The Influence of Nonlinear High-Intensity Dynamic Processes on the Standing Wave Precession of a Non-Ideal Hemispherical Resonator.

The properties of small size, low noise, high performance and no wear-out have made the hemispherical resonator gyroscope a good choice for high-value space missions. To enhance the precision of the hemispherical resonator gyroscope for use in tasks with large angular velocities and angular accelerations, this paper investigates the standing wave precession of a non-ideal hemispherical resonator under nonlinear high-intensity dynamic conditions. Based on the thin shell theory of elasticity, a dynamic model of a hemispherical resonator is established by using Lagrange's second kind equation. Then, the dynamic model is equivalently transformed into a simple harmonic vibration model of a point mass in two-dimensional space, which is analyzed using a method of averaging that separates the slow variables from the fast variables. The results reveal that taking the nonlinear terms about the square of the angular velocity and the angular acceleration in the dynamic equation into account can weaken the influence of the 4th harmonic component of a mass defect on standing wave drift, and the extent of this weakening effect varies with the dimensions of the mass defects, which is very important for steering the development of the high-precision hemispherical resonator gyroscope.

Palmatine inhibits expression fat mass and obesity associated protein (FTO) and exhibits a curative effect in dextran sulfate sodium (DSS)-induced experimental colitis.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory disease whose pathogenesis and mechanisms have not been fully described. The m6A methylation modification is a general mRNA modification in mammalian cells and is closely associated with the onset and progression of inflammatory bowel disease (IBD). Palmatine (PAL) is a biologically active alkaloid with anti-inflammatory and protective effects in animal models of colitis. Accordingly, we examined the role of PAL on colitis by regulating N6-methyladenosine (m6A) methylation. METHODS: A rat experimental colitis model was established by 5 % dextran sulfate sodium (DSS) in drinking water for seven days, then PAL treatment was administered for seven days. The colonic tissue pathology was assessed using hematoxylin-eosin (HE) and disease activity index (DAI). In in vitro studies, a human, spontaneously immortalized non-cancerous colon mucosal epithelial cell line (NCM460) was exposed to 2 % DSS and treated with PAL and cell viability was assayed using Cell Counting Kit-8 (CCK-8). The levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA) kits. The level of Zonula occludens-1 (ZO-1) was dectected by immunofluorescence. Transepithelial electrical resistance (TEER) of cells was also assessed. The methyltransferase-like 3 (METTL3), METTL14, AlkB homologate 5 (ALKBH5), and fat mass and obesity-associated protein (FTO) expression levels were assessed by western blotting. The localized expression of m6A was measured by immunofluorescence. RESULTS: PAL significantly prevented bodyweight loss and shortening of the colon in experimental colitis rats, as well as decreasing the DAI and histological damage scores. Furthermore, PAL inhibited the levels of inflammatory factors (TNF-α, IL-6, IL-8, and IL-1ß) in both DSS treated rats and NCM460 cells. In addition, PAL enhanced the expression level of ZO-1, and increased the transepithelial electrical resistance to repaire intestinal barrier dysfunction. Colitis occurred due to decreased m6A levels, and the increased FTO expression led to a colitis phenotype. PAL markedly enhanced the METTL3 and METTL14 expression levels while decreasing ALKBH5 and FTO expression levels. CONCLUSIONS: The findings demonstrated that PAL improved DSS-induced experimental colitis. This effect was associated with inhibiting FTO expression and regulating m6A methylation.

Minocycline-loaded nHAP/PLGA microspheres for prevention of injury-related corneal angiogenesis.

BACKGROUND: Corneal neovascularization (CoNV) threatens vision by disrupting corneal avascularity, however, current treatments, including pharmacotherapy and surgery, are hindered by limitations in efficacy and adverse effects. Minocycline, known for its anti-inflammatory properties, could suppress CoNV but faces challenges in effective delivery due to the cornea's unique structure. Therefore, in this study a novel drug delivery system using minocycline-loaded nano-hydroxyapatite/poly (lactic-co-glycolic acid) (nHAP/PLGA) nanoparticles was developed to improve treatment outcomes for CoNV. RESULTS: Ultra-small nHAP was synthesized using high gravity technology, then encapsulated in PLGA by a double emulsion method to form nHAP/PLGA microspheres, attenuating the acidic by-products of PLGA degradation. The MINO@PLGA nanocomplex, featuring sustained release and permeation properties, demonstrated an efficient delivery system for minocycline that significantly inhibited the CoNV area in an alkali-burn model without exhibiting apparent cytotoxicity. On day 14, the in vivo microscope examination and ex vivo CD31 staining corroborated the inhibition of neovascularization, with the significantly smaller CoNV area (29.40% ± 6.55%) in the MINO@PLGA Tid group (three times daily) than that of the control group (86.81% ± 15.71%), the MINO group (72.42% ± 30.15%), and the PLGA group (86.87% ± 14.94%) (p < 0.05). Fluorescein sodium staining show MINO@PLGA treatments, administered once daily (Qd) and three times daily (Tid) demonstrated rapid corneal epithelial healing while the Alkali injury group and the DEX group showed longer healing times (p < 0.05). Additionally, compared to the control group, treatments with dexamethasone, MINO, and MINO@PLGA were associated with an increased expression of TGF-ß as evidenced by immunofluorescence, while the levels of pro-inflammatory cytokines IL-1ß and TNF-α demonstrated a significant decrease following alkali burn. Safety evaluations, including assessments of renal and hepatic biomarkers, along with H&E staining of major organs, revealed no significant cytotoxicity of the MINO@PLGA nanocomplex in vivo. CONCLUSIONS: The novel MINO@PLGA nanocomplex, comprising minocycline-loaded nHAP/PLGA microspheres, has shown a substantial capacity for preventing CoNV. This study confirms the complex's ability to downregulate inflammatory pathways, significantly reducing CoNV with minimal cytotoxicity and high biosafety in vivo. Given these findings, MINO@PLGA stands as a highly promising candidate for ocular conditions characterized by CoNV.

Development of a novel bioartificial cornea using 3D bioprinting based on electrospun micro-nanofibrous decellularized extracellular matrix.

Corneal damage contributes to blindness in millions of people. Simulating natural corneas with artificial corneas is challenging due to material and manufacturing limitations, including poor mechanical properties, complex manufacturing processes, and ocular histocompatibility. In this study, electrospun micro-nanofibrous decellularized extracellular matrix (dECM) is combined with digital light processing 3D bioprinting and validated as a bioartificial cornea for the first time. Electrospinning gives the material a controllable shape, and the electrospun micro-nanofibrous dECM, with preserved inherent biochemical components, can better mimic the natural ECM native microenvironment. An efficient platform can be developed for creating novel structural materials, when combined with intelligent manufacturing. Artificial biological corneas developed using this method showed five-fold improvements in mechanical properties (248.5 ± 35.67 kPa vs. 56.91 ± 3.68 kPa,p< 0.001), superior guidance for cell organization and adhesion, and better maintenance of the cellular phenotype of keratocytes. In animal studies,in vivotransplantation of this artificial cornea showed better regeneration, which accelerated corneal epithelialization and maintained corneal transparency. This method has potential for biomedical applications, and bioartificial corneas manufactured by this method have ideal properties as an alternative to lamellar keratoplasty, with promise for clinical transformation.

Role of 2-day critical ultrasound training curriculum in guiding clinical activities in China.

BACKGROUND: The effectiveness of critical care ultrasound has been demonstrated and training for it is urgent. Critical Care Ultrasound Study Group (CCUSG) has been dedicated to ultrasound training. The aim of the study was to evaluate course structure and training effect and provide improvement suggestions for future training. METHODS: A multicenter retrospective study was conducted. All participants went through a 2-day training curriculum based on the critical care ultrasonic examination (CCUE) protocol. Pre- and post-class evaluation were applied and data were collected. Non-parametric tests were adopted for the comparison, and a Generalized Linear Model (GLM) was used for further analysis. RESULTS: A total number of 792 trainees, with a mean age of 35.8, participated in the study. There were more males in the study population. Most of the trainees were attendings, and most of them had bachelor's degrees, worked at tertiary hospitals and had a mean working experience of 6.9 years. The scores of all trainees were improved to various degrees after the course. An increase from 50% to 72% (P≤0.001) was seen in theory test scores. All the competency assessment scores, including IAS (34% to 50% for cardiac images and 30% to 60% for pulmonary images), IPS (30% to 50%) and AAS (31% to 44%), were improved. A questionnaire after class suggested that 88.0% of the participants found the training course very useful. CONCLUSION: 2-day training course can improve the ability of physicians to assess critically ill patients with the help of the ultrasound.

A Nutrient-Deficient Microenvironment Facilitates Ferroptosis Resistance via the FAM60A-PPAR Axis in Pancreatic Ductal Adenocarcinoma.

Ferroptosis, a nonapoptotic form of cell death, is an emerging potential therapeutic target for various diseases, including cancer. However, the role of ferroptosis in pancreatic cancer remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and chemotherapy resistance, attributed to its high Kirsten rats arcomaviral oncogene homolog mutation rate and severe nutritional deficits resulting from a dense stroma. Several studies have linked rat sarcoma (RAS) mutations to ferroptosis, suggesting that inducing ferroptosis may be an effective strategy against oncogenic RAS-bearing tumors. We investigated the role of Family With Sequence Similarity 60 Member A (FAM60A) in this study, a protein closely associated with a poor prognosis and highly expressed in PDAC and tumor tissue from KrasG12D/+;Trp53R172H/+; Pdx1-Cre mice, in regulating ferroptosis, tumor growth, and gemcitabine sensitivity in vitro and in vivo. Our results demonstrate that FAM60A regulates 3 essential metabolic enzymes, ACSL1/4 and GPX4, to protect PDAC cells from ferroptosis. Furthermore, we found that YY1 transcriptionally regulates FAM60A expression by promoting its transcription, and the Hippo-YY1 pathway is restricted in the low-amino-acid milieu in the context of nutrient deprivation, leading to downstream suppression of peroxisome proliferator-activated receptor and ACSL1/4 and activation of GPX4 pathways. Importantly, FAM60A knockdown sensitized PDAC cells to gemcitabine treatment. A new understanding of FAM60A transcriptional regulation pattern in PDAC and its dual function in ferroptosis reliever and chemotherapy resistance is provided by our study. Targeting FAM60A may therefore offer a promising therapeutic approach for PDAC by simultaneously addressing 2 major features of the disease (high RAS mutation rate and tumor microenvironment nutrient deficiency) and preventing tumor cell metabolic adaptation.

Hydroxysafflor Yellow A and Tenuigenin Exhibit Neuroprotection Effects Against Focal Cerebral Ischemia Via Differential Regulation of JAK2/STAT3 and SOCS3 Signaling Interaction.

Numerous natural bioactive compounds extracted from Chinese medicines have been proved to be promising and potent agents in the treatment of ischemic stroke. Hydroxysafflor yellow A (HSYA), separated from Carthamus tinctorius, has increasingly attracted attention for its broad spectrum of pharmacological effects, especially of its neuroprotective action. Our previous studies revealed that HSYA plays significant beneficial roles in a dose-dependent manner in rats with focal cerebral ischemia. However, treatment with higher doses of HSYA appeared to bring about adverse reactions in the rats. In present study, we adopted tenuigenin (TEN), extracted from the Polygala tenuifolia root, in combination with HSYA to optimize the therapeutic strategy against ischemic stroke, and further explored the underlying mechanisms of action of the combination in vivo and in vitro. We firstly confirmed the pharmacological efficacies of co-treatment of HSYA and TEN in middle cerebral ischemia occlusion (MCAO) rats and observed the synergistic improvement of infarct volume, cerebral edema, and morphology of neuron cell body. Behavioral experiments indicated that combination of HSYA and TEN could synergistically improve motor and cognitive function in MCAO rats. We also observed increased viability and suppressed cell apoptosis after HSYA and TEN co-treatments in the oxygen-glucose deprivation/reperfusion (OGD/R) SH-SY5Y cells. Furthermore, JAK2/STAT3 and SOCS3 signaling interaction was demonstrated to be a critical responsor to the co-treatment of HSYA and TEN. In the subsequent experiments with silencing SOCS3 in OGD/R-exposed cells, we found that HSYA and TEN might suppress JAK2/STAT3 pathway through different regulatory mechanisms targeting SOCS3-negative feedback signaling. HSYA seemed to impose excessive activation of JAK2/STAT3 to trigger SOCS3-negative feedback signaling, while TEN appeared to provoke SOCS3 inhibitory feedback role directly to further attenuate JAK2-mediated signaling. Collectively, HSYA and TEN might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways in different manners that eventually contributed to their synergistic therapeutic effects against cerebral ischemic stroke.

Unsupervised corneal contour extraction algorithm with shared model for dynamic deformation videos: improving accuracy and noise resistance.

BACKGROUND: In this study, an automatic corneal contour extraction algorithm with a shared model is developed to extract contours from dynamic corneal videos containing noise, which improves the accuracy of corneal biomechanical evaluation and clinical diagnoses. The algorithm does not require manual labeling and completes the unsupervised semantic segmentation of each frame in corneal dynamic deformation videos based on a fully convolutional deep-learning network using corneal geometry and texture information. RESULTS: We included 1027 corneal videos at Tianjin Eye Hospital (Nankai University Affiliated Eye Hospital) from May 2020 to November 2021. The videos were obtained by the ultra-high-speed Scheimpflug camera, and then we used the shared model mechanism to accelerate the segmentation of corneal regions in videos, effectively resist noise, determine corneal regions based on shape factors, and finally achieve automatic and accurate extraction of corneal region contours. The Intersection over Union (IoU) of the extracted and real corneal contours using this algorithm reached 95%, and the average overlap error was 0.05, implying that the extracted corneal contour overlapped almost completely with the real contour. CONCLUSIONS: Compared to other algorithms, the method introduced in this study does not require manual annotation of corneal contour data in advance and can still extract accurate corneal contours from noisy corneal videos with good repeatability.

Prediction of immune infiltration and prognosis for patients with cholangiocarcinoma based on a cuproptosis-related lncRNA signature.

Objective: Cholangiocarcinoma (CHOL) is a malignant disease that affects the digestive tract, and it is characterized by a poor prognosis. This research sought to explore the involvement of cuproptosis-related lncRNAs (CRLs) in the prognostic prediction and immune infiltration of cholangiocarcinoma. Methods: The expression profiles and clinical data of CHOL patients were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and CRLs were defined via co-expression analysis. Two molecular clusters distinguished by cuproptosis-related genes (CRGs) were produced. Then a risk signature consisted by four CRLs was formed, and all samples were separated into low- and high-risk groups using a risk score. Kaplan-Meier survival analysis, principal component analysis, differentially expressed analysis, immune cell infiltration analysis, and sensitivities analysis of chemotherapy drugs were conducted between the two groups. Simultaneously, the expression values of four lncRNAs confirmed by real-time PCR in our own 20 CHOL samples were brought into the risk model. Results: The CHOL samples could be differentiated into two molecular clusters, which displayed contrasting survival times. Additionally, patients with higher risk scores had significantly worse prognosis compared to those in the low-risk group. Furthermore, both immune infiltration and enrichment analysis revealed significant discrepancies in the tumor immune microenvironment (TIME) between different risk groups. Moreover, the predictive power and the correlation with CA19-9 and CEA of risk signature were validated in our own samples. Conclusion: We developed a risk signature which could serve as an independent prognostic factor and offer a promising prediction for not only prognosis but also TIME in CHOL patients.

Identifying hub genes of sepsis-associated and hepatic encephalopathies based on bioinformatic analysis-focus on the two common encephalopathies of septic cirrhotic patients in ICU.

BACKGROUND: In the ICU ward, septic cirrhotic patients are susceptible to suffering from sepsis-associated encephalopathy and/or hepatic encephalopathy, which are two common neurological complications in such patients. However, the mutual pathogenesis between sepsis-associated and hepatic encephalopathies remains unclear. We aimed to identify the mutual hub genes, explore effective diagnostic biomarkers and therapeutic targets for the two common encephalopathies and provide novel, promising insights into the clinical management of such septic cirrhotic patients. METHODS: The precious human post-mortem cerebral tissues were deprived of the GSE135838, GSE57193, and GSE41919 datasets, downloaded from the Gene Expression Omnibus database. Furthermore, we identified differentially expressed genes and screened hub genes with weighted gene co-expression network analysis. The hub genes were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analyses, and protein-protein interaction networks were constructed. Receiver operating characteristic curves and correlation analyses were set up for the hub genes. Finally, we explored principal and common signaling pathways by using Gene Set Enrichment Analysis and the association between the hub genes and immune cell subtype distribution by using CIBERSORT algorithm. RESULTS: We identified seven hub genes-GPR4, SOCS3, BAG3, ZFP36, CDKN1A, ADAMTS9, and GADD45B-by using differentially expressed gene analysis and weighted gene co-expression network analysis method. The AUCs of these genes were all greater than 0.7 in the receiver operating characteristic curves analysis. The Gene Set Enrichment Analysis results demonstrated that mutual signaling pathways were mainly enriched in hypoxia and inflammatory response. CIBERSORT indicated that these seven hub genes were closely related to innate and adaptive immune cells. CONCLUSIONS: We identified seven hub genes with promising diagnostic value and therapeutic targets in septic cirrhotic patients with sepsis-associated encephalopathy and/or hepatic encephalopathy. Hypoxia, inflammatory, and immunoreaction responses may share the common downstream pathways of the two common encephalopathies, for which earlier recognition and timely intervention are crucial for management of such septic cirrhotic patients in ICU.

Associations between lipid-lowering drugs and pregnancy and perinatal outcomes: a Mendelian randomization study.

INTRODUCTION: Mounting evidence has indicated that maternal dyslipidemia is associated with adverse obstetric outcomes, and the actions of lipid-lowering drugs in pregnant women remain controversial. Hence, this study aimed to appraise the causal relationship of lipid-lowering drugs [hydroxymethylglutaryl-coenzyme reductase (HMGCR) inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors] with pregnancy and perinatal outcomes using drug-targeting Mendelian randomization analysis. METHODS: As a proxy for lipid-lowering drug exposure, two genetic instruments were used: genetic variants within or near the gene linked to low-density lipoprotein cholesterol (LDL-C) and the expression of quantitative trait loci of the drug target gene. Effect estimates were calculated using the inverse variance weighting (IVW) method and summary data-based Mendelian randomization (SMR) method. Heterogeneity and pleiotropy were assessed by Mendelian randomization-Egger regression, the Cochran Q test, and MR-PRESSO analysis. RESULTS: HMGCR inhibitors were ascribed to a reduced risk of preeclampsia in both the IVW-MR method [odds ratio (OR) 0.583; 95% confidence interval (CI) 0.418-0.812; P  = 0.001] and SMR analysis (OR 0.816; 95% CI 0.675-0.986; P  = 0.036). The causal link between HMGCR inhibitors and offspring birthweight was statistically significant only in the analysis using the IVW method (OR, 0.879; 95% CI, 0.788-0.980; P  = 0.020), and the combined results of the OR values supported the potential inhibitory effect of HMGCR inhibitors on offspring birthweight. Causal associations between lipid-lowering drugs and gestational diabetes, preterm birth, and congenital anomalies were not detected in either analysis. CONCLUSION: No causal associations were observed between lipid-lowering drugs and gestational diabetes, preterm birth or congenital anomalies, whereas genetically predicted HMGCR inhibition dramatically reduced the risk of preeclampsia but attenuated offspring birthweight.

Corneal Biomechanical Properties to Predict Prognosis of Abnormal Tomographic Corneas: A Prospective Cohort Study.

PURPOSE: To analyze the corneal biomechanical properties in patients with abnormal corneal tomography (ACT) and predict their stability using the biomechanical stability index (BSI). DESIGN: Prospective cohort study. METHODS: Setting: Multicenter study. STUDY POPULATION: This study included 385 eyes of 278 patients with stable ACT (n = 70), subclinical keratoconus (SKC, n = 65), keratoconus (n = 65), normal controls (NL, n = 142). Forty-three eyes with first-visit ACT were included in a separate cohort (follow-up ACT group). OBSERVATION PROCEDURE: Tomographical and biomechanical parameters (Pentacam and Corvis ST) were recorded. MAIN OUTCOME MEASURES: Nonparametric tests were used for comparison. Logistic regression was employed to introduce BSI to separate stable ACT and SKC accurately. An independent dataset of 43 first-visit ACT eyes was followed up for 1 year to validate BSI's accuracy and positive and negative predictive values (PPV, NPV). RESULTS: The tomographical and biomechanical parameters in patients with Stable ACT remained stable over the follow-up period (12.73 ± 2.57 months, P > .05). Stable ACT had 12/14 biomechanical parameters different (P < .05) from SKC but not different from NL (P > .05). With a cut-off value of 0.585, BSI demonstrated the strongest ability to distinguish between stable ACT and SKC (area under the receiver operating characteristic curve = 0.991), with 93.85% sensitivity and 97.14% specificity. During the 1-year follow-up of 43 eyes (follow-up ACT group), 30 remained stable. The accuracy, PPV, and NPV of the BSI were 95.35%, 100%, and 93.75%, respectively. CONCLUSIONS: Biomechanical properties of patients with stable abnormal tomography corneas were stronger than SKC and close to normal corneas, which may explain the reason for tomographic stability. The BSI may be useful for predicting disease progression in patients with ACT and the possible management of corneal cross-linking at the first visit.

Corneal biomechanics in early diagnosis of keratoconus using artificial intelligence.

Keratoconus is a blinding eye disease that affects activities of daily living; therefore, early diagnosis is crucial. Great efforts have been made toward an early diagnosis of keratoconus. Recent studies have shown that corneal biomechanics is associated with the occurrence and progression of keratoconus. Hence, detecting changes in corneal biomechanics may provide a novel strategy for early diagnosis. However, an early keratoconus diagnosis remains challenging due to the subtle and localized nature of its lesions. Artificial intelligence has been used to help address this problem. Herein, we reviewed the literature regarding three aspects of keratoconus (keratoconus, early keratoconus, and keratoconus grading) based on corneal biomechanical properties using artificial intelligence. Furthermore, we summarized the current research progress, limitations, and possible prospects.

Central venous pressure combined with renal venous impedance index in predicting the acute kidney injury after thoracic and abdominal (non-cardiac) surgery.

BACKGROUND: In the 21st century, 13% of patients undergoing open abdominal surgery, 25% of patients undergoing heart surgery, and 57% of patients admitted to the intensive care unit (ICU) are affected by acute kidney injury (AKI). METHODS: This prospective observational study included patients admitted directly to the ICU between June 2021 and December 2021. RESULTS: A total of 81 patients were enrolled after thoracic and abdominal (non-cardiac) surgery; 36 patients (44.4%) were diagnosed with AKI occurred within 7 days after surgery. Six-hour postoperative central venous pressure(CVP) was a risk factor for AKI in thoracic and abdominal (non-cardiac) postoperative patients (odds ratio [OR], 1.418; 95% confidence intervals [CI], 1.106-1.819; P = 0.006). Six-hour postoperative vein impedance index(VII) and CVP were significantly positively correlated (P = 0.031). The combination of 6-h postoperative VII with CVP (VII ≥0.34, CVP ≥7.5 mmHg) showed an area under the curve (AUC) of 0.787, In the subgroup analysis of patients with 6-h postoperative CVP <7.5 mmHg, there was a significant statistical difference in 6-h postoperative VII between the groups and those without AKI (P = 0.048). At 6-h postoperative CVP <7.5 mmHg, VII of ≥0.44 had a predictive value for AKI after thoracic and abdominal (non-cardiac) surgery, with an AUC of 0.669, a sensitivity of 41.2%, and a specificity of 94.4%. CONCLUSION: Six-hour postoperative CVP combined with VII can better predict the occurrence of AKI occurred within 7 days after thoracic and abdominal (non-cardiac) surgery but cannot predict the severity of AKI.

Roles of Apigenin and Nepetin in the Assembly Behavior and Cytotoxicity of Prion Neuropeptide PrP106-126.

Development of potential inhibitors to prevent prion protein (PrP) fibrillation is a therapeutic strategy for prion diseases. The prion neuropeptide PrP106-126, a research model of abnormal PrP (PrPSc), presents similar physicochemical and biochemical characters to PrPSc, which is also a target of potential inhibitors against prion deposition. Many flavones have antioxidant, anti-inflammatory, and antibacterial properties, and they are applied in treating prion disorder and other amyloidosis as well. However, the inhibition mechanism of flavones on PrP106-126 fibrillation is still unclear. In the current work, apigenin and nepetin were used to suppress the aggregation of PrP106-126 and to alleviate the peptide-induced cytotoxicity. The results showed that apigenin and nepetin impeded the fibril formation of PrP106-126 and depolymerized the preformed fibrils. They were bound to PrP106-126 predominantly by hydrophobic and hydrogen bonding interactions. In addition, both flavones upregulated cell viability and decreased membrane leakage through reducing peptide oligomerization. The differences in inhibition and cell protection between the two small molecules were presumably attributed to the substitution of hydroxyl and methoxy groups in nepetin, which demonstrated the significant structure-function relationship of flavones with prion neuropeptide and the prospect of flavonoids as drug candidates against prion diseases.

Traditional Chinese medicine for the prevention and treatment of presbycusis.

Background: Presbycusis/Age-related hearing loss is a sensorineural hearing loss caused by age-related deterioration of the auditory system that poses a risk to the physical and mental health of older people, including social and cognitive decline. It is also associated with frailty, falls and depression. There are currently no specific medications for the treatment of presbycusis, and early detection and intervention are key to its prevention and management. Traditional Chinese medicine interventions may offer opportunities in the prevention and treatment of presbycusis, but there is no relevant review. Methods: Literature searches was conducted using PubMed, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) databases for review articles, research articles, clinical trials, meta-analyses, and case studies in animal models and clinical trials. Results: We summarized the pathological mechanisms associated with presbycusis, related to genetic factors, environment, lifestyle, and molecular mechanisms related to oxidative stress, mitochondrial dysfunction, and inflammatory pathways. It is suggested that traditional Chinese medicine interventions may offer opportunities in the prevention and treatment of presbycusis using active ingredients of herbs or formulas, acupuncture, and exercise such as Tai Chi Chuan or Ba Duan Jin. The active ingredients of herbs or formulas may exert ear protection through Nrf2-mediated antioxidant pathways, NF-kB and NLRP3-related anti-inflammatory signaling, and regulation of autophagy. Conclusions: Here, we review the pathogenetic factors and pathological mechanisms involved in presbycusis, as well as traditional Chinese medicine interventions and treatments, with the aim of providing a new perspective for the prevention and treatment of hearing loss in the elderly and further improving their quality of life.

A hybrid algorithm of grey wolf optimizer and harris hawks optimization for solving global optimization problems with improved convergence performance.

The grey wolf optimizer is an effective and well-known meta-heuristic algorithm, but it also has the weaknesses of insufficient population diversity, falling into local optimal solutions easily, and unsatisfactory convergence speed. Therefore, we propose a hybrid grey wolf optimizer (HGWO), based mainly on the exploitation phase of the harris hawk optimization. It also includes population initialization with Latin hypercube sampling, a nonlinear convergence factor with local perturbations, some extended exploration strategies. In HGWO, the grey wolves can have harris hawks-like flight capabilities during position updates, which greatly expands the search range and improves global searchability. By incorporating a greedy algorithm, grey wolves will relocate only if the new location is superior to the current one. This paper assesses the performance of the hybrid grey wolf optimizer (HGWO) by comparing it with other heuristic algorithms and enhanced schemes of the grey wolf optimizer. The evaluation is conducted using 23 classical benchmark test functions and CEC2020. The experimental results reveal that the HGWO algorithm performs well in terms of its global exploration ability, local exploitation ability, convergence speed, and convergence accuracy. Additionally, the enhanced algorithm demonstrates considerable advantages in solving engineering problems, thus substantiating its effectiveness and applicability.

Localized Corneal Biomechanical Alteration Detected In Early Keratoconus Based on Corneal Deformation Using Artificial Intelligence.

PURPOSE: This study aimed to develop a novel method to diagnose early keratoconus by detecting localized corneal biomechanical changes based on dynamic deformation videos using machine learning. DESIGN: Diagnostic research study. METHODS: We included 917 corneal videos from the Tianjin Eye Hospital (Tianjin, China) and Shanxi Eye Hospital (Xi'an, China) from February 6, 2015, to August 25, 2022. Scheimpflug technology was used to obtain dynamic deformation videos under forced puffs of air. Fourteen new pixel-level biomechanical parameters were calculated based on a spline curve equation fitting by 115,200-pixel points from the corneal contour extracted from videos to characterize localized biomechanics. An ensemble learning model was developed, external validation was performed, and the diagnostic performance was compared with that of existing clinical diagnostic indices. The performance of the developed machine learning model was evaluated using precision, recall, F1 score, and the area under the receiver operating characteristic curve. RESULTS: The ensemble learning model successfully diagnosed early keratoconus (area under the curve = 0.9997) with 95.73% precision, 95.61% recall, and 95.50% F1 score in the sample set (n=802). External validation on an independent dataset (n=115) achieved 91.38% precision, 92.11% recall, and 91.18% F1 score. Diagnostic accuracy was significantly better than that of existing clinical diagnostic indices (from 86.28% to 93.36%, all P <0.01). CONCLUSIONS: Localized corneal biomechanical changes detected using dynamic deformation videos combined with machine learning algorithms were useful for diagnosing early keratoconus. Focusing on localized biomechanical changes may guide ophthalmologists, aiding the timely diagnosis of early keratoconus and benefiting the patient's vision.

Immunity-and-matrix-regulatory cells enhance cartilage regeneration for meniscus injuries: a phase I dose-escalation trial.

Immunity-and-matrix-regulatory cells (IMRCs) derived from human embryonic stem cells have unique abilities in modulating immunity and regulating the extracellular matrix, which could be mass-produced with stable biological properties. Despite resemblance to mesenchymal stem cells (MSCs) in terms of self-renew and tri-lineage differentiation, the ability of IMRCs to repair the meniscus and the underlying mechanism remains undetermined. Here, we showed that IMRCs demonstrated stronger immunomodulatory and pro-regenerative potential than umbilical cord MSCs when stimulated by synovial fluid from patients with meniscus injury. Following injection into the knees of rabbits with meniscal injury, IMRCs enhanced endogenous fibrocartilage regeneration. In the dose-escalating phase I clinical trial (NCT03839238) with eighteen patients recruited, we found that intra-articular IMRCs injection in patients was safe over 12 months post-grafting. Furthermore, the effective results of magnetic resonance imaging (MRI) of meniscus repair and knee functional scores suggested that 5 × 107 cells are optimal for meniscus injury treatment. In summary, we present the first report of a phase I clinical trial using IMRCs to treat meniscus injury. Our results demonstrated that intra-articular injection of IMRCs is a safe and effective therapy by providing a permissive niche for cartilage regeneration.

Attention-Assisted Feature Comparison and Feature Enhancement for Class-Agnostic Counting.

In this study, we address the class-agnostic counting (CAC) challenge, aiming to count instances in a query image, using just a few exemplars. Recent research has shifted towards few-shot counting (FSC), which involves counting previously unseen object classes. We present ACECount, an FSC framework that combines attention mechanisms and convolutional neural networks (CNNs). ACECount identifies query image-exemplar similarities, using cross-attention mechanisms, enhances feature representations with a feature attention module, and employs a multi-scale regression head, to handle scale variations in CAC. ACECount's experiments on theFSC-147 dataset exhibited the expected performance. ACECount achieved a reduction of 0.3 in the mean absolute error (MAE) on the validation set and a reduction of 0.26 on the test set of FSC-147, compared to previous methods. Notably, ACECount also demonstrated convincing performance in class-specific counting (CSC) tasks. Evaluation on crowd and vehicle counting datasets revealed that ACECount surpasses FSC algorithms like GMN, FamNet, SAFECount, LOCA, and SPDCN, in terms of performance. These results highlight the robust dataset generalization capabilities of our proposed algorithm.