PBMC-mediated modulation of macrophage polarization in RAW264.7 cells through STAT1/STAT6 signaling cascades.

Peripheral blood mononuclear cells (PBMC), sourced autologously, offer numerous advantages when procured: easier acquisition process, no in vitro amplification needed, decreased intervention and overall increased acceptability make PBMC an attractive candidate for cell therapy treatment. However, the exact mechanism by which PBMC treat diseases remains poorly understood. Immune imbalance is the pathological basis of many diseases, with macrophages playing a crucial role in this process. However, research on the role and mechanisms of PBMC in regulating macrophages remains scarce. This study employed an in vitro co-culture model of PBMC and RAW264.7 macrophages to explore the role and mechanisms of PBMC in regulating macrophages. The results showed that the co-culturing led to decreased expression of inflammatory cytokines and increased expression of anti-inflammatory cytokines in RAW264.7 or in the culture supernatant. Additionally, the pro-inflammatory, tissue matrix-degrading M1 macrophages decreased, while the anti-inflammatory, matrix-synthesizing, regenerative M2 macrophages increased in both RAW264.7 and monocytes within PBMC. Moreover, co-cultured macrophages exhibited a significantly decreased p-STAT1/STAT1 ratio, while the p-STAT6/STAT6 ratio significantly increased. This suggests that PBMC may inhibit M1 macrophage polarization by blocking STAT1 signaling cascades and may promote M2 macrophage polarization through the activation of STAT6 signaling cascades. Overall, this study sheds light on the role and mechanism of PBMC in regulating macrophages. Moreover, it was found that monocytes within co-cultured PBMC differentiated into M2 macrophages in the presence of macrophages. This finding provides experimental evidence for the use of PBMC in treating inflammatory diseases, especially macrophage-depleting inflammatory diseases such as osteoarthritis.

Rapid discrimination of African swine fever virus nucleic acid and virions using BenzoNuclease.

African swine fever (ASF) is an acute and severe infectious disease caused by the African Swine Fever Virus (ASFV). ASFV exhibits significant resistance and stability in the environment, which, coupled with its double-stranded DNA and large genome, predisposes it to contaminate laboratory samples. This characteristic can lead to false-positive results in swine farm settings even days after disinfection, as detectable through polymerase chain reaction (PCR) or real-time fluorescent quantitative PCR (qPCR) assays. To meet the demand for efficient clinical methods capable of discriminating between ASFV nucleic acid and ASFV virions, this study aims to ascertain the efficacy of the nuclease "BenzoNuclease" in distinguishing ASFV nucleic acid (ASFV-DNA) from ASFV virions. BenzoNuclease is a versatile nucleic acid enzyme with the capacity to degrade nearly all forms of DNA and RNA. Initially, this research established a highly sensitive general PCR detection method for ASFV. Subsequently, a positive control was constructed using the M13 bacteriophage to substitute for active ASFV, facilitating the development of an improved qPCR method. It is important to note that common disinfectants have the potential to deactivate BenzoNuclease. However, in an environment simulating actual production applications, residual disinfectants do not interfere with the enzymatic efficacy of BenzoNuclease, thus not affecting the detection capabilities of this method. Positive clinical samples from pig farms, upon testing with the improved method, revealed that three samples were positive, indicating the presence of viral particles, while the remaining samples were negative, indicating the presence of nucleic acids. This provides an additional new option for sample testing in pig farms.

Characteristics of deformation and damage of surrounding rock along the top roadway in the working face of an isolated island and its evolution law.

This study investigates the deformation and damage characteristics of the surrounding rock along the top return mining roadway of an isolated island working face at different stages and reveals its damage mechanism and evolution law. Utilizing a mine in Yangquan City, Shanxi Province, China, as the engineering background, this research employs FLAC 3D numerical simulation and on-site measurements. The findings suggest that the evolution of the plastic zone along the top roadway of the 15,106 island face is largely similar during both the excavation and mining periods. The plastic zones on either side of the roadway are expanding asymmetrically and gradually merging into the plastic zone of the coal pillar. In the destructive stage, the sub-gangs of the roadway are penetrated, indicating the progression into the plastic zone. The investigation points to extensive damage on the larger side of the roadway, the development of fissures, and the significant depth of damage as primary causes of roadway deformation. Moreover, the extent of the plastic zones on both sides of the roadway correlates positively with their relative distance. Continuous monitoring reveals an ongoing increase in roadway displacement, consistent with general observations in coal mining. The results provide valuable insights for optimizing support structures in similar mining environments.

ΔNp63α promotes cigarette smoke-induced renal cancer stem cell activity via the Sonic Hedgehog pathway.

Cigarette smoke (CS) has been generally recognized as a chief carcinogenic factor in renal cell carcinoma (RCC). The stimulative effect of CS on renal cancer stem cells (RCSCs) has been described previously. The Sonic Hedgehog (SHH) pathway plays an essential role in self-renewal, cell growth, drug resistance, metastasis, and recurrence of cancer stem cells (CSCs). Renal cancer-related gene ΔNp63α is highly expressed in renal epithelial tissues and contributes to the RCSCs characteristics of tumors. The aim of this study was to elucidate the role of ΔNp63α and the SHH pathway on the activity of RCSCs induced by CS through a series of in vivo and in vitro studies. It was shown that in renal cancer tissues, ΔNp63α and RCSCs markers in smokers are expressed higher than that in non-smokers. RCSCs were effectively enriched by tumor sphere formation assay. Besides, CS increased the expression of RCSCs markers and the capability of sphere-forming in vitro and in vivo. Moreover, the SHH pathway was activated, and the specialized inhibitor alleviated the promotion of CS on RCSCs. ΔNp63α activated the SHH pathway and promoted CS-induced enhancement of RCSCs activity. These findings indicate that ΔNp63α positively regulates the activity of CS-induced RCSCs via the SHH pathway.

Mesenchymal stem cell-derived apoptotic vesicles ameliorate impaired ovarian folliculogenesis in polycystic ovary syndrome and ovarian aging by targeting WNT signaling.

Rationale: It has been emergingly recognized that apoptosis generates plenty of heterogeneous apoptotic vesicles (apoVs), which play a pivotal role in the maintenance of organ and tissue homeostasis. However, it is unknown whether apoVs influence postnatal ovarian folliculogenesis. Methods: Apoptotic pathway deficient mice including Fas mutant (Fasmut ) and Fas ligand mutant (FasLmut ) mice were used with apoV replenishment to evaluate the biological function of apoVs during ovarian folliculogenesis. Ovarian function was characterized by morphological analysis, biochemical examination and cellular assays. Mechanistical studies were assessed by combinations of transcriptomic and proteomic analysis as well as molecular assays. CYP17A1-Cre; Axin1fl /fl mice was established to verify the role of WNT signaling during ovarian folliculogenesis. Polycystic ovarian syndrome (PCOS) mice and 15-month-old mice were used with apoV replenishment to further validate the therapeutic effects of apoVs based on WNT signaling regulation. Results: We show that systemic administration of mesenchymal stem cell (MSC)-derived apoptotic vesicles (MSC-apoVs) can ameliorate impaired ovarian folliculogenesis, PCOS phenotype, and reduced birth rate in Fasmut and FasLmut mice. Mechanistically, transcriptome analysis results revealed that MSC-apoVs downregulated a number of aberrant gene expression in Fasmut mice, which were enriched by kyoto encyclopedia of genes and genomes (KEGG) pathway analysis in WNT signaling and sex hormone biosynthesis. Furthermore, we found that apoptotic deficiency resulted in aberrant WNT/ß-catenin activation in theca and mural granulosa cells, leading to responsive action of dickkopf1 (DKK1) in the cumulus cell and oocyte zone, which downregulated WNT/ß-catenin expression in oocytes and, therefore, impaired ovarian folliculogenesis via NPPC/cGMP/PDE3A/cAMP cascade. When WNT/ß-catenin was specially activated in theca cells of CYP17A1-Cre; Axin1fl /fl mice, the same ovarian impairment phenotypes observed in apoptosis-deficient mice were established, confirming that aberrant activation of WNT/ß-catenin in theca cells caused the impairment of ovarian folliculogenesis. We firstly revealed that apoVs delivered WNT membrane receptor inhibitor protein RNF43 to ovarian theca cells to balance follicle homeostasis through vesicle-cell membrane integration. Systemically infused RNF43-apoVs down-regulated aberrantly activated WNT/ß-catenin signaling in theca cells, contributing to ovarian functional maintenance. Since aging mice have down-regulated expression of WNT/ß-catenin in oocytes, we used MSC-apoVs to treat 15-month-old mice and found that MSC-apoVs effectively ameliorated the ovarian function and fertility capacity of these aging mice through rescuing WNT/ß-catenin expression in oocytes. Conclusion: Our studies reveal a previously unknown association between apoVs and ovarian folliculogenesis and suggest an apoV-based therapeutic approach to improve oocyte function and birth rates in PCOS and aging.

Speech preprocessing and enhancement based on joint time domain and time-frequency domain analysis.

Speech enhancement aims to make noisy speech signals clearer. Traditional time-frequency domain methods struggle to differentiate between speech and noise, leading to a risk of speech distortion. This paper introduces an approach that combines the time domain and time-frequency domain using the W-net module to suppress noise at the front end. The module is an improved version of Wave-U-Net, called TTF-W-Net. We conducted experiments using the TIMIT speech and NOISEX-92 noise datasets to evaluate the enhancement performance achieved by integrating preprocessing networks, specifically Wave-U-Net and our TTF-W-Net, into the baseline methods: Phase, FullSubNet+, and DB-AIAT. Experimental results show that TTF-W-Net outperforms the baseline Wave-U-Net by 15.7% on the PESQ metric and the effect of the network by using our preprocessing method is improved. Consequently, the TTF-W-Net preprocessing Net offers effective speech enhancement.

Corrigendum: Nanofat lysate ameliorates pain and cartilage degradation of osteoarthritis through activation of TGF-ß-Smad2/3 signaling of chondrocytes.

[This corrects the article DOI: 10.3389/fphar.2023.900205.].

Ascorbic Acid Improves Tomato Salt Tolerance by Regulating Ion Homeostasis and Proline Synthesis.

In this study, processing tomato (Solanum lycopersicum L.) 'Ligeer 87-5' was hydroponically cultivated under 100 mM NaCl to simulate salt stress. To investigate the impacts on ion homeostasis, osmotic regulation, and redox status in tomato seedlings, different endogenous levels of ascorbic acid (AsA) were established through the foliar application of 0.5 mM AsA (NA treatment), 0.25 mM lycorine (LYC, an inhibitor of AsA synthesis; NL treatment), and a combination of LYC and AsA (NLA treatment). The results demonstrated that exogenous AsA significantly increased the activities and gene expressions of key enzymes (L-galactono-1,4-lactone dehydrogenase (GalLDH) and L-galactose dehydrogenase (GalDH)) involved in AsA synthesis in tomato seedling leaves under NaCl stress and NL treatment, thereby increasing cellular AsA content to maintain its redox status in a reduced state. Additionally, exogenous AsA regulated multiple ion transporters via the SOS pathway and increased the selective absorption of K+, Ca2+, and Mg2+ in the aerial parts, reconstructing ion homeostasis in cells, thereby alleviating ion imbalance caused by salt stress. Exogenous AsA also increased proline dehydrogenase (ProDH) activity and gene expression, while inhibiting the activity and transcription levels of Δ1-pyrroline-5-carboxylate synthetase (P5CS) and ornithine-δ-aminotransferase (OAT), thereby reducing excessive proline content in the leaves and alleviating osmotic stress. LYC exacerbated ion imbalance and osmotic stress caused by salt stress, which could be significantly reversed by AsA application. Therefore, exogenous AsA application increased endogenous AsA levels, reestablished ion homeostasis, maintained osmotic balance, effectively alleviated the inhibitory effect of salt stress on tomato seedling growth, and enhanced their salt tolerance.

African swine fever virus pB475L evades host antiviral innate immunity via targeting STAT2 to inhibit IFN-I signaling.

African swine fever virus (ASFV) causes severe disease in domestic pigs and wild boars, seriously threatening the development of the global pig industry. Type I interferon (IFN-I) is an important component of innate immunity, inducing the transcription and expression of antiviral cytokines by activating Janus-activated kinase-signal transducer and activator of transcription (STAT). However, the underlying molecular mechanisms by which ASFV antagonizes IFN-I signaling have not been fully elucidated. Therefore, using coimmunoprecipitation, confocal microscopy, and dual luciferase reporter assay methods, we investigated these mechanisms and identified a novel ASFV immunosuppressive protein, pB475L, which interacts with the C-terminal domain of STAT2. Consequently, pB475L inhibited IFN-I signaling by inhibiting STAT1 and STAT2 heterodimerization and nuclear translocation. Furthermore, we constructed an ASFV-B475L7PM mutant strain by homologous recombination, finding that ASFV-B475L7PM attenuated the inhibitory effects on IFN-I signaling compared to ASFV-WT. In summary, this study reveals a new mechanism by which ASFV impairs host innate immunity.

Fragment-Fusion Transformer: Deep Learning-Based Discretization Method for Continuous Single-Cell Raman Spectral Analysis.

Raman spectroscopy has become an important single-cell analysis tool for monitoring biochemical changes at the cellular level. However, Raman spectral data, typically presented as continuous data with high-dimensional characteristics, is distinct from discrete sequences, which limits the application of deep learning-based algorithms in data analysis due to the lack of discretization. Herein, a model called fragment-fusion transformer is proposed, which integrates the discrete fragmentation of continuous spectra based on their intrinsic characteristics with the extraction of intrafragment features and the fusion of interfragment features. The model integrates the intrinsic feature-based fragmentation of spectra with transformer, constructing the fragment transformer block for feature extraction within fragments. Interfragment information is combined through the pyramid design structure to improve the model's receptive field and fully exploit the spectral properties. During the pyramidal fusion process, the information gain of the final extracted features in the spectrum has been enhanced by a factor of 9.24 compared to the feature extraction stage within the fragment, and the information entropy has been enhanced by a factor of 13. The fragment-fusion transformer achieved a spectral recognition accuracy of 94.5%, which is 4% higher compared to the method without fragmentation and fusion processes on the test set of cell Raman spectroscopy identification experiments. In comparison to common spectral classification models such as KNN, SVM, logistic regression, and CNN, fragment-fusion transformer has achieved 4.4% higher accuracy than the best-performing CNN model. Fragment-fusion transformer method has the potential to serve as a general framework for discretization in the field of continuous spectral data analysis and as a research tool for analyzing the intrinsic information within spectra.

Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity.

The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.

Cachexia Index as a Predictor of Reduced Survival in Patients with Gastrointestinal Cancer: A Systematic Review and Meta-Analysis.

The cachexia index is a novel indicator of cachexia, but its prognostic implications for survival outcomes have not been systematically assessed in patients with gastrointestinal cancer. This systematic review and meta-analysis aimed to examine the association between the cachexia index and survival outcomes in gastrointestinal cancer patients. Two independent reviewers searched PubMed, Embase, and Web of Science to identify studies that evaluated the prognostic significance of the cachexia index in patients with gastrointestinal cancer. The prognostic value of the cachexia index was determined by combining the adjusted hazard ratios (HR) and 95% confidence intervals (CI). Thirteen studies were identified, including a total of 4207 patients. Meta-analysis indicated that a lower cachexia index was associated with shorter overall survival (HR 2.18; 95% CI 1.78-2.66) and disease-free survival (HR 1.72; 95% CI 1.50-1.97) in gastrointestinal cancer patients. Further stratified analysis confirmed the significant association between a lower cachexia index and shorter overall survival in different study designs, regions, patients' age, sample sizes, gastrointestinal cancer subtypes, tumor stages, and follow-up duration subgroups. The cachexia index could be utilized as a predictor of overall survival and disease-free survival in patients with gastrointestinal cancer. However, future prospective studies are required to confirm these findings.

[Evaluation of augmented reality technology in the recognizing of oral and maxillofacial anatomy].

OBJECTIVE: To evaluate the outcome of Augmented reality technology in the recognizing of oral and maxillofacial anatomy. METHODS: This study was conducted on the undergraduate students in Peking University School of Stomatology who were learning oral and maxillofacial anatomy. The image data were selected according to the experiment content, and the important blood vessels and bone tissue structures, such as upper and lower jaws, neck arteries and veins were reconstructed in 3D(3-dimensional) by digital software to generate experiment models, and the reconstructed models were encrypted and stored in the cloud. The QR (quick response) code corresponding to the 3D model was scanned by a networked mobile device to obtain augmented reality images to assist experimenters in teaching and subjects in recognizing. Augmented reality technology was applied in both the theoretical explanation and cadaveric dissection respectively. Subjects' feedback was collected in the form of a post-class questionnaire to evaluate the effectiveness of augmented reality technology-assisted recognizing. RESULTS: In the study, 83 undergraduate students were included as subjects in this study. Augmented reality technology could be successfully applied in the recognizing of oral and maxillofacial anatomy. All the subjects could scan the QR code through a connected mobile device to get the 3D anatomy model from the cloud, and zoom in/out/rotate the model on the mobile. Augmented reality technology could provide personalized 3D model, based on learners' needs and abilities. The results of likert scale showed that augmented reality technology was highly recognized by the students (9.19 points), and got high scores in terms of forming a three-dimensional sense and stimulating the enthusiasm for learning (9.01 and 8.85 points respectively). CONCLUSION: Augmented reality technology can realize the three-dimensional visualization of important structures of oral and maxillofacial anatomy and stimulate students' enthusiasm for learning. Besides, it can assist students in building three-dimensional space imagination of the anatomy of oral and maxillofacial area. The application of augmented reality technology achieves favorable effect in the recognizing of oral and maxillofacial anatomy.

Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis.

INTRODUCTION: Cancer cachexia is a complex problem characterized by weight loss due to skeletal muscle and adipose tissue reduction. The purpose of this meta-analysis is to examine the association between cancer cachexia and adverse outcomes in patients with non-small cell lung cancer (NSCLC). METHODS: A comprehensive search was conducted in the PubMed, Web of Science, and Embase databases from their inception to January 15, 2024. Retrospective or prospective studies that investigated the cancer cachexia as a predictor of overall survival (OS), progression-free survival (PFS), overall response rate (ORR), or disease control rate (DCR) in NSCLC patients were included in this analysis. RESULTS: Sixteen studies, comprising 5919 NSCLC patients, were identified. The pooled prevalence of cachexia in NSCLC patients was 39%, with individual studies reporting rates ranging from 19% to 63.8%. A meta-analysis using a random effects model showed that cachexia was associated with reduced OS (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.54-2.21) and PFS (HR 1.49; 95% CI 1.27-1.73). Subgroup analysis indicated that cancer cachexia significantly predicted OS, regardless of study design, NSCLC subtypes, cancer stage, definitions of cachexia, or follow-up duration. However, there was no clear association between cancer cachexia and ORR or DCR. CONCLUSIONS: Cancer cachexia emerges is a negative prognostic factor for OS and PFS in NSCLC patients. Assessing cancer cachexia can improve risk classification for survival outcomes in this patient population.

Pain hypersensitivity is dependent on autophagy protein Beclin 1 in males but not females.

Chronic pain is associated with alterations in fundamental cellular processes. Here, we investigate whether Beclin 1, a protein essential for initiating the cellular process of autophagy, is involved in pain processing and is targetable for pain relief. We find that monoallelic deletion of Becn1 increases inflammation-induced mechanical hypersensitivity in male mice. However, in females, loss of Becn1 does not affect inflammation-induced mechanical hypersensitivity. In males, intrathecal delivery of a Beclin 1 activator, tat-beclin 1, reverses inflammation- and nerve injury-induced mechanical hypersensitivity and prevents mechanical hypersensitivity induced by brain-derived neurotrophic factor (BDNF), a mediator of inflammatory and neuropathic pain. Pain signaling pathways converge on the enhancement of N-methyl-D-aspartate receptors (NMDARs) in spinal dorsal horn neurons. The loss of Becn1 upregulates synaptic NMDAR-mediated currents in dorsal horn neurons from males but not females. We conclude that inhibition of Beclin 1 in the dorsal horn is critical in mediating inflammatory and neuropathic pain signaling pathways in males.

Postoperative Neurologic Outcome in Patients Undergoing Resective Surgery for Parietal Lobe Epilepsy: A Systematic Review.

BACKGROUND AND OBJECTIVES: Parietal lobe epilepsy (PLE) surgery can be an effective treatment for selected patients with intractable epilepsy but can be associated with the risk of serious neurologic deficits. We performed a systematic review of the literature to obtain a comprehensive summary of the frequency and types of new postoperative neurologic deficits in patients undergoing PLE resective surgery. METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published between January 1, 1990, and April 28, 2022. We included studies that reported postoperative neurologic outcome following PLE resective surgery confined to the parietal lobe. We required that studies included ≥5 patients. The data collected included demographic information and specific details of postoperative neurologic deficits. When available, individual patient data were collected. We used the Risk of Bias in Nonrandomized Studies of Interventions tool to assess the risk of bias and Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence. RESULTS: Of the 3,461 articles screened, 33 studies met the inclusion criteria. A total of 370 patients were included. One hundred patients (27.0%) had a new deficit noted postoperatively. Approximately half of the patients with deficits experienced only transient deficits. Motor deficits were the most commonly identified deficit. The rates of motor deficits noted after PLE surgery were 5.7%, 3.2%, and 2.2% for transient, long-term, and duration not specified, respectively. Sensory and visual field deficits were also commonly reported. Gerstmann syndrome was noted postoperatively in 4.9% of patients and was almost always transient. Individual patient data added information on parietal lobe subregion postoperative neurologic outcome. DISCUSSION: Our systematic review provides a comprehensive summary of the frequency and types of neurologic deficits associated with PLE surgery. A significant percentage of postoperative deficits are transient. In addition to the expected sensory and visual deficits, PLE surgery is associated with a notable risk of motor deficits. The available literature has important deficiencies. Our study highlights gaps in the literature and provides recommendations for future directions. TRIAL REGISTRATION INFORMATION: This systematic review was registered on PROSPERO (CRD42022313108, May 26, 2022).

Developing and validating machine learning-based prediction models for frailty occurrence in those with chronic obstructive pulmonary disease.

Background: Frailty is a medical syndrome caused by multiple factors, characterized by decreased strength, endurance, and diminished physiological function, resulting in increased susceptibility to dependence and/or death. Patients with chronic obstructive pulmonary disease (COPD) tend to be more vulnerable to frailty due to their physical and psychological burdens. Therefore, the aim of this study was to develop a reliable and accurate vulnerability risk prediction model for frailty in patients with COPD in order to improve the identification and prediction of patient frailty. The specific objectives of this study were to determine the prevalence of frailty in patients with COPD and develop a prediction model and evaluate its predictive power. Methods: Clinical information was analyzed using data from the 2018 China Health and Retirement Longitudinal Study (CHARLS) database, and 34 indicators, including behavioral factors, health status, mental health parameters, and various sociodemographic variables, were examined in the study. The adaptive synthetic sampling technique was used for unbalanced data. Three methods, ridge regressor, extreme gradient boosting (XGBoost) classifier, and random forest (RF) regressor, were used to filter predictors. Seven machine learning (ML) techniques including logistic regression (LR), support vector machines (SVM), multilayer perceptron, light gradient-boosting machine, XGBoost, RF, and K-nearest neighbors were used to analyze and determine the optimal model. For customized risk assessment, an online predictive risk modeling website was created, along with Shapley additive explanation (SHAP) interpretations. Results: Depression, smoking, gender, social activities, dyslipidemia, asthma, and residence type (urban vs. rural) were predictors for the development of frailty in patients with COPD. In the test set, the XGBoost model had an area under the curve of 0.942 (95% confidence interval: 0.925-0.959), an accuracy of 0.915, a sensitivity of 0.873, and a specificity of 0.911, indicating that it was the best model. Conclusions: The ML predictive model developed in this study is a useful and easy-to-use instrument for assessing the vulnerability risk of patients with COPD and may aid clinical physicians in screening high-risk patients.

The efficacy of clinicopathological and imaging features in differentiating benign from malignant parotid micro- and minitumors: a retrospective analysis.

OBJECTIVE: To compare clinicopathological and imaging features of micro- and minitumors of the parotid gland and provide a reference for preoperative prediction of benign vs malignant status. STUDY DESIGN: Patients with parotid gland tumors treated surgically were selected. Relevant clinicopathological and imaging data were collected for patients with maximum tumor diameters ≤20 mm on preoperative computed tomography (CT). The lesions were divided into 2 groups, microtumors and minitumors, based on maximum tumor diameter. CT imaging features of benign and malignant tumors were compared through binary logistic regression analysis. RESULTS: Microtumors and minitumors were categorized by maximum diameters <10 mm (n = 74) and 10-20 mm (n = 611), respectively. Benign and malignant minitumors exhibited significant differences in boundary, tumor density, margin morphology, spiculation margin, and CT values in the plain and arterial phase (P ≤ .027), resembling those found in typical malignant parotid gland tumors. However, no significant differences were observed between benign and malignant microtumors. Logistic regression analysis identified boundary, margin morphology, and spiculation margin as independent predictors of malignancy. The prediction model excelled in identifying benign lesions but was less successful in identifying malignancies. CONCLUSION: Parotid gland minitumors had imaging features similar to typical larger malignant tumors. Active exclusion of the malignant risk and early surgical treatment is recommended for these tumors.

Highly efficient biosynthesis of 3'-sialyllactose in engineered Escherichia coli.

3'-Sialyllactose (3'-SL), one of the abundant and important sialylated human milk oligosaccharides, is an emerging food ingredient used in infant formula milk. We previously developed an efficient route for 3'-SL biosynthesis in metabolically engineered Escherichia coli BL21(DE3). Here, several promising α2,3-sialyltransferases were re-evaluated from the byproduct synthesis perspective. The α2,3-sialyltransferase from Neisseria meningitidis MC58 (NST) with great potential and the least byproducts was selected for subsequent molecular modification. Computer-assisted mutation sites combined with a semi-rational modification were designed and performed. A combination of two mutation sites (P120H/N113D) of NST was finally confirmed as the best one, which significantly improved 3'-SL biosynthesis, with extracellular titers of 24.5 g/L at 5-L fed-batch cultivations. When NST-P120H/N113D was additionally integrated into the genome of host EZAK (E. coli BL21(DE3)ΔlacZΔnanAΔnanT), the final strain generated 32.1 g/L of extracellular 3'-SL in a 5-L fed-batch fermentation. Overall, we underscored the existence of by-products and improved 3'-SL production by engineering N. meningitidis α2,3-sialyltransferase.

Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma.

Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level was decreased after IOP elevation. Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons, whereas partial or RGC-specific Sirt6 deletion accelerated RGC loss. Importantly, therapeutically targeting Sirt6 with pharmacological activator or AAV2-mediated gene delivery ameliorated high IOP-induced RGC degeneration. Together, our studies reveal a critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma, setting the stage for further exploration of Sirt6 activation as a potential therapy for glaucoma.