HIF-1 Transcriptionally Regulates Basal Expression of STING to Maintain Cellular Innate Immunity.

Stimulator of IFN genes (STING) is a critical component of the innate immune system, playing an essential role in defending against DNA virus infections. However, the mechanisms governing basal STING regulation remain poorly understood. In this study, we demonstrate that the basal level of STING is critically maintained by hypoxia-inducible factor 1 (HIF-1)α through transcription. Under normal conditions, HIF-1α binds constitutively to the promoter region of STING, actively promoting its transcription. Knocking down HIF-1α results in a decrease in STING expression in multiple cell lines and zebrafish, which in turn reduces cellular responses to synthetic dsDNAs, including cell signaling and IFN production. Moreover, this decrease in STING levels leads to an increase in cellular susceptibility to DNA viruses HSV-1 and pseudorabies virus. These findings unveil a (to our knowledge) novel role of HIF-1α in maintaining basal STING levels and provide valuable insights into STING-mediated antiviral activities and associated diseases.

Polyvinylpyrrolidone-Coated Cubic Hollow Nanocages of PdPt3 and PdIr3 as Highly Efficient Self-Cascade Uricase/Peroxidase Mimics.

Uricase-catalyzed uric acid (UA) degradation has been applied for hyperuricemia therapy, but this medication is limited by H2O2 accumulation, which can cause oxidative stress of cells, resulting in many other health issues. Herein, we report a robust cubic hollow nanocage (HNC) system based on polyvinylpyrrolidone-coated PdPt3 and PdIr3 to serve as highly efficient self-cascade uricase/peroxidase mimics to achieve the desired dual catalysis for both UA degradation and H2O2 elimination. These HNCs have hollow cubic shape with average wall thickness of 1.5 nm, providing desired synergy to enhance catalyst's activity and stability. Density functional theory calculations suggest the PdIr3 HNC surface tend to promote OH*/O* desorption for better peroxidase-like catalysis, while the PdPt3 HNC surface accelerates the UA oxidation by facilitating O2-to-H2O2 conversion. The dual catalysis power demonstrated by these HNCs in cell studies suggests their great potential as a new type of nanozyme for treating hyperuricemia.

Interaction of immune cells with renal cancer development: Mendelian randomization (MR) study.

BACKGROUND: Renal cell carcinoma (RCC) is a prevalent and extensively immune-infiltrated malignancy of the urinary system. Immune cells play a crucial role in both the progression and therapeutic interventions targeting RCC. Nevertheless, the interplay between RCC and immune cells remains understudied, lacking substantial evidence supporting their causal relationship. METHODS: For the purpose of investigating the causal connection between RCC and immune cell characteristics, a two-way two-sample Mendelian randomization (MR) analysis was carried out in this study. The aim was to determine whether specific immune cell traits have a causal impact on the risk of RCC. In order to achieve this, publicly accessible genetic data was utilized to examine and establish the potential relationship between 731 immune cell characteristics and the likelihood of developing RCC. Additionally, various techniques were applied to verify the reliability, variability, and presence of horizontal pleiotropy in the outcomes. RESULTS: We found a bidirectional causal relationship between RCC and immune cells according to the MR analysis results. It should be noted that CD4-CD8-T cells (OR = 1.61, 95%CI = 1.02-2.55, P = 4.07 × 10-2) pose a risk for RCC, whereas BAFF-R (OR = 0.69, 95%CI = 0.53-0.89, P = 5.74 × 10-3) and CD19 (OR = 0.59, 95%CI = 1.02-2.55, P = 4.07 × 10-2) on B cells act as protective factors. Furthermore, the presence of RCC reduces the levels of B cells (OR = 1.05, 95%CI = 1.01-1.09, P = 1.19 × 10-2) and CD8 + T cells (OR = 1.04, 95%CI = 1.00-1.08, P = 2.83 × 10-2). CONCLUSIONS: Our research illustrates the intricate correlation between immune cells and RCC, presenting novel insights for the prospective safeguarding against RCC risk and the exploration of fresh therapeutic targets.

Influence of Imbibition Fracturing Fluid on the Original Water and Methane Occurrence in Actual Coalbed Methane Reservoirs Using the Integrated Device of Displacement and Low-Field Nuclear Magnetic Resonance.

The original water in the coal rock pores plays a controlling role in the occurrence of gas. Furthermore, during the hydraulic fracturing process, pressurized fracturing fluid with a higher pressure than the original pore pressure in the fractures drives the fracturing fluid to infiltrate into the coal rock pores, thereby altering the occurrence pattern of gas and water in the original pores. However, due to the limitations of the indoor simulation device, a systematic conclusion on the impact of the original pore water and imbibition fracturing fluid on coalbed methane reservoirs has not yet been formed. In this paper, an integrated device combining displacement and low-field nuclear magnetic resonance was employed using underground cylindrical coal rock samples as experimental subjects. Experimental conditions were maintained at a temperature of 30 °C, a confining pressure of 23 MPa, and an approximate reservoir pressure of 15 MPa. The initial water saturation levels were altered to 0, 27.88, and 42.18% to replicate the conditions of a coalbed methane reservoir at a depth of approximately 1200 m. Fracturing fluid with a pressure of 18 MPa was injected into the experimental samples to simulate the impact of the fracturing fluid on the original reservoir during hydraulic fracturing. This allowed for a realistic assessment of the influence of initial water saturation and fracturing fluid absorption on the coalbed methane recovery rate in the reservoir. The experimental results indicate that the imbibition process promotes the desorption of adsorbed gas, and the desorption amount of adsorbed gas increases with the increase in the original water saturation. This will result in an increase in the gas pressure within the pore system. The conditions of this experiment, in comparison to the previous ones, more closely resemble real reservoir conditions. This enables a realistic assessment of how the presence of the original water content and the absorption of the fracturing fluid affect gas occurrence within the reservoir.

The Role of Long Noncoding RNAs in Vascular Smooth Muscle Cell Phenotype and the Pathogenesis of Cardiovascular and Cerebrovascular Aneurysms.

ABSTRACT: Aneurysms are localized dilations of blood vessels, which can expand to 50% of the original diameter. They are more common in cardiovascular and cerebrovascular vessels. Rupture is one of the most dangerous complications. The pathophysiology of aneurysms is complex and diverse, often associated with progressive vessel wall dysfunction resulting from vascular smooth muscle cell death and abnormal extracellular matrix synthesis and degradation. Multiple studies have shown that long noncoding RNAs (lncRNAs) play a significant role in the progression of cardiovascular and cerebrovascular diseases. Therefore, it is necessary to find and summarize them. LncRNAs control gene expression and disease progression by regulating target mRNA or miRNA and are biomarkers for the diagnosis and prognosis of aneurysmal cardiovascular and cerebrovascular diseases. This review explores the role, mechanism, and clinical value of lncRNAs in aneurysms, providing new insights for a deeper understanding of the pathogenesis of cardiovascular and cerebrovascular aneurysms.

Two High-Nuclear Wheel-Hub-Shaped Transition-Metal-Doped Polyoxovanadates.

The first two unprecedented high-nuclear wheel-hub-shaped transition-metal-doped polyoxovanadates, [M8Mo4W4V20P20] [M = Ni (1), Co (2)], have been assembled under solvothermal conditions. The center of the cluster consists of two {Ni4(oa)4} rings as the center hole, four {MoO4} units acting as the spokes, and four {WV5(PPOA)5} molecular building blocks serving as the tire. Compound 1 exhibits good catalytic properties and recyclability in oxidative desulfurization reactions.

An analysis of differences in Carbapenem-resistant Enterobacterales in different regions: a multicenter cross-sectional study.

OBJECTIVE: This study aimed to explore the characteristics of carbapenem-resistant Enterobacterales (CRE) patients in the intensive care unit (ICU) in different regions of Henan Province to provide evidence for the targeted prevention and treatment of CRE. METHODS: This was a cross-sectional study. CRE screening was conducted in the ICUs of 78 hospitals in Henan Province, China, on March 10, 2021. The patients were divided into provincial capital hospitals and nonprovincial capital hospitals for comparative analysis. RESULTS: This study involved 1009 patients in total, of whom 241 were CRE-positive patients, 92 were in the provincial capital hospital and 149 were in the nonprovincial capital hospital. Provincial capital hospitals had a higher rate of CRE positivity, and there was a significant difference in the rate of CRE positivity between the two groups. The body temperature; immunosuppressed state; transfer from the ICU to other hospitals; and use of enemas, arterial catheters, carbapenems, or tigecycline at the provincial capital hospital were greater than those at the nonprovincial capital hospital (P < 0.05). However, there was no significant difference in the distribution of carbapenemase strains or enzymes between the two groups. CONCLUSIONS: The detection rate of CRE was significantly greater in provincial capital hospitals than in nonprovincial capital hospitals. The source of the patients, invasive procedures, and use of advanced antibiotics may account for the differences. Carbapenem-resistant Klebsiella pneumoniae (CR-KPN) was the most prevalent strain. Klebsiella pneumoniae carbapenemase (KPC) was the predominant carbapenemase enzyme. The distributions of carbapenemase strains and enzymes were similar in different regions.

Evaluation of antioxidant, antidiabetic and antiobesity potential of phenylpropanoids (PPs): Structure-activity relationship and insight into action mechanisms against dual digestive enzymes by comprehensive technologies.

Phenylpropanoids (PPs), a group of natural compounds characterized by one or more C6-C3 units, have exhibited considerable potential in addressing metabolic disease. However, the comprehensive investigation on the relationship of compound structures and involved activity, along with the action mechanisms on the drug target is absent. This study aimed to evaluate the antioxidant and inhibitory activities of 16 PPs against two digestive enzymes, including α-glucosidase and pancreatic lipase, explore the structure-activity relationships and elucidate the mechanisms underlying enzyme inhibition. The findings revealed the similarities in the rules governing antioxidant and enzyme inhibitory activities of PPs. Specifically, the introduction of hydroxyl groups generally exerted positive effects on the activities, while the further methoxylation and glycosylation were observed to be unfavorable. Among the studied PPs, esculetin exhibited the most potent antioxidant activity and dual enzymes inhibition potential, displaying IC50 values of 0.017 and 0.0428 mM for DPPH and ABTS radicals scavenging, as well as 1.36 and 6.67 mM for α-glucosidase and lipase inhibition, respectively. Quantification analysis indicated esculetin bound on both α-glucosidase and lipase successfully by a mixed-type mode. Further analyses by UV-Vis, FT-IR, fluorescence spectra, surface hydrophobicity, SEM, and molecular docking elucidated that esculetin could bind on the catalytic or non-catalytic sites of enzymes to form complex, impacting the normal spatial conformation for hydrolyzing the substrate, thus exhibiting the weakened activity. These results may shed light on the utilization value of natural PPs for the management of hyperglycemia and hyperlipemia, and afford the theoretical basis for designing drugs with stronger inhibition against the dual digestive enzymes based on esculetin.

Constrained motion of self-propelling eccentric disks linked by a spring.

It has been supposed that the interplay of elasticity and activity plays a key role in triggering the non-equilibrium behaviors in biological systems. However, the experimental model system is missing to investigate the spatiotemporally dynamical phenomena. Here, a model system of an active chain, where active eccentric-disks are linked by a spring, is designed to study the interplay of activity, elasticity, and friction. Individual active chain exhibits longitudinal and transverse motions; however, it starts to self-rotate when pinning one end and self-beat when clamping one end. In addition, our eccentric-disk model can qualitatively reproduce such behaviors and explain the unusual self-rotation of the first disk around its geometric center. Furthermore, the structure and dynamics of long chains were studied via simulations without steric interactions. It was found that a hairpin conformation emerges in free motion, while in the constrained motions, the rotational and beating frequencies scale with the flexure number (the ratio of self-propelling force to bending rigidity), χ, as ∼(χ)4/3. Scaling analysis suggests that it results from the balance between activity and energy dissipation. Our findings show that topological constraints play a vital role in non-equilibrium synergy behaviors.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Bioresponsive nanocomplex integrating cancer-associated fibroblast deactivation and immunogenic chemotherapy for rebuilding immune-excluded tumors.

Cancer-associated fibroblasts (CAFs) play a crucial role in creating an immunosuppressive environment and remodeling the extracellular matrix within tumors, leading to chemotherapy resistance and limited immune cell infiltration. To address these challenges, integrating CAFs deactivation into immunogenic chemotherapy may represent a promising approach to the reversal of immune-excluded tumor. We developed a tumor-targeted nanomedicine called the glutathione-responsive nanocomplex (GNC). The GNC co-loaded dasatinib, a CAF inhibitor, and paclitaxel, a chemotherapeutic agent, to deactivate CAFs and enhance the effects of immunogenic chemotherapy. Due to the modification with hyaluronic acid, the GNC preferentially accumulated in the tumor periphery and responsively released cargos, mitigating the tumor stroma as well as overcoming chemoresistance. Moreover, GNC treatment exhibited remarkable immunostimulatory efficacy, including CD8+ T cell expansion and PD-L1 downregulation, facilitating immune checkpoint blockade therapy. In summary, the integration of CAF deactivation and immunogenic chemotherapy using the GNC nanoplatform holds promise for rebuilding immune-excluded tumors.

ZmSMR10 Increases the Level of Endoreplication of Plants through Its Interactions with ZmPCNA2 and ZmCSN5B.

As a plant-specific endoreplication regulator, the SIAMESE-RELATED (SMR) family (a cyclin-dependent kinase inhibitor) plays an important role in plant growth and development and resistance to stress. Although the genes of the maize (Zea mays) SMR family have been studied extensively, the ZmSMR10 (Zm00001eb231280) gene has not been reported. In this study, the function of this gene was characterized by overexpression and silencing. Compared with the control, the transgenic plants exhibited the phenotypes of early maturation, dwarfing, and drought resistance. Expression of the protein in prokaryotes demonstrates that ZmSMR10 is a small protein, and the results of subcellular localization suggest that it travels functionally in the nucleus. Unlike ZmSMR4, yeast two-hybrid experiments demonstrated that ZmSMR10 does not interact strongly with with some cell cycle protein-dependent protein kinase (CDK) family members ZmCDKA;1/ZmCDKA;3/ZmCDKB1;1. Instead, it interacts strongly with ZmPCNA2 and ZmCSN5B. Based on these results, we concluded that ZmSMR10 is involved in the regulation of endoreplication through the interaction of ZmPCNA2 and ZmCSN5B. These findings provide a theoretical basis to understand the mechanism of the regulation of endoreplication and improve the yield of maize through the use of molecular techniques.

[Seminal vesiculoscopy-assisted thulium laser ablation for the treatment of ejaculatory duct obstruction: An analysis of clinical outcomes].

OBJECTIVE: To evaluate the clinical outcomes of seminal vesiculoscopy-assisted thulium laser ablation (SVS-TLA) in the treatment of oligoasthenozoospermia or azoospermia induced by ejaculatory duct obstruction (EDO). METHODS: We retrospectively analyzed the clinical data on 42 cases of EDO-induced oligoasthenozoospermia or azoospermia in our Clinic of Andrology from April 2018 to January 2020, all definitely diagnosed and treated by SVS-TLA. We followed up the patients regularly after operation, obtained their routine semen parameters at 3, 6 and 9 months postoperatively, examined them by t-test and compared them with the baseline. RESULTS: Operations were successfully completed in all the 42 cases, with an average surgery time of 52.7 minutes. Compared with the routine semen parameters collected 2 weeks before surgery, the semen volume, sperm concentration and total sperm motility of the patients were all significantly improved at 3, 6 and 9 months postoperatively (P < 0.01). Sperm were found in 40 cases at 3 months and in the other 2 cases at 6 and 9 months after surgery. Postoperative complications were observed in 7 cases, including epididymitis, perineal or testicular pain, and hematuria, which all disappeared after corresponding symptomatic treatment. No such serious complications as retrograde ejaculation, rectal injury, urethral stricture or urinary incontinence occurred in any of the cases after operation. CONCLUSION: SVS-TLA is a safe and effective option for the treatment of EDO, which can significantly improve the semen quality of the patient without causing serious postoperative complications.

EMCMDA: predicting miRNA-disease associations via efficient matrix completion.

Abundant researches have consistently illustrated the crucial role of microRNAs (miRNAs) in a wide array of essential biological processes. Furthermore, miRNAs have been validated as promising therapeutic targets for addressing complex diseases. Given the costly and time-consuming nature of traditional biological experimental validation methods, it is imperative to develop computational methods. In the work, we developed a novel approach named efficient matrix completion (EMCMDA) for predicting miRNA-disease associations. First, we calculated the similarities across multiple sources for miRNA/disease pairs and combined this information to create a holistic miRNA/disease similarity measure. Second, we utilized this biological information to create a heterogeneous network and established a target matrix derived from this network. Lastly, we framed the miRNA-disease association prediction issue as a low-rank matrix-complete issue that was addressed via minimizing matrix truncated schatten p-norm. Notably, we improved the conventional singular value contraction algorithm through using a weighted singular value contraction technique. This technique dynamically adjusts the degree of contraction based on the significance of each singular value, ensuring that the physical meaning of these singular values is fully considered. We evaluated the performance of EMCMDA by applying two distinct cross-validation experiments on two diverse databases, and the outcomes were statistically significant. In addition, we executed comprehensive case studies on two prevalent human diseases, namely lung cancer and breast cancer. Following prediction and multiple validations, it was evident that EMCMDA proficiently forecasts previously undisclosed disease-related miRNAs. These results underscore the robustness and efficacy of EMCMDA in miRNA-disease association prediction.

The effects of exercise on epigenetic modifications: focus on DNA methylation, histone modifications and non-coding RNAs.

Physical activity on a regular basis has been shown to bolster the overall wellness of an individual; research is now revealing that these changes are accompanied by epigenetic modifications. Regular exercise has been proven to make intervention plans more successful and prolong adherence to them. When it comes to epigenetic changes, there are four primary components. This includes changes to the DNA, histones, expression of particular non-coding RNAs and DNA methylation. External triggers, such as physical activity, can lead to modifications in the epigenetic components, resulting in changes in the transcription process. This report pays attention to the current knowledge that pertains to the epigenetic alterations that occur after exercise, the genes affected and the resulting characteristics.

The emerging roles of glutamine amidotransferases in metabolism and immune defense.

Glutamine amidotransferases (GATs) catalyze the synthesis of nucleotides, amino acids, glycoproteins and an enzyme cofactor, thus serving as key metabolic enzymes for cell proliferation. Carbamoyl-phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is a multifunctional enzyme of the GAT family and catalyzes the first three steps of the de novo pyrimidine synthesis. Following our findings that cellular GATs are involved in immune evasion during herpesvirus infection, we discovered that CAD reprograms cellular metabolism to fuel aerobic glycolysis and nucleotide synthesis via deamidating RelA. Deamidated RelA activates the expression of key glycolytic enzymes, rather than that of the inflammatory NF-κB-responsive genes. As such, cancer cells prime RelA for deamidation via up-regulating CAD activity or accumulating RelA mutations. Interestingly, the recently emerged SARS-CoV-2 also activates CAD to couple evasion of inflammatory response to activated nucleotide synthesis. A small molecule inhibitor of CAD depletes nucleotide supply and boosts antiviral inflammatory response, thus greatly reducing SARS-CoV-2 replication. Additionally, we also found that CTP synthase 1 (CTPS1) deamidates interferon (IFN) regulatory factor 3 (IRF3) to mute IFN induction. Our previous studies have implicated phosphoribosyl formylglycinamidine synthase (PFAS) and phosphoribosyl pyrophosphate amidotransferase (PPAT) in deamidating retinoic acid-inducible gene I (RIG-I) and evading dsRNA-induced innate immune defense in herpesvirus infection. Overall, these studies have uncovered an unconventional enzymatic activity of cellular GATs in metabolism and immune defense, offering a molecular link intimately coupling these fundamental biological processes.

Advances and challenges of first-line immunotherapy for non-small cell lung cancer: A review.

The current use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has dramatically changed the clinical strategy for metastatic non-small cell lung cancer (mNSCLC). As a result of great achievements in clinical trials, 6 programmed death-1 inhibitors (sintilimab, camrelizumab, tislelizumab, pembrolizumab, cemiplimab, and nivolumab), 2 programmed death-ligand 1 inhibitors (sugemalimab and atezolizumab), and 1 cytotoxic T lymphocyte-associated antigen-4 inhibitor (ipilimumab) have been approved as first-line treatment for mNSCLC by the US Food and Drug Administration. Recently, research on ICIs has shifted from a large number of second-line to first-line settings in clinical trials. Results from first-line trials have shown that almost all driver-negative mNSCLC are treated with ICIs and significantly prolong patient survival; however, the low response rate and adverse reactions to immunotherapy remain to be addressed. Here, we summarize the use of ICIs, including monotherapy and combination therapy, in the first-line treatment of mNSCLC in recent years and discuss the low response rate and adverse reactions of ICIs as well as the challenges and expectations for the first-line treatment of mNSCLC in the future.

Comparison of Laminectomy with Fusion and Laminoplasty Treating Multilevel Cervical Spondylotic Myelopathy: A Single-Center Retrospective Study.

OBJECTIVE: Comparing laminectomy with fusion (LF) and laminoplasty (LP) for treating multilevel cervical spondylotic myelopathy (MCSM) and comparative analysis of neck pain and sagittal cervical parameters. METHODS: This single-center study retrospectively analyzed MCSM patients treated with LF or LP in our department between June 2018 and January 2023, with at least a 12-month follow-up. T-tests were used to identify operation time, hemoglobin, hospital stay, modified Japanese Orthopaedic Association (mJOA) score, C2-C7 Cobb angle, C2-C7 sagittal vertical axis, T1 slope, cervical range of motion (cROM), and C4/5 anterior and posterior spinal canal diameter (A-P diameter) and area. Nonparametric tests were used to identify visual analog scale (VAS) score (assessing neck pain). Pearson correlation analyses were used to identify the neck pain. RESULTS: Of all 67 patients (LF: 24, LP: 43), both groups' mJOA scores significantly improved (P < 0.001). The VAS scores had both significantly decreased, with the LF group exhibiting a more marked reduction (LF: P < 0.001, LP: P = 0.037). Both groups' C4/5 A-P diameters and areas increased significantly (P < 0.001). The cROM had both significantly decreased, with the LF group exhibiting a greater reduction. At the last follow-up, the LF group's T1 slope and C2-C7 Cobb angle considerably increased, and pain VAS scores substantially correlated with the C2-C7 Cobb angle (R = -0.451, P < 0.001). CONCLUSIONS: LF and LP were efficacious for MCSM. LF relieved neck pain better but caused greater reduction in cervical mobility. Cervical lordosis improvement was significantly correlated with neck pain alleviation.

Exploring the potential of the sit-to-stand test for self-assessment of physical condition in advanced knee osteoarthritis patients using computer vision.

Introduction: Knee osteoarthritis (KOA) is a prevalent condition often associated with a decline in patients' physical function. Objective self-assessment of physical conditions poses challenges for many advanced KOA patients. To address this, we explored the potential of a computer vision method to facilitate home-based physical function self-assessments. Methods: We developed and validated a simple at-home artificial intelligence approach to recognize joint stiffness levels and physical function in individuals with advanced KOA. One hundred and four knee osteoarthritis (KOA) patients were enrolled, and we employed the WOMAC score to evaluate their physical function and joint stiffness. Subsequently, patients independently recorded videos of five sit-to-stand tests in a home setting. Leveraging the AlphaPose and VideoPose algorithms, we extracted time-series data from these videos, capturing three-dimensional spatiotemporal information reflecting changes in key joint angles over time. To deepen our study, we conducted a quantitative analysis using the discrete wavelet transform (DWT), resulting in two wavelet coefficients: the approximation coefficients (cA) and the detail coefficients (cD). Results: Our analysis specifically focused on four crucial joint angles: "the right hip," "right knee," "left hip," and "left knee." Qualitative analysis revealed distinctions in the time-series data related to functional limitations and stiffness among patients with varying levels of KOA. In quantitative analysis, we observed variations in the cA among advanced KOA patients with different levels of physical function and joint stiffness. Furthermore, there were no significant differences in the cD between advanced KOA patients, demonstrating different levels of physical function and joint stiffness. It suggests that the primary difference in overall movement patterns lies in the varying degrees of joint stiffness and physical function among advanced KOA patients. Discussion: Our method, designed to be low-cost and user-friendly, effectively captures spatiotemporal information distinctions among advanced KOA patients with varying stiffness levels and functional limitations utilizing smartphones. This study provides compelling evidence for the potential of our approach in enabling self-assessment of physical condition in individuals with advanced knee osteoarthritis.

Genotoxicity assessments of N-nitrosoethylisopropylamine (NEIPA) and N-nitrosodiisopropylamine (NDIPA) in the C57BL/6J mouse.

N-Nitrosamines, known as drug impurities and suspected carcinogens, have drawn significant public concern. In response to drug regulatory needs, the European Medicines Agency (EMA) has previously proposed a carcinogenic potency categorization approach based on the N-nitrosamine α-hydroxylation hypothesis, i.e., that N-nitrosamine mutagenicity increases with the number of α-hydrogen atoms. However, this structure-activity relationship has not been fully tested in vivo. NEIPA (N-nitrosoethylisopropylamine) and NDIPA (N-nitrosodiisopropylamine) are small N-Nitrosamines with similar structures, differing in that the former compound has an additional α-hydrogen atom. In this study, NEIPA and NEIPA doses, 25-100 mg/kg, were administered orally to C57BL/6 J mice for seven consecutive days, and their mutation and DNA damage effects were compared. Compared with NDIPA, the mutagenicity and DNA damage potencies of NEIPA (which contains one more α-hydrogen) were much greater. These differences may be related to their distinct metabolic pathways and target organs. This case study confirms the role of α-hydroxyl modification in the mutagenicity of nitrosamines, with oxidation at the α-hydrogen being a crucial step in the formation of mutagens from N-Nitrosamines, and can inform mutagenicity risk assessment and the formulation of regulatory standards for N-nitrosamine impurities.