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Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid. Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients. The response of intestinal epithelial cells to mechanical stimulation is not fully understood. Piezo1, a mechanosensitive ion channel, is widely expressed throughout the digestive tract. However, its function in intestinal nutrient absorption is not yet clear. In our study, excessive lipid deposition was observed in the duodenum of obese patients, while duodenal Piezo1–CaMKK2–AMPKα was decreased when compared to normal-weight individuals. Under high-fat diet condition, the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver. These phenotypes were mainly caused by the inhibition of duodenal CaMKK2–AMPKα and the upregulation of SGLT1 and DGAT2. In contrast, Yoda1, a Piezo1 agonist, was found to reduce intestinal lipid absorption in diet induced obese mice. Overexpression of Piezo1, stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1, whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells. Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells, which may shed new light on the therapy of obesity.

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (Piezo1 IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

Drug combinations and repurposing have recently provided promising alternatives to cope with the increasingly severe issue of antibiotic resistance and depletion of natural drug molecular repertoires that undermine traditional antibacterial strategies. Closantel, an effective adjuvant, reverses antibiotic resistance in gram-negative bacteria. Herein, the combined antibacterial enantioselectivity of closantel is presented through separate enantiomer studies. Despite yielding unexpected differences, two closantel enantiomers (R, S) increased colistin activity against gram-negative bacteria both in vitro and in vivo. The fractional inhibitory concentration indices of R-closantel and S-closantel combined with colistin against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli ranged from 0.0087 to 0.5004 and from 0.0117 to 0.5312, respectively. This difference was further demonstrated using growth inhibition assays and time-killing curves. Mechanistically, a higher intracellular concentration of R-CLO is more effective in enhancing the antimicrobial activity of combination. A mouse cutaneous infection model confirmed the synergistic stereoselectivity of closantel. This discovery provides novel insights for developing precision medication and containment of increasing antibiotic resistance.

The role of human cell division cycle 73 (CDC73) in human cancers has sparked controversy; however, its significance in oesophageal cancer remains elusive. This study aimed to elucidate CDC73 expression and its biological implications in human oesophageal cancer. Our findings unveiled a notable upregulation of CDC73 in both oesophageal cancer cell lines and tissues. Importantly, elevated CDC73 levels in patients with oesophageal cancer correlated with an unfavourable prognosis. Functional investigations revealed that CDC73 knockdown effectively curtailed the proliferation and growth of oesophageal cancer cells both in vitro and in vivo. Mechanistically, RRP15 emerged as a potential downstream target of CDC73 through a screening process involving identification of the top co-expressed genes, subsequent knockdown experiments, and observation of significant inhibition of cell proliferation, with RRP15 showing the most pronounced effect. This finding was further supported by the positive correlation observed between CDC73 and RRP15 in ESCA samples analysed using the ENCORI Pan-Cancer Analysis Platform. Notably, depletion of RRP15 in CDC73-overexpressing cells led to a shift from augmented to diminished tumour growth. Collectively, our findings underscore the pivotal role of CDC73 in oesophageal cancer through the modulation of RRP15 expression, suggesting CDC73 as a potential therapeutic target for treating oesophageal cancer.

Abstract This research proposed the modular prefabricated permanent formwork system made of ultra-high-performance concrete (UHPC). Two kinds of modular formwork shapes were designed: the flat formwork and the ribbed. The experimental investigation on the axial compression performance of the composite columns that consist of the normal strength concrete (NSC) core and the modular UHPC permanent formwork was demonstrated. Compared with the flat formwork, the ribbed formwork exhibited better bonding with the NSC core. As observed from the test results, the composite column with the ribbed formwork presented a similar axial behavior as the NSC column with a slight improvement in ultimate loads. Therefore, the modular UHPC ribbed permanent formwork could be regarded as the additional cover to the conventional NSC column. In addition, the finite element analysis (FEA) model was also developed to simulate the composite columns numerically. The predicted capacities agreed with the experimental results, which validated the numerical models. The crack pattern estimated by the FEA model revealed that the interaction between the permanent formwork and the inner concrete introduced many tiny cracks to the concrete core. However, as protected by the UHPC permanent formwork, the overall durability of the composite columns can still be enhanced.

Abstract With the continuous development of information technology and the running speed of computers, the development of informatization has led to the generation of increasingly more medical data. Solving unmet needs such as employing the constantly developing artificial intelligence technology to medical data and providing support for the medical industry is a hot research topic. Cytomegalovirus (CMV) is a kind of virus that exists widely in nature with strict species specificity, and the infection rate among Chinese adults is more than 95%. Therefore, the detection of CMV is of great importance since the vast majority of infected patients are in a state of invisible infection after the infection, except for a few patients with clinical symptoms. In this study, we present a new method to detect CMV infection status by analyzing high-throughput sequencing results of T cell receptor beta chains (TCRβ). Based on the high-throughput sequencing data of 640 subjects from cohort 1, Fisher’s exact test was performed to evaluate the relationship between TCRβ sequences and CMV status. Furthermore, the number of subjects with these correlated sequences to different degrees in cohort 1 and cohort 2 were measured to build binary classifier models to identify whether the subject was CMV positive or negative. We select four binary classification algorithms: logistic regression (LR), support vector machine (SVM), random forest (RF), and linear discriminant analysis (LDA) for side-by-side comparison. According to the performance of different algorithms corresponding to different thresholds, four optimal binary classification algorithm models are obtained. The logistic regression algorithm performs best when Fisher's exact test threshold is 10−5, and the sensitivity and specificity are 87.5% and 96.88%, respectively. The RF algorithm performs better at the threshold of 10−5, with a sensitivity of 87.5% and a specificity of 90.63%. The SVM algorithm also achieves high accuracy at the threshold value of 10−5, with a sensitivity of 85.42% and specificity of 96.88%. The LDA algorithm achieves high accuracy with 95.83% sensitivity and 90.63% specificity when the threshold value is 10−4. This is probably because the two-dimensional distribution of CMV data samples is linearly separable, and linear division models such as LDA are more effective, while the division effect of nonlinear separable algorithms such as random forest is relatively inaccurate. This new finding may be a potential diagnostic method for CMV and may even be applicable to other viruses, such as the infectious history detection of the new coronavirus.

In order to seal the joints between the ultra-high-performance concrete (UHPC) permanent formworks, the high strength cementitious grout (HSCG) was investigated in the presented work. The water reducer content and the water to binding materials (W/B) ratio of the grout were modified to meet the grout fluidity requirement, and then the effects of three commonly used admixtures (i.e., hydrophobic powders (HP), expansive agents (EA), and redispersible polymer powders (RPP)) and PVA fibers on the compressive, tensile, flexural, and adhesive strengths of the HSCG were investigated. In addition to the normal condition, the adhesive strengths under the soaked condition and the thermal aging condition were also evaluated. The HP worsen all strength index, especially the adhesive strength, while the appropriate utilization of the EA could improve all strength indexes by more than 12%. With the addition of RPP, the adhesive strengths under the soaked and thermal aging conditions could be significantly enhanced by over 85%. The PVA fiber could also enhance the normal adhesive strength by 20.5%. Based on the experimental results, the recommended contents of the EA, RPP, and PVA fibers were 6%, 2%, and 0.3%, respectively, while the HP was not suggested for the HSCG due to its adverse effect on the mechanical performances.

The utilization of ultra-high-performance concrete (UHPC) permanent formwork could facilitate the construction of hydraulic concrete structures. However, the joints between UHPC formwork are the vulnerable parts of a whole permanent formwork system. This study aimed to develop a High Strength Cementitious Grout (HSCG) for filling these joints, integrating the formwork system, and minimizing the adverse influence on these joints. The aggregate size for the HSCG was optimized, and four kinds of admixtures (i.e., hydrophobic powder (HP), expansive agent (EA), redispersible polymer powder (RPP), and cellulose ether (CE)) and PVA fibers were used to improve the HSCG. The HSCG with different aggregate sizes, admixture dosages, and PVA fiber contents were experimentally investigated. By evaluating the compressive, tensile, flexural, and adhesive strengths of the prepared grout, the aggregate size range was recommended to be 0.15–0.30 ​mm, while the suggested contents of HP, EA, RPP, and CE were 0%, 6%, 2%, and 0.1%, respectively, by weight of binding materials. In addition, the optimal volume content of PVA fibers was 0.45%. In order to avoid the introduced foams, 0.2% of the defoamers were used in combination with the CE. After that, six combinations were tested to consider the coupled effect of different admixtures and PVA fibers on the HSCG. In consideration of the strengths, shrinkage, and abrasion resistance to water impact, the HSCG with the combination of (EA ​+ ​RPP ​+ ​CE), the aggregate size of 0.15–0.30 ​mm showed the optimal overall performance and was regarded as the most suitable HSCG for grouting.

ObjectivesThis retrospective analysis aimed to evaluate the early and midterm outcomes of thoracic endovascular aortic repair (TEVAR) with fenestrated surgeon-modified stent-graft (f-SMSG) for type B aortic dissections (TBAD) involving the aortic arch.MethodsFrom March 2016 to April 2021, 47 consecutive patients were treated using TEVAR with f-SMSG. All patients were diagnosed with TBAD involving the aortic arch.ResultsIn total, 47 patients with TBAD involving the aortic arch were treated with f-SMSGs. There were 21 zone 1 and 26 zone 2 TEVAR, and 65 arteries were revascularized successfully with fenestrations. Technical success was achieved in 46 patients (97.88%). The 30-day estimated survival (± SE) and reintervention was 93.6 ± 1.0% (95% Confidence Interval [CI], 92.6–94.6%) and 91.5 ± 1.2% (95% CI, 90.3–92.7%), respectively. During a median follow-up of 51 months (range, 16–71 months), 1 patient died of rupture of aortic dissection (AD) and 3 patients died of non-aortic-related reasons. Reintervention was performed for four patients, including two patients of type IA entry flow and two patients of type IB entry flow. No occlusion of the supra-aortic trunk was observed. The estimated survival and reintervention (± SE) at 4 years was 88.7 ± 1.4% (95% CI, 87.3–90.1%) and 84.8 ± 1.5% (95% CI, 83.3–86.3%), respectively.ConclusionThoracic endovascular aortic repair with f-SMSG is an alternative treatment option for TBAD involving the aortic arch in high-volume centers.

ObjectiveType A aortic dissection (TAAD) is associated with high morbidity and mortality, and open surgery is the best treatment option. Development of endovascular repair devices for TAAD will benefit patients deemed unfit for open surgery. In this study, we performed a thorough investigation of anatomical features in Asian patients with TAAD to learn about the patient eligibility of a novel ascending aortic endograft technique.MethodsComputed tomography angiography (CTA) images of TAAD cases in our institution from January 2015 to November 2021 were reviewed, and three-dimensional reconstructions were performed with the Endosize software (Therenva, Rennes, France). Anatomic structures including length measured along centerline and greater/lesser curvature, ascending aorta/aortic root dimensions, as well as location of entry tear and extent of dissection were analyzed.ResultsA total of 158 patients were included [median age 58 years, interquartile range (IQR), 30–76 years; 115 males, 72.8%]. In 99 (62.7%) of the cases, entry tear was distal to the sinotubular junction (STJ). In 106 (67.1%) of the cases, the pathology proximally extended into the aortic root, which was intramural hematoma in 37 (23.4%) of the cases, and the aortic root was free from the pathology in 52 (32.9%) of the cases. The median distance from the STJ to the proximal edge of the ostium of the innominate artery (IA) measured along the centerline was 65 mm (IQR 58–74 mm). The median distance from the distal edge of the higher coronary ostium to the STJ was 7.95 mm (IQR 5.625–10.9 mm). The bare metal stent part was set between the edge of the higher coronary ostium and the STJ. In our series, 63 (39.9%) of the cases had this distance >10 mm. The relative difference was

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterized by progressive fibro-fatty replacement of cardiac myocytes. Up to now, the existing therapeutic modalities for ACM are mostly palliative. About 50% of ACM is caused by mutations in genes encoding desmosomal proteins including Desmoglein-2 (Dsg2). In the current study, the cardiac fibrosis of ACM and its underlying mechanism were investigated by using a cardiac-specific knockout of Dsg2 mouse model. Methods: Cardiac-specific Dsg2 knockout (CS-Dsg2−/−) mice and wild-type (WT) mice were respectively used as the animal model of ACM and controls. The myocardial collagen volume fraction was determined by histological analysis. The expression levels of fibrotic markers such as α-SMA and Collagen I as well as signal transducers such as STAT3, SMAD3, and PPARα were measured by Western blot and quantitative real-time PCR. Results: Increased cardiac fibrosis was observed in CS-Dsg2−/− mice according to Masson staining. PPARα deficiency and hyperactivation of STAT3 and SMAD3 were observed in the myocardium of CS-Dsg2−/− mice. The biomarkers of fibrosis such as α-SMA and Collagen I were upregulated after gene silencing of Dsg2 in HL-1 cells. Furthermore, STAT3 gene silencing by Stat3 siRNA inhibited the expression of fibrotic markers. The activation of PPARα by fenofibrate or AAV9-Pparα improved the cardiac fibrosis and decreased the phosphorylation of STAT3, SMAD3, and AKT in CS-Dsg2−/− mice. Conclusions: Activation of PPARα alleviates the cardiac fibrosis in ACM.