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An in-depth understanding of the fracture behavior and mechanism of metallic shells under internal explosive loading can help develop material designs for warheads and regulate the quantity and mass distribution of the fragments formed. This study investigated the fragmentation performance of a new high-carbon silicon-manganese (HCSiMn) steel cylindrical shell through fragment recovery experiments. Compared with the conventional 45Cr steel shell, the number of small mass fragments produced by the HCSiMn steel shell was significantly increased with a scale parameter of 0.57 g fitted by the Weibull distribution model. The fragmentation process of the HCSiMn shell exhibited more brittle tensile fracture characteristics, with the microcrack damage zone on the outer surface being the direct cause of its high fragmentation. On the one hand, the doping of alloy elements resulted in grain refinement by forming metallographic structure of tempered sorbite, so that microscopic intergranular fracture reduces the characteristic mass of the fragments; on the other hand, the distribution of alloy carbides can exert a ''pinning'' effect on the substrate grains, causing more initial cracks to form and propagate along the brittle carbides, further improving the shell fragmentation. Although the killing power radius for light armored vehicles was slightly reduced by about 6%, the dense killing radius of HCSiMn steel projectile against personnel can be significantly increased by about 26% based on theoretical assessment. These results provided an experimental basis for high fragmentation warhead design, and to some extent, revealed the correlation mechanism between metallographic structure and shell fragmentation.

The activated persulfate (PS) process could produce sulfate radical (SO4·-) and rapidly degrade organic pollutants. The application of Fe3O4 as a promising PS activator was limited due to the rapid conversion of Fe2+ to Fe3+ on its surface. Mo4+ on MoS2 surface could be used as a reducing site to convert Fe3+ to Fe2+, but the separation and recovery of MoS2 was complex. In this study, MoS2/Fe3O4 was prepared to accelerate the Fe3+/Fe2+ cycle on Fe3O4 surface and achieved efficient separation of MoS2. The results showed that MoS2/Fe3O4 was more effective for PS activation compared to Fe3O4 or MoS2, with a removal efficiency of 91.8% for 20 mg·L−1 tetracycline (TC) solution under the optimal conditions. Fe2+ and Mo4+ on MoS2/Fe3O4 surface acted as active sites for PS activation with the generation of SO4•−, •OH, •O2−, and 1O2. Mo4+ acted as an electron donor to promote the Fe3+/Fe2+ cycling and thus improved the PS activation capability of MoS2/Fe3O4. The degradation pathways of TC were inferred as hydroxylation, ketylation of dimethylamino group and C-N bond breaking. This study provided a promising activated persulfate-based advanced oxidation process for the efficient degradation of TC by employing MoS2/Fe3O4 as an effective activator. HIGHLIGHTS MoS2/Fe3O4 was an effective, recoverable PS activator for tetracycline degradation.; TC was removed by free radical and non-free radical degradation pathways.; Mo4+ promoted the regeneration of Fe2+ on the Fe3O4 surface.;

Taking CL-20 (Hexanitrohexaazaisowurtzitane)-based aluminized explosives with high gurney energy as the research object, this research experimentally investigates the work capability of different aluminized explosive formulations when driving metal flyer plates in the denotation wave propagation direction. The research results showed that the formulations with 43 μm aluminum (Al) powder particles (The particle sizes of Al powder were in the range of 2∼43 μm) exhibited the optimal performance in driving flyer plates along the denotation wave propagation direction. Compared to the formulations with Al powder 13 μm, the formulations with Al powder 2 μm delivered better performance in accelerating metal flyer plates in the early stage, which, however, turned to be poor in the later stage. The CL-20-based explosives containing 25% Al far under-performed those containing 15% Al. Based on the proposed quasi-isentropic hypothesis, relevant isentropy theories, and the functional relationship between detonation parameters and entropy as well as Al reaction degree, the characteristic lines of aluminized explosives in accelerating flyer plates were theoretically studied, a quasi-isentropic theoretical model for the aluminized explosive driving the flyer plate was built and the calculation methods for the variations of flyer plate velocity, Al reaction degree, and detonation product parameters with time and axial positions were developed. The theoretical model built is verified by the experimental results of the CL-20-based aluminized explosive driving flyer plate. It was found that the model built could accurately calculate the variations of flyer plate velocity and Al reaction degree over time. In addition, how physical parameters including detonation product pressure and temperature varied with time and axial positions was identified. The action time of the positive pressure after the detonation of aluminized explosives was found prolonged and the downtrend of the temperature was slowed down and even reversed to a slight rise due to the aftereffect reaction between the Al powder and the detonation products.

Abstract Background Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant type of dementia worldwide. It is characterized by the progressive and irreversible decline of cognitive functions. In addition to the pathological beta-amyloid (Aβ) deposition, glial activation, and neuronal injury in the postmortem brains of AD patients, increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology. Vascular endothelial growth factor (VEGF) plays a critical role in regulating physiological functions and pathological changes in blood vessels, but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear. Methods We used an antiangiogenic agent for clinical cancer treatment, the humanized monoclonal anti-VEGF antibody bevacizumab, to block VEGF binding to its receptors in the 5×FAD mouse model at an early age. After treatment, memory performance was evaluated by a novel object recognition test, and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis. Immunofluorescence staining was used to measure glial activation and Aβ deposits. VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting. RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice. Results Bevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions, reduced glial activation, and restored long-term memory in both sexes of 5×FAD mice. Notably, a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice. Soluble VEGFR1 was decreased in female mice, while full-length VEGFR2 was increased in male mice. Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice. Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood–brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice. Conclusions Our study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice. These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.

Abstract Background Alveolar hypercoagulation and fibrinolytic inhibition are mainly responsible for massive alveolar fibrin deposition, which are closely related with refractory hypoxemia in acute respiratory distress syndrome (ARDS). Our previous study testified runt-related transcription factor (RUNX1) participated in the regulation of this pathophysiology in this syndrome, but the mechanism is unknown. We speculate that screening the downstream genes associated with RUNX1 will presumably help uncover the mechanism of RUNX1. Methods Genes associated with RUNX1 were screened by CHIP-seq, among which the target gene was verified by Dual Luciferase experiment. Then the efficacy of the target gene on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS was explored in vivo as well as in vitro. Finally, whether the regulatory effects of RUNX1 on alveolar hypercoagulation and fibrinolytic in ARDS would be related with the screened target gene was also sufficiently explored. Results Among these screened genes, AKT3 was verified to be the direct target gene of RUNX1. Results showed that AKT3 was highly expressed either in lung tissues of LPS-induced rat ARDS or in LPS-treated alveolar epithelia cell type II (AECII). Tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) were increasingly expressed both in lung tissues of ARDS and in LPS-induced AECII, which were all significantly attenuated by down-regulation of AKT3. Inhibition of AKT3 gene obviously ameliorated the LPS-induced lung injury as well as the collagen I expression in ARDS. RUNX1 overexpression not only promoted the expressions of TF, PAI-1, but also boosted AKT3 expression in vitro. More importantly, the efficacy of RUNX1 on TF, PAI-1 were all effectively reversed by down-regulation of AKT3 gene. Conclusion AKT3 is an important target gene of RUNX1, through which RUNX1 exerted its regulatory role on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS. RUNX1/ATK3 signaling axis is expected to be a new target for the exploration of ARDS genesis and treatment.

Federated learning is a distributed machine learning approach that allows a single server to collaboratively build machine learning models with multiple clients without sharing datasets. Since data distributions may differ across clients, data heterogeneity is a challenging issue in federated learning. To address this issue, numerous federated learning methods have been proposed to build personalized models for clients, referred to as personalized federated learning. Nevertheless, no studies comprehensively investigate the performance of personalized federated learning methods in various experimental settings such as datasets and client settings. Therefore, in this article, we aim to benchmark the performance of existing personalized federated learning methods in various settings. We first survey the experimental settings in existing studies. We then benchmark the performance of existing methods through comprehensive experiments to reveal their characteristics in computer vision and natural language processing tasks which are the most popular tasks based on our survey. Our experimental study shows that (i) large data heterogeneity often leads to highly accurate predictions and (ii) standard federated learning methods (e.g. FedAvg) with fine-tuning often outperform personalized federated learning methods.

Since the discovery of the first “giant virus,” particular attention has been paid toward isolating and culturing these large DNA viruses through Acanthamoeba spp. bait systems. While this method has allowed for the discovery of plenty novel viruses in the Nucleocytoviricota, environmental -omics-based analyses have shown that there is a wealth of diversity among this phylum, particularly in marine datasets. The prevalence of these viruses in metatranscriptomes points toward their ecological importance in nutrient turnover in our oceans and as such, in depth study into non-amoebal Nucleocytoviricota should be considered a focal point in viral ecology. In this review, we report on Kratosvirus quantuckense (née Aureococcus anophagefferens Virus), an algae-infecting virus of the Imitervirales. Current systems for study in the Nucleocytoviricota differ significantly from this virus and its relatives, and a litany of trade-offs within physiology, coding potential, and ecology compared to these other viruses reveal the importance of K. quantuckense. Herein, we review the research that has been performed on this virus as well as its potential as a model system for algal-virus interactions.

Objective: Alveolar type II (ATII) cells produce pulmonary surfactant (PS) essential for maintaining lung function. The aberration or depletion of PS can cause alveolar collapse, a hallmark of acute respiratory distress syndrome (ARDS). However, the intricacies underlying these changes remain unclear. This study aimed to elucidate the mechanisms underlying PS perturbations in ATII cells using transcriptional RNA-seq, offering insights into the pathogenesis of ARDS. Methods: ATII cells were identified using immunofluorescence targeting surface-active protein C. We used 24-h lipopolysaccharide (LPS)-induced ATII cells as an ARDS cell model. The efficacy of the injury model was gauged by detecting the presence of tumour necrosis factor-α and interleukin-6. RNA-seq analysis was performed to investigate the dynamics of PS deviation in unaltered and LPS-exposed ATII cells. Results: Whole-transcriptome sequencing revealed that LPS-stimulated ATII cells showed significantly increased transcription of genes, including Lss, Nsdhl, Hmgcs1, Mvd, Cyp51, Idi1, Acss2, Insig1, and Hsd17b7, which play key roles in regulating cholesterol biosynthesis. We further verified gene levels using real-time quantitative PCR, and the results showed that the mRNA expression of these genes increased, which was consistent with the RNA-seq results. Conclusion: Our study revealed pivotal transcriptional shifts in ATII cells after LPS exposure, particularly in nine key lipid and cholesterol metabolism genes. This altered expression might disrupt the lipid balance, ultimately affecting PS function. This finding deepens our understanding of the aetiology of ARDS and may lead to new therapeutic directions.

The mechanisms underlying sex differences in response to stress are unclear. Here, the authors show that meningeal lymphatics dysfunction modulates the sex difference in the stress susceptibility to depression- and anxiety-like behaviours in mice.

Abstract Background Andrographolide (Andro) has been confirmed to ameliorate alveolar hypercoagulation and fibrinolysis inhibition via NF-κB pathway in acute respiratory distress syndrome (ARDS), but the specific target of Andro is unknown. Purpose Our aim is to explore the specific target of Andro through which the drug exerted its effects on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS. Methods AECII was treated with different doses of Andro for 1 h, and then stimulated with LPS for 24 h. Expressions of tissue factor (TF), plasminogen activator inhibitor (PAI)-1 and tissue factor pathway inhibitor (TFPI) were detected. Concentrations of thrombin-antithrombin complex (TAT), pro-collagen type III peptide (PIIIP), antithrombin III (ATIII) and activated protein C (APC) in cell supernatant were measured by enzyme linked immunosorbent assay (ELISA). NF-κB signaling pathways activation was simultaneously determined. AECII with p65 down-/over-expression were used as control. Results Andro effectively inhibited TF and PAI-1 and promoted TFPI expressions on AECII induced by LPS stimulation. Andro also significantly suppressed the productions of TAT and PIIIP but promoted ATIII and APC secretions from the LPS-treated cell. Furthermore, Andro application obviously inhibited NF-κB signaling pathway activation provoked by LPS, as shown by decreased level of phosphorylation (p‑)-IKKβ/IKKβ, p-p65/p65 and p65 DNA binding activity. The effects of Andro on those factors were obviously strengthened by down- but were weakened by up-regulation of p65 gene in AECII cell. Conclusions Our data demonstrates that targeting AECII is the mechanism by which Andro ameliorates alveolar hypercoagulaiton and fibrinolytic inhibition via NF-κB pathway in ARDS. Andro is worth to be clinically further studied in ARDS treatment.

Objective: The relationship between base excess (BE) and 28-day death in sepsis patients remains to be elucidated. The aim of our clinical study is to explore the association of BE with 28-day mortality in patients with sepsis by using a large sample, multicenter Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Methods: We extracted the data of 35,010 patients with sepsis from the MIMIC-IV database, in which we used BE as an exposure variable and the 28-day mortality as an outcome variable, respectively, so as to explore the impact of BE on the 28-day mortality of patients with sepsis after adjusting for covariates. Results: BE and the 28-day mortality of patients with sepsis appeared to have a U-shaped relationship. The calculated inflection points were −2.5 mEq/L and 1.9 mEq/L, respectively. Our data demonstrated that BE was negatively associated with 28-day mortality in the range of −41.0 mEq/L to −2.5 mEq/L (odds ratio: 0.95; 95% confidence intervals (95%CI): 0.93 to 0.96), p

BackgroundAlthough publications have been increasing rapidly, the research quality has yet to improve in the field of critical care medicine (CCM) in China. This study aimed at investigating the current status of and the influential factors for impactful publications in CCM research by Chinese authors.MethodsPublications by authors with the affiliation of critical care medicine department or intensive care unit (CCM/ICU) in Chinese as well as American hospitals from 2001 to 2020 were retrieved from the Web of Science Core Collection (WoSCC) database for this bibliometric analysis. Moreover, statistical analyses to test factors affecting impactful publications by Chinese authors were performed.ResultsOf 13,487 articles retrieved by this search strategy, 6,622 were published by Chinese authors as first or corresponding authors. The annual publications by Chinese authors have been rapidly increasing from 2001 to 2020, and so did the citations to these articles. However, the proportion in the world of publications by Chinese authors was much less than that by American authors each year [M (IQR): 1.85 (9.592) vs. 27.77 (7.3), p < 0.001]. In addition, impactful articles were significantly less published by Chinese than by American authors, including articles either in journals with a high impact factor (p < 0.001) or in the top 10 journals in the field of CCM (5.4 vs 13.4%, p < 0.001), and articles with high citation frequency as well (p < 0.001). Moreover, the percentage of impactful publications by Chinese authors was likely associated with academic background and regions of the author's affiliations, funds support, public health events of COVID-19, and collaboration between authors.ConclusionOur results demonstrated that CCM research in China grew rapidly in the recent 20 years. However, the impactful publications remained limited, largely owing to the shortage of comprehensive research training, inactive collaboration, and underfunded CCM research.

Janus tyrosine kinase 3 (JAK3) is primarily expressed in immune cells and is needed for signaling by the common gamma chain (γc) family of cytokines. Abnormal JAK3 signal transduction can manifest as hematological disorders, e.g., leukemia, severe combined immunodeficiency (SCID) and autoimmune disease states. While regulatory JAK3 phosphosites have been well studied, here a functional proteomics approach coupling a JAK3 autokinase assay to mass spectrometry revealed ten previously unreported autophosphorylation sites (Y105, Y190, Y238, Y399, Y633, Y637, Y738, Y762, Y824, and Y841). Of interest, Y841 was determined to be evolutionarily conserved across multiple species and JAK family members, suggesting a broader role for this residue. Phospho-substitution mutants confirmed that Y841 is also required for STAT5 tyrosine phosphorylation. The homologous JAK1 residue Y894 elicited a similar response to mutagenesis, indicating the shared importance for this site in JAK family members. Phospho-specific Y841-JAK3 antibodies recognized activated kinase from various T-cell lines and transforming JAK3 mutants. Computational biophysics analysis linked Y841 phosphorylation to enhanced JAK3 JH1 domain stability across pH environments, as well as to facilitated complementary electrostatic JH1 dimer formation. Interestingly, Y841 is not limited to tyrosine kinases, suggesting it represents a conserved ubiquitous enzymatic function that may hold therapeutic potential across multiple kinase families.

A low-driving energy and bistable recoverable MEMS safety and arming device (S&A), based on microcasting technology and deep silicon etching technology, is proposed to meet safety system requirements. A force–electromagnetic combination solution is constructed for the Si MEMS S&A, with parameters and strength verified, ultimately achieving an S&A size of (13 × 13 × 0.4) mm. Additionally, a low-driving energy U-shaped electromagnetic coil (USEC) model is designed using microcasting technology, and an electrical–magnetic–mechanical coupling mathematical model is established to explore the relationship between design parameters and driving capacity and reliability. With a driving power of 8 V/0.5 A, the model achieves a stable electromagnetic driving force of 15 mN with a travel distance of 0.5 mm. Finally, the fabrication and testing of the USEC and S&A are carried out, with driving capability and S&A disarming ability tests conducted to verify the feasibility of the system design. Compared to the existing S&A, this scheme has the advantages of low-driving energy, recoverability, fast response speed, and strong adaptability.

The efficacy and safety of early renal replacement therapy (eRRT) for critically ill patients with acute kidney injury (AKI) remain controversial. Therefore, the purpose of our study was to perform an up-to-date meta-analysis with the trial sequential analysis (TSA) of randomized controlled trials (RCTs) to evaluate the therapeutic effect of eRRT on patients in an intensive care unit (ICU). We extensively searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov, Gray Literature Report, and Bielefeld Academic Search Engine (BASE), and conducted an updated search on December 27, 2021. The included studies were RCTs, which compared the efficacy and safety of eRRT and delayed renal replacement therapy (dRRT) on critically ill patients with AKI. We adopted TSA and sensitivity analysis to strengthen the robustness of the results. About 12 RCTs with a total of 5,423 participants were included. Patients receiving eRRT and dRRT had the similar rate of all-cause mortality at day 28 (38.7% vs. 38.9%) [risk ratio (RR), 1.00; 95%CI, 0.93–1.07, p = 0.93, I2 = 0%, p = 0.93]. A sensitivity and subgroup analysis produced similar results for the primary outcome. TSA showed that the required information size was 5,034, and the cumulative Z-curve crossed trial sequential monitoring boundaries for futility. Patients receiving eRRT had a higher rate of renal replacement therapy (RRT) (RR, 1.50, 95% CI: 1.28–1.76, p < 0.00001, I2 = 96%), and experienced more adverse events comparing to those receiving dRRT (RR: 1.41, 95% CI: 1.22–1.63, p < 0.0001, heterogeneity not applied). The most remarkable and important experimental finding is that, to our knowledge, the current meta-analysis included the largest sample size from the RCTs, which were published in the past 10 years to date, show that eRRT had no significant survival benefit for ill patients with AKI compared with dRRT and TSA indicating that no more studies were needed to confirm it.Trial RegistrationINPLASY, INPLASY2020120030. Registered 04 December 2020.

It is very important to develop a new method of preparing high-performance liquid silicone rubber-reinforcing filler. Herein, the hydrophilic surface of silica (SiO2) particles was modified by a vinyl silazane coupling agent to prepare a new type of hydrophobic reinforcing filler. The structures and properties of modified SiO2 particles were confirmed using Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectrometer (XPS), specific surface area and particle size distribution and thermogravimetric analysis (TGA), the results of which demonstrated that the aggregation of hydrophobic particles is greatly reduced. Additionally, the effects of the vinyl-modified SiO2 particle (f-SiO2) content on the dispersibility, rheology, and thermal and mechanical properties of liquid silicone rubber (SR) composites were studied for application toward high-performance SR matrix. The results showed that the f-SiO2/SR composites possessed low viscosity and higher thermal stability, conductivity, and mechanical strength than of SiO2/SR composites. We believe that this study will provide ideas for the preparation of high-performance liquid silicone rubber with low viscosity.

Artificial intelligence technology shows the advantages of improving efficiency, reducing costs, shortening time, reducing the number of staff on site and achieving precise operations, making impressive research progress in the fields of drug discovery and development, but there are few reports on application in energetic materials. This paper addresses the high safety risks in the current nitrification process of energetic materials, comprehensively analyses and summarizes the main safety risks and their control elements in the nitrification process, proposes possibilities and suggestions for using artificial intelligence technology to enhance the “essential safety” of the nitrification process in energetic materials, reviews the research progress of artificial intelligence in the field of drug synthesis, looks forward to the application prospects of artificial intelligence technology in the nitrification of energetic materials and provides support and guidance for the safe processing of nitrification in the propellants and explosives industry.

Pancreatic adenocarcinoma (PAAD) is characterized by high malignancy, frequent metastasis, and recurrence with an unfavorable prognosis. This study is aimed at constructing a prognostic model for tumor-infiltrating immune cells and a competing endogenous RNA (ceRNA) network in PAAD and analyzing susceptibilities of chemotherapy and immunotherapy of PAAD. Gene expression profiles and clinical information of PAAD were downloaded from The Cancer Genome Atlas (TCGA) database and divided into the tumor group and the normal group. A total of five PAAD survival-related key genes in the ceRNA network and three survival-related immune infiltrating cells were uncovered, and two survival risk models and nomograms were constructed. The efficiency and performance of the two models were verified using multi-index area under the curve analysis at different time points, decision curve analysis, and calibration curves. Co-expression analysis showed that LRRC1, MIR600HG, and RNF166 in the ceRNA network and tumor-infiltrating immune cells including CD8 T cells and M1 macrophages were likely related to the PAAD prognosis, and the expression of key ceRNA-related genes was experimently validated in tissues and cell lines by RT-qPCR. Patients with low risk scores for key genes in the ceRNA network displayed a positive response to anti-programmed death-1 (PD-1) treatment and greater sensitivity to chemotherapeutic drugs such as docetaxel, lapatinib, and paclitaxel. More importantly, our results suggested that the IC50 values of gemcitabine in PAAD were not significantly different between the high and low risk groups. The expression levels of immune checkpoints were significantly different in the high-risk and low-risk groups. The prognostic model, nomogram, and drug analysis may provide an essential reference for PAAD patient management in the clinic.

Hepatocellular carcinoma (HCC) is the most common gastrointestinal tumor with a poor prognosis, which is associated with poor differentiation of tumor cells. However, the potential value of cell differentiation-related molecules in predicting the benefit and prognosis of immune checkpoint inhibitors (ICI) therapy remains unknown. Herein, to investigate the differentiation trajectory of HCC cells and their clinical significance, a differentiation-related gene prognostic index (DRGPI) based on HCC differentiation-related genes (HDRGs) was constructed to elucidate the immune characteristics and therapeutic benefits of ICI in the HCC subgroup defined by DRGPI. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from four HCC samples were integrated for bioinformatics analysis. Then, PON1, ADH4, SQSTM1, HSP90AA1, and STMN1 were screened out to construct a DRGPI. More intriguingly, RT-qPCR validation of the expression of these genes yielded consistent results with the TCGA database. Next, the risk scoring (RS) constructed based on DRGPI suggested that the overall survival (OS) of the DRGPI-high patients was significantly worse than that of the DRGPI-low patients. A nomogram was constructed based on DRGPI-RS and clinical characteristics, which showed strong predictive performance and high accuracy. The comprehensive results indicated that a low DRGPI score was associated with low TP53 mutation rates, high CD8 T cell infiltration, and more benefit from ICI therapy. Homoplastically, the high DRGPI score reflected the opposite results. Taken together, our study highlights the significance of HCC cell differentiation in predicting prognosis, indicating immune characteristics, and understanding the therapeutic benefits of ICI, and suggests that DRGPI is a valuable prognostic biomarker for HCC.

Family planning is a basic national policy in China. An intrauterine device (IUD) is an important method of achieving family planning owing to its high safety, low cost, and convenient use. The indwelling birth control ring has no obvious adverse effects on the sexual life of women after the operation, and the process is reversible. This ring can be removed for women who want to have children again. There are approximately 100 million women with IUDs worldwide, with approximately 80 million in China. This finding accounts for approximately 40% of women of childbearing age in China. Although an IUD is safe, the invasive operation inevitably leads to complications, such as pelvic infection, abnormal menstruation, and damage to adjacent organs. Among them, ectopic bladder stone formation is a rare complication, but several related cases have been reported. We report four cases of heterotopia of an IUD and cystolithiasis, with diagnosis based on the medical history, clinical manifestations, imaging, and cystoscopic findings. The four patients with ectopic IUDs were treated with cystoscopy combined with laparoscopy (or hysteroscopy). We describe the process of diagnosis and treatment of our patients, and the related literature on an ectopic IUD is reviewed.

Viruses modulate the function(s) of environmentally relevant microbial populations, yet considerations of the metabolic capabilities of individual virus particles themselves are rare. We used shotgun proteomics to quantitatively identify 43 virus-encoded proteins packaged within purified Aureococcus anophagefferens Virus (AaV) particles, normalizing data to the per-virion level using a 9.5-Å-resolution molecular reconstruction of the 1900-Å (AaV) particle that we generated with cryogenic electron microscopy. This packaged proteome was used to determine similarities and differences between members of different giant virus families. We noted that proteins involved in sugar degradation and binding (e.g., carbohydrate lyases) were unique to AaV among characterized giant viruses. To determine the extent to which this virally encoded metabolic capability was ecologically relevant, we examined the TARA Oceans dataset and identified genes and transcripts of viral origin. Our analyses demonstrated that putative giant virus carbohydrate lyases represented up to 17% of the marine pool for this function. In total, our observations suggest that the AaV particle has potential prepackaged metabolic capabilities and that these may be found in other giant viruses that are widespread and abundant in global oceans.

At the molecular level, the circadian clock is regulated by a time delayed transcriptional-translational feedback loop in which the core proteins interact with each other rhythmically to drive daily biological rhythms. The C-terminal domain of a key clock protein PER2 (PER2c) plays a critically important role in the loop, not only for its interaction with the binding partner CRY proteins but also for the CRY/PER complex's translocation from the cytosol to the nucleus. Previous circular dichroism (CD) spectroscopic studies have shown that mouse PER2c (mPER2c) is less structured in solution by itself but folded into stable secondary structures upon interaction with mouse CRYs. To understand the stability and folding of human PER2c (hPER2c), we expressed and purified hPER2c. Three oligomerization forms of recombinant hPER2c were identified and thoroughly characterized through a combination of biochemical and biophysical techniques. Different to mPER2c, both thermal unfolding DLS and CD analyses suggested that all forms of hPER2c have very stable secondary structures in solution by themselves with melting temperatures higher than the physiological body temperature, indicating that hPER2c does not require CRY to fold. Furthermore, we examined the effects of EDTA, salt concentration, and a reducing agent on hPER2c folding and oligomerization. The ability of hPER2c forming oligomers reflects the potential role of hPER2c in the assembly of circadian rhythm core protein complexes.

Abstract Whereas the protein composition and overall shape of several giant virus capsids have been described, the mechanism by which these large capsids assemble remains enigmatic. Here, we present a reconstruction of the capsid of Cafeteria roenbergensis virus (CroV), one of the largest viruses analyzed by cryo-electron microscopy (cryo-EM) to date. The CroV capsid has a diameter of 3,000 Å and a Triangulation number of 499. Unlike related mimiviruses, the CroV capsid is not decorated with glycosylated surface fibers, but features 30 Å-long surface protrusions that are formed by loops of the major capsid protein. Based on the orientation of capsomers in the cryo-EM reconstruction, we propose that the capsids of CroV and related giant viruses are assembled by a newly conceived assembly pathway that initiates at a five-fold vertex and continuously proceeds outwards in a spiraling fashion.

Everyone benefits from social networking as a daily tool, but there are potential addictions. However, little is known about the craving and excitability of social networking sites addiction, and mode of change in psychological craving. The study consisted of two experiments that used a cue-reactivity paradigm to study the cravings and excitement of social networking sites (SNSs) addiction and the changing regulars in cravings. Sixty subjects were divided into a high-score group and a low-score group. In Experiment 1, all subjects evaluated word clues. The results showed that the SNS-related clues only induced the craving and excitability of the high-score group, but not the low-score group, and the craving fluctuated. Furthermore, in Experiment 2, image clues were used. The results showed that the craving induced by an image clue is significantly higher than the craving induced by a word clue, and there is no difference in excitability. Taken together, our findings suggest the SNS-related stimulation, especially image clues, could significantly induce subjects for the craving and excitability of social networks, and the craving fluctuates.

Contribution: This research illuminates information entropy's efficacy as a pivotal educational tool in programming, enabling the precise quantification of algorithmic complexity and student abstraction levels for solving problems. This approach can provide students quantitative, comparative insights into the differences between optimal and student implemented solution, and allowing educators to offer targeted feedback, thereby optimizing the learning and abstraction processes in algorithm design through deliberate practice. Background: Abstraction is considered one of the most important skills in problem solving. Many studies in programming have shown that higher abstraction capability can significantly simplify problems, reduce program complexity and improve efficiency. However, it is difficult to develop criteria to measure the level of abstraction, and there is still a lack of relevant systematic research. Research Questions: 1) How can students' abstraction ability in programming be effectively measured? and 2) How to develop programming education and training methods based on the measurement of abstraction ability? Methodology: Forty-six grade 10 students participated in the experiment, divided into two groups for programming training using information-entropy-based assessment and traditional learning methods. Their level of computational thinking, algorithmic efficiency improvements, and test scores were used to measure performance and to analyze the effectiveness of the training methods. Findings: Through empirical research, this article finds that information-entropy-based assessment can reflect the differences in problem solving among students possessing varying capabilities. Information entropy can be crucial for evaluating and improving students' abstraction performance and algorithm efficiency.

In the last three decades, many giant DNA viruses have been discovered. Giant viruses present a unique and essential research frontier for studies of self-assembly and regulation of supramolecular assemblies. The question on how these giant DNA viruses assemble thousands of proteins so accurately to form their protein shells, the capsids, remains largely unanswered. Revealing the mechanisms of giant virus assembly will help to discover the mysteries of many self-assembly biology problems. Paramecium bursaria Chlorella virus-1 (PBCV-1) is one of the most intensively studied giant viruses. Here, we implemented a multi-scale approach to investigate the interactions among PBCV-1 capsid building units called capsomers. Three binding modes with different strengths are found between capsomers around the relatively flat area of the virion surface at the icosahedral 2-fold axis. Furthermore, a capsomer structure manipulation package is developed to simulate the capsid assembly process. Using these tools, binding forces among capsomers were investigated and binding funnels were observed that were consistent with the final assembled capsid. In addition, total binding free energies of each binding mode were calculated. The results helped to explain previous experimental observations. Results and tools generated in this work established an initial computational approach to answer current unresolved questions regarding giant virus assembly mechanisms. Results will pave the way for studying more complicated process in other biomolecular structures.

The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC50 values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 µM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy.

Anthrax toxin receptors act as molecular clamps or switches that control anthrax toxin entry, pH-dependent pore formation, and translocation of enzymatic moieties across the endosomal membranes. We previously reported that reduction of the disulfide bonds in the immunoglobulin-like (Ig) domain of the anthrax toxin receptor 2 (ANTXR2) inhibited the function of the protective antigen (PA) pore. In the present study, the disulfide linkage in the Ig domain was identified as Cys255-Cys279 and Cys230-Cys315. Specific disulfide bond deletion mutants were achieved by replacing Cys residues with Ala residues. Deletion of the disulfide bond C255-C279, but not C230-C315, inhibited the PA pore-induced release of the fluorescence dyes from the liposomes, suggesting that C255-C279 is essential for PA pore function. Furthermore, we found that deletion of C255-C279 did not affect PA prepore-to-pore conversion, but inhibited PA pore membrane insertion by trapping the PA membrane-inserting loops in proteinaceous hydrophobic pockets. Fluorescence spectra of Trp59, a residue adjacent to the PA-binding motif in von Willebrand factor A (VWA) domain of ANTXR2, showed that deletion of C255-C279 resulted in a significant conformational change on the receptor ectodomain. The disulfide deletion-induced conformational change on the VWA domain was further confirmed by single-particle 3D reconstruction of the negatively stained PA-receptor heptameric complexes. Together, the biochemical and structural data obtained in this study provides a mechanistic insight into the role of the receptor disulfide bond C255-C279 in anthrax toxin action. Manipulation of the redox states of the receptor, specifically targeting to C255-C279, may become a novel strategy to treat anthrax.

Along with the emergence of massive graph-modeled data, it is of great importance to investigate graph similarity joins due to their wide applications for multiple purposes, including data cleaning, and near duplicate detection. This paper considers graph similarity joins with edit distance constraints, which return pairs of graphs such that their edit distances are no larger than a given threshold. Leveraging the MapReduce programming model, we propose MGSJoin, a scalable algorithm following the filtering-verification framework for efficient graph similarity joins. It relies on counting overlapping graph signatures for filtering out nonpromising candidates. With the potential issue of too many key-value pairs in the filtering phase, spectral Bloom filters are introduced to reduce the number of key-value pairs. Furthermore, we integrate the multiway join strategy to boost the verification, where a MapReduce-based method is proposed for GED calculation. The superior efficiency and scalability of the proposed algorithms are demonstrated by extensive experimental results.

Grain amaranth (Amaranthus hypochondriacus L.) is abundant in oxalate and can secrete oxalate under aluminium (Al) stress. However, the features of Al-induced secretion of organic acid anions (OA) and potential genes responsible for OA secretion are poorly understood. Here, Al-induced OA secretion in grain amaranth roots was characterized by ion charomatography and enzymology methods, and suppression subtractive hybridization (SSH) together with quantitative real-time PCR (qRT-PCR) was used to identify up-regulated genes that are potentially involved in OA secretion. The results showed that grain amaranth roots secrete both oxalate and citrate in response to Al stress. The secretion pattern, however, differs between oxalate and citrate. Neither lanthanum chloride (La) nor cadmium chloride (Cd) induced OA secretion. A total of 84 genes were identified as up-regulated by Al, in which six genes were considered as being potentially involved in OA secretion. The expression pattern of a gene belonging to multidrug and toxic compound extrusion (MATE) family, AhMATE1, was in close agreement with that of citrate secretion. The expression of a gene encoding tonoplast dicarboxylate transporter and four genes encoding ATP-binding cassette transporters was differentially regulated by Al stress, but the expression pattern was not correlated well with that of oxalate secretion. Our results not only reveal the secretion pattern of oxalate and citrate from grain amaranth roots under Al stress, but also provide some genetic information that will be useful for further characterization of genes involved in Al toxicity and tolerance mechanisms.

Mimivirus is the largest known virus whose genome and physical size are comparable to some small bacteria, blurring the boundary between a virus and a cell. Structural studies of Mimivirus have been difficult because of its size and long surface fibers. Here we report the use of enzymatic digestions to remove the surface fibers of Mimivirus in order to expose the surface of the viral capsid. Cryo-electron microscopy (cryoEM) and atomic force microscopy were able to show that the 20 icosahedral faces of Mimivirus capsids have hexagonal arrays of depressions. Each depression is surrounded by six trimeric capsomers that are similar in structure to those in many other large, icosahedral double-stranded DNA viruses. Whereas in most viruses these capsomers are hexagonally close-packed with the same orientation in each face, in Mimivirus there are vacancies at the systematic depressions with neighboring capsomers differing in orientation by 60 degrees . The previously observed starfish-shaped feature is well-resolved and found to be on each virus particle and is associated with a special pentameric vertex. The arms of the starfish fit into the gaps between the five faces surrounding the unique vertex, acting as a seal. Furthermore, the enveloped nucleocapsid is accurately positioned and oriented within the capsid with a concave surface facing the unique vertex. Thus, the starfish-shaped feature and the organization of the nucleocapsid might regulate the delivery of the genome to the host. The structure of Mimivirus, as well as the various fiber components observed in the virus, suggests that the Mimivirus genome includes genes derived from both eukaryotic and prokaryotic organisms. The three-dimensional cryoEM reconstruction reported here is of a virus with a volume that is one order of magnitude larger than any previously reported molecular assembly studied at a resolution of equal to or better than 65 Angstroms.

Icosahedral double-stranded DNA viruses use a single portal for genome delivery and packaging. The extensive structural similarity revealed by such portals in diverse viruses, as well as their invariable positioning at a unique icosahedral vertex, led to the consensus that a particular, highly conserved vertex-portal architecture is essential for viral DNA translocations. Here we present an exception to this paradigm by demonstrating that genome delivery and packaging in the virus Acanthamoeba polyphaga mimivirus occur through two distinct portals. By using high-resolution techniques, including electron tomography and cryo-scanning electron microscopy, we show that Mimivirus genome delivery entails a large-scale conformational change of the capsid, whereby five icosahedral faces open up. This opening, which occurs at a unique vertex of the capsid that we coined the "stargate", allows for the formation of a massive membrane conduit through which the viral DNA is released. A transient aperture centered at an icosahedral face distal to the DNA delivery site acts as a non-vertex DNA packaging portal. In conjunction with comparative genomic studies, our observations imply a viral packaging pathway akin to bacterial DNA segregation, which might be shared by diverse internal membrane-containing viruses.

The synthesis of bistetrazole via a one-step process including substitution-cyclisation-cracking reaction has been reported for the first time. The combination of a nitrogen-rich energetic framework and a high oxygen detonation group perfectly fulfills the target of maintaining a high level of nitrogen content and good oxygen balance while avoiding the safety risks. H2TT, with 81.5% nitrogen content, demonstrates a very high heat of formation (DHf = 5.54 kJ g-1) and superior detonation velocity (D = 8932 m s-1) to RDX (D = 8795 m s-1). After the introduction of dinitromethyl high oxygen groups, the target compound BDNTT has an oxygen balance of -11.6% and a high crystal density up to 1.914 g cm-3, and exhibited superior detonation performance (D = 9633 m s-1, P = 41.4 GPa) to HMX (D = 9144 m s-1, P = 39.3 GPa). At the same time, the nitrogen content and oxygen balance of the BDNTT reached a decent level of 54.1% and -11.6%, respectively. Future researchers can use this study as experience to design advanced high-energy density materials. [ABSTRACT FROM AUTHOR]