Dendritic cell targeting peptide plus Salmonella FliCd flagellin fused outer membrane protein H (OmpH) demonstrated increased efficacy against infections caused by different Pasteurella multocida serogroups in mouse models.

As the major outer membrane protein (OMP) presents in the Pasteurella multocida envelope, OmpH was frequently expressed for laboratory assessments of its immunogenicity against P. multocida infections, but the results are not good. In this study, we modified OmpH with dendritic cell targeting peptide (Depeps) and/or Salmonella FliCd flagellin, and expressed three types of recombinant proteins with the MBP tag (rDepeps-FliC-OmpH-MBP, rDepeps-OmpH-MBP, rFliC-OmpH-MBP). Assessments in mouse models revealed that vaccination with rDepeps-FliC-OmpH-MBP, rDepeps-OmpH-MBP, or rFliC-OmpH-MBP induced significant higher level of antibodies as well as IFN-γ and IL-4 in murine sera than vaccination with rOmpH-MBP (P < 0.5). Vaccination with the three modified proteins also provided increased protection (rDepeps-FliC-OmpH-MBP, 70 %; rDepeps-OmpH-MBP, 50 %; rFliC-OmpH-MBP, 60 %) against P. multocida serotype D compared to vaccination with rOmpH-MBP (30 %). In mice vaccinated with different types of modified OmpHs, a significantly decreased bacterial strains were recovered from bloods, lungs, and spleens compared to rOmpH-MBP-vaccinated mice (P < 0.5). Notably, our assessments also demonstrated that vaccination with rDepeps-FliC-OmpH-MBP provided good protection against infections caused by a heterogeneous group of P. multocida serotypes (A, B, D). Our above findings indicate that modification with DCpep and Salmonella flagellin could be used as a promising strategy to improve vaccine effectiveness.

Trends in the Prevalence of Common Retinal and Optic Nerve Diseases in China: An Artificial Intelligence Based National Screening.

Purpose: Retinal and optic nerve diseases have become the primary cause of irreversible vision loss and blindness. However, there is still a lack of thorough evaluation regarding their prevalence in China. Methods: This artificial intelligence-based national screening study applied a previously developed deep learning algorithm, named the Retinal Artificial Intelligence Diagnosis System (RAIDS). De-identified personal medical records from January 2019 to December 2021 were extracted from 65 examination centers in 19 provinces of China. Crude prevalence and age-sex-adjusted prevalence were calculated by mapping to the standard population in the seventh national census. Results: In 2021, adjusted referral possible glaucoma (63.29, 95% confidence interval [CI] = 57.12-68.90 cases per 1000), epiretinal macular membrane (21.84, 95% CI = 15.64-29.22), age-related macular degeneration (13.93, 95% CI = 11.09-17.17), and diabetic retinopathy (11.33, 95% CI = 8.89-13.77) ranked the highest among 10 diseases. Female participants had significantly higher adjusted prevalence of pathologic myopia, yet a lower adjusted prevalence of diabetic retinopathy, referral possible glaucoma, and hypertensive retinopathy than male participants. From 2019 to 2021, the adjusted prevalence of retinal vein occlusion (0.99, 95% CI = 0.73-1.26 to 1.88, 95% CI = 1.42-2.44), macular hole (0.59, 95% CI = 0.41-0.82 to 1.12, 95% CI = 0.76-1.51), and hypertensive retinopathy (0.53, 95% CI = 0.40-0.67 to 0.77, 95% CI = 0.60-0.95) significantly increased. The prevalence of diabetic retinopathy in participants under 50 years old significant increased. Conclusions: Retinal and optic nerve diseases are an important public health concern in China. Further well-conceived epidemiological studies are required to validate the observed increased prevalence of diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, and macular hole nationwide. Translational Relevance: This artificial intelligence system can be a potential tool to monitor the prevalence of major retinal and optic nerve diseases over a wide geographic area.

Breaking the symmetry of cell contractility drives tubulogenesis via CXCL1 polarization.

The intricate interplay between biomechanical and biochemical pathways in modulating morphogenesis is an interesting research topic. How biomechanical force regulates epithelial cell tubulogenesis remains poorly understood. Here, we established a model of tubulogenesis by culturing renal proximal tubular epithelial cells on a collagen gel while manipulating contractile force. Epithelial cells were dynamically self-organized into tubule-like structures by augmentation of cell protrusions and cell-cell association. Reduction and asymmetric distribution of phosphorylated myosin light chain 2, the actomyosin contractility, in cells grown on soft matrix preceded tube connection. Notably, reducing matrix stiffness via sonication of collagen fibrils and inhibiting actomyosin contractility with blebbistatin promoted tubulogenesis, whereas inhibition of cytoskeleton polymerization suppressed it. CXC chemokine ligand 1 (CXCL1) expression was transcriptionally upregulated in cells undergoing tubulogenesis. Additionally, inhibiting actomyosin contractility facilitated CXCL1 polarization and cell protrusions preceding tube formation. Conversely, inhibiting the CXCL1-CXC receptor 1 pathway hindered cell protrusions and tubulogenesis. Mechanical property asymmetry with cell-collagen fibril interaction patterns at cell protrusions and along the tube structure supported the association of anisotropic contraction with tube formation. Furthermore, suppressing the mechanosensing machinery of integrin subunit beta 1 reduced CXCL1 expression, collagen remodeling, and impaired tubulogenesis. In summary, symmetry breaking of cell contractility on a soft collagen gel promotes CXCL1 polarization at cell protrusions which in turn facilitates cell-cell association and thus tubule connection.

TEM1/endosialin/CD248 promotes pathologic scarring and TGF-ß activity through its receptor stability in dermal fibroblasts.

BACKGROUND: Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars. METHODS: To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-ß-mediated responses in pathologic scars. RESULTS: The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-ß1 signaling through binding with and stabilizing TGF-ß receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids. CONCLUSIONS: Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-ß signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.

CD248 Regulates Inflammation and Encapsulation in Silicone-Related Capsule Formation.

BACKGROUND: Capsular contracture is the most common reason for having a secondary breast implant operation. The failure of the implanted device and discomfort are related to foreign body response, which involves a pathologic encapsulation. An up-regulated expression of CD248 was previously demonstrated to modulate inflammation and fibrosis. The authors hypothesized that CD248 contributes to foreign body reaction and contracture during silicone-stimulated capsule formation. METHODS: A murine capsular contracture model was established to correlate CD248 with capsular contracture. The timing and site of CD248 expression were characterized by protein analysis and histologic examination. The capsules between wild-type mice and CD248 knockout mice were compared in this model to verify the possible role of CD248 in silicone-related capsule formation. RESULTS: CD248 was expressed in the peri-silicone implant capsule by stromal fibroblast and perivascular fibroblast. CD248 was overexpressed on day 4 and down to a constant level, but it was still up-regulated through day 21 to day 56 after silicone implantation. The CD248 knockout mice showed a prolonged inflammation period, whereas the wild-type mice developed a thinner but more collagenous capsule. CONCLUSIONS: In conclusion, an effective murine capsular contracture model was established to study the relationship between CD248 and capsular contracture. CD248 may play a role in inflammation and encapsulation during silicone implantation. CD248 deletion in mice contributed to a loose and irregular collagen bundle in a capsule area, implying a decrease in contracture. Therefore, CD248 could be a potential therapeutic target in capsular contracture. CLINICAL RELEVANCE STATEMENT: CD248 may play a role in inflammation and encapsulation during silicone implantation. It could be a potential therapeutic target in clinical capsular contracture.

CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation.

BACKGROUND: In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance. METHODS: Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens. FINDINGS: Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3ß, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis. INTERPRETATION: Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance. FUNDING: Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.

Epidemiology of arrhythmogenic ventricular cardiomyopathy in China.

BACKGROUND: Arrhythmogenic ventricular cardiomyopathy (AVC) is a common cause of ventricular arrhythmias and mortality, but limited data are available from large Asian cohorts. Our aim was to explore the current status of AVC and second, we examined the prevalence of ventricular tachycardia (VT), heart failure (HF) and mortality in patients with AVC in the Chinese population. HYPOTHESIS: At present, some studies have reported that the incidence of AVC is on the rise, which may be due to the increasing number of diagnostic methods for AVC. However, there is no epidemiological data on AVC in the Chinese population, so we speculate that the incidence of AVC in the Chinese population is increasing. METHODS AND RESULTS: We studied 15 888 adults from the Beijing Municipal Health Commission Information Center (BMHCIC) registry database in China from January 2010 to December 2020, and calculated the average annual percentage change (AAPC). Second, we determined the incidence of VT, HF and mortality in patients with AVC. Of the 10 318 men and 5570 women who were screened by cardiac magnetic resonance or examined by myocardial biopsy, there were a total of 256 newly diagnosed AVC patients (mean [SD]: 37.54[17.10]; 39.45% female). The incidence of AVC increased from 7.60 (3.12-12.06) in 2010 to 19.62 (11.51-27.75) per 1000 person-years in 2020. Males had higher incidence of AVC than females. The AAPC for the rising incidence of AVC was 8.9 %. Males had similar VT prevalence (70.32% vs. 62.38%, p = 0.19) and mortality (1.94% vs. 1.98%, p = 0.98) but lower HF prevalence (42.58% vs. 60.40%, p = 0.006), when compared to females. Radiofrequency ablation (RFA) was more likely to be performed in males (p = 0.006). CONCLUSIONS: The rising trend in AVC incidence was evident, with two-fold increase by 2020. Males with AVC had similar VT prevalence and mortality rate, but HF prevalence were lower than females, perhaps impacted by RFA use.

A hematological parameter-based model for distinguishing non-puerperal mastitis from invasive ductal carcinoma.

Purpose: Non-puerperal mastitis (NPM) accounts for approximately 4-5% of all benign breast lesions. Ultrasound is the preferred method for screening breast diseases; however, similarities in imaging results can make it challenging to distinguish NPM from invasive ductal carcinoma (IDC). Our objective was to identify convenient and objective hematological markers to distinguish NPM from IDC. Methods: We recruited 89 patients with NPM, 88 with IDC, and 86 with fibroadenoma (FA), and compared their laboratory data at the time of admission. LASSO regression, univariate logistic regression, and multivariate logistic regression were used to screen the parameters for construction of diagnostic models. Receiver operating characteristic curves, calibration curves, and decision curves were constructed to evaluate the accuracy of this model. Results: We found significant differences in routine laboratory data between patients with NPM and IDC, and these indicators were candidate biomarkers for distinguishing between the two diseases. Additionally, we evaluated the ability of some classic hematological markers reported in previous studies to differentiate between NPM and IDC, and the results showed that these indicators are not ideal biomarkers. Furthermore, through rigorous LASSO and logistic regression, we selected age, white blood cell count, and thrombin time to construct a differential diagnostic model that exhibited a high level of discrimination, with an area under the curve of 0.912 in the training set and with 0.851 in the validation set. Furthermore, using the same selection method, we constructed a differential diagnostic model for NPM and FA, which also demonstrated good performance with an area under the curve of 0.862 in the training set and with 0.854 in the validation set. Both of these two models achieved AUCs higher than the AUCs of models built using machine learning methods such as random forest, decision tree, and SVM in both the training and validation sets. Conclusion: Certain laboratory parameters on admission differed significantly between the NPM and IDC groups, and the constructed model was designated as a differential diagnostic marker. Our analysis showed that it has acceptable efficiency in distinguishing NPM from IDC and may be employed as an auxiliary diagnostic tool.

Complications and radiographic changes after implantation of interspinous process devices: average eight-year follow-up.

PURPOSE: This study aims to evaluate complications, clinical outcomes, and radiographic results following Coflex implantation. METHODS: We retrospectively studied 66 patients who had decompressive surgery combined with Coflex implantation to treat lumbar spinal stenosis. All imaging data were collected and examined for imaging changes. Clinical outcomes, included Oswestry Disability Index (ODI), back and leg visual analog scale (VAS) scores, were evaluated before surgery, six months after surgery and at the last follow-up. The number of complications occurring after five years of follow-up was counted. All reoperation cases were meticulously recorded. RESULTS: 66 patients were followed up for 5-14 years. The VAS and ODI scores were significantly improved compared with baseline. Heterotopic Ossification (HO) was detectable in 59 (89.4%). 26 (39.4%) patients had osteolysis at the contact site of Coflex with the spinous process. Coflex loosening was detected in 39 (60%) patients. Spinous process anastomosis was found in 34 (51.5%) patients. There was a statistically significant difference in the VAS score of back pain between patients with and without spinous process anastomosis. Nine cases of lumbar spinal restenosis were observed, and prosthesis fracture was observed in one case. CONCLUSION: Our study identified various imaging changes after Coflex implantation, and majority of them did not affect clinical outcomes. The majority of patients had HO, but osteolysis and Coflex loosening were relatively rare. The VAS score for back pain of these patients was higher if they have spinous process anastomosis. After five-year follow-up, we found lumbar spinal restenosis and prosthesis fracture cases.

Modified sphenoidotomy for isolated sphenoid sinus disease: A series of 117 cases.

BACKGROUND: The atresia rate of sphenoid ostium after endoscopic sphenoidotomy for isolated sphenoid disease is 9.4%-10.2%. AIMS: To reduce sphenoid sinus ostium atresia rate after sphenoidotomy surgery. MATERIALS AND METHODS: The data of patients with isolated sphenoid sinus disease at our hospital between 2015 and 2022 were retrospectively analyzed. The age, gender, disease course, pathology, postoperative follow-up time, anatomy data of sphenoid sinus and postoperative sinus ostium atresia rate were compared between the two groups of patients with traditional sphenoidotomy and modified sphenoidotomy. RESULTS: A total of 117 patients with isolated sphenoid sinus disease underwent endoscopic sphenoidotomy. There were 76 cases in the traditional sphenoidotomy group, fungus ball in 59.2% of patients, the postoperative sinus ostium atresia rate was 14.5%. There were 41 cases in the modified sphenoidotomy group, fungus ball in 53.6% of patients, and 0 case of sinus ostium atresia. Statistical analysis showed significant differences in postoperative sinus ostium atresia rate. There was no significant difference in age, pathology, postoperative follow-up time, anatomy data of sphenoid, and other data. CONCLUSIONS AND SIGNIFICANCE: The modified endoscopic sphenoidotomy may reduce the rate of postoperative sinus ostium atresia.

Prevalence of diminished ovarian reserve in Chinese women with follicular cysts and menstrual disorders.

OBJECTIVES: To assess the prevalence of diminished ovarian reserve (DOR) in Chinese women with follicular cysts and menstrual disorders and relationship to hormonal markers. METHODS: 117 women with follicular cysts and menstrual disorders, aged 24 ∼ 53 (39.19 ± 6.61) years; measurements of height, weight, follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, progesterone (Po), prolactin (PRL), total testosterone, AMH, follicular cyst diameter, endometrial thickness. Three age groups were compared: 1) 21 ∼ 30 years, 2) 30 ∼ 40 years, 3) > 40 years. RESULTS: Total prevalence of DOR 86.3%, in the groups 50%, 81.6%, and 98.4%, in group-3 significantly higher than in group-1 and 2. 34.2% of the 117 patients complained of cessation of regular menstruations or amenorrhea, 65.8% of abnormal uterine bleeding. Follicular cysts disappeard in cycle-1 for 98 (83.8%) and in cycle-2 for 117 (100%) patients. AMH decreased with age, significantly different between the three groups. Total testosterone in group-1 and 2 was significantly higher than in group-3. In total AMH had a negative correlation with age and E2 (p < 0.01) and positive correlation with total testosterone (p < 0.05). CONCLUSIONS: Assessing ovarian reserve with follicular cysts and menstrual disorders is important because often pointing to DOR. The overall prevalence of DOR was high; even young women (<40 years) with follicular cysts and menstrual disorders had a low level of AMH. So AMH can be used as a marker to define DOR with higher sensitivity than other markers like FSH and E2. Primarily, these results only apply to Chinese women and should be confirmed in further studies.

A novel frameshift mutation in DNAH6 associated with male infertility and asthenoteratozoospermia.

Introduction: Asthenoteratozoospermia is one of the most common causes of male infertility. Several genes have been identified as genetic causative factors, but there is a considerable genetic heterogeneity underlying asthenoteratozoospermia. In this study, we performed a genetic analysis of two brothers from a consanguineous Uighur family in China to identify gene mutations causative for asthenoteratozoospermia-related male infertility. Methods: Two related patients with asthenoteratozoospermia from a large consanguineous family were sequenced by whole-exome sequencing and Sanger sequencing to identify disease-causing genes. Scanning and transmission electron microscopy analysis revealed ultrastructural abnormalities of spermatozoa. Quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence (IF) analysis were used to assess the expression of the mutant messenger RNA (mRNA) and protein. Results: A novel homozygous frameshift mutation (c.2823dupT, p.Val942Cysfs*21) in DNAH6 was identified in both affected individuals and was predicted to be pathogenic. Papanicolaou staining and electron microscopy revealed multiple morphological and ultrastructural abnormalities of affected spermatozoa. qRT-PCR and IF analysis showed abnormal expression of DNAH6 in affected sperm, probably due to premature termination code and decay of abnormal 3' untranslated region (UTR) region of mRNA. Furthermore, intracytoplasmic sperm injection could achieve successful fertilization in infertile men with DNAH6 mutations. Discussion: The novel frameshift mutation identified in DNAH6 may contribute to asthenoteratozoospermia. These findings expand the spectrum of genetic mutations and phenotypes associated with asthenoteratozoospermia and may be useful for genetic and reproductive counseling in male infertility.

Value of contrast-enhanced ultrasound in deep angiomyxoma using a biplane transrectal probe: A case report.

BACKGROUND: Deep angiomyxoma (DAM) is a very rare tumor type. Magnetic resonance imaging (MRI) is considered the best imaging modality for diagnosing DAM. Computed tomography (CT) is used mainly to assess the invasion range of DAM. The value of ultrasonography in the diagnosis of DAM is still controversial. Through a literature review, we summarized the current state of ultrasonic examination for DAM and reported for the first time the contrast-enhanced ultrasound (CEUS) features of DAM seen using a biplane transrectal probe. CASE SUMMARY: A 37-year-old woman presented with a sacrococcygeal mass that had gradually increased in size over the previous 6 mo. MRI and CT examinations failed to allow a definite diagnosis to be made. Transperineal core needle biopsy (CNB) guided by transrectal ultrasound and CEUS was suggested after a multidisciplinary discussion. Grayscale ultrasound of the lesion showed a layered appearance with alternating hyperechoic and hypoechoic patterns. Transrectal CEUS showed a laminated distribution of the contrast agent that was consistent with the layered appearance of the tumor on grayscale ultrasound. We performed transperineal CNB of the enhanced area inside the tumor under transrectal CEUS guidance and finally made a definitive diagnosis of DAM through histopathology. The patient underwent laparoscopic-assisted transabdominal surgery combined with transperineal surgery for large pelvic tumor resection and pelvic floor peritoneal reconstruction. No recurrence or metastasis was found at the nine-month follow-up. CONCLUSION: Transrectal CEUS can show the layered perfusion characteristics of the contrast agent, guiding subsequent transperineal CNB of the enhanced area within the DAM.

Chondrocyte Thrombomodulin Protects against Osteoarthritis.

Osteoarthritis (OA) is a prevalent form of arthritis that affects over 32.5 million adults worldwide, causing significant cartilage damage and disability. Unfortunately, there are currently no effective treatments for OA, highlighting the need for novel therapeutic approaches. Thrombomodulin (TM), a glycoprotein expressed by chondrocytes and other cell types, has an unknown role in OA. Here, we investigated the function of TM in chondrocytes and OA using various methods, including recombinant TM (rTM), transgenic mice lacking the TM lectin-like domain (TMLeD/LeD), and a microRNA (miRNA) antagomir that increased TM expression. Results showed that chondrocyte-expressed TM and soluble TM [sTM, like recombinant TM domain 1 to 3 (rTMD123)] enhanced cell growth and migration, blocked interleukin-1ß (IL-1ß)-mediated signaling and protected against knee function and bone integrity loss in an anterior cruciate ligament transection (ACLT)-induced mouse model of OA. Conversely, TMLeD/LeD mice exhibited accelerated knee function loss, while treatment with rTMD123 protected against cartilage loss even one-week post-surgery. The administration of an miRNA antagomir (miR-up-TM) also increased TM expression and protected against cartilage damage in the OA model. These findings suggested that chondrocyte TM plays a crucial role in counteracting OA, and miR-up-TM may represent a promising therapeutic approach to protect against cartilage-related disorders.

Reducing Interface Defects and Porosity of Adhesive Bonded Aluminum Alloy Joints via Ultrasonic Vibration.

The surface microstructure formed by physical or chemical modification is essential for the desired joint strength. However, defects in the bonding interface and adhesive can be found. Such defects decrease shear strength and durability. In this study, ultrasonic vibration was applied to liquid adhesive on the sandblasted aluminum alloy plates. With ultrasonic treatment, the joints obtained the compact bonding interfaces and lower porosity of the adhesive layer. The treatment improved the shear strength by 9.1%. After two weeks of hydrothermal aging, the shear strength of joints only sandblasted decreased drastically by 48.9%, while it was 14% for the joints with ultrasonic vibration. The cavitation effect in the adhesive was detected by the aluminum foil erosion method. The result showed that a great number of micro-jets generated by the cavitation effect have intensive impact on the bonding interface which provide the adhesive with powerful force to fill the micro-grooves. Another finding in this work is that bubbles were gathered in the adhesive away from the vibration area. This mechanism was successfully used to reduce the porosity of the adhesive layer of joints.

Grain Refinement Mechanism of 5A06 Aluminum Alloy Sheets during Cold Rotary Forging.

This paper studies the grain refinement mechanisms of 5A06 aluminum alloy sheets in cold rotary forging (CRF). The results show that the grains are clearly refined from 25.1 µm to 11.8 µm during the CRF process. The grain refinement mechanism can be divided into two modes: (1) The grains with a small Schmid factor (SF) are activated by multi-slip systems, and dense dislocations are segregated along the boundaries of interior regions with different slip systems, which results in a rapidly increasing strain localization along these boundaries. Since the strain localization restrains the coordinate slip deformation between different interior regions, the grains are directly separated into several finer grains. (2) The grains with a large SF are primarily activated by a single slip system, and the dislocation migrates smoothly along most microband boundaries. Then, a more severe lattice rotation causes a transformation to a hard orientation and multi-slip system activation, which contributes to an increase in the rapid misorientation across microband boundaries and thus promotes significant SF grain refinement.

Analysis and validation of diagnostic biomarkers and immune cell infiltration characteristics in pediatric sepsis by integrating bioinformatics and machine learning.

BACKGROUND: Pediatric sepsis is a complicated condition characterized by life-threatening organ failure resulting from a dysregulated host response to infection in children. It is associated with high rates of morbidity and mortality, and rapid detection and administration of antimicrobials have been emphasized. The objective of this study was to evaluate the diagnostic biomarkers of pediatric sepsis and the function of immune cell infiltration in the development of this illness. METHODS: Three gene expression datasets were available from the Gene Expression Omnibus collection. First, the differentially expressed genes (DEGs) were found with the use of the R program, and then gene set enrichment analysis was carried out. Subsequently, the DEGs were combined with the major module genes chosen using the weighted gene co-expression network. The hub genes were identified by the use of three machine-learning algorithms: random forest, support vector machine-recursive feature elimination, and least absolute shrinkage and selection operator. The receiver operating characteristic curve and nomogram model were used to verify the discrimination and efficacy of the hub genes. In addition, the inflammatory and immune status of pediatric sepsis was assessed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). The relationship between the diagnostic markers and infiltrating immune cells was further studied. RESULTS: Overall, after overlapping key module genes and DEGs, we detected 402 overlapping genes. As pediatric sepsis diagnostic indicators, CYSTM1 (AUC = 0.988), MMP8 (AUC = 0.973), and CD177 (AUC = 0.986) were investigated and demonstrated statistically significant differences (P < 0.05) and diagnostic efficacy in the validation set. As indicated by the immune cell infiltration analysis, multiple immune cells may be involved in the development of pediatric sepsis. Additionally, all diagnostic characteristics may correlate with immune cells to varying degrees. CONCLUSIONS: The candidate hub genes (CD177, CYSTM1, and MMP8) were identified, and the nomogram was constructed for pediatric sepsis diagnosis. Our study could provide potential peripheral blood diagnostic candidate genes for pediatric sepsis patients.

Construction of an individualized brain metabolic network in patients with advanced non-small cell lung cancer by the Kullback-Leibler divergence-based similarity method: A study based on 18F-fluorodeoxyglucose positron emission tomography.

Background: Lung cancer has one of the highest mortality rates of all cancers, and non-small cell lung cancer (NSCLC) accounts for the vast majority (about 85%) of lung cancers. Psychological and cognitive abnormalities are common in cancer patients, and cancer information can affect brain function and structure through various pathways. To observe abnormal brain function in NSCLC patients, the main purpose of this study was to construct an individualized metabolic brain network of patients with advanced NSCLC using the Kullback-Leibler divergence-based similarity (KLS) method. Methods: This study included 78 patients with pathologically proven advanced NSCLC and 60 healthy individuals, brain 18F-FDG PET images of these individuals were collected and all patients with advanced NSCLC were followed up (>1 year) to confirm their overall survival. FDG-PET images were subjected to individual KLS metabolic network construction and Graph theoretical analysis. According to the analysis results, a predictive model was constructed by machine learning to predict the overall survival of NSLCL patients, and the correlation with the real survival was calculated. Results: Significant differences in the degree and betweenness distributions of brain network nodes between the NSCLC and control groups (p<0.05) were found. Compared to the normal group, patients with advanced NSCLC showed abnormal brain network connections and nodes in the temporal lobe, frontal lobe, and limbic system. The prediction model constructed using the abnormal brain network as a feature predicted the overall survival time and the actual survival time fitting with statistical significance (r=0.42, p=0.012). Conclusions: An individualized brain metabolic network of patients with NSCLC was constructed using the KLS method, thereby providing more clinical information to guide further clinical treatment.

Constant p.L424H Mutation in GTF2I in Micronodular Thymomas With Lymphoid Stroma: Evidence Supporting Close Relationship With Type A and AB Thymomas.

Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I.