the low frequency favors the formation of orderly and dense structures excepting slightly increased roughness. This study provides critical insights into understanding the microscopic mechanisms of atomic-scale electrodeposition processes and achieving atomically controlled tip-based electrochemical additive manufacturing of micro/nanodevices.

The advancement of industrialization and urbanization has exacerbated global water pollution. Chemical Oxygen Demand (COD) serves as a crucial metric for assessing organic contamination in aquatic environments. Consequently, the spatiotemporal characteristics and driving factors of COD emissions have emerged as a significant area of current research interest. This study employs spatial autocorrelation and geodetector methods to rigorously analyze the spatial–temporal patterns and principal drivers of COD emissions in China’s wastewater, drawing on eleven geographic and socio-economic datasets spanning from 2011 to 2019. This study indicates that COD emissions in China’s wastewater have consistently decreased annually between 2011 and 2019, with a marked reduction observed post-2016. Regarding spatial distribution, COD emissions in the eastern region significantly surpass those in the western region, highlighting pronounced regional disparities. The analysis of the global Moran’s Index indicates that the COD emissions across China’s provincial regions demonstrate spatial clustering of similar values, with this clustering intensifying annually. Furthermore, the local Moran’s Index identifies the precise locations of these spatial clusters. Geodetector analysis identified that the consumption of nitrogen fertilizers and the consumption of chemical fertilizers had substantial impacts on COD emissions, whereas the proportion of urban population at year-end and the number of granted inventions exerted lesser effects. Furthermore, the interaction between two factors notably enhances the explanatory power regarding COD emissions. This research underpins the formulation of efficacious pollution control and environmental protection strategies, contributing vital insights for the stewardship of water quality.

The capacity of conventional overhead transmission lines (OTL) has been exceeded by the energy consumption of Cambodia's flourishing cities. Underground transmission lines (UTL) provide a unique solution due to their technical and environmental advantages. However, engineers must contend with high UTL costs and the need for effective conduit cable installation. This study presents a solution that automates the shortest route method for determining the optimal path for routing UTL power supply cables between any two substations. Multiple algorithms are evaluated to identify the most effective solution to this design's inherent shortest-path problem. Using Geographic Information System (GIS) data, potential UTL network routes in Phnom Penh, Cambodia can be investigated. The ultimate product is an automated route planning support tool that has the potential to revolutionize energy project planning by generating optimal routes for UTL. This will increase efficiency and lower costs, making UTL a more viable option for meeting the energy demands of modern infrastructure. This study contributes significantly to the field of energy infrastructure planning and has the potential to be replicated in cities around the world.

Objective To better understand the state of research on the effects of climate change on human health, including exposures, health conditions, populations, areas of the world studied, funding sources, and publication characteristics, with a focus on topics that are relevant for populations at risk.Design Cross sectional study.Data sources The National Institute of Environmental Health Sciences climate change and human health literature portal, a curated bibliographical database of global peer reviewed research and grey literature was searched. The database combines searches of multiple search engines including PubMed, Web of Science, and Google Scholar, and includes added-value expert tagging of climate change exposures and health impacts.Eligibility criteria Inclusion criteria were peer reviewed, original research articles that investigated the health effects of climate change and were published in English from 2012 to 2021. After identification, a 10% random sample was selected to manually perform a detailed characterisation of research topics and publication information.Results 10 325 original research articles were published between 2012 and 2021, and the number of articles increased by 23% annually. In a random sample of 1014 articles, several gaps were found in research topics that are particularly relevant to populations at risk, such as those in the global south (134 countries established through the United Nations Office for South-South Cooperation) (n=444; 43.8%), adults aged 65 years or older (n=195; 19.2%), and on topics related to human conflict and migration (n=25; 2.5%) and food and water quality and security (n=148; 14.6%). Additionally, fewer first authors were from the global south (n=349; 34.4%), which may partly explain why research focusing on these countries is disproportionally less.Conclusions Although the body of research on the health effects of climate change has grown substantially over the past decade, including those with a focus on the global south, a disproportionate focus continues to be on countries in the global north and less at risk populations. Governments are the largest source of funding for such research, and governments, particularly in the global north, need to re-orient their climate and health research funding to support researchers in the global south and to be more inclusive of issues that are relevant to the global south.

Bathymodioline mussels dominate deep-sea methane seep and hydrothermal vent habitats and obtain nutrients and energy primarily through chemosynthetic endosymbiotic bacteria in the bacteriocytes of their gill. However, the molecular mechanisms that orchestrate mussel host–symbiont interactions remain unclear. Here, we constructed a comprehensive cell atlas of the gill in the mussel Gigantidas platifrons from the South China Sea methane seeps (1100 m depth) using single-nucleus RNA-sequencing (snRNA-seq) and whole-mount in situ hybridisation. We identified 13 types of cells, including three previously unknown ones, and uncovered unknown tissue heterogeneity. Every cell type has a designated function in supporting the gill’s structure and function, creating an optimal environment for chemosynthesis, and effectively acquiring nutrients from the endosymbiotic bacteria. Analysis of snRNA-seq of in situ transplanted mussels clearly showed the shifts in cell state in response to environmental oscillations. Our findings provide insight into the principles of host–symbiont interaction and the bivalves' environmental adaption mechanisms.

PurposeTo enhance the accuracy of real-time four-dimensional cone beam CT (4D-CBCT) imaging by incorporating spatiotemporal correlation from the sequential projection image into the single projection-based 4D-CBCT estimation process.MethodsWe first derived 4D deformation vector fields (DVFs) from patient 4D-CT. Principal component analysis (PCA) was then employed to extract distinctive feature labels for each DVF, focusing on the first three PCA coefficients. To simulate a wide range of respiratory motion, we expanded the motion amplitude and used random sampling to generate approximately 900 sets of PCA labels. These labels were used to produce 900 simulated 4D-DVFs, which in turn deformed the 0% phase 4D-CT to obtain 900 CBCT volumes with continuous motion amplitudes. Following this, the forward projection was performed at one angle to get all of the digital reconstructed radiographs (DRRs). These DRRs and the PCA labels were used as the training data set. To capture the spatiotemporal correlation in the projections, we propose to use the convolutional LSTM (ConvLSTM) network for PCA coefficient estimation. For network testing, when several online CBCT projections (with different motion amplitudes that cover the full respiration range) are acquired and sent into the network, the corresponding 4D-PCA coefficients will be obtained and finally lead to a full online 4D-CBCT prediction. A phantom experiment is first performed with the XCAT phantom; then, a pilot clinical evaluation is further conducted.ResultsResults on the XCAT phantom and the patient data show that the proposed approach outperformed other networks in terms of visual inspection and quantitative metrics. For the XCAT phantom experiment, ConvLSTM achieves the highest quantification accuracy with MAPE(Mean Absolute Percentage Error), PSNR (Peak Signal-to-Noise Ratio), and RMSE(Root Mean Squared Error) of 0.0459, 64.6742, and 0.0011, respectively. For the patient pilot clinical experiment, ConvLSTM also achieves the best quantification accuracy with that of 0.0934, 63.7294, and 0.0019, respectively. The quantification evaluation labels that we used are 1) the Mean Absolute Error (MAE), 2) the Normalized Cross Correlation (NCC), 3)the Structural Similarity Index Measurement(SSIM), 4)the Peak Signal-to-Noise Ratio (PSNR), 5)the Root Mean Squared Error(RMSE), and 6) the Absolute Percentage Error (MAPE).ConclusionThe spatiotemporal correlation-based respiration motion modeling supplied a potential solution for accurate real-time 4D-CBCT reconstruction.

Summary: Background: The long-term survival and perioperative outcomes of robotic-assisted lobectomy (RAL) and video-assisted lobectomy (VAL) in resectable non-small-cell lung cancer (NSCLC) were found to be comparable in retrospective studies, but they have not been investigated in a randomized trial setting. We conducted the RVlob trial to investigate if RAL was non-inferior to VAL in patients with resectable NSCLC. Methods: In this single-center, open-label, and parallel-arm randomized controlled trial conducted in Ruijin Hospital (Shanghai, China) between May 2017 and May 2020, we randomly assigned patients with resectable NSCLC in a 1:1 ratio to receive either RAL or VAL. One of the primary endpoints was 3-year overall survival. Secondary endpoints included 3-year disease-free survival. The Kaplan–Meier approach was used to calculate overall survival and disease-free survival at 3 years. This study was registered with ClinicalTrials.gov, NCT03134534. Findings: A total of 320 patients were randomized to receive RAL (n = 157) or VAL (n = 163). The baseline characteristics of patients were well balanced between the two groups. After a median follow-up of 58.0 months, the 3-year overall survival was 94.6% (95% confidence interval [CI], 91.0–98.3) in the RAL group and 91.5% (95% CI, 87.2–96.0) in the VAL group (hazard ratio [HR] for death, 0.65; 95% CI, 0.33–1.28; P = 0.21); noninferiority of RAL was confirmed according to the predefined margin of −5% (absolute difference, 2.96%; a one-sided 90% CI, −1.39% to ∞; P = 0.0029 for noninferiority). The 3-year disease-free survival was 88.7% (95% CI, 83.6–94.1) in the RAL group and 85.4% (95% CI, 80.0–91.2) in the VAL group (HR for disease recurrence or death, 0.87; 95% CI, 0.50–1.52; P = 0.62). Interpretation: This study is the first randomized trial to show that RAL resulted in non-inferior overall survival compared with VAL in patients with resectable NSCLC. Based on our results, RAL is an equally oncologically effective treatment and can be considered as an alternative to VAL for resectable NSCLC. Funding: National Natural Science Foundation of China (82072557), National Key Research and Development Program of China (2021YFC2500900), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20172005, the 2nd round of disbursement), program of Shanghai Academic Research Leader from Science and Technology Commission of Shanghai Municipality (20XD1402300), Novel Interdisciplinary Research Project from Shanghai Municipal Health Commission (2022JC023), and Interdisciplinary Program of Shanghai Jiao Tong University (YG2023ZD04).

Sugar-based block co-oligomer (BCO) consisting of saccharide block exhibits high segregation strength that overcomes the limitation of the traditional block copolymers for accessing the ordered nanostructures with ultrasmall feature size. This study explores the influence of molecular chirality on the self-assembly behavior of glucose-block-tocopherol (Glc-b-Toc) BCOs, wherein the Toc blocks were either pure in chirality or being a mixture of the stereoisomers. Both the chiral and racemic BCOs formed a hexagonal perforated layer (HPL) structure with an unusually small aspect ratio (c/a) of the unit cell, attributable to the propensity of the Glc block to enhance hydrogen bonding formation. As the temperature was increased, the dominance of hydrogen bonding interactions diminished, resulting in a gradual increase in the c/a ratio and eventually a transformation of the HPL structure to a double gyroid (DG) phase. The chirality of the Toc block enhanced the effective segregation strength of the BCO, leading to elevated order-order transition temperatures associated with the HPL-to-DG and DG-to-hexagonally packed cylinder (HEX) transitions. Within the HPL phase window, the chiral BCO exhibited significantly slower kinetics during thermally-induced structural reorganization in adjusting the c/a ratio, especially in the cooling process. Consequently, a pronounced hysteresis in the structural reorganization of the chiral BCO was observed. This phenomenon was ascribed to the chiral interaction between the Toc blocks, which limited the diffusion of the BCO molecules for the structural reorganization.

Accurate localization of objects of interest in remote sensing images (RSIs) is of great significance for object identification, resource management, decision-making and disaster relief response. However, many difficulties, like complex backgrounds, dense target quantities, large-scale variations, and small-scale objects, which make the detection accuracy unsatisfactory. To improve the detection accuracy, we propose an Adaptive Adjacent Context Negotiation Network (A2CN-Net). Firstly, the composite fast Fourier convolution (CFFC) module is given to reduce the information loss of small objects, which is inserted into the backbone network to obtain spectral global context information. Then, the Global Context Information Enhancement (GCIE) module is given to capture and aggregate global spatial features, which is beneficial for locating objects of different scales. Furthermore, to alleviate the aliasing effect caused by the fusion of adjacent feature layers, a novel Adaptive Adjacent Context Negotiation network (A2CN) is given to adaptive integration of multi-level features, which consists of local and adjacent branches, with the local branch adaptively highlighting feature information and the adjacent branch introducing global information at the adjacent level to enhance feature representation. In the meantime, considering the variability in the focus of feature layers in different dimensions, learnable weights are applied to the local and adjacent branches for adaptive feature fusion. Finally, extensive experiments are performed in several available public datasets, including DIOR and DOTA-v1.0. Experimental studies show that A2CN-Net can significantly boost detection performance, with mAP increasing to 74.2% and 79.2%, respectively.

Abstract Background The presence of lymph node (LN) metastasis directly affects the treatment strategy for lung adenocarcinoma (LUAD). Next‐generation sequencing (NGS) has been widely used in patients with advanced LUAD to identify targeted genes, while early detection of pathologic LN metastasis using NGS has not been assessed. Methods Clinicopathologic features and molecular characteristics of 224 patients from Ruijin Hospital were analyzed to detect factors associated with LN metastases. Another 140 patients from Huashan Hospital were set as a test cohort. Results Twenty‐four out of 224 patients were found to have lymph node metastases (10.7%). Pathologic LN‐positive tumors showed higher mutant allele tumor heterogeneity (p

Due to the uncertainty in soil landslide failure mechanisms, lack of early warning systems for soil landslides and adoption of improper excavation configurations, soil landslides accidents triggered by highway excavation in Chinese mountainous areas generally require expensive remedial measures. This paper describes a soil landslide associated with excavation through integrating field reconnaissance and finite element method simulation. According to the obtained results, the adoption of toe excavation and the presence of a silty clay layer are the two main factors contributing to the failure of the soil landslide, and a strong negative correction was observed between the toe excavation and surface displacement and the safety factor of the investigated cut slope; therefore, a four-level early warning system for this excavation-induced soil landslide was established by employing toe excavation and surface displacement thresholds as the warning indicators. Lastly, a preferable excavation configuration was proposed to facilitate excavation designs in similar landslide-prone areas.

The diversity and practicability of terahertz metamaterials have experienced rapid development in the past decade due to the increasing demand for various devices. This topic has attracted significant interest from researchers. Among the key functional devices in terahertz metamaterial systems, the active control ability of terahertz metamaterials is highly valuable and captivating. This implies that the electromagnetic properties of metamaterials can be modulated over a wide dynamic range by external stimuli. This review categorizes the different types of tunable terahertz metamaterials based on the external stimuli to which they respond, namely, mechanical modulation, electrical modulation, magnetic modulation, and optical modulation. Mechanically modulated devices offer simple yet efficient modulation, while electrical and magnetic modulation provide effective active modulation through electrical mechanisms. Optical modulation, in contrast, focuses on incorporating various materials to achieve active modulation.

The direct feeding value of distillers grains is low due to the presence of higher cellulose, lignin and anti-nutritional factors such as mannan and xylan. In this study, complex enzymes and probiotic flora based on “probiotic enzyme synergy” technology were used to produce fermented distillers grains. The optimal substrate ratio, moisture content, fermentation time and temperature were determined. Subsequently, scale-up experiments were conducted to determine the performance of fermented feed. The results showed that multi-probiotic (Lactobacillus casei, Bacillus subtilis, Saccharomyces cerevisiae, and Aspergillus oryzae) cooperated with complex enzymes (glucanase, mannanase, xylanase) showed excellent fermentation effect, crude protein, trichloroacetic acid soluble protein and fat increased by 31.25, 36.68, and 49.11% respectively, while crude fiber, acidic fiber and neutral fiber decreased by 34.24, 26.91, and 33.20%, respectively. The anti-nutritional factors mannan and arabinoxylan were reduced by 26.96 and 40.87%, respectively. Lactic acid, acetic acid, and propionic acid in the fermented organic acids increased by 240.93, 76.77, and 89.47%, respectively. Butyric acid increased significantly from scratch, and the mycotoxin degradation effect was not significant. This study provides a potential approach for high-value utilization of distillers grains.

Objective To establish an effective quality monitoring indicator system for blood quality control in blood banks, in order to analyze the quality control indicators for blood collection and supply, and evaluate blood quality control process, thus promoting continuous improvement and standardizing management of blood quality control in blood banks. Methods A quality monitoring indicator system covering the whole process of blood collection and supply, including blood donation services, component preparation, blood testing, blood supply and quality control was established. The Questionnaire of Quality Monitoring Indicators for Blood Collection and Supply Process was distributed to 17 blood banks in Shandong, which clarified the definition and calculation formula of indicators. The quality monitoring indicator data from January to December 2022 in each blood bank were collected, and 20 quality control indicators data were analyzed by SPSS25.0 software. Results The average pass rate of key equipment monitoring, environment monitoring, key material monitoring, and blood testing item monitoring of 17 blood banks were 99.47%, 99.51%, 99.95% and 98.99%, respectively. Significant difference was noticed in the pass rate of environment monitoring among blood banks of varied scales(P

Abstract Balantidium ctenopharyngodoni is identified as the sole ciliate species that exclusively resides within the hindgut of grass carp with high prevalence and intensity. In this study, the successful cultivation of B. ctenopharyngodoni enabled us to collect enough cells for genome sequencing. Consequently, we acquired a high-quality genome assembly spanning 68.66 Mb, encompassing a total of 22,334 nanochromosomes. Furthermore, we predicted 29,348 protein-coding genes, and 95.5% of them was supported by the RNA-seq data. The trend of GC content in the subtelomeric regions of single-gene chromosomes was similar to other ciliates containing nanochromosomes. A large number of genes encoding carbohydrate-binding modules with affinities for starch and peptidoglycans was identified. The identification of mitochondrion-related organelles (MROs) within genome indicates its well-suited adaptation to the anaerobic conditions in the hindgut environment. In summary, our results will offer resources for understanding the genetic basis and molecular adaptations of balantidia to hindgut of herbivorous fish.

Abstract The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.

Abstract Zygotic genome activation (ZGA) is a universal process in early embryogenesis of metazoan, when the quiescent zygotic nucleus initiates global transcription. However, the mechanisms related to massive genome activation and allele-specific expression (ASE) remain not well understood. Here, we develop hybrids from two deeply diverged (120 Mya) ascidian species to symmetrically document the dynamics of ZGA. We identify two coordinated ZGA waves represent early developmental and housekeeping gene reactivation, respectively. Single-cell RNA sequencing reveals that the major expression wave exhibits spatial heterogeneity and significantly correlates with cell fate. Moreover, allele-specific expression occurs in a species- rather than parent-related manner, demonstrating the divergence of cis-regulatory elements between the two species. These findings provide insights into ZGA in chordates.

Dislocation recovery lowering the driving force for recrystallization would be able to suppress the latter in Ni-based superalloy single crystals, but was believed unlikely due to their low stacking-fault energy. Defying this traditional wisdom, here we show that efficient recovery can be realized once the γ′-precipitates start to dissolve. Our microscopy evidence tracking the distribution/configuration of dislocations reveals that the shifting γ/γ′ interphase boundaries release the dislocations trapped there, facilitating their annihilation and rearrangement into low-energy network configurations. Our finding explains the success of a recent recovery protocol that kept superalloys as single crystals after supersolvus homogenization heat treatment.

The production performance and rumen bacterial diversity were compared for different silage-based diets supplemented with common concentrate or bio-concentrate to develop an alternative of common concentrate for fatten cattle feeding. The daily gain of fattening cattle was increased by 0. 99 kg and 1.04 kg, respectively, when fed with single corn silage or mixed silage-based diet supplemented with bio-concentrate. There was no significant difference in water loss rate and cooked meat rate among groups (P>0.05), but the tenderness of beef in the bio-concentrate group was significantly higher than that in the common concentrate group (P