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Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation., (© 2024 McKimpson et al.)

The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Purpose: This study aims to develop a machine learning diagnostic model for parotid gland tumors based on preoperative contrast-enhanced CT imaging features to assist in clinical decision-making., Materials and Methods: Clinical data and contrast-enhanced CT images of 144 patients with parotid gland tumors from the Peking University School of Stomatology Hospital, collected from January 2019 to December 2022, were gathered. The 3D slicer software was utilized to accurately annotate the tumor regions, followed by exploring the correlation between multiple preoperative contrast-enhanced CT imaging features and the benign or malignant nature of the tumor, as well as the type of benign tumor. A prediction model was constructed using the k-nearest neighbors (KNN) algorithm., Results: Through feature selection, four key features-morphology, adjacent structure invasion, boundary, and suspicious cervical lymph node metastasis-were identified as crucial in preoperative discrimination between benign and malignant tumors. The KNN prediction model achieved an accuracy rate of 94.44%. Additionally, six features including arterial phase CT value, age, delayed phase CT value, pre-contrast CT value, venous phase CT value, and gender, were also significant in the classification of benign tumors, with a KNN prediction model accuracy of 95.24%., Conclusion: The machine learning model based on preoperative contrast-enhanced CT imaging features can effectively discriminate between benign and malignant parotid gland tumors and classify benign tumors, providing valuable reference information for clinicians., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Study Design: A retrospective, cross-sectional cohort study., Objective: This study aims to investigate the association between paraspinal muscle parameters and single-segment degenerative lumbar spondylolisthesis (DLS)., Summary of Background Data: The relationship between lumbar paraspinal muscles morphology and single-segment DLS remains unclear., Methods: A retrospective review was conducted on 115 patients with L4/5 single-segment DLS and 105 subjects without DLS. Two independent investigators assessed the relative cross-sectional area and fat infiltration rate of the multifidus, erector spinae, and psoas major at L3/4, L4/5, and L5/S1 levels, comparing these measurements between the two groups. Additionally, binary logistic regression analysis was performed with DLS as the dependent variable to analyze the relative cross-sectional area and fat infiltration rate of different paraspinal muscles. Within the DLS group, the correlation between paraspinal muscle characteristics and the anteroposterior diameter of the spinal canal was examined., Results: The fat infiltration rate of multifidus, erector spinae, and psoas major were higher in the DLS group than in the control group, while the relative cross-sectional area of multifidus and psoas major were lower in the DLS group. Binary logistic regression analysis revealed a significant correlation between fat infiltration rate of multifidus and psoas major and DLS. The relative cross-sectional area of multifidus and erector spinae was significantly smaller below the affected segment in the DLS group compared to the control group. A significant positive correlation was observed between the relative cross-sectional area of multifidus and erector spinae and the anteroposterior diameter of the spinal canal., Conclusion: There is a close association between paraspinal muscle degeneration and single-segment DLS, with increased relative cross-sectional area of the multifidus and psoas major possibly being risk factors for single-segment DLS. The restoration or enhancement of paraspinal muscle function could potentially serve as a pivotal target for the prevention and treatment of single-segment DLS., Level of Evidence: III., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Reconstruction of maxillary defects may lead to changes in the upper airway. These changes may cause postoperative airway obstruction issues., Purpose: The purpose was to evaluate the postoperative changes in the upper airway following maxillary reconstruction with an anterolateral thigh flap (ALTF) and to identify the factors associated with these changes., Study Design, Setting, Sample: This retrospective cohort study involved 26 patients who underwent maxillectomy for maxillary tumors, followed by reconstruction using an ALTF. Patients with a history of upper respiratory system disease and sleep-disorder breathing were excluded., Predictor Variable: The predictor variable was the residual rate of ALTF volume (ALTF-RS), calculated as the ratio of ALTF volume at 6 months postsurgery (T2) to that at 2 weeks postsurgery (T1)., The Outcome Variables: The outcome variables were the upper airway parameters. The upper airway was assessed at 3 time points: 1 week preoperatively (T0), T1, and T2. Ratios were used to represent airway changes over time., Covariates: The covariates are age, sex, Brown classification, body mass index, hypertension, neck dissection, and tracheostomy, etc. ANALYSES: Airway measurement differences between the three time points were analyzed by one-way analysis of variance. Pearson correlation and Spearman correlation analysis were used to analyze the correlation coefficients between airway changes and ALTF-RS. Statistical significance was established at a P value < .05., Results: The sample included 26 subjects with a mean age of 55.6 ± 15.2 years and 15/26 (57.7%) were male. Compared to T0, the nasopharyngeal and retropalatal airway volumes at T1 significantly decreased (P < .05) but recovered or surpassed preoperative levels by T2. The minimum cross-sectional airway area significantly decreased by T1 (P < .05), but increased by T2 (P < .05). The narrowest airway section was predominantly in the palatopharyngeal airway. The airway changes of T2/T1 and ALTF-RS were not correlated (P > .05) except for anterior-inferior point of the 4th cervical vertebra cross-sectional area (P < .05)., Conclusion and Relevance: The volumetric changes in the airway were not associated with ALTF-RS. The substantial narrowing of minimum cross-sectional airway area at T1 emphasized the need for vigilant airway management in these patients., (Copyright © 2024 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Sex chromosomes display remarkable diversity and variability among vertebrates. Compared with research on the X/Y and Z/W chromosomes, which have long evolutionary histories in mammals and birds, studies on the sex chromosomes at early evolutionary stages are limited. Here, we precisely assembled the genomes of homozygous XX female and YY male Lanzhou catfish (Silurus lanzhouensis) derived from an artificial gynogenetic family and a self-fertilized family, respectively. Chromosome 24 (Chr24) was identified as the sex chromosome based on resequencing data. Comparative analysis of the X and Y chromosomes showed an approximate 320 kb Y-specific region with a Y-specific duplicate of anti-Mullerian hormone type II receptor (amhr2y), which is consistent with findings in 2 other Silurus species but on different chromosomes (Chr24 of Silurus meridionalis and Chr5 of Silurus asotus). Deficiency of amhr2y resulted in male-to-female sex reversal, indicating that amhr2y plays a male-determining role in S. lanzhouensis. Phylogenetic analysis and comparative genomics revealed that the common sex-determining gene amhr2y was initially translocated to Chr24 of the Silurus ancestor along with the expansion of transposable elements. Chr24 was maintained as the sex chromosome in S. meridionalis and S. lanzhouensis, whereas a sex-determining region transition triggered sex chromosome turnover from Chr24 to Chr5 in S. asotus. Additionally, gene duplication, translocation, and degeneration were observed in the Y-specific regions of Silurus species. These findings present a clear case for the early evolutionary trajectory of sex chromosomes, including sex-determining gene origin, repeat sequence expansion, gene gathering and degeneration in sex-determining region, and sex chromosome turnover., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Aims: To investigate the relationship between peripheral blood lymphocyte subsets and prognosis in patients with acute ischemic stroke (AIS)., Methods: We enrolled 294 patients with AIS and collected peripheral blood samples for analysis of lymphocyte subsets. Prognosis was assessed at 3 months using the modified Rankin Scale (mRS). Association between lymphocyte count and poor outcomes (mRS score >2) was assessed using logistic regression. Individualized prediction models were developed to predict poor outcomes., Results: Patients in the mRS score ≤2 group had higher T-cell percentage (odds ratio [OR] = 0.947; 95% confidence interval [CI]: 0.899-0.998; p = 0.040), CD3 + T-cell count (OR = 0.999; 95% CI: 0.998-1.000; p = 0.018), and CD4 + T-cell count (OR = 0.998; 95% CI: 0.997-1.000; p = 0.030) than those in the mRS score >2 group 1-3 days after stroke. The prediction model for poor prognosis based on the CD4 + T-cell count showed good discrimination (area under the curve of 0.844), calibration (p > 0.05), and clinical utility., Conclusion: Lower T cell percentage, CD3 + , and CD4 + T-cell counts 1-3 days after stroke were independently associated with increased risk of poor prognosis. Individualized predictive model of poor prognosis based on CD4 + T-cell count have good accuracy and may predict disease prognosis., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Glioblastoma (GBM) is the most common and aggressive primary brain cancer; angiogenesis and immunosuppression exacerbate GBM progression. COUP-TFII demonstrates pro-angiogenesis activity; however, its role in glioma progression remains unclear. This study revealed that COUP-TFII promotes angiogenesis in gliomas by inducing transdifferentiation of glioma cells into endothelial-like cells. Mechanistic investigation suggested that COUP-TFII as a transcription factor exerts its function via binding to the promoter of TXNIP. Interestingly, COUP-TFII knockdown attenuated tumorigenesis and tumor progression in an immunocompetent mouse model but promoted tumor progression in an immuno-deficient mouse model. As an explanation, repression of COUP-TFII induces cellular senescence and activates immune surveillance in glioma cells in vitro and in vivo. In addition, we used heparin-polyethyleneimine (HPEI) nanoparticles to deliver COUP-TFII shRNA, which regulated tumor angiogenesis and immunosuppression in an in situ GBM mouse model. This study provides a novel strategy and potential therapeutic targets to treat GBM., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: This study aims to introduce a novel predictive model for the post-operative facial contours of patients with mandibular defect, addressing limitations in current methodologies that fail to preserve geometric features and lack interpretability., Methods: Utilizing surface mesh theory and deep learning, our model diverges from traditional point cloud approaches by employing surface triangular mesh grids. We extract latent variables using a Mesh Convolutional Restricted Boltzmann Machines (MCRBM) model to generate a three-dimensional deformation field, aiming to enhance geometric information preservation and interpretability., Results: Experimental evaluations of our model demonstrate a prediction accuracy of 91.2 %, which represents a significant improvement over traditional machine learning-based methods., Conclusions: The proposed model offers a promising new tool for pre-operative planning in oral and maxillofacial surgery. It significantly enhances the accuracy of post-operative facial contour predictions for mandibular defect reconstructions, providing substantial advancements over previous approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Pneumoconiosis mostly combines pulmonary and cardiovascular diseases, among which pulmonary heart disease (PHD) is of major concern due to its significant impact on the survival of pneumoconiosis patients. White cell count (WCC), red cell distribution width (RDW) and platelet parameters are thought to affect inflammatory responses and may be predictors of various cardiovascular diseases. However, very few studies have focused on PHD., Objectives: To examine the relationship between baseline complete blood count parameters (WCC, RDW, platelet parameters) and the risk of incident PHD in pneumoconiosis patients., Design: A retrospective cohort study., Setting: This was a single-centre, retrospective cohort study that used data from an Occupational Disease Hospital, Chengdu, Sichuan., Participants: A total of 946 pneumoconiosis patients from January 2012 to November 2021 were included in the study. Female patients and patients who had PHD, coronary heart disease, hypertensive heart disease, cardiomyopathy, heart failure, oncological disease, multiple organ dysfunction, AIDS at baseline and follow-up time of less than 6 months were also excluded., Outcome Measures: We identified PHD according to the patient's discharge diagnosis. We constructed Cox proportional hazard regression models to assess the HR of incident PHD in pneumoconiosis, as well as 95% CIs., Results: In the multiple Cox proportional hazard regression analysis, platelet count (PLT) and plateletcrit (PCT) above the median at baseline were associated with an increased risk of PHD in pneumoconiosis with adjusted HR of 1.52 (95% CI 1.09 to 2.12) and 1.42 (95% CI 1.02 to 1.99), respectively., Conclusion: Higher baseline PLT and PCT are associated with a higher risk of PHD in pneumoconiosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Shiga toxin-producing Escherichia coli (STEC) causes a wide spectrum of diseases including hemorrhagic colitis and hemolytic uremic syndrome (HUS). Previously, we developed a rapid, sensitive, and potentially portable assay that identified STEC by detecting Shiga toxin (Stx) using a B-cell based biosensor platform. We applied this assay to detect Stx2 present in food samples that have been implicated in previous STEC foodborne outbreaks (milk, lettuce, and beef). The STEC enrichment medium, modified Tryptone Soy Broth (mTSB), inhibited the biosensor assay, but dilution with the assay buffer relieved this effect. Results with Stx2a toxoid-spiked food samples indicated an estimated limit of detection (LOD) of ≈4 ng/mL. When this assay was applied to food samples inoculated with STEC, it was able to detect 0.4 CFU/g or 0.4 CFU/mL of STEC at 16 h post incubation (hpi) in an enrichment medium containing mitomycin C. Importantly, this assay was even able to detect STEC strains that were high expressors of Stx2 at 8 hpi. These results indicate that the STEC CANARY biosensor assay is a rapid and sensitive assay applicable for detection of STEC contamination in food with minimal sample processing that can complement the current Food Safety Inspection Service (US) methodologies for STEC.

Background: Statins are widely used for treating patients with ischemic stroke at risk of secondary cerebrovascular events. It is unknown whether Asian populations benefit from more intensive statin-based therapy for stroke recurrence. Therefore, in the present study we evaluated the effectiveness and safety of high-dose and moderate-dose statins for patients who had experienced mild ischemic stroke during the acute period., Methods and Results: This multicenter prospective study included patients with mild ischemic stroke who presented within 72 hours of symptom onset. The outcomes of patients in the high-intensity and moderate-intensity statin treatment groups were compared, with the main efficacy outcome being stroke recurrence and the primary safety end point being intracranial hemorrhage. The propensity score matching method was employed to control for imbalances in baseline variables. Subgroup analyses were conducted to evaluate group differences. In total, the data of 2950 patients were analyzed at 3 months, and the data of 2764 patients were analyzed at 12 months due to loss to follow-up. According to the multivariable Cox analyses adjusted for potential confounders, stroke recurrence occurred similarly in the high-intensity statin and moderate-intensity statin groups (3 months: adjusted hazard ratio [HR], 1.12 [95% CI, 0.85-1.49]; P =0.424; 12 months: adjusted HR, 1.08 [95% CI, 0.86-1.34]; P =0.519). High-intensity statin therapy was associated with an increased risk of intracranial hemorrhage (3 months: adjusted HR, 1.81 [95% CI, 1.00-3.25]; P =0.048; 12 months: adjusted HR, 1.86 [95% CI, 1.10-3.16]; P =0.021). The results from the propensity score-matched analyses were consistent with those from the Cox proportional hazards analysis., Conclusions: Compared with moderate-intensity statin therapy, high-dose statin therapy may not decrease the risk of mild, noncardiogenic ischemic stroke recurrence but may increase the risk of intracranial hemorrhage., Registration: URL: www.chictr.org.cn/. Unique Identifier: ChiCTR1900025214.

Background: This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression., Methods: We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m 2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations., Results: The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P  = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR ( P  = .009) was associated with faster IgAN progression., Conclusion: The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine., Competing Interests: All the authors declared no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Nirmatrelvir, a pivotal component of the oral antiviral Paxlovid for COVID-19, targets the SARS-CoV-2 main protease (M pro ) as a covalent inhibitor. Here, we employed combined computational methods to explore how the prevalent Omicron variant mutation P132H, alone and in combination with A173V (P132H-A173V), affects nirmatrelvir's efficacy. Our findings suggest that P132H enhances the noncovalent binding affinity of M pro for nirmatrelvir, whereas P132H-A173V diminishes it. Although both mutants catalyze the rate-limiting step more efficiently than the wild-type (WT) M pro , P132H slows the overall rate of covalent bond formation, whereas P132H-A173V accelerates it. Comprehensive analysis of noncovalent and covalent contributions to the overall binding free energy of the covalent complex suggests that P132H likely enhances M pro sensitivity to nirmatrelvir, while P132H-A173V may confer resistance. Per-residue decompositions of the binding and activation free energies pinpoint key residues that significantly affect the binding affinity and reaction rates, revealing how the mutations modulate these effects. The mutation-induced conformational perturbations alter drug-protein local contact intensities and the electrostatic preorganization of the protein, affecting noncovalent binding affinity and the stability of key reaction states, respectively. Our findings inform the mechanisms of nirmatrelvir resistance and sensitivity, facilitating improved drug design and the detection of resistant strains.

Insulin-deficient (type 1) diabetes is treated by providing insulin to maintain euglycemia. The current standard of care is a quasi-closed loop integrating automated insulin delivery with a continuous glucose monitoring sensor. Cell replacement technologies are advancing as an alternative treatment and have been tested as surrogates to cadaveric islets in transplants. In addition, immunomodulatory treatments to delay the onset of type 1 diabetes in high-risk (stage 2) individuals have gained regulatory approval. We have pioneered a cell conversion approach to restore insulin production through pharmacological conversion of intestinal epithelial cells into insulin-producing cells. We have advanced this approach along a translational trajectory through the discovery of small molecule forkhead box protein O1 inhibitors. When administered to different rodent models of insulin-deficient diabetes, these inhibitors have resulted in robust glucose-lowering responses and generation of insulin-producing cells in the gut epithelium. We review past work and delineate a path to human clinical trials., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

This study aimed to compare and rank the effectiveness of optimal exercise intensity in improving executive function in patients with ADHD (Attention deficit hyperactivity disorder, ADHD) through a comprehensive comparison of direct and indirect evidence. A systematic search was performed in five electronic databases to explore the optimal exercise intensity for improving executive function in patients with ADHD by directly and indirectly comparing a variety of exercise intervention intensities. In addition, the isolated effects of exercise on improving executive function in patients with ADHD were explored through classical meta-analysis of paired direct comparisons. Twenty-nine studies were retrieved and included in this study. Classical paired meta-analysis showed that for the patients with ADHD in the age group of 7-17 years, statistical difference was observed for all the parameters of exercise interventions (intensity, frequency, period, and training method), the three dimensions of executive function, the use of medication or not, the high and low quality of the methodological approach. Network meta-analysis showed that high-intensity exercise training was optimal for improving working memory (97.4%) and inhibitory function (85.7%) in patients with ADHD. Meanwhile, moderate-intensity exercise training was optimal for improving cognitive flexibility (77.3%) in patients with ADHD. Moderate to high intensity exercise training shows potential for improving executive function in these patients. Therefore, we recommend applying high-intensity exercise intervention to improve executive function in patients with ADHD to achieve substantial improvement., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

The development of ectodermal organs begins with the formation of a stratified epithelial placode that progressively invaginates into the underlying mesenchyme as the organ takes its shape. Signaling by secreted molecules is critical for epithelial morphogenesis, but how that information leads to cell rearrangement and tissue shape changes remains an open question. Using the mouse dentition as a model, we first establish that non-muscle myosin II is essential for dental epithelial invagination and show that it functions by promoting cell-cell adhesion and persistent convergent cell movements in the suprabasal layer. Shh signaling controls these processes by inducing myosin II activation via AKT. Pharmacological induction of AKT and myosin II can also rescue defects caused by the inhibition of Shh. Together, our results support a model in which the Shh signal is transmitted through myosin II to power effective cellular rearrangement for proper dental epithelial invagination., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Du et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Examining the relationship between the responses of a number of different cognitive trainings on cognitive functioning in middle-aged and elderly patients with mild cognitive impairment., Methods: Randomized controlled experimental studies published publicly from the time of inception to October 30, 2023 were searched through Web of Science, PubMed, Embase, and Cochrane library databases. Traditional and network meta-analyses were performed using Stata 17.0 software., Results: Fifty papers on 4 types of cognitive training were included. Traditional meta-analysis showed that virtual reality training (SMD = 0.53, 95%CI: [0.36,0.70], P = 0.00), neuropsychological training (SMD = 0.44, 95%CI: [0.18,0.70], P = 0.00), cognitive strategy training (SMD = 0.26, 95%CI: [0.16,0.36], P = 0.00), and cognitive behavioral therapy (SMD = 0.25, 95%CI: [0.08,0.41], P = 0.00) all had significant improvement effects on the cognitive function of middle-aged and elderly patients with mild cognitive impairment. Network meta-analysis revealed neuropsychological training as the best cognitive training, and subgroup analysis of cognitive function subdimensions showed that neuropsychological training had the best effects on working memory, lobal cognitive function, memory, and cognitive flexibility improvement. Meanwhile, virtual reality training had the best effects on processing speed, verbal ability, overall executive function, spatial cognitive ability, and attention improvement., Conclusion: Cognitive training can significantly improve the cognitive function of middle-aged and elderly patients with mild cognitive impairment, and neuropsychological training is the best intervention, most effective in interventions lasting more than 8 weeks., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Shiraia bambusicola is a typical parasitic medicinal fungus of the family Shiraiaceae. The fruiting bodies of S. bambusicola cannot be cultivated artificially, and active substances can be effectively produced via fermentation. The mechanism of conidia production is a research hotspot in the industrial utilization and growth development of S. bambusicola . This study is the first to systematically study the proteomics of conidiospore formation from S. bambusicola. Near-spherical conidia were observed and identified by internal transcribed spacer (ITS) sequence detection. A total of 2,840 proteins were identified and 1,976 proteins were quantified in the mycelia and conidia of S. bambusicola . Compared with mycelia, 445 proteins were differentially expressed in the conidia of S. bambusicola , with 165 proteins being upregulated and 280 proteins being downregulated. The Gene Ontology (GO) annotation results of differential proteomics showed that the biological process of S. bambusicola sporulation is complex. The Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway analysis showed that the differential proteins were mainly involved in starch and sucrose metabolism, biosynthesis of secondary metabolites, microbial metabolism in diverse environments, and other processes. Our in-depth speculative analysis showed that proteins related to carbohydrate metabolism were differentially expressed in conidiospore formation of S. bambusicola , suggesting the involvement of saccharides. Conidiation may increase the synthesis and release of ethanol and polysaccharide proteins such as glycoside hydrolase (GH), suppress host immunity, and facilitate S. bambusicola to infect and colonize of the host. In-depth analysis of differential proteomes will help reveal the molecular mechanism underlying the conidiospore formation of S. bambusicola , which has strong theoretical and practical significance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Du, Sun, Wu, Li, Dong, Wang, Shang, Yang, Huang and Chen.)

The purpose of this study is to clarify the role of IL-33 in the immune response to angiostrongyliasis, especially in terms of antibody production and isotype switching. In our experiment, C57BL/6 mice were each infected with 35 infectious larvae and were divided into groups that received an intraperitoneal injection of IL-33, anti-IL-33 monoclonal antibody (mAb), or anti-ST2 mAb 3 days post-infection (dpi) and were subsequently administered booster shots at 5-day intervals with the same dose. Serum samples from each group were collected weekly for ELISA assays. The levels of total IgG, IgG1, and IgG3 were significantly increased in A. cantonensis -infected mice that were treated with IL-33, and the levels decreased significantly in infected groups treated with anti-IL-33 or anti-ST2 mAb. These results suggest that IL-33 may play a critical role in the pathogenesis of human angiostrongyliasis and could be useful for understanding protective immunity against this parasitic infection.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease and currently there is no pharmacological therapy. Sympathetic nerve overactivity plays an important role in the development of TAAD. Sympathetic innervation is mainly controlled by nerve growth factor (NGF, a key neural chemoattractant) and semaphoring 3A (Sema3A, a key neural chemorepellent), while the roles of these two factors in aortic sympathetic innervation and especially TAAD are unknown. We hypothesized that genetically manipulating the NGF/Sema3A ratio by the Ngf -driven Sema3a expression approach may reduce aortic sympathetic nerve innervation and mitigate TAAD progression. A mouse strain of Ngf gene-driven Sema3a expression (namely NgfSema3a/Sema3a mouse) was established by inserting the 2A-Sema3A expression frame to the Ngf terminating codon using CRISPR/Cas9 technology. TAAD was induced by β-aminopropionitrile monofumarate (BAPN) both in NgfSema3a/Sema3a mice and wild type (WT) littermates. Contrary to our expectation, the BAPN-induced TAAD was severer in NgfSema3a/Sema3a mice than in wild-type (WT) mice. In addition, NgfSema3a/Sema3a mice showed higher aortic sympathetic innervation, inflammation and extracellular matrix degradation than the WT mice after BAPN treatment. The aortic vascular smooth muscle cells isolated from NgfSema3a/Sema3a mice and pretreated with BAPN in vivo for two weeks showed stronger capabilities of proliferation and migration than that from the WT mice. We conclude that the strategy of Ngf -driven Sema3a expression cannot suppress but worsens the BAPN-induced TAAD. By investigating the aortic phenotype of NgfSema3a/Sema3a mouse strain, we unexpectedly find a path to exacerbate BAPN-induced TAAD which might be useful in future TAAD studies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Kluyveromyces marxianus has become an attractive non-conventional yeast cell factory due to its advantageous properties such as high thermal tolerance and rapid growth. Succinic acid (SA) is an important platform molecule that has been applied in various industries such as food, material, cosmetics, and pharmaceuticals. SA bioproduction may be compromised by its toxicity. Besides, metabolite-responsive promoters are known to be important for dynamic control of gene transcription. Therefore, studies on global gene transcription under various SA concentrations are of great importance. Here, comparative transcriptome changes of K. marxianus exposed to various concentrations of SA were analyzed. Enrichment and analysis of gene clusters revealed repression of the tricarboxylic acid cycle and glyoxylate cycle, also activation of the glycolysis pathway and genes related to ergosterol synthesis. Based on the analyses, potential SA-responsive promoters were investigated, among which the promoter strength of IMTCP2 and KLMA&#95;50231 increased 43.4% and 154.7% in response to 15 g/L SA. In addition, overexpression of the transcription factors Gcr1, Upc2, and Ndt80 significantly increased growth under SA stress. Our results benefit understanding SA toxicity mechanisms and the development of robust yeast for organic acid production. KEY POINTS: • Global gene transcription of K. marxianus is changed by succinic acid (SA) • Promoter activities of IMTCP2 and KLMA&#95;50123 are regulated by SA • Overexpression of Gcr1, Upc2, and Ndt80 enhanced SA tolerance., (© 2024. The Author(s).)

The cigarette filter is an essential component of modern cigarettes and studying the flow distribution within the cigarette filter is of great significance in reducing the harm of cigarettes and optimizing smoking sensations. As the object of numerical simulation research, a three-dimensional model of the cigarette was accurately constructed through micro-CT reverse engineering, achieving a scanning accuracy of 4.05 μm. An overall porous media model of the cigarette filter was established to characterize the pressure distribution inside the filter. Based on the three-dimensional reconstruction, a local simulation model of the cavity-filtered filter was created by extracting a 1/36 geometric model. The simulation results of the overall porous media model of the cigarette filter were used as the pressure boundary conditions for the local simulation model of the cavity-filtered filter, and the effects of the wrapped paper and cavity on the flow field were analyzed. The results show that the simulated pressure drop in the overall porous media model of the cigarette filter had a deviation of less than 3.5% compared to the experimental results. This suggests that the porous media model can effectively predict the changes in pressure drop within the filter. When both wrapped paper and cavity were present, the velocity at the interface between acetate fiber and wrapped paper increased by 141.54%, while the pressure approached 0 Pa. Similarly, at the interface between acetate fiber and cavity, the velocity increased by 130.77%. It indicates that both wrapped paper and cavity significantly influenced the flow field characteristics within the cigarette filter. Additionally, as the porosity of the wrapped paper gradually increased from 0.69 to 0.99 in the radial direction, the fluid velocity increased by 14.46%, while the fluid pressure decreased by 29.09%. These changes were particularly evident when the porosity was below 0.87., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

To investigate the association between autonomic dysfunction (AutD) and motor as well as non-motor symptoms (NMS) in patients with Parkinson's disease (PD). Fifty-three PD patients were divided into two groups based on the number of domains affected by AutD: a multi-domain AutD group (AutD-M) and a single-domain AutD group (AutD-S), as evaluated using the Scale for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT), which assesses autonomic symptoms, one of the NMS. A comprehensive comparison was conducted between the two groups, including clinical measures such as clinical scales, quantitative evaluations of motor function and exercise capacity. Spearman correlation analysis was employed to investigate the relationship between AutD severity and PD symptoms. Additionally, we performed multiple linear regression model analysis to determine whether associations between SCOPA-AUT scores and clinical assessments remained significant after adjusting for Hoehn and Yahr stage, sex, and age. PD patients in the AutD-M group exhibited significantly more severe NMS and motor symptoms compared to those in the AutD-S group. In correlation analysis, SCOPA-AUT scores showed significant correlations with multiple clinical symptoms, such as most of the NMS, 10-MWT and CPET parameters. Furthermore, regression analysis also revealed that more pronounced fatigue, anxiety, depressive symptoms, worse walking speed and impaired exercise capacity were associated with higher SCOPA-AUT scores. The presence of AutD is correlated with emotional disturbances, decreased exercise endurance, and impaired gait function in patients with PD. Early management of AutD may prove beneficial in alleviating some NMS and motor symptoms in PD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Mastitis causes significant losses in the global dairy industry, and the health of animals has been linked to their intestinal microbiota. To better understand the relationship between gastrointestinal microbiota and mastitis in dairy cows, we collected blood, rumen fluid, and fecal samples from 23 dairy cows, including 13 cows with mastitis and 10 healthy cows. Using ELISA kit and high-throughput sequencing, we found that cows with mastitis had higher concentrations of TNF-α, IL-1, and LPS than healthy cows ( p  < 0.05), but no significant differences in microbiota abundance or diversity ( p  > 0.05). Principal coordinate analysis (PCOA) revealed significant differences in rumen microbial structure between the two groups ( p  < 0.05), with Moryella as the signature for rumen in cows with mastitis. In contrast, fecal microbial structure showed no significant differences ( p  > 0.05), with Aeriscardovia , Lactococcus , and Bacillus as the signature for feces in healthy cows. Furthermore, the results showed distinct microbial interaction patterns in the rumen and feces of cows with mastitis compared to healthy cows. Additionally, we observed correlations between the microbiota in both the rumen and feces of cows and blood inflammatory indicators. Our study sheds new light on the prevention of mastitis in dairy cows by highlighting the relationship between gastrointestinal microbiota and mastitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guo, Liu, Wei, Du and Li.)

Bacterial nanocellulose (BNC) is an attractive green-synthesized biomaterial for biomedical applications and various other applications. However, effective engineering of BNC production has been limited by our poor knowledge of the related metabolic processes. In contrast to the traditional perception that genome critically determines biosynthesis behaviors, here we discover that the glucose metabolism could also drastically affect the BNC synthesis in Gluconacetobacter hansenii . The transcriptomic profiles of two model BNC-producing strains, G. hansenii ATCC 53582 and ATCC 23769, which have highly similar genomes but drastically different BNC yields, were compared. The results show that their BNC synthesis capacities were highly related to metabolic activities such as ATP synthesis, ion transport protein assembly, and carbohydrate metabolic processes, confirming an important role of metabolism-related transcriptomes in governing the BNC yield. Our findings provide insights into the microbial biosynthesis behaviors from a transcriptome perspective, potentially guiding cellular engineering for biomaterial synthesis.

Shiga-toxin-producing Escherichia coli (STEC) causes a wide spectrum of diseases including hemorrhagic colitis and hemolytic uremic syndrome (HUS). The current Food Safety Inspection Service (FSIS) testing methods for STEC use the Food and Drug Administration (FDA) Bacteriological Analytical Manual (BAM) protocol, which includes enrichment, cell plating, and genomic sequencing and takes time to complete, thus delaying diagnosis and treatment. We wanted to develop a rapid, sensitive, and potentially portable assay that can identify STEC by detecting Shiga toxin (Stx) using the CANARY (Cellular Analysis and Notification of Antigen Risks and Yields) B-cell based biosensor technology. Five potential biosensor cell lines were evaluated for their ability to detect Stx2. The results using the best biosensor cell line (T5) indicated that this biosensor was stable after reconstitution with assay buffer covered in foil at 4 °C for up to 10 days with an estimated limit of detection (LOD) of ≈0.1-0.2 ng/mL for days up to day 5 and ≈0.4 ng/mL on day 10. The assay detected a broad range of Stx2 subtypes, including Stx2a, Stx2b, Stx2c, Stx2d, and Stx2g but did not cross-react with closely related Stx1, abrin, or ricin. Additionally, this assay was able to detect Stx2 in culture supernatants of STEC grown in media with mitomycin C at 8 and 24 h post-inoculation. These results indicate that the STEC CANARY biosensor developed in this study is sensitive, reproducible, specific, rapid (≈3 min), and may be applicable for surveillance of the environment and food to protect public health.

Long term exposure to silica particles leads to various diseases, among which silicosis is of great concern. Silicosis is an interstitial lung disease caused by inhalation of silica particles in production environments. However, the mechanisms underlying silicosis remains unclear. Our previous studies revealed that progranulin (Pgrn) promoted the expression of pro-inflammatory factors in alveolar macrophages treated with silica particles and the secretion of extracellular matrix of pulmonary fibroblasts. Nevertheless, the role of Pgrn in silica particles-induced silicosis in vivo was unknown. This study found that silica particles increased Pgrn expression in silicosis patients. Pgrn deficiency reduced lung inflammation and fibrosis in silica particles-induced silicosis mouse models. Subsequently, based on transcriptional sequencing and interleukin (Il) -6 knockout mouse models, results demonstrated that Pgrn deficiency might decrease silicosis inflammation by reducing the production of Il-6, thereby modulating pulmonary fibrosis in the early stage of silicosis mouse models. Furthermore, another mechanism through which Pgrn deficiency reduced fibrosis in silicosis mouse models was the regulation of the transforming growth factor (Tgf) -β1/Smad signaling pathway. Conclusively, Pgrn contributed to silicosis inflammation and fibrosis induced by silica particles, indicating that Pgrn could be a promising therapeutic target., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Dento-maxillofacial deformities are common problems. Orthodontic-orthognathic surgery is the primary treatment but accurate diagnosis and careful surgical planning are essential for optimum outcomes. This study aimed to establish and verify a machine learning-based decision support system for treatment of dento-maxillofacial malformations., Methods: Patients (n = 574) with dento-maxillofacial deformities undergoing spiral CT during January 2015 to August 2020 were enrolled to train diagnostic models based on five different machine learning algorithms; the diagnostic performances were compared with expert diagnoses. Accuracy, sensitivity, specificity, and area under the curve (AUC) were calculated. The adaptive artificial bee colony algorithm was employed to formulate the orthognathic surgical plan, and subsequently evaluated by maxillofacial surgeons in a cohort of 50 patients. The objective evaluation included the difference in bone position between the artificial intelligence (AI) generated and actual surgical plans for the patient, along with discrepancies in postoperative cephalometric analysis outcomes., Results: The binary relevance extreme gradient boosting model performed best, with diagnostic success rates > 90% for six different kinds of dento-maxillofacial deformities; the exception was maxillary overdevelopment (89.27%). AUC was > 0.88 for all diagnostic types. Median score for the surgical plans was 9, and was improved after human-computer interaction. There was no statistically significant difference between the actual and AI- groups., Conclusions: Machine learning algorithms are effective for diagnosis and surgical planning of dento-maxillofacial deformities and help improve diagnostic efficiency, especially in lower medical centers., (© 2024. The Author(s).)

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-born zoonotic bunyavirus that causes severe hemorrhagic fever and death in humans. CCHFV enters the cell via clathrin-mediated endocytosis which is dependent on its surface glycoproteins. However, the cellular receptors that are required for CCHFV entry are unknown. Here we show that the low density lipoprotein receptor (LDLR) is an entry receptor for CCHFV. Genetic knockout of LDLR impairs viral infection in various CCHFV-susceptible human, monkey and mouse cells, which is restored upon reconstitution with ectopically-expressed LDLR. Mutagenesis studies indicate that the ligand binding domain (LBD) of LDLR is necessary for CCHFV infection. LDLR binds directly to CCHFV glycoprotein Gc with high affinity, which supports virus attachment and internalization into host cells. Consistently, a soluble sLDLR-Fc fusion protein or anti-LDLR blocking antibodies impair CCHFV infection into various susceptible cells. Furthermore, genetic knockout of LDLR or administration of an LDLR blocking antibody significantly reduces viral loads, pathological effects and death following CCHFV infection in mice. Our findings suggest that LDLR is an entry receptor for CCHFV and pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever., (© 2023. The Author(s).)

Background: The vasoplegic syndrome is one of the major consequences of cardiac surgery. If pulmonary hypertension is additionally involved with vasoplegic syndrome, circulation management becomes much more complicated. According to previous studies, pituitrin (a substitute for vasopressin, which contains vasopressin and oxytocin) not only constricts systemic circulation vessels and increases systemic circulation pressure but also likely decreases pulmonary artery pressure and pulmonary vascular resistance. The aim of this study is to investigate whether pituitrin is beneficial for the postoperative outcomes in patients with pulmonary hypertension undergoing cardiac surgery., Methods and Analysis: The randomized controlled trial will include an intervention group continuously infused with 0.04 U/(kg h) of pituitrin and a control group. Adult patients with pulmonary hypertension undergoing elective cardiac surgery will be included in this study. Patients who meet the conditions and give their consent will be randomly assigned to the intervention group or the control group. The primary outcome is the composite endpoint of all-cause mortality within 30 days after surgery or common complications after cardiac surgery. Secondary outcomes include the incidence of other postoperative complications, length of hospital stay, and so on., Discussion: Pituitrin constricts systemic circulation vessels, increases systemic circulation pressure, and may reduce pulmonary artery pressure and pulmonary vascular resistance, which makes it a potentially promising vasopressor during the perioperative period in patients with pulmonary hypertension. Therefore, evidence from randomized controlled trials is necessary to elucidate whether pituitrin influences outcomes in patients with pulmonary hypertension following cardiac surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kong, Lv, Qiao, Sun, Du and Li.)

Background: A range of imaging modalities have reported Alzheimer's disease-related abnormalities in individuals experiencing subjective cognitive decline (SCD). However, there has been no consistent local abnormality identified across multiple neuroimaging modalities for SCD., Objective: We aimed to investigate the convergent local alterations in amyloid-β (Aβ) deposition, glucose metabolism, and resting-state functional MRI (RS-fMRI) metrics in SCD., Methods: Fifty SCD patients (66.4±5.7 years old, 19 men [38%]) and 15 normal controls (NC) (66.3±4.4 years old, 5 men [33.3%]) were scanned with both [18F]-florbetapir PET and [18F]-fluorodeoxyglucose PET, as well as simultaneous RS-fMRI from February 2018 to November 2018. Voxel-wise metrics were retrospectively analyzed, including Aβ deposition, glucose metabolism, amplitude of low frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality(DC)., Results: The SCD group showed increased Aβ deposition and glucose metabolism (p < 0.05, corrected), as well as decreased ALFF, ReHo, and DC (p < 0.05, uncorrected) in the left dorsal precuneus (dPCu). Furthermore, the dPCu illustrated negative resting-state functional connectivity with the default mode network. Regarding global Aβ deposition positivity, the Aβ deposition in the left dPCu showed a gradient change, i.e., Aβ positive SCD > Aβ negative SCD > Aβ negative NC. Additionally, both Aβ positive SCD and Aβ negative SCD showed increased glucose metabolism and decreased RS-fMRI metrics in the dPCu., Conclusions: The dorsal precuneus, an area implicated in early AD, shows convergent neuroimaging alterations in SCD, and might be more related to other cognitive functions (e.g., unfocused attention) than episodic memory.

Objective: To explore the changes of serum-related indexes at different time points, so as to identify the critical time of converting from simple premature thelarche (PT) to idiopathic central precocious puberty (ICPP)., Methods: This is a retrospective study. The subjects of the study were 50 girls with PT who were admitted to the Children's Hospital of Hebei Province from January 2019 to September 2020. The enrolled 50 children were divided into the conversion group(n=12) and the non-conversion group(n=38) according to whether PT was converted into ICPP during follow-up. Furthermore, the levels of serum-related indexes and uterine and ovarian volumes were compared after the diagnosis of PT., Results: The IGF-1 and IGFBP-3 levels of children in the conversion group began to change significantly from six months after the diagnosis, with statistically significant differences when compared with the levels of children at the initial diagnosis, three months and those of the non-conversion group at the same time points ( p< 0.05). The levels of vitamin-D, DHEA and leptin began to change significantly at nine months after the diagnosis ( p< 0.05). Besides, uterine and ovarian volumes in the conversion group began to increase significantly six months after the diagnosis, with statistically significant differences when compared with those in the non-conversion group ( p< 0.05)., Conclusion: Findings in our study suggest that regular monitoring of vitamin-D, IGF-1, IGFBP-3, DHEA and leptin levels, and uterine and ovarian volumes can predict the conversion from PT to ICPP at an early stage., Competing Interests: Conflict of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)

Objectives: In this study, we constructed and validated models based on deep learning and radiomics to facilitate preoperative diagnosis of cervical lymph node metastasis (LNM) using contrast-enhanced computed tomography (CECT)., Materials and Methods: CECT scans of 100 patients with OSCC (217 metastatic and 1973 non-metastatic cervical lymph nodes: development set, 76 patients; internally independent test set, 24 patients) who received treatment at the Peking University School and Hospital of Stomatology between 2012 and 2016 were retrospectively collected. Clinical diagnoses and pathological findings were used to establish the gold standard for metastatic cervical LNs. A reader study with two clinicians was also performed to evaluate the lymph node status in the test set. The performance of the proposed models and the clinicians was evaluated and compared by measuring using the area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE)., Results: A fusion model combining deep learning with radiomics showed the best performance (ACC, 89.2%; SEN, 92.0%; SPE, 88.9%; and AUC, 0.950 [95% confidence interval: 0.908-0.993, P < 0.001]) in the test set. In comparison with the clinicians, the fusion model showed higher sensitivity (92.0 vs. 72.0% and 60.0%) but lower specificity (88.9 vs. 97.5% and 98.8%)., Conclusion: A fusion model combining radiomics and deep learning approaches outperformed other single-technique models and showed great potential to accurately predict cervical LNM in patients with OSCC., Clinical Relevance: The fusion model can complement the preoperative identification of LNM of OSCC performed by the clinicians., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

After drawing comparisons between the reaction pathways of cytochrome c oxidase (CcO, Complex 4) and the preceding complex cytochrome bc 1 (Complex 3), both being proton pumping complexes along the electron transport chain, we provide an analysis of the reaction pathways in bacterial ba 3 class CcO, comparing spectroscopic results and kinetics observations with results from DFT calculations. For an important arc of the catalytic cycle in CcO, we can trace the energy pathways for the chemical protons and show how these pathways drive proton pumping of the vectorial protons. We then explore the proton loading network above the Fe heme a 3 -Cu B catalytic center, showing how protons are loaded in and then released by combining DFT-based reaction energies with molecular dynamics simulations over states of that cycle. We also propose some additional reaction pathways for the chemical and vector protons based on our recent work with spectroscopic support., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Noodleman, Götz, Han Du and Hunsicker-Wang.)

The lytic polysaccharide monooxygenase (LPMO) in the auxiliary active protein family (AA family) catalyzes the oxidative depolymerization of various refractory carbohydrates including cellulose, chitin and starch. While accumulating studies investigate the enzymology of LPMO, the research on the inactivation of LPMO genes has been rarely explored. In this study, five LPMO genes PaLPMO11A (Pa&#95;4&#95;4790), PaLPMO11B (Pa&#95;1&#95;5310), PaLPMO11C (Pa&#95;2&#95;7840), PaLPMO11D (Pa&#95;2&#95;8610) and PaLPMO11E (Pa&#95;3&#95;9420) of the AA11 family in the filamentous fungus Podospora anserina were knocked out by homologous recombination. Single mutants ΔPaLPMO11A (ΔA), ΔPaLPMO11B (ΔB), ΔPaLPMO11C (ΔC), ΔPaLPMO11D (ΔD) and ΔPaLPMO11E (ΔE) were constructed, and then all polygenic mutants were constructed via genetic crosses. The differences in the growth rate and sexual reproduction between wild type and mutant strains were observed on different carbon source media. The alteration of oxidative stress and cellulose degradation ability were found on DAB and NBT staining and cellulase activity determination. These results implicated that LPMO11 genes play a key role in the growth, development, and lignocellulose degradation of P. anserina. The results showed that the spore germination efficiency, growth rate and reproductive capacity of mutant strains including ΔBΔCΔE, ΔAΔBΔCΔE, ΔAΔCΔDΔE and ΔAΔBΔCΔDΔE was significantly decreased on different cellulose carbon sources and the remaining strains have no difference. The reduced utilization of various carbon sources, the growth rate, the spore germination rate, the number of fruiting bodies, the normal fruiting bodies, the shortened life span and the ability to degrade cellulose were found in strains which all five genes in the PaLPMO11 family were deleted. However, the strain still had 45% cellulase activity compared to wild type. These results suggest that LPMO11 genes may be involved in the growth and development, sexual reproduction, senescence and cellulose degradation of P. anserina. This study provides information for systematically elucidating the regulatory mechanism of lignocellulose degradation in filamentous fungus P. anserina.

Numerous studies have proven the critical role of macrophages in the renal fibrosis process. Notably, G Protein-coupled Estrogen Receptor 1 (GPER1), a novel estrogen receptor, has been shown to play a ubiquitous role in regulating macrophage activities and proinflammatory pathways. However, the precise role of GPER1 in macrophage-mediated renal fibrosis is unknown. In this study, we aimed to investigate the function of macrophage GPER1 in the UUO-induced renal fibrosis model. Compared to vehicle-treated ovariectomized (OVX) female and male unilateral ureteral obstruction (UUO) models, we observed that G-1 (GPER1 agonist)-treated OVX female and male UUO mice had fewer renal fibrotic lesions and less M1 and M2 macrophage infiltration in the kidney tissues. Conversely, Gper1 deletion in male UUO mice accelerated renal fibrosis and increased inflammation. In vitro studies also revealed that GPER1 activation reduced M0 macrophage polarization towards M1 or M2 phenotypes. The RNA-sequencing analysis and immunoblotting indicated that GPER1 activation was primarily involved in downregulating immune pathways activation and inactivating MAPK pathways. Tubular epithelial cells co-cultured with G-1-pretreated M1 macrophages exhibited fewer injuries and immune activation. In addition, fibroblasts co-cultured with G-1-pretreated M2 macrophages showed downregulated extracellular matrix expression. Overall, this is the first study to demonstrate the effect of GPER1 on macrophage-mediated renal fibrosis via inhibition of M1 and M2 macrophage activation. These findings indicate that GPER1 may be a promising therapeutic target for treating renal fibrosis., (© 2023. The Author(s).)

China is the largest country in road construction due to rapid economy growth, which results in a large number of exposed slopes. Vegetation restoration of these road slopes has become the dominant method in ecological restoration. We reviewed research progress from three aspects, including key technologies for road slope vegetation restoration, application of vegetation restoration engineering, and factors influencing the vegetation restoration efforts. The slope protection technologies commonly used in road slope vegetation restoration include soil spraying technology, vegetation concrete slope protection technology, thick base material technology, and hydraulic spraying technology. In engineering applications, slope vegetation has the functions such as soil and water conservation, air purification, and landscape restoration. Currently, the most common community configuration is shrub and grass configuration. The main influencing factors of vegetation restoration on road slopes are climate, soil substrate, slope direction, plant species and community configuration used, human factors, and other natural factors (such as hydrology, altitude, microtopography, and wildlife). Future researches should focus on the mechanisms of different factors affecting road slope vegetation restoration, and study ecological substrates and slope protection technologies, plant species and diverse community configuration models suitable for road slope restoration in different climatic regions and site conditions.

Objective: Resuscitation with whole blood is known to be better than that with saline in attaining the return of spontaneous circulation (ROSC) and improving the short-term survival rate for hemorrhage-induced traumatic cardiac arrest (HiTCA). However, the resuscitation with whole blood alone fails to address the pathophysiological abnormalities, including hyperglycemia, hyperkalemia and coagulopathy, after HiTCA. The present study aimed to determine whether the modified glucose-insulin-potassium (GIK) therapy can ameliorate the above-mentioned pathophysiological abnormalities, enhance the ROSC, improve the function of key organs, and reduce the mortality after HiTCA., Methods: HiTCA was induced in rabbits (n=36) by controlled hemorrhage. Following arrest, the rabbits were randomly divided into three groups (n=12 each): group A (no resuscitation), group B (resuscitation with whole blood), and group C (resuscitation with whole blood plus GIK). The GIK therapy was administered based on the actual concentration of glucose and potassium. The ROSC rate and survival rate were obtained. Hemodynamical and biochemical changes were detected. Thromboelastography (TEG) was used to measure coagulation parameters, and enzyme-linked immunosorbent assay to detect parameters related to inflammation, coagulation and the function of brain., Results: All animals in groups B and C attained ROSC. Two rabbits died 24-48 h after HiTCA in group B, while no rabbits died in group C. The GIK therapy significantly reduced the levels of blood glucose, potassium, and biological markers for inflammatory reaction, and improved the heart, kidney, liver and brain function in group C when compared to group B. Furthermore, the R values of TEG were significantly lower in group C than in group B, and the maximum amplitude of TEG was slightly lower in group B than in group C, with no significant difference found., Conclusion: Resuscitation with whole blood and modified GIK therapy combined can ameliorate the pathophysiological disorders, including hyperglycemia, hyperkalemia and coagulopathy, and may improve the function of key organs after HiTCA., (© 2023. Huazhong University of Science and Technology.)

Nuclear magnetic resonance (NMR) is a crucial technique for analyzing mixtures consisting of small molecules, providing non-destructive, fast, reproducible, and unbiased benefits. However, it is challenging to perform mixture identification because of the offset of chemical shifts and peak overlaps that often exist in mixtures such as plant flavors. Here, we propose a deep-learning-based mixture identification method (DeepMID) that can be used to identify plant flavors (mixtures) in a formulated flavor (mixture consisting of several plant flavors) without the need to know the specific components in the plant flavors. A pseudo-Siamese convolutional neural network (pSCNN) and a spatial pyramid pooling (SPP) layer were used to solve the problems due to their high accuracy and robustness. The DeepMID model is trained, validated, and tested on an augmented data set containing 50,000 pairs of formulated and plant flavors. We demonstrate that DeepMID can achieve excellent prediction results in the augmented test set: ACC = 99.58%, TPR = 99.48%, FPR = 0.32%; and two experimentally obtained data sets: one shows ACC = 97.60%, TPR = 92.81%, FPR = 0.78% and the other shows ACC = 92.31%, TPR = 80.00%, FPR = 0.00%. In conclusion, DeepMID is a reliable method for identifying plant flavors in formulated flavors based on NMR spectroscopy, which can assist researchers in accelerating the design of flavor formulations.

Traditional plastic products have caused serious environmental pollution due to difficulty to be degraded in the natural environment. In the recent years, biodegradable plastics are receiving increasing attention due to advantages in natural degradability and environmental friendliness. Biodegradable plastics have potential to be used in food, agriculture, industry, medicine and other fields. However, the high production cost of such plastics is the bottleneck that limits their commercialization and application. Yeasts, including budding yeast and non-conventional yeasts, are widely studied to produce biodegradable plastics and their organic acid monomers. Compared to bacteria, yeast strains are more tolerable to multiple stress conditions including low pH and high temperature, and also have other advantages such as generally regarded as safe, and no phage infection. In addition, synthetic biology and metabolic engineering of yeast have enabled its rapid and efficient engineering for bioproduction using various renewable feedstocks, especially lignocellulosic biomass. This review focuses on the recent progress in biosynthesis technology and strategies of monomeric organic acids for biodegradable polymers, including polylactic acid (PLA), polyhydroxyalkanoate (PHA), polybutylene succinate (PBS), and polybutylene adipate terephthalate (PBAT) using yeast cell factories. Improving the performance of yeast as a cell factory and strategies to improve yeast acid stress tolerance are also discussed. In addition, the critical challenges and future prospects for the production of biodegradable plastic monomer using yeast are also discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Simple indigestion in cows leads to substantial economic losses in the dairy industry. Despite ongoing efforts, an effective treatment for this issue remains elusive. Previous studies have emphasized the vital role of rumen microbes in maintaining ruminant health. To deepen our comprehension of the intricate interplay between rumen microbiota and simple indigestion, we undertook a study involving the analysis of rumen fluid from eight cows with simple indigestion and ten healthy cows. Additionally, we collected data pertaining to milk production, rumination behavior, and rumen characteristics. The results showed that cows with simple indigestion displayed significantly lower milk yield, reduced rumination duration, and weakened rumen contraction when contrasted with the healthy cows ( p < 0.05). However, no significant difference in microbiota α-diversity emerged ( p > 0.05). Principal coordinate analysis (PCoA) illuminated substantial variations in rumen microbial structure among the two groups ( p < 0.05). Further analysis spotlighted distinctive bacteria in the rumen of the cows with indigestion, including Allisonella , Synergistes , Megasphaera , Clostridium&#95;XIVb , Campylobacter , and Acidaminococcus . In contrast, Coraliomargarita , Syntrophococcus , and Coprococcus are the dominant bacterial genera in the rumen of healthy dairy cows. Importantly, these key bacterial genera also dominated the overarching microbial interaction network. The observation suggests that changes in the abundance of these dominant bacterial genera potentially underlie the principal etiology of cows with simple indigestion. The present findings can provide insights into simple indigestion prevention and treatment in dairy cows.

Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells derived from dental pulp that serves as an important model for investigating biological regeneration. DPSCs have a multipotent differentiation capacity and can promote different biological processes, including osteogenesis, odontogenesis, chondrogenesis, and angiogenesis. These biological processes are regulated by an extensive range of intra- and extra-cellular factors. Further, biomechanical cues, such as substrate stiffness, physical stress, and cell spreading, have been highlighted as particularly important modulators of DPSC function. This review sought to discuss various related signaling components involved in biomechanical cues and their respective roles in cellular and tissue responses in DPSCs, summarize current findings, and provide an outlook on the potential applications of biomechanics in regenerative medicine and tissue engineering., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Background: Non-communicable diseases (NCDs) pose a major challenge to health economic cost and residents' health status. Community health workers (CHWs) are the gatekeeper of primary health care., Objective: This study aimed to conduct a situational analysis of current human resource and requirements of NCDs-related training among CHWs in Chengdu with regard to address to understand the suggestions for improvement of challenges and barriers., Methods: A descriptive online cross-sectional survey was conducted among CHWs (doctors and nurses) from 23 districts and counties in Chengdu. Sociodemographic and NCDs-related variables were collected. Univariate analysis and multiple response analysis were used to describe the characteristics of these variables., Results: 711 doctors and 637 nurses completely responded. There were significant differences among gender, age, educational levels, professional title, working year, type of institution, urban circle and registration in general practice between doctors and nurses (P < 0.001). 60.6% of doctors were female, compared to 98.0% for nurses. 58.2% of doctors held a bachelor's degree compared with 45.4% of nurses, while 48.3% of nurses held a junior college degree compared with 25.7% of doctors. Higher levels of professional title and registration in general practice were found in doctors compared with nurses. The proportions of NCDs' category, NCDs-related roles and tasks, NCDs-related training contents and forms that CHWs have attend and hoped to gain more were significantly different between doctors and nurses (P < 0.001). In general, the proportions in nurses were much lower than those of doctors (P < 0.05). The top five diseases managed by CHWs were hypertension, diabetes, cerebrovascular disease, chronic respiratory diseases and mental diseases. The five most reported roles performed among doctors included the distribution of health education (91.4%), following up (85.9%), establishing archives (71.3%), medicine adjustment (64.7%) and treatment implementation (52.0%). The top three diseases managed by nurses were same with doctors. The top four and five tasks were contact with patients or health services (39.6%) and referral (16.6%) in nurses. Most CHWs had received primary and common diseases-related trainings, but they had few opportunities to study in a tertiary hospital (40.4% in doctors and 20.9% in nurses, respectively), attend domestic academic conferences (26.9% in doctors vs. 9.7% in nurses), and take part in training courses (44.9% in nurses). CHWs hoped that the above-discussed training contents and forms could be provided more in the future. Besides basic skills related trainings, some specific skills related trainings should be strengthened., Conclusion: The qualifications in doctors were much better than those of nurses. The roles performed by CHWs in NCDs management are varied form common and frequent disease management to subsequent follow up and supervision. CHWs hope to receive more desired and oriented trainings. There is a need for building capacity of CHWs, optimizing and defining CHWs' role, facilitating postgraduate medical education support and strengthening multidisciplinary collaboration would be effective in NCDs management., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Hepatic stellate cell (HSC) activation is the central event in hepatic fibrosis. The cross-talk between HSCs and hepatocytes, which is mediated by extracellular vesicles (EVs), affects HSC activation. This study aimed to investigate whether Catalpol (CTP) attenuated hepatic fibrosis via modulating EVs. Mice were injected intraperitoneally with CCl 4 for 4 weeks to induce hepatic fibrosis. They were gavaged with CTP daily. Mouse serum EVs were isolated and identified using nanoparticle tracking analysis and transmission electron microscopy. Mouse hepatocytes (AML12) and primary HSCs were used to investigate the cell-to-cell crosstalk. The autophagosome-autolysosome fusion was determined using the autophagic flux assay. Hepatic fibrosis was attenuated by CTP, with a decrease of the myofibroblast marker, alpha-smooth muscle actin. The CTP treatment lowered the serum EVs. The co-culture of HSCs and the EVs derived from the CTP-treated mice or hepatocytes reduced HSC proliferation and the expressions of ACTA2 and Col1a1. After the CCl 4 treatment, the autophagosomes in AML12 cells were increased, while the autolysosomes were reduced. The decrease of autophagic cargo receptor SQSTM1 in the CTP group suggested that autophagic degradation was sustained. After inhibiting the endogenous Rac1-GTP of hepatocytes, the co-culture of EVs and HSCs reduced Rac1-GTP. The Rac1-GTP level in serum EVs from the CTP-treated mice was reduced in vivo. CTP inhibited autophagy in hepatocytes by reducing Rac1-GTP and thus affect the amount of Rac1-GTP in hepatocyte-derived EVs and the formation of EVs, which attenuated hepatic fibrosis via inhibiting HSC activation., (© 2022. The International CCN Society.)

Introduction: Little research has explored galactagogue food consumption in China. This study aims to investigate consumption patterns and how they relate to perceived insufficient milk supply and exclusive breastfeeding., Methods: Data were collected from postpartum women in China at six time points: baseline demographic questionnaire before hospital discharge (T0), galactagogue food questionnaire at 1 month postpartum (T1), Hill and Humenick Lactation Scale at 6 weeks postpartum (T2), and breastfeeding practices at 1, 2, 3 and 4 months postpartum (T1, T3, T4, T5)., Results: Of 218 participants who completed the galactagogue food questionnaire, 64.68% were consumers. No association was found between galactagogue food consumption and perceived insufficient milk supply. Consumers were less likely to breastfeed exclusively., Discussion: Future research should emphasize a deeper understanding of consumer behaviors and family support in providing professional guidance on postpartum nutrition that considers not only social and cultural experiences but also broader medical aspects.

Due to poor T cell infiltration, tumors evade immune surveillance. Increased CD8 + T cell infiltration in breast cancer suggests a satisfactory response to immunotherapy. COPS6 has been identified as an oncogene, but its role in regulating antitumor immune responses has not been defined. In this study, we investigated the impact of COPS6 on tumor immune evasion in vivo. Tumor transplantation models were established in C57BL/6 J mice and BALB/c nude mice. Flow cytometry was conducted to identify the role of COPS6 on tumor-infiltrating CD8 + T cells. By analyzing the TCGA and GTEx cohort, we found that COPS6 expression was significantly up-regulated in a variety of cancers. In human osteosarcoma cell line U2OS and non-small cell lung cancer cell line H1299, we showed that p53 negatively regulated COPS6 promoter activity. In human breast cancer MCF-7 cells, COPS6 overexpression stimulated p-AKT expression as well as the proliferation and malignant transformation of tumor cells, whereas knockdown of COPS6 caused opposite effects. Knockdown of COPS6 also significantly suppressed the growth of mouse mammary cancer EMT6 xenografts in BALB/c nude mice. Bioinformatics analysis suggested that COPS6 was a mediator of IL-6 production in the tumor microenvironment and a negative regulator of CD8 + T cell tumor infiltration in breast cancer. In C57BL6 mice bearing EMT6 xenografts, COPS6 knockdown in the EMT6 cells increased the number of tumor-infiltrating CD8 + T cells, while knockdown of IL-6 in COPS6KD EMT6 cells diminished tumor infiltrating CD8 + T cells. We conclude that COPS6 promotes breast cancer progression by reducing CD8 + T cell infiltration and function via the regulation of IL-6 secretion. This study clarifies the role of p53/COPS6/IL-6/CD8 + tumor infiltrating lymphocytes signaling in breast cancer progression and immune evasion, opening a new path for development of COPS6-targeting therapies to enhance tumor immunogenicity and treat immunologically "cold" breast cancer., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)