Activation of Wnt signaling mitigates blood-brain barrier disruption by inhibiting vesicular transcytosis after traumatic brain injury in mice.

Elevated transport of Caveolin-1 (CAV-1) vesicles within vascular endothelial cells constitutes a significant secondary pathogenic event contributing to the compromise of the blood-brain barrier (BBB) post-traumatic brain injury (TBI). While Wnt/ß-catenin signaling is recognized for its critical involvement in angiogenesis and the maintenance of BBB integrity, its influence on vascular endothelial transcytosis in the aftermath of TBI is not well-defined. This study aims to elucidate the impact of Wnt/ß-catenin signaling on cerebrovascular vesicular transcytosis following TBI. In this experiment, adult male wild-type (WT) C57BL/6 mice underwent various interventions. TBI was induced utilizing the controlled cortical impact technique. Post-TBI, mice were administered either an inhibitor or an agonist of Wnt signaling via intraperitoneal injection. Recombinant adeno-associated virus (rAAV) was administered intracerebroventricularly to modulate the expression of the CAV-1 inhibitory protein, Major facilitator superfamily domain-containing 2a (Mfsd2a). This research utilized Evans blue assay, Western blot analysis, immunofluorescence, transmission electron microscopy, and neurobehavioral assessments. Post-TBI observations revealed substantial increases in macromolecule (Evans blue and albumin) leakage, CAV-1 transport vesicle count, astrocyte end-feet edema, and augmented aquaporin-4 (AQP4) expression, culminating in BBB disruption. The findings indicate that Wnt signaling pathway inhibition escalates CAV-1 transport vesicle activity and aggravates BBB compromise. Conversely, activating this pathway could alleviate BBB damage by curtailing CAV-1 vesicle presence. Post-TBI, there is a diminution in Mfsd2a expression, which is directly influenced by the modulation of WNT signals. Employing a viral approach to regulate Mfsd2a, we established that its down-regulation undermines the protective benefits derived from reducing CAV-1 transport vesicles through WNT signal enhancement. Moreover, we verified that the WNT signaling agonist LiCl notably ameliorates neurological deficits following TBI in mice. Collectively, our data imply that Wnt/ß-catenin signaling presents a potential therapeutic target for safeguarding against BBB damage and enhancing neurological function after TBI.

Fabrication of Large-Area Silicon Spherical Microlens Arrays by Thermal Reflow and ICP Etching.

In this paper, we proposed an efficient and high-precision process for fabricating large-area microlens arrays using thermal reflow combined with ICP etching. When the temperature rises above the glass transition temperature, the polymer cylinder will reflow into a smooth hemisphere due to the surface tension effect. The dimensional differences generated after reflow can be corrected using etching selectivity in the following ICP etching process, which transfers the microstructure on the photoresist to the substrate. The volume variation before and after reflow, as well as the effect of etching selectivity using process parameters, such as RF power and gas flow, were explored. Due to the surface tension effect and the simultaneous molding of all microlens units, machining a 3.84 × 3.84 mm2 silicon microlens array required only 3 min of reflow and 15 min of ICP etching with an extremely low average surface roughness Sa of 1.2 nm.

Acetyl-CoA metabolic accumulation promotes hepatocellular carcinoma metastasis via enhancing CXCL1-dependent infiltration of tumor-associated neutrophils.

High levels of acetyl-CoA are considered a key metabolic feature of metastatic cancers. However, the impacts of acetyl-CoA metabolic accumulation on cancer microenvironment remodeling are poorly understood. In this study, using human hepatocellular carcinoma (HCC) tissues and orthotopic xenograft models, we found a close association between high acetyl-CoA levels in HCCs, increased infiltration of tumor-associated neutrophils (TANs) in the cancer microenvironment and HCC metastasis. Cytokine microarray and enzyme-linked immunosorbent assays (ELISA) revealed the crucial role of the chemokine (C-X-C motif) ligand 1(CXCL1). Mechanistically, acetyl-CoA accumulation induces H3 acetylation-dependent upregulation of CXCL1 gene expression. CXCL1 recruits TANs, leads to neutrophil extracellular traps (NETs) formation and promotes HCC metastasis. Collectively, our work linked the accumulation of acetyl-CoA in HCC cells and TANs infiltration, and revealed that the CXCL1-CXC receptor 2 (CXCR2)-TANs-NETs axis is a potential target for HCCs with high acetyl-CoA levels.

CFD simulation of cannabidiol delivery through microneedle patches.

This study investigates the efficiency and influence of microneedle parameters, specifically Needle Point Angle (a) and Needle Height (h), on the diffusion of Cannabidiol (CBD) across varying skin depths. Utilizing the Latin Hypercube Sampling method, twelve distinct cases were analyzed. Observations reveal a consistent high concentration of CBD delivered via the microneedle patch, with a notable decrease in concentration as the depth increases, displaying a non-linear trend. Multivariate polynomial regression offers a quantitative relationship between the variables, with the third-order bivariate fitting providing the most accurate representation. Compared to other CBD delivery mechanisms, microneedle patches present enhanced CBD concentrations, circumventing challenges faced by other methods such as dosage inaccuracy, systemic absorption issues, and CBD degradation. The results highlight the potential of microneedle patches as a promising avenue for optimized transdermal drug delivery.

Survival outcomes following complete mediastinal lymphadenectomy or selective mediastinal lymphadenectomy in patients with stage I-IIIA non-small cell lung cancer: protocol for a systematic review and meta-analysis.

INTRODUCTION: Lung cancer remains the largest cause of cancer-related deaths worldwide. Surgical removal of non-small cell lung cancer (NSCLC) has the potential to achieve a cure, although there is ongoing debate regarding the significance of removing mediastinal nodes and the optimal extent of lymph node excision. The purpose of this research is to assess the survival outcomes in patients diagnosed with stage I-IIIA NSCLC who received either complete mediastinal lymphadenectomy (CML) or selective mediastinal lymphadenectomy (SML). METHODS AND ANALYSIS: The protocol follows the guidelines recommended in Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, and this meta-analysis will be conducted in accordance with the standard methodology recommended by the Cochrane Collaboration and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidance. We will conduct a comprehensive search for randomised controlled trials and non-randomised studies examining the effectiveness of CML compared with SML in patients with stage I-IIIA NSCLC. Two authors will perform a comprehensive search of the MEDLINE/PubMed, Embase, the Cochrane Library, CNKI, WanFang, Sinomed, VIP and Web of Science databases. There will be no restrictions on language or publication date, and the search will be conducted on 10 April 2024, with ongoing searches for new research. Reference lists will also be checked and pertinent journals will be hand searched. The primary outcomes include overall survival (OS) and disease-free survival (DFS), while the secondary outcomes consist of 1-year, 3-year and 5-year OS rates and 1-year, 3-year and 5-year DFS rates. Two independent reviewers will screen, extract data, assess quality and evaluate the potential for bias in the selected research, with a third acting as arbitrator. Subgroup analyses and sensitivity analyses are planned. The quality of the evidence will be evaluated using Grading of Recommendations Assessment, Development and Evaluation. Review Manager V.5.4 will be used for the analysis and synthesis process. ETHICS AND DISSEMINATION: Ethical review and approval are not necessary for this study because it is based on a secondary analysis of the literature. The results will be submitted for reporting in a peer-reviewed publication. STUDY REGISTRATION: Open Science Framework (https://doi.org/10.17605/OSF.IO/PN7UQ).

Combined polygenic scores for ischemic stroke risk factors aid risk assessment of ischemic stroke.

BACKGROUND: Current risk assessment for ischemic stroke (IS) is limited to clinical variables. We hypothesize that polygenic scores (PGS) of IS (PGSIS) and IS-associated diseases such as atrial fibrillation (AF), venous thromboembolism (VTE), coronary artery disease (CAD), hypertension (HTN), and Type 2 diabetes (T2D) may improve the performance of IS risk assessment. METHODS: Incident IS was followed for 479,476 participants in the UK Biobank who did not have an IS diagnosis prior to the recruitment. Lifestyle variables (obesity, smoking and alcohol) at the time of study recruitment, clinical diagnoses of IS-associated diseases, PGSIS, and five PGSs for IS-associated diseases were tested using the Cox proportional-hazards model. Predictive performance was assessed using the C-statistic and net reclassification index (NRI). RESULTS: During a median average 12.5-year follow-up, 8374 subjects were diagnosed with IS. Known clinical variables (age, gender, clinical diagnoses of IS-associated diseases, obesity, and smoking) and PGSIS were all independently associated with IS (P < 0.001). In addition, PGSIS and each PGS for IS-associated diseases was also independently associated with IS (P < 0.001). Compared to the clinical model, a joint clinical/PGS model improved the C-statistic for predicting IS from 0.71 to 0.73 (P < 0.001) and significantly reclassified IS risk (NRI = 0.017, P < 0.001), and 6.48% of subjects were upgraded from low to high risk. CONCLUSIONS: Adding PGSs of IS and IS-associated diseases to known clinical risk factors statistically improved risk assessment for IS, demonstrating the supplementary value of inherited susceptibility measurement . However, its clinical utility is likely limited due to modest improvements in predictive values.

Selective Laser Melting of the Porous Ta Scaffold with Mg-Doped Calcium Phosphate Coating for Orthopedic Applications.

Addressing the repair of large-scale bone defects has become a hot research topic within the field of orthopedics. This study assessed the feasibility and effectiveness of using porous tantalum scaffolds to treat such defects. These scaffolds, manufactured using the selective laser melting (SLM) technology, possessed biomechanical properties compatible with natural bone tissue. To enhance the osteogenesis bioactivity of these porous Ta scaffolds, we applied calcium phosphate (CaP) and magnesium-doped calcium phosphate (Mg-CaP) coatings to the surface of SLM Ta scaffolds through a hydrothermal method. These degradable coatings released calcium and magnesium ions, demonstrating osteogenic bioactivity. Experimental results indicated that the Mg-CaP group exhibited biocompatibility comparable to that of the Ta group in vivo and in vitro. In terms of osteogenesis, both the CaP group and the Mg-CaP group showed improved outcomes compared to the control group, with the Mg-CaP group demonstrating superior performance. Therefore, both CaP and magnesium-CaP coatings can significantly enhance the osseointegration of three-dimensional-printed porous Ta, thereby increasing the surface bioactivity. Overall, the present study introduces an innovative approach for the biofunctionalization of SLM porous Ta, aiming to enhance its suitability as a bone implant material.

Novel reference range values for serum testosterone: a cross-sectional study of 200,000 males.

PURPOSE: To better understand the effects of aging, metabolic syndrome, diurnal variation, and seasonal variation on serum testosterone levels in the context of current guideline statements on testosterone deficiency. METHODS: This cross-sectional study utilized the United Kingdom Biobank. Physical examination, anthropomorphic measurements, and laboratory evaluation were performed at the time of enrollment from 2006 to 2010. The primary outcomes were the effect of age, the presence of metabolic syndrome, the time of day, and the month of the year on serum testosterone levels. RESULTS: Among 197,883 included men, the 5th, 25th, 50th, 75th and 95th percentile testosterone levels in men without metabolic syndrome were significantly higher than those in men with metabolic syndrome at every decade of life (p < 0.001). The average testosterone level within each group (men without metabolic syndrome vs. men with) was clinically similar across decade of life (12.43 in 40's 12.29 in 50's 12.24 in 60's vs. 10.69 in 40's 10.56 in 50's 10.63 in 60's respectively). Average testosterone levels decreased with blood draws later in the day ranging from 10.91 to 12.74 nmol/L (p < 0.01). Similarly, there was seasonal variation in serum testosterone ranging from 11.86 to 12.18 nmol/L (p < 0.01). CONCLUSIONS: We found significant variation in serum testosterone according to the presence of metabolic syndrome and time of laboratory draw, but not according to age. These data challenge the prior dogma of age-related hypogonadism and favor an individualized approach towards serum testosterone measurement and interpretation. However, further studies are needed to correlate these population-based data with individuals' hypogonadal symptoms.

[A Review on Automatic Detection Algorithm for Patient-Ventilator Asynchrony during Mechanical Ventilation].

This study summarizes the application of automatic recognition technologies for patient-ventilator asynchrony (PVA) during mechanical ventilation. In the early stages, the method of setting rules and thresholds relied on manual interpretation of ventilator parameters and waveforms. While these methods were intuitive and easy to operate, they were relatively sensitive in threshold setting and rule selection and could not adapt well to minor changes in patient status. Subsequently, machine learning and deep learning technologies began to emerge and develop. These technologies automatically extract and learn data characteristics through algorithms, making PVA detection more robust and universal. Among them, logistic regression, support vector machines, random forest, hidden Markov models, convolutional autoencoders, long short-term memory networks, one-dimensional convolutional neural networks, etc., have all been successfully used for PVA recognition. Despite the significant advancements in feature extraction through deep learning methods, their demand for labelled data is high, potentially consuming significant medical resources. Therefore, the combination of reinforcement learning and self-supervised learning may be a viable solution. In addition, most algorithm validations are based on a single dataset, so the need for cross-dataset validation in the future will be an important and challenging direction for development.

Imaging diagnosis and efficacy monitoring by [89Zr]Zr-DFO-KN035 immunoPET in patients with PD-L1-positive solid malignancies.

Rationale: Although programmed death-ligand 1 (PD-L1) inhibitors have achieved efficacy in cancer therapy, their response rate is low. Differences in the prognosis of patients with cancer under anti-PD-L1 treatment are related to the PD-L1 level in tumors. Accurate PD-L1 detection can optimize the accuracy of tumor immunotherapy and avoid ineffective clinical diagnosis and treatments. Methods: We investigated the imaging efficiency and therapy monitoring capacity of [89Zr]Zr-DFO-KN035 immunoPET for tumors. We labeled the monodomain anti-PD-L1 antibody KN035 with the radionuclide zirconium-89 and used this tracer for PET imaging. [89Zr]Zr-DFO-KN035 uptakes in patients with PD-L1-positive tumors, including primary and metastatic tumors, as well as in normal tissues, were comparatively assessed by using positron emission tomography/computed tomography imaging. Results: In PD-L1-positive patients, [89Zr]Zr-DFO-KN035 was sensitive in tumor-targeting imaging and could detect multiple metastatic foci, including multiple bone metastases (tumor-to-muscle ratios of 7.102 and 6.118 at 55 and 120 h, respectively) and lymph-node metastases (tumor-to-muscle ratios of 11.346 and 6.542 at 55 and 120 h, respectively). The needed radioactive dose of [89Zr]Zr-DFO-KN035 (55.5-92.5 MBq) used in this study was considerably lower than that of [18F]FDG (370-555 MBq). [89Zr]Zr-DFO-KN035 monitored and predicted the site of adverse reactions in antitumor immunotherapy. Moreover, after antitumor treatment, [89Zr]Zr-DFO-KN035 enabled observational imaging for therapeutic efficacy evaluation, which can help predict patient prognosis. Conclusion: [89Zr]Zr-DFO-KN035 can be used for the diagnosis and therapy monitoring of PD-L1-positive tumors and provide noninvasive and comprehensive observations for tumor diagnostic imaging, prognosis prediction, and efficacy evaluation.

Multimodal epigenetic sequencing analysis (MESA) of cell-free DNA for non-invasive colorectal cancer detection.

BACKGROUND: Detecting human cancers through cell-free DNA (cfDNA) in blood is a sensitive and non-invasive option. However, capturing multiple forms of epigenetic information remains a technical and financial challenge. METHODS: To address this, we developed multimodal epigenetic sequencing analysis (MESA), a flexible and sensitive approach to capturing and integrating a diverse range of epigenetic features in cfDNA using a single experimental assay, i.e., non-disruptive bisulfite-free methylation sequencing, such as Enzymatic Methyl-seq. MESA enables simultaneous inference of four epigenetic modalities: cfDNA methylation, nucleosome occupancy, nucleosome fuzziness, and windowed protection score for regions surrounding gene promoters and polyadenylation sites. RESULTS: When applied to 690 cfDNA samples from 3 colorectal cancer clinical cohorts, MESA's novel modalities, which include nucleosome fuzziness, and genomic features, including polyadenylation sites, improve cancer detection beyond the traditional epigenetic markers of promoter DNA methylation. CONCLUSIONS: Together, MESA stands as a major advancement in the field by utilizing comprehensive and complementary epigenetic profiles of cfDNA for effective non-invasive cancer detection.

Investigation on the machinability of polycrystalline ZnSe by elliptical vibration diamond cutting.

Polycrystalline zinc selenide is widely used in advanced optical systems due to its superior optical properties. However, the soft and brittle properties bring a challenge for high-quality surface processing. In recent years, elliptical vibration cutting has been proven as a promising method for machining brittle materials. In the present research, a series of grooving and planning experiments were carried out to investigate the machinability of zinc selenide with elliptical vibration cutting. The removal mechanism was analyzed from fracture characteristics, chip morphology, and phase transformation. The results show that elliptical vibration cutting is effective in suppressing cleavage-induced craters. Reducing the nominal cutting speed is beneficial to inhibit the spring back-induced tearing of grains. A 94-time increase in the critical depth of cut was achieved by vibration trajectory optimization compared to ordinary cutting. Moreover, the influence mechanism of feed on the evolution of surface morphology was revealed. Finally, a zinc selenide microlens array was successfully fabricated. The performance was evaluated by geometric parameter measurements and a multiple imaging test. The findings provide a prospective method for ductile regime machining of zinc selenide.

Characteristics associated with response to subcutaneously administered anti-CGRP monoclonal antibody medications in a real-world community cohort of persons living with migraine: A retrospective clinical and genetic study.

OBJECTIVE: To evaluate response to anti-calcitonin gene-related peptide (CGRP) migraine preventives in a real-world community cohort of persons living with migraine and to identify clinical and genetic characteristics associated with efficacious response. BACKGROUND: Erenumab-aooeb, fremanezumab-vrfm, and galcanezumab-gnlm target CGRP or its receptor; however, many patients are non-responsive. METHODS: In this retrospective clinical and genetic study, we identified 1077 adult patients who satisfied the International Classification of Headache Disorders, 3rd edition, criteria for migraine without aura, migraine with aura, or chronic migraine and who were prescribed an anti-CGRP migraine preventive between May 2018 and May 2021. Screening of 558 patients identified 289 with data at baseline and first follow-up visits; data were available for 161 patients at a second follow-up visit. The primary outcome was migraine days per month (MDM). In 198 genotyped patients, we evaluated associations between responders (i.e., patients with ≥50% reduction in MDM at follow-up) and genes involved in CGRP signaling or pharmacological response, and genetic and polygenic risk scores. RESULTS: The median time to first follow-up was 4.4 (0.9-22) months after preventive start. At the second follow-up, 5.7 (0.9-13) months later, 145 patients had continued on the same preventive. Preventives had strong, persistent effects in reducing MDM in responders (follow-up 1: η2 = 0.26, follow-up 2: η2 = 0.22). At the first but not second follow-up: galcanezumab had a larger effect than erenumab, while no difference was seen at either follow-up between galcanezumab and fremanezumab or fremanezumab and erenumab. The decrease in MDM at follow-up was generally proportional to baseline MDM, larger in females, and increased with months on medication. At the first follow-up only, patients with prior hospitalization for migraine or who had not responded to more preventive regimens had a smaller decrease in MDM. Reasons for stopping or switching a preventive varied between medications and were often related to cost and insurance coverage. At both follow-ups, patient tolerance (1: 92.2% [262/284]; 2: 95.2% [141/145]) and continued use (1: 77.5% [224/289]; 2: 80.6% [116/145]) were high and similar across preventives. Response consistency (always non-responders: 31.7% [46/145]; always responders: 56.5% [82/145], and one-time only responders: 11.7% [17/145]) was also similar across preventives. Non-responder status had nominally significant associations with rs12615320-G in RAMP1 (odds ratio [95% confidence interval]: 4.7 [1.5, 14.7]), and rs4680-A in COMT (0.6[0.4, 0.9]). Non-responders had a lower mean genetic risk score than responders (1.0 vs. 1.1; t(df) = -1.75(174.84), p = 0.041), and the fraction of responders increased with genetic and polygenic risk score percentile. CONCLUSIONS: In this real-world setting, anti-CGRP preventives reduced MDM persistently and had similar and large effect sizes on MDM reduction; however, clinical and genetic factors influenced response.

Personalized medicine in a community health system: the NorthShore experience.

Genomic and personalized medicine implementation efforts have largely centered on specialty care in tertiary health systems. There are few examples of fully integrated care systems that span the healthcare continuum. In 2014, NorthShore University HealthSystem launched the Center for Personalized Medicine to catalyze the delivery of personalized medicine. Successful implementation required the development of a scalable family history collection tool, the Genetic and Wellness Assessment (GWA) and Breast Health Assessment (BHA) tools; integrated pharmacogenomics programming; educational programming; electronic medical record integration; and robust clinical decision support tools. To date, more than 225,000 patients have been screened for increased hereditary conditions, such as cancer risk, through these tools in primary care. More than 35,000 patients completed clinical genetic testing following GWA or BHA completion. An innovative program trained more than 100 primary care providers in genomic medicine, activated with clinical decision support and access to patient genetic counseling services and digital healthcare tools. The development of a novel bioinformatics platform (FLYPE) enabled the incorporation of genomics data into electronic medical records. To date, over 4,000 patients have been identified to have a pathogenic or likely pathogenic variant in a gene with medical management implications. Over 33,000 patients have clinical pharmacogenomics data incorporated into the electronic health record supported by clinical decision support tools. This manuscript describes the evolution, strategy, and successful multispecialty partnerships aligned with health system leadership that enabled the implementation of a comprehensive personalized medicine program with measurable patient outcomes through a genomics-enabled learning health system model that utilizes implementation science frameworks.

Right paraduodenal hernia, classification, and selection of surgical methods: a case report and review of the literature.

BACKGROUND: Considering that right paraduodenal hernia is a rare internal hernia with abnormal anatomy and is often encountered during an emergency, surgeons may lack knowledge about it and choose incorrect treatment. Thus, this case report is a helpful complement to the few previously reported cases of right paraduodenal hernia. Additionally, we reviewed all the reported right paraduodenal hernia cases and proposed appropriate surgical strategies according to different anatomical features. CASE PRESENTATION: The case involved a 33-year-old Chinese male patient who was admitted to the hospital due to abdominal pain. The patient was initially diagnosed with small bowel obstruction, and conservative treatment failed. An emergency operation was arranged, during which a diagnosis of right paraduodenal hernia was made instead. After surgery, the patient recovered well without abdominal pain for 2 years. CONCLUSION: Although right paraduodenal hernia accounts only for a small proportion of paraduodenal hernia, its anatomical characteristics can vary considerably. We divided right paraduodenal hernia into three types, with each type requiring a different surgical strategy.

[Bone/cartilage immunomodulating hydrogels: construction strategies and applications].

Objective: To review the research progress in the construction strategy and application of bone/cartilage immunomodulating hydrogels. Methods: The literature related to bone/cartilage immunomodulating hydrogels at home and abroad in recent years was reviewed and summarized from the immune response mechanism of different immune cells, the construction strategy of immunomodulating hydrogels, and their practical applications. Results: According to the immune response mechanism of different immune cells, the biological materials with immunoregulatory effect is designed, which can regulate the immune response of the body and thus promote the regeneration of bone/cartilage tissue. Immunomodulating hydrogels have good biocompatibility, adjustability, and multifunctionality. By regulating the physical and chemical properties of hydrogel and loading factors or cells, the immune system of the body can be purposively regulated, thus forming an immune microenvironment conducive to osteochondral regeneration. Conclusion: Immunomodulating hydrogels can promote osteochondral repair by affecting the immunomodulation process of host organs or cells. It has shown a wide application prospect in the repair of osteochondral defects. However, more data support from basic and clinical experiments is needed for this material to further advance its clinical translation process.

Angiotensin-(1-7) suppresses airway inflammation and airway remodeling via inhibiting ATG5 in allergic asthma.

BACKGROUND: Angiotensin (Ang)-(1-7) can reduce airway inflammation and airway remodeling in allergic asthma. Autophagy-related 5 (ATG5) has attracted wide attentions in asthma. However, the effects of Ang-(1-7) on ATG5-mediated autophagy in allergic asthma are unclear. METHODS: In this study, human bronchial epithelial cell (BEAS-2B) and human bronchial smooth muscle cell (HBSMC) were treated with different dose of Ang-(1-7) to observe changes of cell viability. Changes of ATG5 protein expression were measured in 10 ng/mL of interleukin (IL)-13-treated cells. Transfection of ATG5 small interference RNA (siRNA) or ATG5 cDNA in cells was used to analyze the effects of ATG5 on secretion of cytokines in the IL-13-treated cells. The effects of Ang-(1-7) were compared to the effects of ATG5 siRNA transfection or ATG5 cDNA transfection in the IL-13-treated cells. In wild-type (WT) mice and ATG5 knockout (ATG5-/-) mice, ovalbumin (OVA)-induced airway inflammation, fibrosis and autophagy were observed. In the OVA-induced WT mice, Ang-(1-7) treatment was performed to observe its effects on airway inflammation, fibrosis and autophagy. RESULTS: The results showed that ATG5 protein level was decreased with Ang-(1-7) dose administration in the IL-13-treated BEAS-2B and IL13-treated HBSMC. Ang-(1-7) played similar results to ATG5 siRNA that it suppressed the secretion of IL-25 and IL-13 in the IL-13-treated BEAS-2B cells, and inhibited the expression of transforming growth factor (TGF)-ß1 and α-smooth muscle actin (α-SMA) protein in the IL-13-treated HBSMC cells. ATG5 cDNA treatment significantly increased the secretion of IL-25 and IL-13 and expression of TGF-ß1 and α-SMA protein in IL-13-treated cells. Ang-(1-7) treatment suppressed the effects of ATG5 cDNA in the IL-13-treated cells. In OVA-induced WT mice, Ang-(1-7) treatment suppressed airway inflammation, remodeling and autophagy. ATG5 knockout also suppressed the airway inflammation, remodeling and autophagy. CONCLUSIONS: Ang-(1-7) treatment suppressed airway inflammation and remodeling in allergic asthma through inhibiting ATG5, providing an underlying mechanism of Ang-(1-7) for allergic asthma treatment.

Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort.

BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the digestive tract with increasing prevalence globally. Although venous thromboembolism (VTE) is a major complication in IBD patients, it is often underappreciated with limited tools for risk stratification. AIM: To estimate the proportion of VTE among IBD patients and assess genetic risk factors (monogenic and polygenic) for VTE. METHODS: Incident VTE was followed for 8465 IBD patients in the UK Biobank (UKB). The associations of VTE with F5 factor V leiden (FVL) mutation, F2 G20210A prothrombin gene mutation (PGM), and polygenic score (PGS003332) were tested using Cox hazards regression analysis, adjusting for age at IBD diagnosis, gender, and genetic background (top 10 principal components). The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve (AUC). RESULTS: The overall proportion of incident VTE was 4.70% in IBD patients and was similar for CD (4.46%), UC (4.49%), and unclassified (6.42%), and comparable to that of cancer patients (4.66%) who are well-known at increased risk for VTE. Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers, hazard ratio (HR) was 1.94, 95% confidence interval (CI): 1.42-2.65. In contrast, patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores (middle 8 deciles), HR was 2.06 (95%CI: 1.57-2.71). The AUC for differentiating VTE diagnosis was 0.64 (95%CI: 0.61-0.67), 0.68 (95%CI: 0.66-0.71), and 0.69 (95%CI: 0.66-0.71), respectively, for F5/F2 mutation carriers, PGS, and combined. CONCLUSION: Similar to cancer patients, VTE complications are common in IBD patients. PGS provides more informative risk information than F5/F2 mutations (FVL and PGM) for personalized thromboprophylaxis.

Bifunctional Thiourea-Catalyzed Enantioselective Aza-Friedel-Crafts Reaction of 3-Aminobenzofurans with Isatin-Derived Ketimines.

A quinine-derived thiourea-promoted enantioselective aza-Friedel-Crafts reaction of 3-aminobenzofurans with isatin-derived ketimines is developed, providing a variety of 3-benzofuran-3-amino-2-oxindoles bearing a quaternary stereocenter with good to excellent yields (72-95%) and moderate to excellent enantioselectivities (48-97%). The synthetic potential of this concise and efficient protocol is revealed by gram-scale preparation and further transformation of the adduct to an optically pure spirocyclic oxindole.

Numerical Investigation on the Effects of Grain Size and Grinding Depth on Nano-Grinding of Cadmium Telluride Using Molecular Dynamics Simulation.

Cadmium telluride (CdTe) is known as an important semiconductor material with favorable physical properties. However, as a soft-brittle material, the fabrication of high-quality surfaces on CdTe is quite challenging. To improve the fundamental understanding of the nanoscale deformation mechanisms of CdTe, in this paper, MD simulation was performed to explore the nano-grinding process of CdTe with consideration of the effects of grain size and grinding depth. The simulation results indicate that during nano-grinding, the dominant grinding mechanism could switch from elastic deformation to ploughing, and then cutting as the grinding depth increases. It was observed that the critical relative grain sharpness (RGS) for the transition from ploughing to cutting is greatly influenced by the grain size. Furthermore, as the grinding depth increases, the dominant subsurface damage mechanism could switch from surface friction into slip motion along the <110> directions. Meanwhile, as the grain size increases, less friction-induced damage is generated in the subsurface workpiece, and more dislocations are formed near the machined groove. Moreover, regardless of the grain size, it was observed that the generation of dislocation is more apparent as the dominant grinding mechanism becomes ploughing and cutting.