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To clarify the allometric growth pattern and hunger tolerance of Hemibarbus maculatus Bleeker larvae, the morphological lengths of their functional organs were measured continuously and their primary feeding rates under a state of starvation were studied. A control group and starvation group were set up for this study, and 10 larvae were sampled from each group every day in order to study their allometric growth pattern and starvation tolerance. The results indicated that the Hemibarbus maculatus larvae opened their mouths for feeding at 4 days after hatching, and that the yolk sac disappeared completely at 11 days after hatching. The Hemibarbus maculatus larvae preferentially developed their heads, fins, and eyes, related to the functions of feeding, balancing, and swimming, in order to cope with complex environments. The growth inflection points for the head length, pectoral fin length, dorsal fin length, eye diameter, eye spacing, snout length, and body height were characterized by total lengths of 10.93 mm, 11.67 mm, 11.67 mm, 13.17 mm, 16.53 mm, 15.13 mm, and 15.13 mm, respectively. Prior to and following the inflection point, positive allometric growth was observed in all organs. After the inflection point, the dorsal fin continued to maintain positive allometric growth, while the others changed to isometric allometric growth. A growth inflection point was not observed for trunk length or the lengths of the tail and anal fins. The trunk length always maintained negative allometry, while the tail and anal fin lengths were reversed. The growth inflection point of the tail length was at a total length of 13.68 mm. Before and after the growth inflection point, negative and isometric allometric growths were observed, respectively. According to the relationship between the total length and number of days after hatching, the growth inflection point of the Hemibarbus maculatus larvae was concentrated at TL = 10.93–16.53 mm, which was observed 14–20 days after hatching. The point of no return for the Hemibarbus maculatus larvae was 12–13 days after hatching, and the ratio of days after hatching in the mixed trophic period to the endotrophic period was 1.75, indicating that the larvae had strong hunger tolerance. Therefore, when considering a water temperature of 22.66 ± 1.56 °C, 4–5 days after hatching is the best time to cultivate in the pond, and it should not be carried out later than 12 days after hatching.

Abstract Background Multiple myeloma (MM) is a hematological malignancy characterized by clonal proliferation of malignant plasma cells. Despite extensive research, molecular mechanisms in MM that drive drug sensitivity and clinic outcome remain elusive. Results Single-cell RNA sequencing was applied to study tumor heterogeneity and molecular dynamics in 10 MM individuals before and after 2 cycles of bortezomib–cyclophosphamide–dexamethasone (VCD) treatment, with 3 healthy volunteers as controls. We identified that unfolded protein response and metabolic-related program were decreased, whereas stress-associated and immune reactive programs were increased after 2 cycles of VCD treatment. Interestingly, low expression of the immune reactive program by tumor cells was associated with unfavorable drug response and poor survival in MM, which probably due to downregulation of MHC class I mediated antigen presentation and immune surveillance, and upregulation of markers related to immune escape. Furthermore, combined with immune cells profiling, we uncovered a link between tumor intrinsic immune reactive program and immunosuppressive phenotype in microenvironment, evidenced by exhausted states and expression of checkpoint molecules and suppressive genes in T cells, NK cells and monocytes. Notably, expression of YBX1 was associated with downregulation of immune activation signaling in myeloma and reduced immune cells infiltration, thereby contributed to poor prognosis. Conclusions We dissected the tumor and immune reprogramming in MM during targeted therapy at the single-cell resolution, and identified a tumor program that integrated tumoral signaling and changes in immune microenvironment, which provided insights into understanding drug sensitivity in MM.

Abstract Background Antiangiogenic drugs have shown initial efficacy in the treatment of advanced thymic carcinomas (TCs); however, data are limited. In this study, we provide real-world data relating to the efficacy of antiangiogenic drugs for the treatment of patients with TCs. Methods We retrospectively collected data on clinical progress after first-line chemotherapy in TCs patients who were treated with small molecule antiangiogenic drugs at our institution between January 2010 and December 2021. Tumor response was evaluated according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Progression free survival and overall survival were calculated using the Kaplan-Meier method. Results Of the 17 patients enrolled, 13 (76.5%) received apatinib and four (23.5%) anlotinib monotherapy with an objective response rate of 23.5%. Eleven (64.7%) patients had stable disease. The median follow-up period was 46.0 months (95% confidence interval [CI], 33.0–59.0 months). The median progression survival and overall survival were 7.9 months (95% CI, 6.5–9.3) and 47.0 months (95% CI, 35.4–58.6), respectively. In the 13 patients receiving apatinib, the median PFS was 7.0 months (95% CI, 5.0–9.0), compared with 8.0 months (95% CI, 2.7–13.3 months) for patients in the anlotinib group (P = 0.945). The most common grade 3 adverse events (AEs) were hypertension (n = 3, 23.1%), followed by proteinuria and hand-foot syndrome (HFS, n = 2, 15.4%). There were no grade 4 AEs although eight patients (47.1%) required mid-course discontinuation. Conclusion For refractory TCs, small molecule antiangiogenic drugs are efficacious as second- or post-line treatments. The toxicity of antiangiogenic therapy is manageable.

Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage (ICH). Withaferin A (WFA), a natural compound, exhibits a positive effect on a number of neurological diseases. However, the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown. In this study, we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis. We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH. WFA was injected intracerebroventricularly at 0.1, 1 or 5 µg/kg once daily for 7 days, starting immediately after ICH operation. WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage. Through in vitro experiments, cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury. Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde, an oxidative stress marker, and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH. Western blot assay, quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling axis, promoted translocation of Nrf2 from the cytoplasm to nucleus, and increased HO-1 expression. Silencing Nrf2 with siRNA completely reversed HO-1 expression, oxidative stress and protective effects of WFA. Furthermore, WFA reduced hemin-induced ferroptosis. However, after treatment with an HO-1 inhibitor, the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened. MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell injury. Our findings reveal that WFA treatment alleviated ICH injury-induced ferroptosis and oxidative stress through activating the Nrf2/HO-1 pathway, which may highlight a potential role of WFA for the treatment of ICH.

Background: B3 type thymoma is defined as a well-differentiated thymic carcinoma and is similar to a thymic carcinoma. However, the differences between them are not well defined. In addition, the data to compare the efficacy and safety of platinum-based chemotherapy as first-line therapy between B3 thymoma and thymic carcinoma are lacking. Methods: The efficacy and safety of platinum-based chemotherapy as first-line therapy was retrospectively compared between a group of 36 patients with type B3 thymoma and a group of 127 patients with thymic carcinoma treated between January 2009 and March 2022 at the Zhejiang Cancer Hospital. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events were analyzed. Results: The ORRs for B3 thymoma and thymic carcinoma were 36.1% and 28.3%, respectively (p = 0.370). Among all patients, the difference in PFS between B3 thymoma and thymic carcinoma was not significant (11.3 vs. 10.1 months, p = 0.118). The squamous carcinoma subgroup did not exhibit any differences in PFS compared to B3 thymoma (11.7 vs. 11.3 months, p = 0.161). The result for the non-squamous carcinoma subgroup was similar (6.5 vs. 11.3 months, p = 0.128). Furthermore, the OS values for B3 thymoma and thymic carcinoma were not significantly different (58.3 vs. 35.1 months, p = 0.067). However, there were differences in OS between B3 thymoma and non-squamous carcinoma (58.3 vs. 30.6 months, p = 0.031). Conclusions: B3 thymoma and especially squamous carcinoma patients may be treated using a similar therapy scheme as that utilized for thymic carcinoma.

The bias correction method (BCM) is useful in reducing the statistically downscaled biases of global climate models’ (GCM) outputs and preserving statistical moments of the hydrological series. However, BCM is less efficient under changed future conditions due to the stationary assumption and performs poorly in removing bias at extremes, thereby producing unreliable bias-corrected data. Thus, the existing BCM with normal distribution is improved by incorporating skewed distributions into the model with linear covariate (BCM-QMskewed). In this study, BCM-QMskewed is developed to reduce biases in the extreme temperature data of peninsular Malaysia. The input is the MIROC5 model output gridded data and observations sourced by the Malaysian Department of Irrigation and Drainage (1976–2005). BCM-QMskewed with lognormal (LGNORM) and Gumbel (GUM) has shown considerable skill in correcting biases, capturing extreme and nonstationarity of current and future extreme temperatures data series corresponding to the representative concentration pathways (RCPs) for 2006–2100 based on model diagnostics and precision analysis. Higher projection of extreme temperatures is more pronounced under RCP8.5 than RCP4.5 with precise estimates ranging from 33 to 42 °C and 30 to 32 °C, respectively. Finally, the projection of extreme temperatures is used to calculate cardiovascular disease (CVD) mortality rate which coincides with high extreme temperatures ranging between 0.002 and 0.014. HIGHLIGHTS BCM-QMskewed with LGNORM and GUM was considered to capture the extreme values.; The linear covariate model was considered to capture the nonstationary trend in extreme temperatures series.; Results indicate the model's ability to correct the biases of extreme temperatures data for both RCPs in the study area with decent accuracy.; Higher mortality rate of CVD is consistent with higher extreme temperatures.;

Abstract Background Colorectal cancer (CRC) is a heterogeneous disease with different responses to targeted therapies due to various factors, and the treatment effect differs significantly between individuals. Personalize medical treatment (PMT) is a method that takes individual patient characteristics into consideration, making it the most effective way to deal with this issue. Patient similarity and clustering analysis is an important aspect of PMT. This paper describes how to build a knowledge base using formal concept analysis (FCA), which clusters patients based on their similarity and preserves the relations between clusters in hierarchical structural form. Methods Prognostic factors (attributes) of 2442 CRC patients, including patient age, cancer cell differentiation, lymphatic invasion and metastasis stages were used to build a formal context in FCA. A concept was defined as a set of patients with their shared attributes. The formal context was formed based on the similarity scores between each concept identified from the dataset, which can be used as a knowledge base. Results A hierarchical knowledge base was constructed along with the clinical records of the diagnosed CRC patients. For each new patient, a similarity score to each existing concept in the knowledge base can be retrieved with different similarity calculations. The ranked similarity scores that are associated with the concepts can offer references for treatment plans. Conclusions Patients that share the same concept indicates the potential similar effect from same clinical procedures or treatments. In conjunction with a clinician’s ability to undergo flexible analyses and apply appropriate judgement, the knowledge base allows faster and more effective decisions to be made for patient treatment and care.

Abstract Background Anemia is relatively common in cancer patients, and baseline anemia is associated with poor survival in patients with non-small cell lung cancer (NSCLC). However, there is a lack of large-sample studies of patients with NSCLC with epidermal growth factor receptor (EGFR) mutations. Methods We retrospectively analyzed anemia‑related data for patients with NSCLC and EGFR mutations who were admitted to Zhejiang Cancer Hospital from January 2013 to June 2019 and treated with targeted therapy. The patients’ clinicopathological features were evaluated by χ2 tests and the relationships between clinical characteristics and prognosis were investigated using Kaplan–Meier and multivariate Cox regression analyses. Results A total of 2,029 patients treated with EGFR-tyrosine kinase inhibitors (TKIs) were finally enrolled in this study, of whom 24.6% had baseline anemia. Patients without baseline anemia had longer median overall survival (OS) than patients with baseline anemia (36.10 vs. 29.10 months, P = 0.001), and patients with grade

Abstract Background Lung adenocarcinoma (LUAD) is a leading cause of cancer-related death worldwide. Ferroptosis, a form of cell death characterized by iron-dependent lipid peroxidation. However, the involvement of ferroptosis in the regulation of immune cell infiltration and its immunotherapeutic efficacy in LUAD remain unclear. Methods The Cancer Genome Atlas (TCGA) LUAD cohort was used to assess the survival prognosis of FRGs and construct a seven-gene risk signature. Correlation tests, difference tests, and a cluster analysis were performed to explore the role of FRGs in the immune microenvironment and their immunotherapeutic efficacy in LUAD. The effects of FRGs on LUAD cells were assessed by Western blot, iron assay, and lipid peroxidation assay. Results The seven-gene risk signatures of patients with LUAD were established and validated. FRG clustering based on 70 differentially expressed FRGs was associated with the immune microenvironment and indicated potential immune subtypes of LUAD. The seven-gene risk signature was an independent prognostic factor for LUAD and was used to divide the LUAD cohort into a high-risk and a low-risk group. Immunocyte infiltration levels, immune checkpoints, and immunotherapy response rates were significantly different between the two groups. Patients with high risk scores had lower overall levels of immunocyte infiltration but higher immunotherapy response rates. The key gene ribonucleotide reductase subunit M2 (RRM2) was associated with LUAD prognosis, which may be related to its ability to regulate the infiltration levels of activated mast cells and activated CD4 memory T cells. In addition, RRM2 was involved in ferroptosis, and its expression was up regulated in lung cancer tissues and the LUAD cell lines. Silencing RRM2 can inhibit the proliferation and induce ferroptosis of H1975 cells suggesting that silencing RRM2 could promote ferroptosis in H1975 cells. Conclusion Our results revealed RRM2 as a promising biomarker and therapeutic target associated with tumor immune infiltration in patients with LUAD.

Characterisation of gut microbiota shows that low-dose radiation enhances the metabolic defects induced by high-fat diet in mice, in a manner involving increased levels of pyrrolidinecarboxylic acid.

In order to improve the corrosion resistance of AZ31 magnesium alloy, a chemical conversion coating was prepared on the surface of AZ31 magnesium alloy by adding an appropriate amount of rare earth oxide (ie, cerium oxide and lanthanum oxide respectively) in an ultrasonic environment. Through the hydrogen evolution experiment, it was found that the AZ31 magnesium alloy chemical conversion coating sample added with cerium oxide had the lowest hydrogen evolution, indicating that its corrosion resistance was optimal. Through the corrosion morphology observation by SEM, it was found that the surface of the chemical conversion coating sample added with cerium oxide was relatively smooth and flat after immersion, indicating that this coating could protect the magnesium alloy substrate well. From the results of polarization curve experiment, it was found that the corrosion potential of the conversion coating sample added with cerium oxide moved positively in comparison with the original magnesium alloy, and its corrosion current density was lower than that of the original alloy. Therefore, the corrosion resistance of AZ31 magnesium alloy could be improved by the chemical conversion coating formed by adding cerium oxide under ultrasonic environment.

Improving the corrosion protection level of metal materials for ocean engineering equipment is of great significance for the improvement of the abilities to explore ocean resources. The macro corrosion mechanism of such metal materials have been investigated extensively, but the micro corrosion mechanism is still unclear. In this paper, the research progress of molecular dynamics simulation of metal materials for ocean engineering equipment was summarized. Besides, the potential function and model describing the reaction between metal and solution/gas, and the influence of different factors on metal corrosion were introduced respectively. Finally, in order to provide a reference for the study of more efficient and inexpensive corrosion protection methods, the problems existing in the current calculation and simulation of metal material corrosion were also analyzed and the prospects were put forward.

A suite of stress-controlled cyclic triaxial tests were performed on frozen, fine-grained soils to assess the characteristics of the accumulated and cyclic behaviours under packets of cyclic stress with variable amplitude. The influence of cyclic stress sequences is highlighted, and the results of the variable amplitude cyclic tests indicate that the applied cyclic stress amplitude sequence is of importance regarding the final accumulated deformations. A step change is observed in the accumulated strain when the applied cyclic stress amplitude is beyond that of the previous stress package, while a decreasing level of cyclic stress below the previous loading package results in slight additional strain accumulation. The results of these tests also indicate that the cyclic stiffness is dependent on both the past accumulated strain and the current cyclic stress amplitude. For frozen soil, a higher past accumulated strain and lower cyclic stress levels yield a higher cyclic stiffness. An empirical approach for representing the response of frozen, fine-grained soils under multiple packets of cyclic loading is proposed and then verified by the test data. The results show that the proposed empirical model is able to extract and predict the accumulated and cyclic behaviours under multiple packets of cyclic loading. Key words: frozen soils, cyclic stress with variable amplitude, accumulated strain, cyclic stiffness, empirical approach. Une succession complete d'essais triaxiaux cycliques sous contrainte a ete realisee sur des sols geles a grains fins pour determiner les caracteristiques des comportements accumules et cycliques sous des ensembles de contraintes cycliques d'amplitude variable. Les resultats des essais cycliques a amplitude variable indiquent que la sequence d'amplitude de la contrainte cyclique appliquee est d'une importance significative pour les deformations accumulees finales. On observe une evolution en escalier de la deformation accumulee lorsque l'amplitude de la contrainte cyclique appliquee est superieure a celle de la sequence de chargement precedente, tandis qu'un niveau decroissant de contrainte cyclique en dessous de la sequence de chargement precedente entraine une legere accumulation supplementaire de deformation. Les resultats de ces tests indiquent egalement que la rigidite cyclique depend a la fois de la deformation accumulee passee et de l'amplitude de la contrainte cyclique actuelle. Pour un sol gele, une deformation accumulee anterieure plus elevee et des niveaux de contrainte cyclique plus faibles donnent une rigidite cyclique plus elevee. Le programme de recherche propose une approche empirique pour representer la reponse des sols geles a grain fin sous des paquets multiples de chargement cyclique, puis verifie les donnees d'essai. Les resultats montrent que le modele empirique propose est capable d'extraire et de prevoir les comportements accumules et cycliques sous des paquets multiples de chargement cyclique. [Traduit par la Redaction] Mots-cles : sols geles, contrainte cyclique a amplitude variable, deformation accumulee, rigidite cyclique, approche empirique., 1. Introduction In the world, approximately 50% of the land surface is occupied by frozen soils, and the distribution of permafrost regions accounts for approximately 23% of the world's land [...]

Niclosamide (NIC) is the only commercially available molluscicide for controlling schistosomiasis, and its negative effects on aquatic animals had been frequently reported in recent years. However, the toxicity mechanism of NIC on the Chinese soft-shelled turtle (Pelodiscus sinensis) have not yet been investigated. Therefore, juvenile turtles were exposed to 0 (control group), 10 (low NIC, L), and 50 (high NIC, H) μg/L NIC for 120 h and our results demonstrated that NIC exposure induced severe pathological changes in the liver of P. sinensis. And the typical symptom included edema, nuclear migration and deformation, and vacuolization. Compared with the liver, the NIC exposure did not cause significant damage in the gut tissue. In addition, the DHE staining demonstrated that the ROS production of liver and gut increased with the increase in concentration of NIC. The activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) was inhibited with increased malondialdehyde (MDA) content, indicating that the antioxidant defense was significantly perturbed. Further, the transcriptome sequencing and was applied to evaluate the underlying toxicity mechanisms of NIC exposure in liver and gut of P. sinensis. Pathway enrichment showed that the disorder of lipid metabolism and innate immune regulation, including Toll-like receptors (TLRs), tumor necrosis factor (TNF), lectins, and complement and coagulation cascades, were toxicological properties of NIC on P. sinensis. Overall, the current study provides valuable information to understand the toxic effect of NIC on Chinese soft-shelled turtle.

Abstract 2-Thioadenosine monohydrate (1) is a vital intermediate in the synthesis of cangrelor. However, its industrial-scale preparation process and the analysis of the impurities formed during this process remained largely unknown. Herein, cangrelor was synthesized from oxidate adenosine, and the key step involved in the synthesis of compound 1 from intermediate 5. The effects of key synthesis parameters that influenced the reaction, including reaction temperature and time, were discussed. Moreover, four process-related impurities were purified, synthesized, and identified via nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The process can be utilized to produce 1 on a kilogram scale, with a high-performance liquid chromatography purity of 98.0%. The study sheds light on and helps drug manufacturers further understand the formation process of impurities in the preparation of cangrelor.

Abstract Ionizing radiation (IR) has been extensively used for cancer therapy, but the radioresistance hinders and undermines the radiotherapy efficacy in clinics greatly. Here, we reported that the spliceosomal protein thioredoxin‐like 4B (TXNL4B) is highly expressed in lung tissues from lung cancer patients with radiotherapy. Lung cancer cells with TXNL4B knockdown illustrate increased sensitivity to IR. Mechanistically, TXNL4B interacts with RNA processing factor 3 (PRP3) and co‐localizes in the nucleus post‐IR. Nuclear localization of PRP3 promotes the alternative splicing of the Fanconi anemia group I protein (FANCI) transcript variants, FANCI‐12 and FANCI‐13. PRP3 regulates alternative splicing of FANCI toward the two variants, FANCI‐12 and FANCI‐13. Radioresistance was greatly enhanced through the combination of PRP31 and PRP8, the critical components of core spliceosome promoted by PRP3. Notably, the inhibition of PRP3 to suppress the production of FANCI‐12 would deprive PRP31 and PRP8 of such interaction. As a result, cell cycle G2/M arrest was induced, DNA damage repair was delayed, and radiosensitivity was improved. Collectively, our study highlights potential novel underlying mechanisms of the involvement of TXNL4B and alternative splicing in radioresistance. The results would benefit potential cancer radiotherapy.

Boron neutron capture therapy (BNCT) induces intracellular nuclear reaction to destroy cancer cells during thermal neutron irradiation. To selectively eliminate cancer cells but avoid harmful effects on normal tissues, novel boron-peptide conjugates with angiopep-2, namely ANG-B, were constructed and evaluated in preclinical settings. Boron-peptide conjugates were synthesized using solid-phase peptide synthesis, and the molecular mass was validated by mass spectrometry afterwards. Boron concentrations in 6 cancer cell lines and an intracranial glioma mouse model after treatments were analyzed by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Phenylalanine (BPA) was tested in parallel for comparison. In vitro treatment with boron delivery peptides significantly increased boron uptake in cancer cells. BNCT with 5 mM ANG-B caused 86.5% ± 5.3% of clonogenic cell death, while BPA at the same concentration caused 73.3% ± 6.0% clonogenic cell death. The in vivo effect of ANG-B in an intracranial glioma mouse model was evaluated by PET/CT imaging at 31 days after BNCT. The mouse glioma tumours in the ANG-B-treated group were shrunk by 62.9% on average, while the BPA-treated tumours shrank by only 23.0%. Therefore, ANG-B is an efficient boron delivery agent, which has low cytotoxicity and high tumour-to-blood ratio. Based on these experimental results, we expected that ANG-B may leverage BNCT performance in clinical applications in future.

This article aims to fill a gap in existing studies by examining methanol's prospects as a cleaner marine vessel fuel and addressing the industry's challenges in reducing pollution from ship oil. The analysis focuses on methanol as a decarbonization fuel option, following its advantages compared to others through data triangulation that uses both bottom-up and top-down approaches to examine the safety concerns and environmental impacts of methanol. The findings support its use as a promising alternative to conventional marine fuels, considering regulations and safety codes related to low-flashpoint fuels and specifying key safety measures. Also, container vessels (6% of the global fleet) consume 23% of all annual bunker volume and require nearly two-thirds of the global bunker demand, along with liquid bulk tankers and dry bulk carriers. These findings, along with the current regulatory landscape and infrastructure requirements for methanol fuel distribution, pose the greatest challenges to its widespread adoption, despite successes by MAN and Wärtsilä engine manufacturers in offering high-pressure diesel combustion technology engines for burning methanol. This study provides insights that can help ASEAN adopt methanol fuel while complying with emission standards and reducing its environmental impacts.

Abstract Introduction Individual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF). Materials and Methods From June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti‐Factor Xa (anti‐FXa) level 3 h after rivaroxaban administration as peak concentration. Whole‐exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496). Results The bleeding events within 12 months were significantly related to the peak anti‐FXa level (p = .027). SUSD3 rs76292544 was associated with 12‐month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17–8.14, p = 6.43×10−5). Five SNPs including NCMAP rs4553122 (p = 2.29×10−5), PRF1 rs885821 (p = 7.02×10−5), PRKAG2 rs12703159 (p = 7.97×10−5), PRKAG2 rs13224758 (p = 8.70×10−5), and POU2F3 rs2298579 (p = 8.24×10−5) were associated with peak anti‐FXa level. Genetic variants of 52 SNPs from 36 genes including GOT2 rs14221 and MMP13 rs640198 were potentially related to 12‐month bleeding events caused by rivaroxaban's efficacy. Conclusions Peak anti‐FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban. SUSD3 rs76292544 was suggestively associated with 12‐month bleeding events and five SNPs (NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, rs13224758 and POU2F3 rs2298579) were suggestively associated with peak anti‐FXa level.

Aiming at improving the corrosion resistance of AZ31 magnesium alloy in 3.5% (mass fraction) NaCl solution, the effects of CeO2 concentration and ultrasonic and non - ultrasonic assisted processes on chemical conversion film of AZ31 magnesium alloy prepared in the mixed bath of 0.300 mol/L Na2MoO4+0.120 mol/L NaF +0.050 mol/L Na3PO4+0.075 mol/L K2FeO4 were studied. In addition, the influence of the chemical conversion film on the corrosion resistance of AZ31 magnesium alloy was also studied. Results showed that in the case of ultrasonic assisted process, when the coating was prepared with an addition of 0.050 mol/L CeO2 in the mixed bath, the corrosion potential of magnesium alloy shifted to be more positive and the corrosion current density decreased significantly. After 96 h immersion in 3.5% NaCl solution, the surface of magnesium alloy was still relatively smooth without obvious cracks, indicating that the magnesium alloy substrate was effectively protected.

Abstract Background Sepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication. Methods Preliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results. Results Four hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally. Conclusions We identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

Abstract Ferroptosis is a novel type of cell death depending on iron and is strongly related to the development of tumors. Hepatocellular carcinoma (HCC) is a malignancy with high incidence. Despite some reports demonstrating the relation between ferroptosis-related genes and HCC, more details have not been excavated. In the present study, we collected and analyzed HCC patients' datasets from the TCGA-LIHC project and ICGC portal, respectively. Through the bioinformatic methods, we screened 126 differentially expressed genes. Then a prognostic model was established with four genes (GPX2, MT3, PRDX1, and SRXN1). PRDX1 is the hub gene of the prognosis model and has a high expression in hepatocellular carcinoma tumor tissue and cell lines. We further found that silencing PRDX1 increased the accumulation of ferrous ions and lipid peroxidation accumulation in HEPG2 cells and promoted ferroptosis in hepatocellular carcinoma. In conclusion, the study demonstrated the four-gene signature can be used to predict HCC prognosis. It also revealed the potential function of the ferroptosis-related gene PRDX1 in HCC, which can be a biomarker of the prediction for HCC outcome.

SUR2-containing KATP channels are drug targets for certain vasodilators. Here, the authors determine high-resolution cryo-EM structures of SUR2 in complex with two vasodilators, P1075 and levcromakalim, uncovering the mechanisms of these drugs.

KATP channels are energy sensors. Here, authors report the Cryo-EM structures of pancreatic KATP in both the closed state and the pre-open state. These structures illuminate the mechanism of KATP channel regulation by the intracellular nucleotides.