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Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment.

AimCompared with the C57BL/6N substrain, the C57BL/6J substrain is more susceptible to the angiotensin II (Ang II)-induced development of dissected abdominal aortic aneurysms (AAAs). The aim of this study was to elucidate whether the widely used C57BL/6N mouse substrain is as susceptible as the C57BL/6J mouse substrain to porcine pancreatic elastase (PPE) infusion-induced experimental nondissected AAA development.MethodsExperimental nondissected AAAs were induced in C57BL/6J and C57BL/6N mice via transient aortic luminal infusion of PPE. On Day 0 (baseline) and Day 14 after PPE infusion, the abdominal aortic diameter was directly measured. Aortic aneurysmal segment samples were collected, and histopathological analysis was performed.ResultsOn Day 14 after PPE infusion, aortic diameters were significantly increased in both mouse substrains (from approximately 0.51 to 1.24 mm in C57BL/6J mice and from 0.51 to 1.18 mm in C57BL/6N mice). The increase in diameter of all the mice exceeded 50% and met the criteria for AAA model establishment (143% and 135% in C57BL/6J mice and C57BL/6N mice, respectively). PPE infusion also induced obvious local aortic wall macrophage and T-cell infiltration, elastin degradation, smooth muscle cell depletion and high metallopeptidase (MMP)-2 and MMP-9 expression levels in C57BL/6N mice, but these differences were not significant compared with those in C57BL/6J mice. However, PPE infusion led to the recruitment of more B cells and the sprouting of more neovessels at the aneurysmal lesion site in C57BL/6J mice than in C57BL/6N mice.ConclusionThe C57BL/6N mouse substrain is suitable for establishing a model of AAA via elastase infusion.

Mosquitoes are the vectors of numerous diseases such as malaria, Dengue and Zika. Controlling mosquito vectors is essential for preventing and managing diseases transmitted by mosquitoes. Larvicides target larvae within their breeding habitats before they mature into adult mosquitoes and disperse. In this study, using α-hexyl cinnamaldehyde (HCA) as a lead compound, three series of derivatives comprising a total of 78 compounds were designed and synthesized. The larvicidal activities of these compounds against Aedes albopictus were evaluated, resulting in the identification of ten promising compounds. Among them, furan-3-ylmethyl cinnamate (compound 2v) and (E)-allyl 3-(4-chlorophenyl)acrylate (compound 4c) exhibited the lowest LC50 values (8.0 ppm and 7.2 ppm respectively). In a 96-h acute toxicity assay conducted on zebrafish, 2v showed no or very low toxicity with an LC50 higher than 100 ppm. To elucidate their mode of action, morphological and histopathologic analyses were performed, and the effects of the compounds on the acetylcholinesterase (AChE) and phosphatase activities were evaluated. Results suggested that the active HCA derivatives induce injury to intestinal epithelial cells by inhibiting phosphatase activity, ultimately resulting in the mortality of mosquito larvae.

IntroductionApolipoprotein E (apoE) acts as a binding molecule for both the low-density lipoprotein receptor and the lipoprotein receptor-related protein and this function is essential for facilitating the hepatocyte uptake of lipoproteins containing apoB. The absence of apoE leads to increased atherogenicity in both humans and mice, although the precise molecular mechanisms remain incompletely understood.ObjectivesThis study aimed to investigate the susceptibility of apoE knockout (KO) rabbits, in comparison with wild-type (WT) rabbits, to diet-induced hyperlipidemia and atherosclerosis.MethodsApoE KO rabbits and WT rabbits were fed a diet containing 0.3% cholesterol for 16 weeks. Plasma lipid levels, lipoproteins, and apolipoproteins were analyzed. Atherosclerosis was evaluated at the endpoint of experiments. In addition, we evaluated the oxidizability of those lipoproteins containing apoB to investigate the possible mechanisms of atherosclerosis.ResultsMale apoE KO rabbits showed significantly elevated levels of total cholesterol and triglycerides compared to WT rabbits, while female apoE KO rabbits displayed similar high total cholesterol levels, albeit with significantly higher triglycerides levels than WT controls. Notably, both male (2.1-fold increase) and female (1.6-fold increase) apoE KO rabbits exhibited a significantly augmented aortic lesion area compared to WT controls. Pathological examination showed that the increased intimal lesions in apoE KO rabbits were featured by heightened infiltration of macrophages (2.7-fold increase) and smooth muscle cells (2.5-fold increase). Furthermore, coronary atherosclerotic lesions were also increased by 1.3-fold in apoE KO rabbits. Lipoprotein analysis revealed that apoB48-rich beta-very-low-density lipoproteins were notably abundant in apoE KO rabbits, suggesting that these remnant lipoproteins of intestinal origin serve as the primary atherogenic lipoproteins. Moreover, apoB48-rich remnant lipoproteins isolated from apoE KO rabbits exhibited heightened susceptibility to copper-induced oxidation.ConclusionsThe findings indicate that apoB48-rich remnant lipoproteins, resulting from apoE deficiency, possess greater atherogenic potential than apoB100-rich remnant lipoproteins, regardless of plasma TC levels.

Exposure to ozone has been associated with metabolic disorders in humans, but the underlying mechanism remains unclear. In this study, the role of the gut-liver axis and the potential mechanism behind the metabolic disorder were investigated by histological examination, microbiome and metabolome approaches in mice during the subacute (4-week) and subchronic (12-week) exposure to 0.5 ppm and 2.5 ppm ozone. Ozone exposure resulted in slowed weight gain and reduced hepatic lipid contents in a dose-dependent manner. After exposure to ozone, the number of intestinal goblet cells decreased, while the number of tuft cells increased. Tight junction protein zonula occludens-1 (ZO-1) was significantly downregulated, and the apoptosis of epithelial cells increased with compensatory proliferation, indicating a compromised chemical and physical layer of the intestinal barrier. The hepatic and cecal metabolic profiles were altered, primarily related to lipid metabolism and oxidative stress. The abundance of Muribaculaceae increased dose-dependently in both colon and cecum, and was associated with the decrease of metabolites such as bile acids, betaine, and L-carnitine, which subsequently disrupted the intestinal barrier and lipid metabolism. Overall, this study found that subacute and subchronic exposure to ozone induced metabolic disorder via disturbing the gut-liver axis, especially the intestinal barrier. These findings provide new mechanistic understanding of the health risks associated with environmental ozone exposure and other oxidative stressors.

Introduction The preliminary result of the TORCH trial has shown a promising complete response (CR) for managing locally advanced rectal cancer with neoadjuvant short-course radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor. For locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4, neoadjuvant chemotherapy followed by colectomy with en bloc removal of regional lymph nodes is the suggested treatment. However, the CR rate is less than 5%. TORCH-C will aim to investigate neoadjuvant SCRT combined with chemotherapy and PD-1 inhibitor in LACC.Methods and analysis TORCH-C is a randomised, prospective, multicentre, double-arm, open, phase II trial of SCRT combined with chemotherapy and immunotherapy in LACC with microsatellite stable (MSS) patients and cT4 or bulky nodes. Eligible patients will be identified by the multidisciplinary team. 120 patients will be randomised 1:1 to the intervention or control arm. The patients in the control arm will receive four cycles of capecitabine plus oxaliplatin (CAPOX). The patients in the intervention arm will receive SCRT, followed by four cycles of CAPOX and PD-1 inhibitor (serplulimab). Both arms will receive curative surgery, followed by four cycles of CAPOX. The primary endpoint is pathological complete regression.TORCH-C (TORCH-colon) trial aims to investigate whether the combination of immunotherapy and chemoradiotherapy improves the treatment effect in LACC with MSS. TORCH-C will establish the TORCH platform, a key part of our long-term strategy to develop neoadjuvant treatment for colorectal cancer.Ethics and dissemination This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 2211265-12).Trial registration number NCT05732493

Magnetic reconnection plays a crucial role in the energy release process for different kinds of solar eruptions and activities. The rapid solar eruption requires a fast reconnection model. Plasmoid instability in the reconnecting current sheets is one of the most acceptable fast reconnection mechanisms for explaining the explosive events in the magnetohydrodynamics (MHD) scale, which is also a potential bridge between the macroscopic MHD reconnection process and microscale dissipations. Plenty of high-resolution observations indicate that the plasmoid-like structures exist in the high-temperature solar corona, but such evidences are very rare in the lower solar atmosphere with partially ionized plasmas. Utilizing joint observations from the Goode Solar Telescope and the Solar Dynamics Observatory, we discovered a small-scale eruptive phenomenon in NOAA Active Region 13085, characterized by clear reconnection cusp structures, supported by nonlinear force-free field extrapolation results. The plasmoid-like structures with a size of about 150 km were observed to be ejected downward from the current sheet at a maximum velocity of 24 km s ^−1 in the H α line wing images, followed by enhanced emissions at around the postflare loop region in multiple wavelengths. Our 2.5D high-resolution MHD simulations further reproduced such a phenomenon and revealed reconnection fine structures. These results provide comprehensive evidences for the plasmoid-mediated reconnection in partially ionized plasmas, and suggest a unified reconnection model for solar flares with different length scales from the lower chromosphere to the corona.

For patients with locally recurrent rectal cancer (LRRC), the response rate to chemoradiotherapy is 40%–50%. Additionally, only approximately 40%–50% of patients with recurrent rectal cancer are able to undergo R0 resection. Recent studies in locally advanced rectal cancer (LARC) have shown promising synergistic effects when combining immunotherapy (PD-1/PD-L1 antibodies) with neoadjuvant chemoradiotherapy (nCRT). Therefore, incorporating immunotherapy into the treatment regimen for LRRC patients has the potential to further improve response rates and prognosis. To investigate this, the TORCH-R trial was conducted. This prospective, single-arm, two-cohort, phase II trial focuses on the use of hypofractionated radiotherapy, chemotherapy, and immunotherapy in LRRC patients without or with oligometastases. The trial will include two cohorts: cohort A consists of rectal cancer patients who are treatment-naive for local recurrence, and cohort B includes patients with progressive disease after first-line chemotherapy. Cohort A and cohort B patients will receive 25–40 Gy/5 Fx irradiation or 15–30 Gy/5 Fx reirradiation for pelvic recurrence, respectively. Subsequently, they will undergo 18 weeks of chemotherapy, toripalimab, and stereotactic ablative radiotherapy (SABR) for all metastatic lesions between chemoimmunotherapy cycles. Decisions regarding follow-up of complete response (CR), radical surgery, sustained treatment of non-resection, or exiting the trial are made by a multidisciplinary team (MDT). The primary endpoint of this study is the local objective response rate (ORR). The secondary endpoints include the extrapelvic response rate, duration of response, local recurrence R0 resection rate, progression-free survival (PFS), overall survival (OS), and safety and tolerability. Notably, this trial represents the first clinical exploration of inducing hypofractionated radiotherapy, chemotherapy, and immunotherapy in LRRC patients.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05628038, identifier NCT05628038.

ObjectiveUsing Mesh Meta Analysis to evaluate the efficacy of Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene for treating Polycystic Ovary Syndrome (PCOS), in order to provide evidence-based medical evidence for whether to recommend Acupuncture & Moxibustion or Combine western medicine to treat PCOS.MethodsEight databases including The Cochrane Library, Pubmed, Embase, Web of Science, CNKI, Wanfang Date, VIP and CBM were searched by computer. The included research period is from the establishment of the database to May 2023, which concerned with randomized controlled trials involving Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene on ovulation induction and pregnancy outcome in patients with PCOS. The duration of the research paper is from 2016 to 2023.The inclusion criteria refer to the Rotterdam standards issued by the European Center for Human Reproduction and Embryology and the American Society of Reproductive Medicine in January 2003, or the Expert Consensus on the Diagnosis and Treatment of Polycystic Ovarian Syndrome by the Endocrinology Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association. Simultaneously exclude related diseases, repetitive literature, as well as literature with incomplete abstract information and no original data provided. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias included in the study, using Stata17.0 software for a mesh meta-analysis.ResultsSix randomized controlled trials were included, covering 1410 PCOS patients. Three interventions included Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene. Mesh Meta Analysis showed that in terms of improving ovulation rate, there was no statistical difference between Acupuncture & Moxibustion (A), Clomiphene (B), Clomiphene combined with Acupuncture & Moxibustion (C) (P>0.05).Acupuncture & Moxibustion (A) versus Clomiphene (B) [MD=0.15,95% CI (-0.51,0.80)], Acupuncture & Moxibustion (A) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.60,95% CI (0.97,2.23)], Clomiphene (B) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.45,95% CI (0.91,1.99)]. In terms of pregnancy outcome, the difference between the three intervention methods was statistically significant (P

Introduction Current standard treatment for patients with early rectal cancer is radical surgical resection. Although radical surgery provides effective local tumour control, it also increases the mortality risk and considerable adverse effects, including bowel, bladder, sexual dysfunction and loss of anal function, especially in patients with low-lying rectal cancer. Recent studies have shown promising synergistic effects of the combination of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors and radiotherapy in improving tumour regression. For patients who reach a clinical complete response (cCR) after neoadjuvant therapy, a ‘Watch & Wait’ (W&W) approach can be adopted to preserve anorectal function and improve quality of life. Thus, this study aims to explore the efficacy and safety of radiotherapy combined with chemotherapy and PD-1 antibody in patients with low early rectal cancer.Methods and analysis TORCH-E study is designed as a multicentre, prospective, phase II trial of short-course radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor in patients with cT1-3bN0M0 low rectal cancer. The trial was initiated in December 2022 and is currently recruiting patients, with an anticipated completion of participant enrolment by June of the following year. The enrolled 34 patients will receive SCRT (25 Gy/5 Fx), followed by four cycles of capecitabine plus oxaliplatin chemotherapy and PD-1 antibody (toripalimab) and finally receive surgery or the W&W strategy. The primary endpoint is the complete response (CR) rate, that is, the rate of pathological complete response (pCR) plus cCR. The secondary endpoints include organ preservation rate, 3-year local recurrence-free survival rate, 3-year disease-free survival rate, 3-year overall survival rate, grade 3–4 adverse effects rate and patients’ quality of life.Ethics and dissemination This trial has been approved by the Ethics Committee of Fudan University Shanghai Cancer Center. Trial results will be disseminated via peer-reviewed journals and conference presentations.Trial registration number NCT05555888 (ClinicalTrials.gov).

Combination strategies to improve immunotherapy response in microsatellite stable metastatic colorectal cancer (MSS mCRC) remain an unmet need. Several single-arm clinical trials have shown promising synergistic effects between regorafenib and ICIs; however, some contradictory results have also been reported. Randomized controlled trials are needed to further validate the combination of regorafenib with ICIs. In addition, low-dose radiotherapy has been demonstrated to induce local immune responses by reprogramming the tumor microenvironment when combined with high-dose radiotherapy and ICIs. In this study, we designed a prospective, randomized, controlled phase II trial to investigate the efficacy and safety of regorafenib in combination with high/low-dose radiotherapy plus toripalimab in MSS mCRC compared to regorafenib alone. Patients with MSS metastatic adenocarcinoma of the colon or rectum will be enrolled and randomly assigned into two arms: a control arm and an experimental arm. Patients in the control arm will receive regorafenib monotherapy (120 mg once daily on days 1-21 of each 28 days cycle). Patients in the experimental arm will first receive one cycle of regorafenib (80 mg once daily on days 1-21 of each 28 days cycle) and toripalimab (240mg, q3w), followed by high-dose (4-8 fractions of 8-12Gy) and low-dose (1-10Gy at 0.5-2Gy/fraction) radiotherapy, and then continue regorafenib and toripalimab treatment. The primary endpoint is the objective response rate, and the secondary endpoints are disease control rate, duration of remission, median progress-free survival, median overall survival, and adverse events. Recruitment started in August 2023 and is ongoing.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT05963490?cond=NCT05963490&rank=1, identifier NCT05963490.

The most common cause of electric motor failure is the bearings, and so methods for fast and accurate diagnosis of motor bearing failure are urgently needed. Traditional fault diagnosis methods have high uncertainty and complexity since they require manual extraction of features. Deep learning has shown good performance in electrical equipment fault detection, and it can directly complete end-to-end diagnosis of motor faults, avoiding human involvement. Here, a new fault diagnosis method is presented which combines Gramian angular field (GAF) image coding, extreme learning machine (ELM) and convolutional neural network (CNN). The method has three main stages: First of all, GAF is utilized to convert the acquired vibration break signals into 2-D pictures. Next, the enhanced CNN model is taken to identify the elements of the converted image quickly and accurately. Finally, the ELM is used as the final classifier to gain further accuracy and diagnostic speed of fault classification. Experiments were designed to validate the proposed method using two different motor bearing fault datasets at Case Western Reserve University and autonomous experiment and performance is compared with several commonly used intelligent diagnosis algorithms. The proposed method’s accuracy in the experiment designed in this paper can reach 99.2% at most, and it only takes 0.835s to complete the diagnosis, which outperforms traditional diagnostic methods on both datasets and improving the maximum diagnostic accuracy by 33.6%. The findings indicate that this method can classify various fault types efficaciously, and has the benefits of quick diagnosis, high accuracy, and good generalization ability.

Sauropterygia was a taxonomically and ecomorphologically diverse clade of Mesozoic marine reptiles spanning the Early Triassic to the Late Cretaceous. Sauropterygians are traditionally divided into two groups representing two markedly different body plans – the short-necked, durophagous Placodontia and the long-necked Eosauropterygia – whereas Saurosphargidae, a small clade of armoured marine reptiles, is generally considered as the sauropterygian sister-group. However, the early evolutionary history of sauropterygians and their phylogenetic relationships with other groups within Diapsida are still incompletely understood. Here, we report a new saurosphargid from the Early Triassic (Olenekian) of South China – Prosaurosphargis yingzishanensis gen. et sp. nov. – representing the earliest known occurrence of the clade. An updated phylogenetic analysis focussing on the interrelationships among diapsid reptiles recovers saurosphargids as nested within sauropterygians, forming a clade with eosauropterygians to the exclusion of placodonts. Furthermore, a clade comprising Eusaurosphargis and Palatodonta is recovered as the sauropterygian sister-group within Sauropterygomorpha tax. nov. The phylogenetic position of several Early and Middle Triassic sauropterygians of previously uncertain phylogenetic affinity, such as Atopodentatus, Hanosaurus, Majiashanosaurus, and Corosaurus, is also clarified, elucidating the early evolutionary assembly of the sauropterygian body plan. Finally, our phylogenetic analysis supports the placement of Testudines and Archosauromorpha within Archelosauria, a result strongly corroborated by molecular data, but only recently recovered in a phylogenetic analysis using a morphology-only dataset. Our study provides evidence for the rapid diversification of sauropterygians in the aftermath of the Permo-Triassic mass extinction event and emphasises the importance of broad taxonomic sampling in reconstructing phylogenetic relationships among extinct taxa.

Different solar atmospheric layers are connected by the magnetic field of the Sun, which is the primary source for various types of solar activity. The magnetic activity of the Sun has a significant impact on the solar-terrestrial environment and human life. Understanding the phenomena occurring in the solar atmosphere relies on a thorough understanding of the solar magnetic field. However, up to now, only the magnetic field at the photospheric level can be measured with precision on a daily basis. No routine measurements have been carried out for the magnetic field in the upper layers of the solar atmosphere, particularly the solar corona. The lack of coronal magnetic field measurements has limited our investigation of many important topics in solar physics research including the driving mechanism of solar eruptions and the heating process of corona. In the past several decades, a number of techniques that may be useful for coronal magnetic field diagnostics have been developed, such as the techniques based on infrared spectro-polarimetry of coronal lines, the diagnosis utilizing coronal radio observations, magneto-seismology using observations of coronal magnetohydrodynamics waves and the measurements based on the magnetic-field-induced transition of coronal extreme ultraviolet spectral lines. Meanwhile, a few attempts have been made to measure the coronal magnetic field based on these techniques. This review summarizes the physical principles and important progress of coronal magnetic field measurements, and discuss future perspectives on related research.

IntroductionPulmonary fibrosis is a consequential complication of microbial infections, which has notably been observed in SARS-CoV-2 infections in recent times. Macrophage polarization, specifically the M2-type, is a significant mechanism that induces pulmonary fibrosis, and its role in the development of Post- COVID-19 Pulmonary Fibrosis is worth investigating. While pathological examination is the gold standard for studying pulmonary fibrosis, manual review is subject to limitations. In light of this, we have constructed a novel method that utilizes artificial intelligence techniques to analyze fibro-pathological images. This method involves image registration, cropping, fibrosis degree classification, cell counting and calibration, and it has been utilized to analyze microscopic images of COVID-19 lung tissue.MethodsOur approach combines the Transformer network with ResNet for fibrosis degree classification, leading to a significant improvement over the use of ResNet or Transformer individually. Furthermore, we employ semi-supervised learning which utilize both labeled and unlabeled data to enhance the ability of the classification network in analyzing complex samples. To facilitate cell counting, we applied the Trimap method to localize target cells. To further improve the accuracy of the counting results, we utilized an effective area calibration method that better reflects the positive density of target cells.ResultsThe image analysis method developed in this paper allows for standardization, precision, and staging of pulmonary fibrosis. Analysis of microscopic images of COVID-19 lung tissue revealed a significant number of macrophage aggregates, among which the number of M2-type macrophages was proportional to the degree of fibrosis.DiscussionThe image analysis method provids a more standardized approach and more accurate data for correlation studies on the degree of pulmonary fibrosis. This advancement can assist in the treatment and prevention of pulmonary fibrosis. And M2-type macrophage polarization is a critical mechanism that affects pulmonary fibrosis, and its specific molecular mechanism warrants further exploration.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder. With the improvement in human living standards, the prevalence of NAFLD has been increasing in recent years. Endocrine-disrupting chemicals (EDCs) are a class of exogenous chemicals that simulate the effects of hormones in the body. There has been growing evidence regarding the potential effects of EDCs on liver health, especially in NAFLD. This paper aims to summarize the major EDCs that contribute to the growing burden of NAFLD and to raise public awareness regarding the hazards posed by EDCs with the objective of reducing the incidence of NAFLD.

The deltex family protein DTX3 is believed to possess E3 ubiquitin ligase activity, as it contains a classic RING finger domain. However, its biological role and the underlying mechanism in cancer remain largely elusive. Here, we identified DTX3 as a novel mutant p53-interacting protein in ovarian carcinoma. Mechanistically, DTX3 mediated mutant p53 ubiquitination and stabilization by perturbing the MDM2-mutant p53 interaction, consequently leading to activation of diverse mutant p53 target genes. Importantly, a positive correlation between the expression of DTX3 and mutant p53 target genes was further validated in ovarian carcinomas. Ectopic DTX3 promoted, while depletion of DTX3 suppressed, ovarian cancer cell proliferation and invasion. Remarkably, the pro-tumorigenic effect of DTX3 is dependent on mutant p53, because ablation of mutant p53 significantly impaired DTX3-induced gene expression and ovarian cancer cell growth and propagation. Furthermore, DTX3 elevated the expression of mutant p53 target genes and boosted ovarian tumor growth in vivo. Finally, DTX3 was amplified and overexpressed in ovarian carcinomas, which is significantly associated with unfavorable prognosis. Altogether, our findings unveil the oncogenic role of DTX3 in ovarian cancer development by bolstering mutant p53 activity.

Abdominal aortic aneurysm (AAA) is pathologically characterized by intimal atherosclerosis, disruption and attenuation of the elastic media, and adventitial inflammatory infiltrates. Although all these pathological events are possibly involved in the pathogenesis of AAA, the functional roles contributed by adventitial inflammatory macrophages have not been fully documented. Recent studies have revealed that increased expression of matrix metalloproteinase-12 (MMP-12) derived from macrophages may be particularly important in the pathogenesis of both atherosclerosis and AAA. In the current study, we developed a carrageenan-induced abdominal aortic adventitial inflammatory model in hypercholesterolemic rabbits and evaluated the effect of adventitial macrophage accumulation on the aortic remodeling with special reference to the influence of increased expression of MMP-12. To accomplish this, we compared the carrageenan-induced aortic lesions of transgenic (Tg) rabbits that expressed high levels of MMP-12 in the macrophage lineage to those of non-Tg rabbits. We found that the aortic medial and adventitial lesions of Tg rabbits were greater in degree than those of non-Tg rabbits, with the increased infiltration of macrophages and prominent destruction of elastic lamellae accompanied by the frequent appearance of dilated lesions, while the intimal lesions were slightly increased. Enhanced aortic lesions in Tg rabbits were focally associated with increased dilation of the aortic lumens. RT-PCR and Western blotting revealed high levels of MMP-12 in the lesions of Tg rabbits that were accompanied by elevated levels of MMP-2 and -3, which was caused by increased number of macrophages. Our results suggest that adventitial inflammation constitutes a major stimulus to aortic remodeling and increased expression of MMP-12 secreted from adventitial macrophages plays an important role in the pathogenesis of vascular diseases such as AAA.

Abstract Serious infection caused by drug-resistant gram-negative bacteria and their secreted toxins (e.g., lipopolysaccharide) is a serious threat to human health. Thus, treatment strategies that efficiently kill bacteria and reducing the impact of their toxins simultaneously are urgently required. Herein, a novel antibacterial platform composed of a mesoporous copper silicate microsphere (CSO) core and a platelet membrane (PM) shell was prepared (CSO@PM). CSO@PM specifically targets bacteria owing to formyl peptide receptors on the PM and, combined with photothermal therapy (PTT), exhibits highly effective bacter icidal activity. Importantly, CSO@PM can adsorb lipopolysaccharide secreted by gram-negative bacteria, resulting in inflammation reduction. Thus, CSO@PM stimulates re-epithelialization and granulation-tissue formation, promoting wound healing. Moreover, this antibacterial platform exhibits no obvious toxicity at all the test concentrations in vitro and in vivo. Thus, CSO@PM exhibits a robust antibacterial effect and a strong toxin-adsorption capacity, facilitating the clinical treatment of many bacterial infections and the development of next-generation antibacterial nanoagents. Graphical Abstract

Sarcocystis spp., Neospora caninum and Toxoplasma gondii are globally ubiquitous pathogens, and domestic sheep are considered to be one of the intermediate hosts. 83 myocardial samples of sheep were collected from 12 retail stores in Beijing, China. Sarcocystis spp., N. caninum and T. gondii were identified by PCR amplification of the 18S rRNA gene, Nc-5 gene and 529bp DNA fragment with a prevalence of 86.7% (95% CI: 77.5–93.2) and 43.4% (95% CI: 32.5–54.7) for Sarcocystis spp. and N. caninum infections, respectively, and no T. gondii was detected. The co-infection prevalence of Sarcocystis and N. caninum was 38.6% (95% CI: 28.1–49.9). Two Sarcocystis species were subtyped by analyzing 18SrRNA sequences and were identified as Sarcocystis tenella and Sarcocystis arieticanis. The prevalence of S. tenella and S. arieticanis infections was 84.3% (95% CI: 74.7–91.4) and 56.6% (95% CI: 45.3–67.5), respectively. This study shows that sheep have a high risk of infection with Sarcocystis and N. caninum, suggests that effective prevention measures are needed to avoid the spread of these parasites in sheep. Toxoplasmosis in sheep poses a threat to human and animal health and requires monitoring and preventing continuously.

To reduce seat vibration caused by uneven road surfaces, the time-delay feedback control into the seat suspension system was introduced and an active seat suspension control method based on time-delay feedback was proposed in this paper. A three-degree-of-freedom (3-DOF) suspension model with time-delay feedback control was established. The time-delay independent stability region and critical stability curve of the system were derived using the method of characteristic root and stability switching. The effect of feedback control parameters on system vibration was investigated in the stability region. The seat acceleration (SA), body acceleration (BA), suspension dynamic deflection (SDD), and tire dynamic displacement (TDD) were used as multi-objective optimization functions and the optimal values of feedback control parameters were obtained based on the particle swarm algorithm (PSO) with above optimization functions. The numerical simulation was conducted to validate the proposed model. The simulated results show that the time-delay feedback control can significantly suppress the vibration response of the seat and effectively improve the suspension performance under different road excitation compared with the passive suspension. It can be seen that the active seat suspension with time-delay control significantly improve ride comfort and handling stability of the vehicle, which can be used as a reference for the active control technology of vehicle suspension.

The fallopian tube (FT) is an important reproductive organ in females. Ample evidence suggests that the distal end of FT is the original site of high-grade serous ovarian carcinoma (HGSC). FT may suffer from repeated injury and repair stimulated by follicular fluid (FF); however, this hypothesis has not been examined. In fact, the molecular mechanism of homeostasis, differentiation, and the transformation of fallopian tube epithelial cells (FTECs) resulting from the stimulation of FF are still enigmatic. In this study, we examined the effects of FF along with factors present in the FF on a variety of FTEC models, including primary cell culture, ALI (air–liquid interface) culture, and 3D organ spheroid culture. We found that FF plays a similar role to estrogen in promoting cell differentiation and organoid formation. Moreover, FF significantly promotes cell proliferation and induces cell injury and apoptosis in high concentrations. These observations may help us to investigate the mechanisms of the initiation of HGSC.

IntroductionSleep health is an important part of health and has become a common concern of society. For anxiety insomnia, the commonly used clinical therapies have limitations. Alternative and complementary therapy is gradually rising and showing remarkable effect in clinical practice. This is the first study to evaluate the therapeutic effect of Taijiquan combined with acupoint pressing in the treatment of anxiety insomnia in college students and to compare the difference in intervention before and after sleep, to choose the best treatment time.Methods and analysisThis is a multicenter, single-blind, randomized controlled trial. A total of 126 eligible subjects who have passed the psychological evaluation and met inclusion criteria by completing a psychometric scale will be randomly divided into treatment group A (treat before sleep), treatment group B (treat after sleep) and control group C (waiting list group) in a ratio of 1:1:1. All the three groups will receive regular psychological counseling during the trial, and the treatment groups will practice 24-style Taijiquan and do meridian acupuncture at Baihui (DU20), Shenting (DU24), Yintang (EX-HN3), Shenmen (HT7) and Sanyinjiao (SP6). This RCT includes a 2-week baseline period, a 12-week intervention period, and a 12-week follow-up period. The main results will be measured by changes in the Pittsburgh sleep quality index (PSQI) and Hamilton anxiety scale (HAMA). The secondary results will be measured by the generalized anxiety scale (GAD-7) and insomnia severity index (ISI). The safety of the intervention will be evaluated at each assessment. The statistical analysis of data will be carried out by SPSSV.26.0 software.DiscussionWe expect this trial to explore the effectiveness of Taijiquan combined with acupoint pressing in the treatment of anxiety insomnia in college students and choose the best treatment time by comparison.Clinical trial registration[www.ClinicalTrials.gov], identifier [ChiCTR2200057003].

In aquatic ecosystems, pesticide residues meanly present as mixtures of varying complexity, which may lead to compound pollution of organisms. Therefore, it is of great practical importance to evaluate the combined toxic effects of pesticides. In this study, the mixture acute toxicities of fenvalerate with tebuconazole on zebrafish larvae and adults were investigated. The effects of mixture toxicity on swimming behavior of larvae were also analyzed. The mixture acute toxicity of the systems showed antagonistic effects on adult zebrafish when the mixing ratios of fenvalerate and tebuconazole were equal, but the other two ratios of the mixes both showed synergistic effects. The strongest synergistic effect was observed when fenvalerate was mixed with tebuconazole in the ratio of 8:2. The swimming behavior of zebrafish larvae was significantly inhibited after exposure to single or mixed systems for 2 days. However, significant up-regulation of behavioral indicators in zebrafish larvae was observed at the beginning of exposure in the mixture exposure groups. The results showed that fenvalerate and tebuconazole had the risk of synergistic toxic effect on zebrafish. It is recommended that the simultaneous use of both pesticides in agricultural activities near water bodies should be scientifically controlled to avoid adverse effects on aquatic organisms.

Continuous body temperature measurement is an important means of studying inflammation and metabolic changes using experimental animals. Although expensive telemetry equipment for collecting multiple parameters is available for small animals, readily used devices for mediate- or large-sized animals are rather limited. In this study, we developed a new telemetry sensor system that can continuously monitor rabbit body temperature. The telemetry sensor was easily implanted subcutaneously in rabbits housed in the animal facility while temperature changes were continuously recorded by a personal computer. Temperature data obtained by the telemetry was consistent with the rectal temperature measured by a digital device. Analysis of body temperature changes of unstrained rabbits, either under the normal condition or fever induced by endotoxin confirms the reliability and usefulness of this system.

A photonic nanojet (PNJ) is a highly confined light beam that focuses from the shadow side of microparticles. In $46.47\lambda $this work, we propose a PNJ with ultrahigh quality factor formed by dielectric truncated microtoroid. The key properties of PNJ, such as the maximum intensity, the length of PNJ, the full-width at half maximum (FWHM), are studied in detail using finite-difference time-domain (FDTD) analysis. The results show that a PNJ with an enhanced intensity of 55.21 times to the incident light, superlong length of $46.47\lambda $ and subwavelength FWHM of $0.77\lambda $ is formed by semi-microtoroid, thus, an ultrahigh quality factor of 3308.68 is achieved. More importantly, the properties of the PNJ are tunable by changing the truncated proportions of the microtoroid. The structure we proposed has the advantages of compact structure and simple experimental operation, which is expected to apply in many research fields, including optical detection, optical data storage, super-resolution image, nanopattern, nanolithography, and so on.

Helicobacter pylori (H. pylori) uses several outer membrane proteins for adhering to its host's gastric mucosa, an important step in establishing and preserving colonization. Several adhesins (SabA, BabA, HopQ) have been characterized in terms of their three-dimensional structure. A recent addition to the growing list of outer membrane porins is LabA (LacdiNAc-binding adhesin), which is thought to bind specifically to GalNAcβ1-4GlcNAc, occurring in the gastric mucosa. LabA47-496 protein expressed as His-tagged protein in the periplasm of E. coli and purified via subtractive IMAC after TEV cleavage and subsequent size exclusion chromatography, resulted in bipyramidal crystals with good diffraction properties. Here, we describe the 2.06 ​Å resolution structure of the exodomain of LabA from H. pylori strain J99 (PDB ID: 6GMM). Strikingly, despite the relatively low levels of sequence identity with the other three structurally characterized adhesins (20–49%), LabA shares an L-shaped fold with SabA and BabA. The ‘head’ region contains a 4 ​+ ​3 α-helix bundle, with a small insertion domain consisting of a short antiparallel beta sheet and an unstructured region, not resolved in the crystal structure. Sequence alignment of LabA from different strains shows a high level of conservation in the N- and C-termini, and identifies two main types based on the length of the insertion domain (‘crown’ region), the ‘J99-type’ (insertion ~31 ​amino acids), and the H. pylori ‘26695 type’ (insertion ~46 ​amino acids). Analysis of ligand binding using Native Electrospray Ionization Mass Spectrometry (ESI-MS) together with solid phase-bound, ELISA-type assays could not confirm the originally described binding of GalNAcβ1-4GlcNAc-containing oligosaccharides, in line with other recent reports, which also failed to confirm LacdiNAc binding.

BackgroundIntracranial atherosclerosis (ICAS) is one of the most common causes of ischemic stroke, but there are few animal models that can recapitulate its pathological features. In this study, we examined ICAS pathological features and anatomic distributions using three types of hyperlipidemic rabbit models. We also investigated the effect of different lipoprotein profiles and hypertension on ICAS.Materials and MethodsWe examined Watanabe heritable hyperlipidemic (WHHL) rabbits, apoE knockout (KO) rabbits and wild-type rabbits (WT) fed a cholesterol diet, in addition to WT rabbits fed a standard diet as a control. The whole brain was dissected and embedded in paraffin. Serial sections were stained with either hematoxylin/eosin or elastica van Gieson, or immunohistochemically stained with monoclonal antibodies against macrophages and smooth muscle cells. We investigated (1) the presence of cerebral atherosclerosis; (2) the lesion locations in the cerebral arteries; (3) the degree of lumen stenosis; (4) pathological features and cellular components of the lesions in these rabbits; and (5) whether hypertension affects ICAS.ResultsICAS was detected in apoE and WHHL rabbits, but not in WT rabbits. Compared with apoE KO rabbits, WHHL rabbits had greater ICAS. The lesions of cerebral atherosclerosis were mainly distributed at the bifurcations of the posterior cerebral artery, basilar artery and vertebral artery, and they were basically characterized by smooth muscle cells and extracellular matrix with few macrophages. The extent of the ICAS in WHHL rabbits was significantly increased by hypertension.ConclusionsICAS was detected in WHHL and apoE KO rabbits, and occurred in specific locations in the cerebral arteries. Hypertension promotes the development of ICAS in the setting of hypercholesterolemia.

BackgroundAcute kidney injury (AKI) is a morbid complication and the main cause of multiple organ failure and death in severely burned patients. The objective of this study was to explore epidemiology, risk factors, and outcomes of AKI for severely burned patients.MethodsThis retrospective study was performed with prospectively collected data of severely burned patients from the Institute of Burn Research in Southwest Hospital during 2011–2017. AKI was diagnosed according to Kidney Disease Improving Global Outcomes (KDIGO) criteria (2012), and it was divided into early and late AKIs depending on its onset time (within the first 3 days or >3 days post burn). The baseline characteristics, clinical data, and outcomes of the three groups (early AKI, late AKI and non-AKI) were compared using logistic regression analysis. Mortality predictors of patients with AKI were assessed.ResultsA total of 637 adult patients were included in analysis. The incidence of AKI was 36.9% (early AKI 29.4%, late AKI 10.0%). Multiple logistic regression analysis revealed that age, gender, total burn surface area (TBSA), full-thickness burns of TBSA, chronic comorbidities (hypertension or/and diabetes), hypovolemic shock of early burn, and tracheotomy were independent risk factors for both early and late AKIs. However, sepsis was only an independent risk factor for late AKI. Decompression escharotomy was a protective factor for both AKIs. The mortality of patients with AKI was 32.3% (early AKI 25.7%, late AKI 56.3%), and that of patients without AKI was 2.5%. AKI was independently associated with obviously increased mortality of severely burned patients [early AKI, OR = 12.98 (6.08–27.72); late AKI, OR = 34.02 (15.69–73.75)]. Compared with patients with early AKI, patients with late AKI had higher 28-day mortality (34.9% vs. 19.4%, p = 0.007), 90-day mortality (57.1% vs. 27.4%, p

Abstract Introduction We systematically reviewed the efficacy and safety of Calcitonin Gene‐Related Peptide (CGRP) antagonists for migraine treatment. Methods Various databases including PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), WanFang Data were electronically searched for randomized controlled trials (RCTs) on CGRP antagonists for migraine treatment since inception to March 2021. The trials were screened for inclusion, after which the methodological quality of the included trials was assessed. Then meta‐analysis was performed using the Revman 5.3 software. Results A total of 26 RCTs involving 21,736 patients were included. The CGRP antagonists group included 13,635 patients while the control group included 8101 patients. Meta‐analysis showed that compared to the control group, CGRP antagonists were associated with various significant effects, including the following outcome indicators: (1) number of patients with ≥50% reduction from baseline in mean monthly migraine days (RR = 1.50, 95% CI [1.39,1.62], p < .00001); (2) number of patients with pain free at 2 h postdose (RR = 1.98, 95% CI [1.77, 2.20], p < .00001), and (3) number of patients with 2–24 h sustained pain free postdose (RR = 2.18, 95% CI [1.93, 2.46], p < .00001). However, the number of patients with any adverse events was significantly high in the antagonists group, relative to the control group (RR = 1.08, 95% CI [1.04, 1.12], p < .0001). Conclusions CGRP antagonists are significantly effective for migraine treatment; however, they are associated with various adverse events. Due to limitations with regards to quantity and quality of the included studies, the above conclusions should be verified by more high quality studies.

The combination of dynamic vibration absorber and partial state feedback with time-delay is called delayed resonator. In order to suppress the seat vibration caused by uneven road surface and improve ride comfort, the delayed resonator is applied to the seat suspension to realize active control of the seat suspension system. The dynamic model of the half-vehicle suspension system is established, and the time-delay differential equation of the system under external excitation is solved by the precise integration method. The root mean square of the time-domain vibration response of seat displacement, seat acceleration and vehicle acceleration are selected as the objective function. Then, the optimal time-delay control parameters are obtained by particle swarm optimization algorithm. The frequency sweeping method is used to obtain the critical time-delay value and time-delay stable interval of the system. Finally, an active seat suspension model with delayed resonator is established for numerical simulation. The results show that the delayed resonator can greatly suppress the seat vibration response regardless of the road simple harmonic excitation or random excitation. Compared with dynamic vibration absorber, it has a better vibration absorption effect and a wider vibration reduction frequency band.

Mosquitoes are one of the most important disease vectors from a medical viewpoint in that they transmit several diseases such as malaria, filariasis, yellow and Dengue fever. Mosquito vector control and personal protection from mosquito bites are currently the most efficient ways to prevent these diseases. Several synthetic repellents such as DEET, ethyl butylacetylaminopropionate (IR3535) and 1-(1-methylpropoxycarbonyl)-2-(2-hydroxyethyl)piperidine) (Picaridin), have been widely used to prevent humans from receiving mosquito bites. However, the use of synthetic repellents has raised several environment and health concerns. Therefore, essential oils (EOs) as natural alternatives receive our attention. In order to discover highly effective mosquito repellents from natural sources, the repellent activity of 60 commercial EOs against Ae. albopictus was screened in this study. Eight EOs including cinnamon, marjoram, lemongrass, bay, chamomile, jasmine, peppermint2, and thyme, showed a suitable repellent rate (>40%) at the tested dose of 10 μg/cm2. Then, their main constituents were analyzed by GC-MS, and the active constituents were identified. The most active compounds including cinnamaldehyde, citral and terpinen-4-ol, exhibited an 82%, 65% and 60% repellent rate, respectively. Moreover, the nanoemulsions of the three active compounds were prepared and characterized. In the arm-in-cage assay, the protection times of the nanoemulsions of cinnamaldehyde and citral were significantly extended compared with their normal solutions. This study provides several lead compounds to develop new mosquito repellents, and it suggests that nanoemulsification is an effective method for improving the duration of the activity of natural repellents.

N6-methyladenosine (m6A) is a very common and abundant RNA modifications occurring in nearly all types of RNAs. Although the dysregulated expression of m6A regulators is implicated in cancer progression, our understanding of the prognostic value of the m6A regulators in rectal cancer is still quite limited. In this study, we analyzed the RNA expression levels of the 17 m6A regulator genes of 95 rectal cancer and 10 normal rectal samples from the The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) dataset. Lasso regression analysis was conducted to build a prognostic model and calculate the risk score. The rectal cancer patients were then devided into the high-risk and low-risk groups according to the mean risk score. The prognostic value of the identified model was separately evaluated in the TCGA-READ and GSE87211 datasets. GSEA was conducted to analyze the functional difference of high-risk and low-risk rectal cancer patients. Our analysis revealed that rectal cancer patients with lower expression of YTHDC2 and METTL14 had a remarkable worse overall survival (P < 0.05). The prognostic value of the model was validated in GSE87211 datasets, with AUC = 0.612 for OS and AUC = 0.651 for RFS. Furthermore, the m6A modification-based risk score system is associated with activation of distinct signaling pathways, such as DNA repair, epithelial-mesenchymal transition, G2M checkpoint and the MYC pathway, that may contribute to the progression of rectal cancer. In conclusion, our findings demonstrated that the m6A RNA methylation regulators, specifically YTHDC2 and METTL14, were significantly down-regulated and might be potential prognostic biomarkers in rectal cancer.

Abstract Objective To generate novel rabbit models with a large-fragment deletion of either LDL receptor (LDLR) and/or apolipoprotein (apoE) genes for the study of hyperlipidemic and atherosclerosis. Methods CRISPR/Cas9 system directed by a multiple sgRNAs system was used in rabbit embryos to edit their LDLR and apoE genes. The LDLR and apoE genes of founder rabbits were sequenced, and their plasma lipids and lipoprotein profiles on a normal chow diet were analyzed, western blotting was also performed to evaluate the expression of apolipoprotein. Sudan IV and HE staining of aortic were performed to confirm the formation of atherosclerosis. Results Six knockout (KO) rabbits by injection of both LDLR and apoE sgRNAs were obtained, including four LDLR KO rabbits and two LDLR/apoE double- KO rabbits. Sequence analysis of these KO rabbits revealed that they contained multiple mutations including indels, deletions, and substitutions, as well as two rabbit lines containing biallelic large fragment deletion in the LDLR region. Analysis of their plasma lipids and lipoprotein profiles of these rabbits fed on a normal chow diet revealed that all of these KO rabbits exhibited remarkable hyperlipidemia with total cholesterol levels increased by up to 10-fold over those of wild-type rabbits. Pathological examinations of two founder rabbits showed that KO rabbits developed prominent aortic and coronary atherosclerosis. Conclusion Large fragment deletions can be achieved in rabbits using Cas9 mRNA and multiple sgRNAs. LDLR KO along with LDLR/apoE double KO rabbits should provide a novel means for translational investigations of human hyperlipidemia and atherosclerosis.

Pressure injury (PI) prevention is a huge industry and involves various interventions. Temperature and moisture are important factors for wound healing; however, the active mechanism by which “moist heat” affects PI prevention has not yet been clarified. Thus, we explored the protective and therapeutic effects of hydrotherapy on PI based on the preconditioning (PC) principle, which might be useful for clinical practice. This study aimed to investigate the preventive mechanisms of heat shock preconditioning on PIs in rat models. The experiment was performed in the basic medical laboratory of Nagano College of Nursing in Japan. Ten rats were divided into two groups, with five rats in each group. Rats in the control group were not bathed. Rats in the preconditioning group (PC group) were bathed with hot tap-water. Bathing was conducted thrice a week. After bathing for 4 weeks, the PI model was constructed on the rats’ dorsal skin. The skin temperature, skin moisture, and area of ulcers were compared between the two groups. In vitro, we investigated the expression of heat shock protein 27 (Hsp27) in 6, 12, and 24 h after the PI model was constructed through Western blot analysis. Ulcers occurred in the control group 24 h after the PI model constructed, wheras the PC group exhibited ulcers after 36 h. The ulcer area was larger in the control group than that in the PC group after 24 h (all p < 0.05). The temperatures of PI wounds in the control group decreased and were lower than those in the PC group after 1, 6, 12, 36, and 48 h (all p < 0.05). However, the skin moisture levels of PI wounds increased in the control group and were higher than those in the PC group at the same time (all p < 0.05). Using Western blot analysis, hydrotherapy preconditioning showed the potential to increase Hsp27 expression after pressure was released (p < 0.05). We determine that heat shock preconditioning had a preventive effect on PIs in rat models, a result that may be associated with their actions in the upregulation of Hsp27.

To improve the overall performance of four-wheel steering vehicles under different working conditions and solve the problem of the unbalanced comprehensive control effect of a single controller, a multi-mode optimal decision control system is proposed based on the linear 2-DOF dynamic model of the vehicle, which can make the vehicle have better performance under different working conditions. The system is composed of multiple controllers, in which the self-tuning dual yaw rate feedback controller can create timely feedback and make adjustments according to the driving state of the vehicle, which is optimal under the condition of a small rotation angle at medium and high speeds. The system can match the corresponding controller according to the optimal performance of different control strategies at different speeds and angles. The simulation results show that the multi-mode optimal selection system can make the vehicle perform optimally under different working conditions, and that comprehensive performance is more prominent than that of a single controller.

Antimicrobial resistance (AMR) is one of the most significant threats to global public health. As antibiotic failure is increasing, phages are gradually becoming important agents in the post-antibiotic era. In this study, the therapeutic effects and safety of kpssk3, a previously isolated phage infecting carbapenem-resistant hypermucoviscous Klebsiella pneumoniae (CR-HMKP), were evaluated in a mouse model of systemic CR-HMKP infection. The therapeutic efficacy experiment showed that intraperitoneal injection with a single dose of phage kpssk3 (1 × 107 PFU/mouse) 3 h post infection protected 100% of BALB/c mice against bacteremia induced by intraperitoneal challenge with a 2 × LD100 dose of NY03, a CR-HMKP clinical isolate. In addition, mice were treated with antibiotics from three classes (polymyxin B, tigecycline, and ceftazidime/avibactam plus aztreonam), and the 7 days survival rates of the treated mice were 20, 20, and 90%, respectively. The safety test consisted of 2 parts: determining the cytotoxicity of kpssk3 and evaluating the short- and long-term impacts of phage therapy on the mouse gut microbiota. Phage kpssk3 was shown to not be cytotoxic to mammalian cells in vitro or in vivo. Fecal samples were collected from the phage-treated mice at 3 time points before (0 day) and after (3 and 10 days) phage therapy to study the change in the gut microbiome via high-throughput 16S rDNA sequence analysis, which revealed no notable alterations in the gut microbiota except for decreases in the Chao1 and ACE indexes.

Background: The N6-methyladenosine (m6A) modification plays a critical role in cancer development. Little is known about the m6A modification in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Thus, the prognostic value of m6A RNA methylation in TNBC deserves exploration.Methods: The expression levels of the 13 m6A methylation regulators were compared between the 98 TNBC tumor samples and normal tissue samples based on the transcriptome profiles from The Cancer Genome Atlas (TCGA). The association between the m6A regulators and patients' overall survival was assessed by Kaplan-Meier survival analysis and Cox regression analysis. Lasso regression analysis was conducted to construct a prognostic model based on the m6A methylation system. The prognostic performance of the identified model was validated in GSE88847 and GSE135565 datasets. A nomogram combining the TNM stage and the m6A prognostic model was further constructed for the survival prediction of TNBC patients.Results: The m6A regulator genes were remarkably dysregulated in TNBC tumor tissues, with ALKBH5, YTHDF2, HNRNPC, KIAA1429, and RBM15 significantly up-regulated and FTO, YTHDC1, YTHDC2, METTL3, METTL14, and ZC3H13 significantly down-regulated (P < 0.01). The expression level of ALKBH5 was an independent unfavorable prognostic factor (HR = 3.327, P = 0.006), while METTL14 (HR = 0.425, P = 0.009) was an independent favorable prognostic factor for TNBC patients. A prognostic model consisting of ALKBH5 and METTL14 was therefore proposed displaying higher accuracy of risk prediction when combined with TNM stage with an AUC of 0.791. The prognostic value of the identified signature remained consistent within the two external validation datasets.Conclusion: The m6A methylation regulators were significantly dysregulated in TNBC tissues and could constitute a novel prognostic signature for the survival prediction of TNBC patients.

To address the contradiction between ride comfort and handling stability, a new vibration-absorbing wheel structure with time-delay feedback control was proposed by applying a time-delay feedback-controlled dynamic vibration absorber to the wheel structure. Using H2 optimization and the particle swarm optimization algorithm (PSO), the design parameters of the time-delay vibration-absorbing wheel structure were obtained with sprung mass acceleration (SMA), suspension deflection (SD) and dynamic tire deflection (DTD) as the optimization objective functions. The stability interval of the system was analyzed using the Routh–Hurwitz criterion and the Sturm criterion. The vehicle vibration reduction performance of the new vibration-absorbing wheel structure was simulated and verified in the time domain under harmonic excitation and random excitation. The simulation results show this new structure can effectively solve the contradiction between the ride comfort and handling stability. It provides a new technical idea for reducing vehicle vibration.

Rabbits (Oryctolagus cuniculus) have been the very frequently used as animal models in the study of human lipid metabolism and atherosclerosis, because they have similar lipoprotein metabolism to humans. Most of hyperlipidemia and atherosclerosis rabbit models are produced by feeding rabbits a high-cholesterol diet. Gene editing or knockout (KO) offered another means of producing rabbit models for study of the metabolism of lipids and lipoproteins. Even so, apolipoprotein (Apo)E KO rabbits must be fed a high-cholesterol diet to induce hyperlipidemia.In this study, we used the CRISPR/Cas9 system anchored exon 7 of low-density lipoprotein receptor (LDLR) in an attempt to generate KO rabbits. We designed two sgRNA sequences located in E7:g.7055–7074 and E7:g.7102–7124 of rabbit LDLR gene, respectively. Seven LDLR-KO founder rabbits were generated, and all of them contained biallelic modifications. Various mutational LDLR amino acid sequences of the 7 founder rabbits were subjected to tertiary structure modeling with SWISS-MODEL, and results showed that the structure of EGF-A domain of each protein differs from the wild-type. All the founder rabbits spontaneously developed hypercholesterolemia and atherosclerosis on a normal chow (NC) diet. Analysis of their plasma lipids and lipoproteins at the age of 12 weeks revealed that all these KO rabbits exhibited markedly increased levels of plasma TC (the highest of which was 1013.15 mg/dl, 20-fold higher than wild-type rabbits), LDL-C (the highest of which was 730.00 mg/dl, 35-fold higher than wild-type rabbits) and TG accompanied by reduced HDL-C levels. Pathological examinations of a founder rabbit showed prominent aortic atherosclerosis lesions and coronary artery atherosclerosis.In conclusion, we have reported the generation LDLR-KO rabbit model for the study of spontaneous hypercholesterolemia and atherosclerosis on a NC diet. The LDLR-KO rabbits should be a useful rabbit model of human familial hypercholesterolemia (FH) for the simulations of human primary hypercholesterolemia and such models would allow more exact research into cardio-cerebrovascular disease. Keywords: LDLR, Hypercholesterolemia, Atherosclerosis, Rabbits, Cas9, Knockout

Abstract Ellerman bombs (EBs) are believed to be small-scale reconnection events occurring around the temperature minimum region in the solar atmosphere. They are often identified as significant enhancements in the extended Hα wings without obvious signatures in the Hα core. Here we explore the possibility of using the 1700 Å images taken by the Atmospheric Imaging Assembly (AIA) onboard the Solar Dynamics Observatory (SDO) to study EBs. From the Hα wing images obtained with the New Vacuum Solar Telescope (NVST) on 2015 May 2, we have identified 145 EBs and 51% of them clearly correspond to the bright points (BPs) in the AIA 1700 Å images. If we resize the NVST images using a linear interpolation to make the pixel sizes of the AIA and NVST images the same, some previously identified EBs disappear and about 71% of the remaining EBs are associated with BPs. Meanwhile, 66% of the compact brightenings in the AIA 1700 Å images can be identified as EBs in the Hα wings. The intensity enhancements of the EBs in the Hα wing images reveal a linear correlation with those of the BPs in the AIA 1700 Å images. Our study suggests that a significant fraction of EBs can be observed with the AIA 1700 Å filter, which is promising for large-sample statistical study of EBs as the seeing-free and full-disk SDO/AIA data are routinely available.

Background: Thermal injury is the main cause of pulmonary disease in stroke after burn and can be life threatening. Heat-induced inflammation is an important factor that triggers a series of induces pathological changes. However, this mechanism underlying heat-induced inflammation in thermal inhalation injury remains unclear. Studies have revealed that astragaloside-IV (AS-IV), a natural compound extracted from Astragalus membranaceus, has protective effects in inflammatory diseases. Here, we investigated whether the protective effects of AS-IV occur because of the suppression of heat-induced endoplasmic reticulum (ER) stress and excessive autophagy Methods: AS-IV was administered to Wistar rats after thermal inhalation injury and 16HBE140-cells were treated with AS-IV. TNF-α, IL-6, and IL-8 levels were determined by ELISA and real-time PCR. ER stress and autophagy were determined by western blot. Autophagic flux was measured by recording the fluorescence emission of the fusion protein mRFP-GFP-LC3 by dynamic live-cell imaging. Results: AS-IV had protective effects against heat-induced reactive oxygen species production and attenuated ER stress. AS IV alleviated heat-induced excessive autophagy in vitro and in vivo. Excessive autophagy was attenuated by the PERK inhibitor GSK2656157 and eIF2α siRNA, suggesting that heat stress-induced autophagy can activate the PERK-eIF2α pathway. Beclin 1 and Atg5 siRNAs inhibited the upregulation of the inflammatory cytokines TNF-α, IL-6, and IL-8 after heat exposure. Conclusions: Thus, AS-IV may attenuate inflammatory responses by disrupting the crosstalk between autophagy and the PERK-eIF2α pathway and may be an ideal agent for treating inflammatory pulmonary diseases.

Background: Heat causes airway damage during inhalation injury because of bronchial epithelial cell damage. Accumulating evidence shows that mitochondrial uniporter (MCU) is involved in cell damage. We investigated the MCU activity after heat treatment and assessed whether Astragaloside-IV (AS-IV) suppresses heat-induced apoptosis in bronchial epithelial cells by inhibiting the activation of the mitochondrial Ca2+ uniporter (MCU), mitochondrial depolarisation and reactive oxygen species (ROS) production. Methods: The bronchial epithelial cell line 16HBE14o- was heat treated, and cell apoptosis was induced in vitro and in vivo. AS-IV was inorganically administered to Wistar rats twice a day after thermal inhalation injury, and 16HBE140- cells were treated with AS-IV after incubation at 47°C for 5 min. Protein expression was determined using Western blotting and commercial kits, apoptosis with TUNEL staining, mitochondrial channel activity by patch clamp, reactive oxygen species by MitoSOXTM fluorescence, ATP levels and enzyme activities by commercial kits as well as mitochondrial respiration and calcium by fluorescence. Results: AS-IV markedly inhibited heat-induced apoptosis, as indicated by the increased expression of the pro-apoptotic genes Bak, Bik and Bmf and increased expression of the apoptosis markers Bax, cleaved parp, cleaved caspase3 and cytochrome C. We found that MCU activation promoted mitochondrial Ca2+ overload, ATP depletion, mitochondrial ROS production and cytochrome c release and rapidly induced apoptosis. However, AS-IV treatment reduced excessive MCU activation and led to resistance against mitochondrial Ca2+ overload and excessive cytochrome C release; these effects were blocked by the MCU activator spermine. AS-IV treatment elevated ATP production and decreased ROS activity. Conclusions: MCU plays crucial roles in heat-induced mitochondrial apoptosis in 16HBE140- cells, suggesting a potential target for AS-IV treatment.

Background/Aims: Skin transplantation aims to cover skin defects but often fails due to immune rejection of the transplantated tissue. Immature dendritic cells (imDCs) induce immune tolerance but have a low migration rate. After stimulation, imDCs transform into mature DCs, which activate immune rejection. Thus, inducing imDC to obtain a high migration counteracts development of immune tolerance. Methods & Results: We transfected imDCs with a recombinant adenovirus carrying the CCR7 gene (Ad-CCR7) and a small interfering RNA targeting RelB (RelB-siRNA) to concurrently overexpress CCR7 and downregulate RelB expression. Functionally, such cells showed a significantly enhanced migration rate in the chemotactic assay and decreased T-cell proliferation after lipopolysaccharide stimulation in mixed lymphocyte reactions. Cotransfected cells showed an increased ability to induce immune tolerance by upregulating T regulatory (Treg) cells and shifting the Th1/Th2 ratio. Cotransfection of Ad-CCR7 and RelB-siRNA endowed imDCs with resistance to apoptosis and cell death. CCR7 overexpression and RelB knockdown (KD) in imDCs improve skin-graft survival in a murine skin-transplantation model. Conclusion: Transfection with Ad-CCR7 and RelB KD in imDCs may be an effective approach inducing immune tolerance, thus being potentially valuable for inhibiting allograft rejection.

Hyperlipidemia or dyslipidemia is a major risk factor for atherosclerotic diseases. Experimental animals play an important role in elucidating the molecular mechanisms of the pathophysiology of hyperlipidemia as well as in drug development. Rabbits are one of the most suitable models to study human hyperlipidemia because many features of the lipoprotein metabolism of rabbits are similar to those of humans such as LDL-rich lipoproteins in plasma, apolipoprotein B mRNA editing, and cholesteryl ester transfer protein. Currently, three types of rabbit models are commonly used for studying hyperlipidemia: (1) diet-induced hyperlipidemic rabbits, (2) spontaneous hyperlipidemic rabbits, and (3) gene-manipulated rabbits (transgenic and knockout rabbits). In this review, we give an overview of the features of hyperlipidemic rabbits and discuss the usefulness of rabbits for the development of anti-atherogenic drugs.

Background: CFTR is implicated in cutaneous wound healing although the underlying mechanisms are not fully understood. In other cell types, CFTR is reported to regulate MAPK/ NF-κB signaling. We undertook the present study to explore a possible role of CFTR in regulating MAPK/NF-κB during cutaneous wound healing. Methods& Results: The splint-excisional and incisional wound healing models were used in CFTR mutant (DF508) mice. The cell-scratch model was used in a human keratinocyte line, HaCaT, in conjunction with CFTR knockdown or overexpression. The epidermal inflammation, keratinocyte proliferation and differentiation, as well as MAPK/NF-κB signaling were examined. Inhibitors of MAPK/NF-κB were also used. Results: Both DF508 mice and HaCaT cells with CFTR knockdown exhibited delayed cutaneous wound healing with exuberant inflammation, increased proliferation and aberrant differentiation. Knockdown of CFTR in HaCaT cells resulted in phosphorylation of ERK, p38 and IκBα. The disturbance of inflammation, proliferation and differentiation in HaCaT cells were reversed by CFTR overexpression or inhibition of MAPK or NF-κB. Conclusion: CFTR plays a role in suppressing MAPK/NF-κB to relieve inflammation, reduce proliferation and promote differentiation of keratinocytes, and thus promotes cutaneous wound healing.

Background: Previous studies have established that estrogen is capable of accelerating cutaneous wound healing through multiple mechanisms, one of which involves affecting keratinocytes biological properties, such as migration, proliferation, etc. This study aims to reveal the underlying molecular mechanisms of estrogen promoting epidermal keratinocytes proliferation. Method & Results: We found that compared with female mice with a normal estrous cycle, female mice with their ovaries removed before puberty exhibited a delayed cutaneous wound healing, thinner epidermis, and significantly fewer proliferating cell nuclear antigen (PCNA)-positive keratinocytes. Moreover, a significant increase in HaCaT proliferation was detected by a CCK8 assay when treated with 17 β-estradiol compared with those treated with control vehicle. Consistent with the results of the CCK8 assay, flow cytometry indicated a high proportion of 17 β-estradiol-treated HaCaT cells in S phase compared with vehicle-treated cells. Western blot analysis demonstrated the activation of Akt, Erk and upregulation of PCNA in HaCaT cells treated with 17 β-estradiol. Interestingly, Erk activation occurred prior to Akt activation. Upregulation of PCNA expression, elevated proliferation and high S phase fraction of HaCaT cell by 17 β-estradiol could be reversed by an Akt or Erk inhibitor. Moreover, Erk inhibition reversed 17 β-estradiol-induced Akt activation, whereas an Akt inhibitor exhibited no effect on Erk, further suggesting that Erk was on the upstream while Akt on the downstream of the signaling pathway. Conclusion: This study demonstrates that one of the critical mechanisms underlying 17 β-estradiol promoting skin wound healing is through regulation of keratinocyte proliferation via Erk/Akt signaling pathway.

Gastric cancer is the most common malignant tumor of the digestive tract and is great challenge in clinical treatment. N6-(2-Hydroxyethyl)-adenosine (HEA), widely present in various fungi, is a natural adenosine derivative with many biological and pharmacological activities. Here, we assessed the antineoplastic effect of HEA on gastric carcinoma. HEA exerted cytotoxic effects against gastric carcinoma cells (SGC-7901 and AGS) in a dose and time-dependent manner. Additionally, we found that HEA induced reactive oxygen species production and mitochondrial membrane potential depolarization. Moreover, it could trigger caspase-dependent apoptosis, promoting intracellular Ca2+-related endoplasmic reticulum (ER) stress and autophagy. On the other hand, HEA could significantly inhibit the growth of transplanted tumors in nude mice and induce apoptosis of tumor tissues cells in vivo. In conclusion, HEA induced apoptosis of gastric carcinoma cells in vitro and in vivo, demonstrating that HEA is a potential chemotherapeutic agent for gastric carcinoma.