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Hot deformation is a commonly employed processing technique to enhance the ductility and workability of Mg alloy. However, the hot deformation of Mg alloy is highly sensitive to factors such as temperature, strain rate, and strain, leading to complex flow behavior and an exceptionally narrow processing window for Mg alloy. To overcome the shortcomings of the conventional Arrhenius-type (AT) model, this study developed machine learning-based Arrhenius-type (ML-AT) models by combining the genetic algorithm (GA), particle swarm optimization (PSO), and artificial neural network (ANN). Results indicated that when describing the flow behavior of the AQ80 alloy, the PSO-ANN-AT model demonstrates the most prominent prediction accuracy and generalization ability among all ML-AT and AT models. Moreover, an activation energy-processing (AEP) map was established using the reconstructed flow stress and activation energy fields based on the PSO-ANN-AT model. Experimental validations revealed that this AEP map exhibits superior predictive capability for microstructure evolution compared to the one established by the traditional interpolation methods, ultimately contributing to the precise determination of the optimum processing window. These findings provide fresh insights into the accurate constitutive description and workability characterization of Mg alloy during hot deformation.

Abstract Background Gallbladder cancer (GBC) is the most common and lethal malignancy of the biliary tract that lacks effective therapy. In many GBC cases, infiltration into adjacent organs or distant metastasis happened long before the diagnosis, especially the direct liver invasion, which is the most common and unfavorable way of spreading. Methods Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), proteomics, and multiplexed immunohistochemistry (mIHC) were performed on GBC across multiple tumor stages to characterize the tumor microenvironment (TME), focusing specifically on the preferential enrichment of neutrophils in GBC liver invasion (GBC-LI). Results Multi-model Analysis reveals the immunosuppressive TME of GBC-LI that was characterized by the enrichment of neutrophils at the invasive front. We identified the context-dependent transcriptional states of neutrophils, with the Tumor-Modifying state being associated with oxidized low-density lipoprotein (oxLDL) metabolism. In vitro assays showed that the direct cell-cell contact between GBC cells and neutrophils led to the drastic increase in oxLDL uptake of neutrophils, which was primarily mediated by the elevated OLR1 on neutrophils. The oxLDL-absorbing neutrophils displayed a higher potential to promote tumor invasion while demonstrating lower cancer cytotoxicity. Finally, we identified a neutrophil-promoting niche at the invasive front of GBC-LI that constituted of KRT17+ GBC cells, neutrophils, and surrounding fibroblasts, which may help cultivate the oxLDL-absorbing neutrophils. Conclusions Our study reveals the existence of a subset of pro-tumoral neutrophils with a unique ability to absorb oxLDL via OLR1, a phenomenon induced through cell-cell contact with KRT17+ GBC cells in GBC-LI.

Background: Ferroptosis is an important type of cell death contributing to myocardial dysfunction induced by whole body ischemia reperfusion following cardiac arrest (CA) and resuscitation. Sulforaphane (SFN), known as the activator of the nuclear factor E2-related factor 2 (Nrf2), has been proven to effectively alleviate regional myocardial ischemia reperfusion injury. The present study was designed to investigate whether SFN could improve post-resuscitation myocardial dysfunction by inhibiting cardiomyocytes ferroptosis and its potential regulatory mechanism. Methods and results: An in vivo pig model of CA and resuscitation was established. Hypoxia/reoxygenation (H/R)-stimulated AC16 cardiomyocytes was constructed as an in vitro model to simulate the process of CA and resuscitation. In vitro experiment, SFN reduced ferroptosis-related ferrous iron, lipid reactive oxygen species, and malondialdehyde, increased glutathione, and further promoted cell survival after H/R stimulation in AC16 cardiomyocytes. Mechanistically, the activation of Nrf2 with the SFN decreased interferon regulatory factor 1 (IRF1) expression, then reduced its binding to the promoter of glutathione peroxidase 4 (GPX4), and finally recovered the latter’s transcription after H/R stimulation in AC16 cardiomyocytes. In vivo experiment, SFN reversed abnormal expression of IRF1 and GPX4, inhibited cardiac ferroptosis, and improved myocardial dysfunction after CA and resuscitation in pigs. Conclusions: SFN could effectively improve myocardial dysfunction after CA and resuscitation, in which the mechanism was potentially related to the inhibition of cardiomyocytes ferroptosis through the regulation of Nrf2/IRF1/GPX4 pathway.

Atherosclerosis, characterized by the accumulation of plaque within the arterial walls, is an intricate cardiovascular disease that often results in severe health issues. Recent studies have emphasized the importance of ferroptosis, a controlled type of cell death dependent on iron, as a critical factor in this disease state. Ferroptosis, distinguished by its reliance on iron and the accumulation of lipid hydroperoxides, offers a unique insight into the pathology of atherosclerotic lesions. This summary encapsulates the current knowledge of the intricate role ferroptosis plays in the onset and progression of atherosclerosis. It explores the molecular processes through which lipid peroxidation and iron metabolism contribute to the development of atheromatous plaques and evaluates the possibility of utilizing ferroptosis as a novel treatment approach for atherosclerosis. By illuminating the intricate relationship between ferroptosis-related processes and atherosclerosis, this review paves the way for future clinical applications and personalized medicine approaches aimed at alleviating the effects of atherosclerosis.

ABSTRACT: The laying hen is the spontaneous model of ovarian tumor. A comprehensive comparison based on RNA-seq from hens and women may shed light on the molecular mechanisms of ovarian cancer. We performed next-generation sequencing of microRNA and mRNA expression profiles in 9 chicken ovarian cancers and 4 normal ovaries, which has been deposited in GSE246604. Together with 6 public datasets (GSE21706, GSE40376, GSE18520, GSE27651, GSE66957, TCGA-OV), we conducted a comparative transcriptomics study between chicken and human. In the present study, miR-451, miR-2188-5p, and miR-10b-5p were differentially expressed in normal ovaries, early- and late-stage ovarian cancers. We also disclosed 499 up-regulated genes and 1,061 down-regulated genes in chicken ovarian cancer. The molecular signals from 9 cancer hallmarks, 25 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and 369 Gene Ontology (GO) pathways exhibited abnormalities in ovarian cancer compared to normal ovaries via Gene Set Enrichment Analysis (GSEA). In the comparative analysis across species, we have uncovered the conservation of 5 KEGG and 76 GO pathways between chicken and human including the mismatch repair and ECM receptor interaction pathways. Moreover, a total of 174 genes contributed to the core enrichment for these KEGG and GO pathways were identified. Among these genes, the 22 genes were found to be associated with overall survival in patients with ovarian cancer. In general, we revealed the microRNA profiles of ovarian cancers in hens and updated the mRNA profiles previously derived from microarrays. And we also disclosed the molecular pathways and core genes of ovarian cancer shared between hens and women, which informs model animal studies and gene-targeted drug development.

Abstract Abnormal lipid metabolism promotes hepatocellular carcinoma (HCC) progression, which engenders therapeutic difficulties owing to unclear mechanisms of the phenomenon. We precisely described a special steatotic HCC subtype with HBV-related cirrhosis and probed its drivers. Hematoxylin-eosin (HE) staining of 245 HCC samples revealed a special HCC subtype (41 cases) characterized by HBV-related cirrhosis and intratumoral steatosis without fatty liver background, defined as steatotic HCC with HBV-related cirrhosis (SBC-HCC). SBC-HCC exhibits a larger tumor volume and worse prognosis than non-SBC-HCC. Screening for driver genes promoting fatty acid (FA) biosynthesis in the Gao’s HBV-related cirrhosis HCC cases and GSE121248’ HBV-related HCC cases revealed that high expression of SOCS5 predicts increased FA synthesis and that SOCS5 is upregulated in SBC-HCC. Through proteomics, metabolomics, and both in vivo and in vitro experiments, we demonstrated that SOCS5 induces lipid accumulation to promote HCC metastasis. Mechanistically, through co-IP and GST-pulldown experiments, we found that the SOCS5-SH2 domain, especially the amino acids Y413 and D443, act as critical binding sites for the RBMX-RRM domain. SOCS5-RBMX costimulates the promoter of SREBP1, inducing de novo lipogenesis, while mutations in the SH2 domain, Y413, and D443 reverse this effect. These findings precisely identified SBC-HCC as a special steatotic HCC subtype and highlighted a new mechanism by which SOCS5 promotes SBC-HCC metastasis.

Abstract Background To characterize the current state of emergency medicine (EM) and the requirements for advancing EM clinical practice, education and research in China. Methods An anonymous electronic survey was conducted by Chinese Society of Emergency Medicine during September to October 2021. The survey contained 30 questions divided into 2 sections: the current state of EM development and the requirements for EM growth. Results 722 hospitals were included, of 487 were Level III and 235 were Level II hospitals. We found that after 40 years of development, EM had established a mature disciplinary system and refined sub-specialties including critical care, cardiopulmonary resuscitation, toxicology, disaster and emergency rescue. In Level III hospitals, 70.8% of EDs were standardized training centers for EM residents, but master’s degree program, Doctor Degree program and post-doctoral degree program was approved in only 37.8%, 8.4% and 2.9% of EDs respectively and postgraduate curriculum was available in 1/4 of EDs. Only 8% have national or provincial key laboratories. In addition to advance clinical practice, there was also a high demand to improve teaching and research capacities, mainly focusing on literature review, research design and delivery, paper writing, residency training. Conclusions EM has built a mature discipline system and refined sub-specialties in China. Teaching and research developed parallel with clinical practice. However, there was still a lack of EM master’s and doctoral programs and research capacities need to be improved. More outstanding clinical and academic training should be provided to promote the rapid growth of EM in China.

Sophora davidii is a cross-pollinated plant with important ecological protection and medicinal value in China, but its seed yield is low due to backward and nonstandard production technology. Therefore, we divide the flowering period of Sophora davidii into initial, full and final flowering period, measuring the floral morphology, pollen viability, stigma receptivity, nectar volume and nectar concentration, foraging behavior of pollinators, fertilization physiology, seed yield and quality through field observation and indoor testing to explore whether the flowering period affects the floral traits, pollinator behavior and seed production of plants. Our results revealed that the nectar volume, nectar concentration, pollen viability and stigma receptivity at full flowering period were the highest. The single visit time and visit time per flower of Chinese honey bees were the longest in the full flowering period, while the number of transfer, visit frequency and number of touching stigma were the least. The visiting number of the bees was the most and the most active in the full flowering period. The bees pollination not only improved the pollen amount, germination rate, pollen tube length and the ovule number of S. davidii, but also their effect was the most obvious in full flowering period. The principal component analysis showed that pollination by Chinese honey bees during the whole flowering period of S. davidii was the best way to produce seeds. We can conclude that flowering period affects flower traits, foraging behavior of pollinators, seed yield and quality of S. davidii.

ABSTRACT The entomopathogenic fungus Beauveria bassiana provides an eco-friendly substitute to chemical insecticides for mosquito control. Nevertheless, its widespread application has been hindered by its comparatively slow efficacy in eliminating mosquitoes. To augment the potency of B. bassiana against Aedes mosquitoes, a novel recombinant strain, Bb-Cyt1Aa, was developed by incorporating the Bacillus thuringiensis toxin gene Cyt1Aa into B. bassiana. The virulence of Bb-Cyt1Aa was evaluated against Aedes aegypti and Aedes albopictus using insect bioassays. Compared to the wild-type (WT) strain, the median lethal time (LT50) for A. aegypti larvae infected with Bb-Cyt1Aa decreased by 33.3% at a concentration of 1 × 108 conidia/mL and by 22.2% at 1 × 107 conidia/mL. The LT50 for A. aegypti adults infected with Bb-Cyt1Aa through conidia ingestion was reduced by 37.5% at 1 × 108 conidia/mL and by 33.3% at 1 × 107 conidia/mL. Likewise, the LT50 for A. aegypti adults infected with Bb-Cyt1Aa through cuticle contact decreased by 33.3% and 30.8% at the same concentrations, respectively. Furthermore, the Bb-Cyt1Aa strain also demonstrated increased toxicity against both larval and adult A. albopictus, when compared to the WT strain. In conclusion, our study demonstrated that the expression of B. thuringiensis toxin Cyt1Aa in B. bassiana enhanced its virulence against Aedes mosquitoes. This suggests that B. bassiana expressing Cyt1Aa has potential value for use in mosquito control.IMPORTANCEBeauveria bassiana is a naturally occurring fungus that can be utilized as a bioinsecticide against mosquitoes. Cyt1Aa is a delta-endotoxin protein produced by Bacillus thuringiensis that exhibits specific and potent insecticidal activity against mosquitoes. In our study, the expression of this toxin Cyt1Aa in B. bassiana enhances the virulence of B. bassiana against Aedes aegypti and Aedes albopictus, thereby increasing their effectiveness in killing mosquitoes. This novel strain can be used alongside chemical insecticides to reduce dependence on harmful chemicals, thereby minimizing negative impacts on the environment and human health. Additionally, the potential resistance of B. bassiana against mosquitoes in the future could be overcome by acquiring novel combinations of exogenous toxin genes. The presence of B. bassiana that expresses Cyt1Aa is of significant importance in mosquito control as it enhances genetic diversity, creates novel virulent strains, and contributes to the development of safer and more sustainable methods of mosquito control.

Abstract The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut–liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.

Abstract Background Acute compartment syndrome (ACS) is one of the most common complications of musculoskeletal injury, leading to the necrosis and demise of skeletal muscle cells. Our previous study showed that embryonic stem cells-derived mesenchymal stem cells (ESC–MSCs) are novel therapeutics in ACS treatment. As extracellular vesicles (EVs) are rapidly gaining attention as cell-free therapeutics that have advantages over parental stem cells, the therapeutic potential and mechanisms of EVs from ESC–MSCs on ACS need to be explored. Method In the present study, we examined the protective effects in the experimental ACS rat model and investigated the role of macrophages in mediating these effects. Next, we used transcriptome sequencing to explore the mechanisms by which ESC–MSC-EVs regulate macrophage polarization. Furthermore, miRNA sequencing was performed on ESC–MSC-EVs to identify miRNA candidates associated with macrophage polarization. Results We found that intravenous administration of ESC–MSC-EVs, given at the time of fasciotomy, significantly promotes the anti-inflammation process, angiogenesis, and functional recovery of muscle in ACS. The beneficial effects were associated with ESC–MSC-EVs affecting macrophage polarization by delivering various miRNAs which regulate NF-κB, JAK/STAT, and PI3K/AKT pathways. Our data further illustrate that ESC–MSC-EVs mainly modulate macrophage polarization via the miR-21/PTEN, miR-320a/PTEN, miR-423/NLRP3, miR-100/mTOR, and miR-26a/TLR3 axes. Conclusion Together, our results demonstrated the beneficial effects of ESC–MSC-EVs in ACS, wherein the miRNAs present in ESC–MSC-EVs regulate the polarization of macrophages.

The ratiometric fluorescent probe UiO-OH@Tb, a zirconium-based MOF functionalized with Tb3+, was synthesized using a hydrothermal method. This probe employs the fluorescence resonance energy transfer (FRET) mechanism between Tb3+ and malachite green (MG) for the double-inverse signal ratiometric fluorescence detection of MG. The probe’s color shifts from lime green to blue with an increasing concentration of MG. In contrast, the monometallic MOFs’ (UiO-OH) probe shows only blue fluorescence quenching due to the inner filter effect (IFE) after interacting with MG. Additionally, the composite fluorescent probe (UiO-OH@Tb) exhibits superior sensitivity, with a detection limit (LOD) of 0.19 μM, which is significantly lower than that of the monometallic MOFs (25 μM). Moreover, the content of MG can be detected on-site (LOD = 0.94 μM) using the RGB function of smartphones. Hence, the UiO-OH@Tb probe is proven to be an ideal material for MG detection, demonstrating significant practical value in real-world applications.

In this study, we developed well-aligned ZnO nanoflowers coated with poly-10,12-pentacosadiyonic acid (p-PCDA@ZnO) and modified with Pt nanoparticle (Pt/p-PCDA@ZnO) hybrid photoanodes for highly efficient photoelectrochemical (PEC) water splitting. The scanning electron microscope (SEM) image shows that thin films of the p-PCDA layer were well coated on the ZnO nanoflowers and that Pt nanoparticles were on it. The photoelectrochemical characterizations were made under simulated solar irradiation AM 1.5. The current density of the p-PCDA@ZnO and the Pt/p- PCDA@ZnO was 0.227 mA/cm2 and 0.305 mA/cm2, respectively, and these values were three times and four times higher compared to the 0.071 mA/cm2 of the bare ZnO nanoflowers. The UV–visible spectrum showed that the absorbance of coated p-PCDA films was extended in visible light region, which agrees with the enhanced PEC data for p-PCDA@ZnO. Also, adding Pt nanoparticles on top of the films as co-catalysts enhanced the PEC performance of Pt/p-PCDA@ZnO further. This indicates that Pt/p- PCDA@ZnO has a great potential to be implemented in solar water splitting.

Chronic atrophic gastritis is a serious health issue beyond the stomach health problems that affect normal life. This study aimed to explore the influencing factors related to chronic atrophic gastritis (CAG) using non-invasive indicators and establish an optimal prediction model to aid in the clinical diagnosis of CAG. Electronic medical record data from 20,615 patients with CAG were analyzed, including routine blood tests, liver function tests, and coagulation tests. The logistic regression algorithm revealed that age, hematocrit, and platelet distribution width were significant influences suggesting chronic atrophic gastritis in the Chongqing population (p < 0.05), with an area under the curve (AUC) of 0.879. The predictive model constructed based on the Random Forest algorithm exhibited an accuracy of 83.15%, precision of 97.38%, recall of 77.36%, and an F1-score of 70.86%, outperforming the models constructed using XGBoost, KNN, and SVC algorithms in a comprehensive comparison. The prediction model derived from this study serves as a valuable tool for future studies and can aid in the prediction and screening of chronic atrophic gastritis.

Titanium carbide (TiC) coatings were prepared on the surface of AlFeCoCrNiCu high-entropy alloy blocks using electro-spark deposition (ESD). The microhardness and corrosion resistance of the TiC coatings prepared under different voltage and capacitance process parameters were studied. The research shows that the maximum microhardness of the TiC coating on sample 4 (working voltage of 20 V, working capacitance of 1000 μF) is 844.98 HV, which is 81.5% higher than the microhardness of the substrate. This is because the deposition energy increases with the increase in voltage, and the adhesion and aggregation between the coating and the substrate are enhanced, increasing the hardness of the coating. It is worth noting that excessive deposition energy can increase surface defects and reduce the microhardness of the coating surface. Electrochemical testing analysis shows that the corrosion current density of the TiC coating is the lowest (9.475 × 10−7 ± 0.06 × 10−7), and the coating impedance is the highest (2.502 × 103 Ω·com2). The absolute phase angle value is the highest (about 72°). The above indicates that the TiC coating prepared with a working voltage of 20 V and a working capacitance of 1000 μF has better microhardness and corrosion resistance.

Summary: The accumulation of omics and biobank resources allows for a genome-wide understanding of the shared pathologic mechanisms between diseases and for strategies to identify drugs that could be repurposed as novel treatments. Here, we present a computational protocol, implemented as a Snakemake workflow, to identify shared transcriptional processes and screen compounds that could result in mutual benefit. This protocol also includes a description of a pharmacovigilance study designed to validate the effect of compounds using electronic health records.For complete details on the use and execution of this protocol, please refer to Gao et al.1 and Baylis et al.2 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Quantum speed limit focuses on the minimum time scale for a fixed mission and hence is important in quantum information where fast dynamics is usually beneficial. Most existing tools for the depiction of quantum speed limit are the lower-bound-type tools, which are in fact difficult to reveal the true minimum time, especially for many-body systems or complex dynamics. Therefore, the evaluation of this true minimum time in these scenarios is still an unsolved problem. Hereby we provide the operational definition of quantum speed limit for a general target and propose a three-step (classification-regression-calibration) methodology based on machine learning to evaluate the true minimum time in complex dynamics. Moreover, the analytical expression of the true minimum time is also provided for the time-dependent Hamiltonians with time-independent eigenstates.

Abstract Candida albicans is a benign member of gut microbiota, but also causes life-threatening disseminated infections, suggesting that this fungus commensalism has evolved with retention of virulence traits. Here we reveal that N-acetylglucosamine (GlcNAc) enables C. albicans to balance between commensalism and pathogenesis. Although GlcNAc catabolism is beneficial for commensal growth of C. albicans, deleting GlcNAc sensor-transducer Ngs1 confers enhanced fitness, indicating that GlcNAc signaling is detrimental to commensalism. Interestingly, addition of GlcNAc attenuates commensal fitness of gut-evolved C. albicans but retains its disease-causing potential. We further demonstrate that GlcNAc is a major inducer of hypha-associated transcription in the gut, which represents the key determinant for commensal-pathogenic equilibrium. In addition to yeast-to-hypha morphogenesis, we also identify other factors, including Sod5 and Ofi1, that contribute to the balance. Thus, C. albicans uses GlcNAc to build up a tradeoff between fungal programs supporting commensalism and virulence, which may explain its success as a commensal and pathogen.

Tweek atmospherics are extremely low frequency and very low frequency pulse signals with frequency dispersion characteristics that originate from lightning discharges and that propagate in the Earth–ionosphere waveguide over long distances. In this study, we developed an automatic method to recognize tweek atmospherics and diagnose the lower ionosphere based on the machine learning method. The differences (automatic − manual) in each ionosphere parameter between the automatic method and the manual method were −0.07 ± 2.73 km, 0.03 ± 0.92 cm−3, and 91 ± 1,068 km for the ionospheric reflection height (h), equivalent electron densities at reflection heights (Ne), and propagation distance (d), respectively. Moreover, the automatic method is capable of recognizing higher harmonic tweek sferics. The evaluation results of the model suggest that the automatic method is a powerful tool for investigating the long-term variations in the lower ionosphere.

As medical education evolves, Problem-Based Learning (PBL) and Case-Based Learning (CBL) methodologies have emerged as vital pedagogical tools. This study aims to delve into the application and effectiveness of a hybrid PBL-CBL approach in clinical teaching for vascular surgery. By conducting a comparative analysis through concrete teaching practices, this research evaluates the impact on students' clinical knowledge retention, advancement in clinical reasoning skills, and proficiency in resolving real-world clinical challenges. The findings reveal that the integrated PBL-CBL methodology substantially enhances learning outcomes in vascular surgery clinical teaching, ultimately fostering significant development in students' comprehensive clinical abilities.

We generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of breast cancer patients carrying germline ATM mutations, a gene associated with a 7% prevalence in breast cancer. These iPSC lines displayed typical morphology, expressed pluripotency markers, maintained a stable karyotype, and retained the ability to differentiate into the three germ layers. These patient-specific iPSC lines hold great potential for mechanistic investigations and the development of drug screening strategies aimed at addressing ATM-related cancer.

Abstract Background Aedes aegypti is a vector that transmits various viral diseases, including dengue and Zika. The radiation-based sterile insect technique (SIT) has a limited effect on mosquito control because of the difficulty in irradiating males without reducing their mating competitiveness. In this study, the insect sex pheromone heptacosane was applied to Ae. aegypti males to investigate whether it could enhance the mating competitiveness of irradiated males. Methods Heptacosane was smeared on the abdomens of Ae. aegypti males that were allowed to mate with untreated virgin females. The insemination rate was used to assess the attractiveness of heptacosane-treated males to females. The pupae were irradiated with different doses of X-rays and γ-rays, and the emergence, survival time, egg number, and hatch rate were detected to find the optimal dose of X-ray and γ-ray radiation. The males irradiated at the optimal dose were smeared with heptacosane, released in different ratios with untreated males, and mated with females. The effect of heptacosane on the mating competitiveness of irradiated mosquitoes was then evaluated by the hatch rate, induced sterility, and mating competitiveness index. Results Applying heptacosane to Ae. aegypti males significantly increased the insemination rate of females by 20%. Pupal radiation did not affect egg number but significantly reduced survival time and hatch rate. The emergence of the pupae was not affected by X-ray radiation but was affected by γ-ray radiation. Pupae exposed to 60 Gy X-rays and 40 Gy γ-rays were selected for subsequent experiments. After 60 Gy X-ray irradiation or 40 Gy γ-ray irradiation, the average hatch rate was less than 0.1%, and the average survival time was more than 15 days. Moreover, at the same release ratio, the hatch rate of the irradiated group perfumed with heptacosane was lower than that of the group without heptacosane. Conversely, the male sterility and male mating competitiveness index were significantly increased due to the use of heptacosane. Conclusions The sex pheromone heptacosane enhanced the interaction between Ae. aegypti males and females. Perfuming males irradiated by X-rays or γ-rays with heptacosane led to a significant increase in mating competitiveness. This study provided a new idea for improving the application effect of SIT. Graphical Abstract

Germline pathogenic variants in the BRCA2 gene are strongly correlated with an elevated risk of developing breast cancer. Two specific BRCA2 variants, c.8167G>C (p.Asp2723His) and c.1583del (p.Asn528fs), have been identified from individuals with a family history of breast cancer. Here we generated two iPSC lines from breast cancer patients who are heterozygous carriers of these two variants. These iPSCs exhibit pluripotency and demonstrate the capability to differentiate into three germ layers. These iPSC lines represent a valuable resource for personalized pre-clinical research, offering new opportunities to explore the underlying mechanisms of breast cancer and develop targeted therapeutic approaches.

BackgroundDysregulated inflammation is associated with many skeletal diseases and disorders, such as osteolysis, non-union of fractures, osteonecrosis, osteoarthritis and orthopaedic infections. We previously showed that continuous infusion of lipopolysaccharide (LPS) contaminated polyethylene particles (cPE) caused prolonged inflammation and impaired bone formation. However, the metabolic and bioenergetic processes associated with inflammation of bone are unknown. Mitochondria are highly dynamic organelles that modulate cell metabolism and orchestrate the inflammatory responses that involve both resident and recruited cells. Glycolytic reprogramming, the shift from oxidative phosphorylation (OXPHOS) to glycolysis causes inappropriate cell activation and function, resulting in dysfunctional cellular metabolism. We hypothesized that impaired immunoregulation and bone regeneration from inflammatory states are associated with glycolytic reprogramming and mitochondrial dysfunction in macrophages (Mφ) and mesenchymal stromal cells (MSCs).MethodsWe used the Seahorse XF96 analyzer and real-time qPCR to study the bioenergetics of Mφ and MSCs exposed to cPE. To understand the oxygen consumption rate (OCR), we used Seahorse XF Cell Mito Stress Test Kit with Seahorse XF96 analyzer. Similarly, Seahorse XF Glycolytic Rate Assay Kit was used to detect the extracellular acidification rate (ECAR) and Seahorse XF Real-Time ATP Rate Assay kit was used to detect the real-time ATP production rates from OXPHOS and glycolysis. Real-time qPCR was performed to analyze the gene expression of key enzymes in glycolysis and mitochondrial biogenesis. We further detected the gene expression of proinflammatory cytokines in Mφ and genes related to cell differentiation in MSC during the challenge of cPE.ResultsOur results demonstrated that the oxidative phosphorylation of Mφ exposed to cPE was significantly decreased when compared with the control group. We found reduced basal, maximal and ATP-production coupled respiration rates, and decreased proton leak in Mφ during challenge with cPE. Meanwhile, Mφ showed increased basal glycolysis and proton efflux rates (PER) when exposed to cPE. The percentage (%) of PER from glycolysis was higher in Mφ exposed to cPE, indicating that the contribution of the glycolytic pathway to total extracellular acidification was elevated during the challenge of cPE. In line with the results of OCR and ECAR, we found Mφ during cPE challenge showed higher glycolytic ATP (glycoATP) production rates and lower mitochondrial ATP (mitoATP) production rates which is mainly from OXPHOS. Interestingly, MSCs showed enhanced glycolysis during challenge with cPE, but no significant changes in oxygen consumption rates (OCR). In accordance, seahorse assay of real-time ATP revealed glycoATP rates were elevated while mitoATP rates showed no significant differences in MSC during challenge with cPE. Furthermore, Mφ and MSCs exposed to cPE showed upregulated gene expression levels of glycolytic regulators and Mφ exposed to cPE expressed higher levels of pro-inflammatory cytokines.ConclusionThis study demonstrated the dysfunctional bioenergetic activity of bone marrow-derived Mφ and MSCs exposed to cPE, which could impair the immunoregulatory properties of cells in the bone niche. The underlying molecular defect related to disordered mitochondrial function could represent a potential therapeutic target during the resolution of inflammation.

Abstract The Pringle maneuver (PM) is widely used during hepatocellular carcinoma (HCC) resection. However, it inevitably leads to ischemia and hypoxia, which promotes tumor metastasis. In this study, immunohistochemical staining of specimens from 130 HCC patients revealed that long-time PM significantly affected the prognosis of patients with high expression of suppressor of cytokine signaling 5 (SOCS5), but did not affect the prognosis of patients with low expression of SOCS5. The TCGA database showed that patients with high expression of SOCS5 had higher hypoxia scores, and it was proved that SOCS5 could promote the expression of hypoxia-inducible factor 1 subunit alpha (HIF-1α) protein by clinical tissue samples, cell experiments, lung metastases, and subcutaneous tumorigenesis experiments. Then, we used CoCl2 to construct a hypoxia model, and confirmed that SOCS5 knockdown resisted hypoxia-induced mitochondrial damage by inhibiting the expression of HIF-1α, thereby inhibiting the invasion and migration of HCC cells by immunofluorescence, electron microscopy, migration, invasion, and other experiments. We performed rescue experiments using LY294002 and rapamycin and confirmed that the knockdown of SOCS5-inhibited HCC cell invasion and migration by inhibiting the PI3K/Akt/mTOR/HIF-1α signaling axis. More importantly, we obtained consistent conclusions from clinical, cellular, and animal studies that the hypoxia-induced invasion and migration ability of SOCS5-inhibited HCC were weaker than that of normal HCC. In conclusion, we identified a novel role for SOCS5 in regulating HIF-1α-dependent mitochondrial damage and metastasis through the PI3K/Akt/mTOR pathway. The development of a SOCS5-specific inhibitor, an indirect inhibitor of HIF-1α, might be effective at controlling PM-induced tumor micrometastases during HCC resection.

The recrystallization and grain growth behavior of CoCrFeMnNi high-entropy alloys (HEAs) with different plastic deformations were studied. Differential scanning calorimetry (DSC) tests were novelly adopted to characterize the recrystallization process. Experimental results suggest that pre-deformation has great promotion on the recrystallization rate and degree. The recrystallized grain size decreases with increasing deformation due to increased potential nucleation sites. Severe deformation and low annealing temperature are helpful to refine annealed grains. A static recrystallization model for variously deformed HEAs was developed, in which the recrystallization rate was expressed as a function of strain and annealing temperature. An improved grain growth model was established, which takes the recrystallization process into consideration and declares that the annealed grain size decreases first and then increases. The recrystallization fraction and the annealed grain size of the HEAs with different deformations annealed at different temperatures can be predicted.

As a new type of impact welding technology, Vaporizing Foil Actuator Welding (VFAW) has the advantages of high welding efficiency and small heat affected zone, which could avoid the decline of shape memory properties of the NiTi alloy in the NiTi/metals joint of fusion welding. Therefore, NiTi/Al–Mg VFAW experiments under different discharge voltages and standoffs were carried out to analyze the effects of process parameters on interface morphology, mechanical and functional properties. The results showed that high strength welding between NiTi and Al–Mg alloys were realized. With the increase of discharge voltage and standoff, the interface morphology changed to flat, a small amount of melting layer, wave, continuous melting layer, and the joint performance increased first and then decreased. The difference in properties between NiTi and Al–Mg alloys led to the change of microstructure and nano-hardness at the interface. Equiaxed recrystallized grains and small slender grains appeared on Al–Mg and NiTi alloy respectively. The nano-hardness of both sides increased, but the hardening range of the Al–Mg alloy side was smaller. The changes of phase transformation temperatures of the NiTi/Al–Mg joints were small compared to NiTi base, indicating the VFAWed NiTi alloy still maintained the original shape memory function. This work deepens the understanding about the properties of NiTi/Al–Mg VFAW, and is helpful for expanding the application of NiTi shape memory alloy.

Despite the importance of temperature distribution in spark plasma sintering of metallic glasses, its quantification has been experimentally laborious. This work proposes an experimental strategy to determine the sintering temperature by establishing a quantitative relationship between the temperature-thermal signal. We reproduced the thermal profiles of spark plasma sintering by isothermal annealing and found a correlation between annealing temperature and isothermal crystallization time. This strong correlation indicates the temperature-dependent structural evolution of glassy powders. Using isothermal crystallization time as the measuring gauge, we correlated the annealing temperature to the sintering temperature and obtained the sample temperature map. The sample temperature is at least 19 ​°C higher than the nominal temperature of 425 ​°C measured by the thermocouple. Meanwhile, the sample temperature shows a hump-shaped pattern closely correlated with the current density. The maximum temperature of 453 ​°C occurs on the sample/punches contact surfaces. Temperature heterogeneity within the sample induces diverse microstructures and porous structures. We elucidate that the temperature inhomogeneity is intrinsic, given the presence of contact interfaces. Contact resistances affect the current distribution and heat transfer, resulting in a larger temperature gradient than the traditional powder metallurgy process.

Abstract Plasmonic nanostructured metals have many advantages for applications in high‐performance surface‐enhanced Raman scattering (SERS) spectroscopy. In particular, unique designing nanostructures with bicontinuous ligaments surrounded by cylindrical voids with tunable dense pores from a few to hundreds of nanometers can be utilized for the high‐performance SERS‐active substrate. Here, a fabrication strategy is reported to prepare hierarchically arranged micro/nanostructures of wrinkled nanoporous gold (WNPG) films, which involves laminating of the dealloyed Au film on the heat‐shrinkable shape‐memory polymer film and geometrical modulation of the substrate. As a result, the various types of WNPG films are crafted with a remarkable density of cracks in the structured surface area. Specifically, the WNPG films consisting of multilayered overlapping features are explored and used as the SERS‐active substrate. This dual porosity coupled with localized surface plasmon resonance estimated by numerical simulation in a suitable model of bicontinuous ligaments is found to be the core mechanism for the enhancement of SERS sensitivity, which quantitatively characterizes the “hot spots” from the surface to interlayers. These suggested characteristic features are fully assessed by applying a series of dye molecules and DNA strands on the prepared SERS substrate, demonstrating the enhanced intensity of the Raman scattering signals on the optimized WNPG surface.

BackgroundPrehabilitation has been demonstrated to positively impact postoperative recovery in patients undergoing selective cardiac surgery. However, the optimal modules included in prehabilitation programs are yet to be fully explored, as existing studies have primarily focused on exercise. This study will explore the effectiveness of a three-arm prehabilitation program among adult patients awaiting selective cardiac surgery.Methods and analysisA single-center, parallel-group randomized controlled trial will be conducted at the Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU). A total of 152 adult patients scheduled for elective cardiac surgery (coronary artery bypass grafting or valvular surgery) will be recruited from a tertiary teaching hospital. The patients will be randomly assigned to either the control group or the prehabilitation group. Patients assigned to the control group will receive standard care, which includes patient education and counseling as well as personal guidance on exercise, breathing, and coughing. Patients in the intervention group will be provided a multimodal prehabilitation program, including nutrition guidance, a diet journal, mindfulness training, and exercise guidance. The interventions will begin with home-based training and continue after hospital admission and before surgery. The primary outcome will be the perioperative 6-minute walk distance (6 MWD). The secondary outcomes will include preoperative readiness, postoperative recovery, and patient experience with the program.DiscussionThe purpose of the study is to examine whether a short-term multimodal prehabilitation program will be associated with improved preoperative readiness and postoperative outcomes. The findings of this study will provide evidence to support the development of a perioperative program aimed at enhancing patient recovery.Clinical Trial Registrationwww.ClinicalTrials.gov; identifier: NCT05503004.

The formability at room temperature and low speed limits the application of aluminum alloy, while high strain rates positively improve the formability of materials. The constitutive behaviors of materials under high strain rates or impact loadings are significantly different from those under quasi-static conditions, while few constitutive models consider the effect of the mobile dislocation and forest dislocation evolution on the dynamic strain aging (DSA) over a wide strain-rate range. The 5052 aluminum alloy, of which the primary source of strain-hardening is dislocation–dislocation interaction, is widely used in manufacturing automotive covering parts and is considered one of the most promising alloys. Therefore, this study conducts uniaxial tensile tests on AA5052-O under conditions of temperatures ranging from 293 K to 473 K and strain rates ranging from 0.001 s−1 to 3000 s−1, and compares the stress–strain relationships of AA5052-O under different conditions to illustrate the constitutive relationship affected by the dislocation evolution over a wide strain-rate range. The Arrhenius model based on the thermal activation mechanism is modified and extended by considering the effects of dynamic strain aging (DSA), drag stress, and the evolution of mobile dislocation and forest dislocation. Thus, a new physics-based constitutive model for AA5052-O is proposed, which can well reflect the change in strain-rate sensitivity with the strain rate increasing. The mobile dislocation density and total dislocation density are predicted with a modified Kubin–Estrin (KE) model, and the influences of variable mobile dislocation on DSA and dislocation drag are discussed as well. In order to verify the reliability of the new constitutive model, the dislocation densities of the specimens before and after deformation are obtained with TEM and XRD, which are in good agreement with the predicted values. This study also compares the newly proposed model with classic constitutive models using multiple statistical evaluation methods, which shows that the new physics-based constitutive model has not only more clear physical meanings for its parameters but also has a higher prediction accuracy.

As industrial modernization surges forward, the heat treatment industry strives for lower pollution, reduced oxidation and defects, minimized waste, and automatization. This paper reviews the mechanisms, processes, equipment, and simulations of the vacuum gas quenching technology, presenting a comprehensive account of the structure and working principle of a typical vacuum gas quenching furnace. Firstly, the mechanism of the heat transfer process, flow process, and flow–heat transfer–phase transition coupling were summarized. Then, the influences of process parameters on the mechanical properties and distortion of vacuum gas quenched workpieces, as well as the process optimization methods, were discussed. Finally, the advantages of vacuum gas quenching in energy saving, low pollution, and high efficiency were introduced, with the future development directions figured out.

Abstract Background Acute compartment syndrome (ACS), a well-known complication of musculoskeletal injury, results in muscle necrosis and cell death. Embryonic stem cell-derived mesenchymal stem cells (ESC-MSCs) have been shown to be a promising therapy for ACS. However, their effectiveness and potentially protective mechanism remain unknown. The present study was designed to investigate the efficacy and underlying mechanism of ESC-MSCs in ACS-induced skeletal muscle injury. Method A total of 168 male Sprague–Dawley (SD) rats underwent 2 h of intracompartmental pressure elevation by saline infusion into the anterior compartment of the left hindlimb to establish the ACS model. ESC-MSCs were differentiated from the human embryonic stem cell (ESC) line H9. A dose of 1.2 × 106 of ESC-MSCs was intravenously injected during fasciotomy. Post-ACS assessments included skeletal edema index, serum indicators, histological analysis, apoptosis, fibrosis, regeneration, and functional recovery of skeletal muscle. Then, fluorescence microscopy was used to observe the distribution of labeled ESC-MSCs in vivo, and western blotting and immunofluorescence analyses were performed to examine macrophages infiltration in skeletal muscle. Finally, we used liposomal clodronate to deplete macrophages and reassess skeletal muscle injury in response to ESC-MSC therapy. Result ESC-MSCs significantly reduced systemic inflammatory responses, ACS-induced skeletal muscle edema, and cell apoptosis. In addition, ESC-MSCs inhibited skeletal muscle fibrosis and increased regeneration and functional recovery of skeletal muscle after ACS. The beneficial effects of ESC-MSCs on ACS-induced skeletal muscle injury were accompanied by a decrease in CD86-positive M1 macrophage polarization and an increase in CD206-positive M2 macrophage polarization. After depleting macrophages with liposomal clodronate, the beneficial effects of ESC-MSCs were attenuated. Conclusion Our findings suggest that embryonic stem cell-derived mesenchymal stem cells infusion could effectively alleviate ACS-induced skeletal muscle injury, in which the beneficial effects were related to the regulation of macrophages polarization.

Introduction and Objectives: Large primary hepatocellular carcinoma (HCC) has a high mortality rate and a variety of treatments. Surgery and transcatheter arterial chemoembolization (TACE) are important treatments. Which could be better remain debatable. The objective of the study is to compare the long-term overall survival of surgical resection (SR) and the use of TACE in patients with large hepatocellular carcinoma. Materials and Methods: We assessed clinical trials through PubMed, Medline, Embase, and the Cochrane Library up to March 2022. Two researchers independently screened articles, extracted data, and assessed the study quality according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses)guidelines. The primary outcome was overall survival (OS). The secondary outcomes were OS after propensity scores matching (PSM) and progression-free survival (PFS). Results: A total of 14 studies, including 3609 patients, were enrolled in the meta-analysis. The meta-analysis indicated a significant improvement in the 1-year OS, 3-year OS, and 5-year OS favoring SR over TACE (OR = 2.19, 95% CI 1,60–3.00; OR = 3.47, 95% CI 2.47–4.88; OR = 2.72, 95% CI 2.03–3.64, p 0.05). The pooled outcome indicated that 1-year OS, 3-year OS, and 5-year OS after PSM were higher in the SR group than in the TACE group (p

AimThe primary mission of cardiopulmonary resuscitation (CPR) is to provide adequate blood flow and oxygen delivery for restoring spontaneous circulation from cardiac arrest (CA) events. Previously, studies demonstrated that chest compression synchronized ventilation (CCSV) improved systemic oxygen supply during CPR, and aortic balloon occlusion (ABO) augments the efficacy of external CPR by increasing blood perfusion to vital organs. However, both them failed to make a significant improvement in return of spontaneous circulation (ROSC). In this study, we investigated the effects of combined CCSV and ABO on the outcomes of CPR in swine.MethodsThirty-one male domestic swine were subjected to 8 min of electrically induced and untreated CA followed by 8 min of CPR. CPR was performed by continuous chest compressions and mechanical ventilation. At the beginning of CPR, the animals were randomized to receive intermittent positive pressure ventilation (IPPV, n = 10), CCSV (n = 7), IPPV + ABO (n = 7), or CCSV + ABO (n = 7). During CPR, gas exchange and systemic hemodynamics were measured, and ROSC was recorded. After resuscitation, the function and injury biomarkers of vital organs including heart, brain, kidney, and intestine were evaluated.ResultsDuring CPR, PaO2 was significantly higher accompanied by significantly greater regional cerebral oxygen saturation in the CCSV and CCSV + ABO groups than the IPPV group. Coronary perfusion pressure, end-tidal carbon dioxide, and carotid blood flow were significantly increased in the IPPV + ABO and CCSV + ABO groups compared with the IPPV group. ROSC was achieved in five of ten (IPPV), five of seven (CCSV), six of seven (IPPV + ABO), and seven of seven (CCSV + ABO) swine, with the rate of resuscitation success being significantly higher in the CCSV + ABO group than the IPPV group (P = 0.044). After resuscitation, significantly improved myocardial and neurological function, and markedly less cardiac, cerebral, renal, and intestinal injuries were observed in the CCSV + ABO group compared with the IPPV group.ConclusionThe combination of CCSV and ABO improved both ventilatory and hemodynamic efficacy during CPR, promoted ROSC, and alleviated post-resuscitation multiple organ injury in swine.

Summary: The molecular landscape and pathogenesis of focal nodular hyperplasia (FNH) have yet to be elucidated. We performed multi-omics approaches on FNH and paired normal liver tissues from 22 patients, followed by multi-level bioinformatic analyses and experimental validations. Generally, FNH had low mutation burden with low variant allele frequencies, and the mutation frequency significantly correlated with proliferation rate. Although no recurrently deleterious genomic events were found, some putative tumor suppressors or oncogenes were involved. Mutational signatures indicated potential impaired mismatch function and possible poison contact. Integrated analyses unveiled a group of FNH specific endothelial cells that uniquely expressed SOST and probably had strong interaction with fibroblasts through PDGFB/PDGFRB pathway to promote fibrosis. Notably, in one atypical FNH (patient No.11) with pronounced copy number variations, we observed a unique immune module. Most FNH are benign, but molecularly atypical FNH still exist; endothelial cell derived PDGFB probably promotes the fibrogenic process in FNH.

The observations of transient luminous events from space-borne platform extend our exploration on the mysteries of sprite phenomenology from continental thunderstorms to oceanic thunderstorms. By combining with ground-based measurements of causative strokes for hundreds of red sprites observed by the Imager of Sprites and Upper Atmospheric Lightnings (ISUAL) during 2004–2016, there is a consensus that negative cloud-to-ground (CG) strokes spawned by oceanic thunderstorms are more readily to produce sprites. The existing ground-based observations in both Caribbean Sea and near the coast of South China, mainly due to the contributions from numerous amateurs, are generally consistent with the implications of ISUAL observations. However, the physical mechanisms that might cause the enhancement of negative CG strength in the ocean remain not completely understood. There have been analyses on several cases of oceanic thunderstorms abundant in producing negative sprites. It seems that the production of negative sprites heavily depends on the size of parent thunderstorms, and they are often generated by thunderstorm conditions that are also favorable for gigantic jets.

In the last decade, there have been substantial improvements in the outcome of the management of metastatic hormone-sensitive prostate cancer (mHSPC) following the development of several novel agents as well as by combining several therapeutic strategies. Although the overall survival (OS) of mHSPC is shown to improve with intense androgen deprivation therapy (ADT), combined with docetaxel, as well as other novel hormonal therapy agents, or alongside local intervention to the primary neoplasm. Notably, luteinizing hormone-releasing hormone (LHRH) antagonists are known to cause fewer cardiovascular side effects compared with LHRH agonists. Thus, in this mini review, we explore the different approaches in the management of mHSPC, with the aim that we may provide useful information for both basic scientists and clinicians when managing relevant clinical situations.

Cu(In,Ga)Se2 (CIGS) light absorption films were synthesized by co-sputtering method on Mo/soda-lime glass, and the mechanical behavior of the films was investigated by nanoindentation. The Young's modulus and hardness of the films were approximately 88.5 ± 2.2 and 5.89 ± 0.23 GPa, respectively. The comparison graph of indentation load–displacement curve with the curve based on the theoretical elastic films, while considering the curvature of the indenter tip, revealed that cracks initiated in the CIGS films at approximately 25 mN indentation load. The transmission electron microscopy (TEM) analysis revealed that most of the cracks exhibited intergranular fracture, and the fracture toughness of the films was ~0.22 MPa√m, which is greater than the brittleness of soda-lime glass. Both Palmqvist radial and lateral cracks are observed. Results also reveal that the indentation pressure caused grain subdivision (before cracking initiated), and indentation stress may be absorbed by relatively less dense microstructures of the films.

The RTK/RAS pathway is an oncogenic signaling pathway for which many targeted drugs have been developed; however, survival remains poor. A combination of targeted therapy and immunotherapy has emerged as an option for improving cancer treatment responses. In this study, on the basis of the expression, survival, single nucleotide variation (SNV), copy number variation (CNV), and methylation data of lung adenocarcinoma (LUAD) from The Cancer Genome Atlas database, we comprehensively analyzed the genomic changes in the RTK/RAS pathway and their associations with tumor-infiltrating lymphocytes (TIL) and prognosis in LUAD to provide the genomics landscape of RTK/RAS with TIL and prognosis. We found that two rarely mutated genes, mitogen-activated protein kinase kinase 1 and insulin-like growth factor 1 receptor, were significantly associated with the worse survival of patients with LUAD. Patients with LUAD and co-mutation of KRAS proto-oncogene (KRAS) and neurofibromin 1 genes had worse survival, and the underlying mechanism could be insufficient for protein synthesis and intracellular signal deactivation. Methylation of the Rac family small GTPase 1 (RAC1) was associated with better survival. The SNVs of the top mutated genes, including epidermal growth factor receptor (12.7%), neurotrophic receptor tyrosine kinase 3 (7.8%), erb-b2 receptor tyrosine kinase 4 (8.5%), and KRAS (29.6%), were associated with T cell exhaustion in LUAD. To construct nomograms, we further screened the genes whose genomic changes were closely associated with survival and immune infiltration. The nomograms performed well in predicting disease-specific survival (DSS) with a concordance index of 0.7 (0.589, 0.811) and overall survival with a concordance index of 0.689 (0.603, 0.775) in test set; they also showed good correspondence between actual and ideal nomogram predictions. Tumor stage, RAC1 methylation, and type 1 regulatory T cells greatly contributed to DSS and OS nomograms. In summary, we provided a comprehensive genomic profile of the RTK/RAS pathway in LUAD and its association with immune cell infiltration and prognosis of LUAD. This profile would serve as a basis for developing better therapeutic strategies, improving patient prognosis, and understanding the mechanisms of immune disturbance from the perspective of oncogenic pathways of LUAD.

Background Immune microenvironment is well recognized as a critical regulator across cancer types, despite its complex roles in different disease conditions. Intrahepatic cholangiocarcinoma (iCCA) is characterized by a tumor-reactive milieu, emphasizing a deep insight into its immunogenomic profile to provide prognostic and therapeutic implications.Methods We performed genomic, transcriptomic, and proteomic characterization of 255 paired iCCA and adjacent liver tissues. We validated our findings through H&E staining (n=177), multiplex immunostaining (n=188), single-cell RNA sequencing (scRNA-seq) (n=10), in vitro functional studies, and in vivo transposon-based mouse models.Results Integrated multimodule data identified three immune subgroups with distinct clinical, genetic, and molecular features, designated as IG1 (immune-suppressive, 25.1%), IG2 (immune-exclusion, 42.7%), and IG3 (immune-activated, 32.2%). IG1 was characterized by excessive infiltration of neutrophils and immature dendritic cells (DCs). The hallmark of IG2 was the relatively higher tumor-proliferative activity and tumor purity. IG3 exhibited an enrichment of adaptive immune cells, natural killer cells, and activated DCs. These immune subgroups were significantly associated with prognosis and validated in two independent cohorts. Tumors with KRAS mutations were enriched in IG1 and associated with myeloid inflammation-dominated immunosuppression. Although tumor mutation burden was relatively higher in IG2, loss of heterozygosity in human leucocyte antigen and defects in antigen presentation undermined the recognition of neoantigens, contributing to immune-exclusion behavior. Pathological analysis confirmed that tumor-infiltrating lymphocytes and tertiary lymphoid structures were both predominant in IG3. Hepatitis B virus (HBV)-related samples tended to be under-represented in IG1, and scRNA-seq analyses implied that HBV infection indeed alleviated myeloid inflammation and reinvigorated antitumor immunity.Conclusions Our study elucidates that the immunogenomic traits of iCCA are intrinsically heterogeneous among patients, posing great challenge and opportunity for the application of personalized immunotherapy.

Allogeneic stem cell transplantation is a curative immunotherapy where patients receive myeloablative chemotherapy and/or radiotherapy, followed by donor stem cell transplantation. Graft versus host disease (GVHD) is a major complication caused by dysregulated donor immune system, thus a novel strategy to modulate donor immunity is needed to mitigate GVHD. Tissue damage by conditioning regimen is thought to initiate the inflammatory milieu that recruits various donor immune cells for cross-priming of donor T cells against alloantigen and eventually promote strong Th1 cytokine storm escalating further tissue damage. Bilirubin nanoparticles (BRNP) are water-soluble conjugated of bilirubin and polyethylene glycol (PEG) with potent anti-inflammatory properties through its ability to scavenge reactive oxygen species generated at the site of inflammation. Here, we evaluated whether BRNP treatment post-transplantation can reduce initial inflammation and subsequently prevent GVHD in a major histocompatibility (MHC) mismatched murine GVHD model. After myeloablative irradiation, BALB/c mice received bone marrow and splenocytes isolated from C57BL/6 mice, with or without BRNP (10 mg/kg) daily on days 0 through 4 post-transplantation, and clinical GVHD and survival was monitored for 90 days. First, BRNP treatment significantly improved clinical GVHD score compared to untreated mice (3.4 vs 0.3, p=0.0003), and this translated into better overall survival (HR 0.0638, p=0.0003). Further, BRNPs showed a preferential accumulation in GVHD target organs leading to a reduced systemic and local inflammation evidenced by lower pathologic GVHD severity as well as circulating inflammatory cytokines such as IFN-γ. Lastly, BRNP treatment post-transplantation facilitated the reconstitution of CD4+ iNK T cells and reduced expansion of proinflammatory CD8α+ iNK T cells and neutrophils especially in GVHD organs. Lastly, BRNP treatment decreased ICOS+ or CTLA-4+ T cells but not PD-1+ T cells suggesting a decreased level of T cell activation but maintaining T cell tolerance. In conclusion, we demonstrated that BRNP treatment post-transplantation ameliorates murine GVHD via diminishing the initial tissue damage and subsequent inflammatory responses from immune subsets.

Two new genera of velvety shore bugs, Arcochterus Zhang, Ren and Yao gen. nov. and Parvochterus Zhang, Ren and Yao gen. nov. are described, with three new species between them—Arcochterus fuscus Zhang, Ren and Yao sp. nov., Parvochterus reticulatus Ren and Yao sp. nov., and P. lanceolarus Zhang, Ren and Yao sp. nov. Based on the combination of fossil and extant taxa, a cladistic analysis is conducted to confirm the phylogenetic position of these species and allows reconstruction of the inter-genus relationships within the superfamily Ochteroidea. Major conclusions of the phylogenetic analysis: (1) these new species and Grimaldinia pronotalis belong to Ochteridae; (2) Ochteroidea is a monophyletic group, Ochteridae and Gelastocoridae are sister group and monophyletic, respectively. (3) The ancestral character state reconstruction (ACSR) shows that the length of the rostrum has occurred in at least three independent transitions during the evolution of the superfamily Ochteroidea.