The Host Protein CAD Regulates the Replication of FMDV through the Function of Pyrimidines' De Novo Synthesis.

Foot-and-mouth disease virus (FMDV) is a single-stranded picornavirus that causes economically devastating disease in even-hooved animals. There has been little research on the function of host cells during FMDV infection. We aimed to shed light on key host factors associated with FMDV replication during acute infection. We found that HDAC1 overexpression in host cells induced upregulation of FMDV RNA and protein levels. Activation of the AKT-mammalian target of rapamycin (mTOR) signaling pathway using bpV(HOpic) or SC79 also promoted FMDV replication. Furthermore, short hairpin RNA (shRNA)-induced suppression of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), a transcription factor downstream of the AKT-mTOR signaling pathway, resulted in downregulation of FMDV RNA and protein levels. Coimmunoprecipitation assays showed that the ACTase domain of CAD could interact with the FMDV 2C protein, suggesting that the ACTase domain of CAD may be critical in FMDV replication. CAD proteins participate in de novo pyrimidine synthesis. Inhibition of FMDV replication by deletion of the ACTase domain of CAD in host cells could be reversed by supplementation with uracil. These results revealed that the contribution of the CAD ACTase domain to FMDV replication is dependent on de novo pyrimidine synthesis. Our research shows that HDAC1 promotes FMDV replication by regulating de novo pyrimidine synthesis from CAD via the AKT-mTOR signaling pathway. IMPORTANCE Foot-and-mouth disease virus is an animal virus of the Picornaviridae family that seriously harms the development of animal husbandry and foreign trade of related products, and there is still a lack of effective means to control its harm. Replication complexes would generate during FMDV replication to ensure efficient replication cycles. 2C is a common viral protein in the replication complex of Picornaviridae virus, which is thought to be an essential component of membrane rearrangement and viral replication complex formation. The host protein CAD is a key protein in the pyrimidines de novo synthesis. In our research, the interaction of CAD and FMDV 2C was demonstrated in FMDV-infected BHK-21 cells, and it colocalized with 2C in the replication complex. The inhibition of the expression of FMDV 3D protein through interference with CAD and supplementation with exogenous pyrimidines reversed this inhibition, suggesting that FMDV might recruit CAD through the 2C protein to ensure pyrimidine supply during replication. In addition, we also found that FMDV infection decreased the expression of the host protein HDAC1 and ultimately inhibited CAD activity through the AKT-mTOR signaling pathway. These results revealed a unique means of counteracting the virus in BHK-21 cells lacking the interferon (IFN) signaling pathway. In conclusion, our study provides some potential targets for the development of drugs against FMDV.

Unequal Health Risks and Attributable Mortality Burden of Source-Specific PM2.5 in China.

Anthropogenic emissions, originating from human activities, stand as the primary contributors to PM2.5, which is recognized as a global health threat. The disease burden associated with PM2.5 has been extensively documented. However, the prevailing estimations have predominantly relied on PM2.5 exposure-response functions, neglecting the distinct risks posed by PM2.5 from various sources. China has experienced a significant reduction in the PM2.5 concentration due to stringent emission controls. With diverse sources and abundant mortality data, this situation provides a unique opportunity to estimate short-term source-specific attributable mortality. Our approach involves an integrated unequal health risk-oriented modeling in China, incorporating a source-oriented Community Multiscale Air Quality model, an adjustment and downscaling method for exposure measurement, a generalized linear model with random-effects meta-analysis, and premature mortality estimation. Adhering to the unequal health risk concept, we calculated the attributable mortality of multiple PM2.5 sources by determining the source risk-adjusted factor. In this study, we observed varying excess risks associated with multiple PM2.5 sources, with transportation-related PM2.5 exhibiting the most substantial association. An interquartile range increase (7.65 µg/m3) was linked to a 1.98% higher daily nonaccidental mortality. Residential use- and transportation-related PM2.5 emerged as the two principal sources of premature mortality. In 2018, a remarkable 53,381 avoiding deaths were estimated compared to 2013, and over 67% of these were attributed to reductions in coal-dependent sources. Notably, transportation-related PM2.5 emerged as the largest contributor to premature mortality in 2018. This study underscores the significance of a new source-oriented health risk assessment to support actions aimed at reducing air pollution. It strongly advocates for heightened attention to PM2.5 reductions in the transportation sector in China.

Globally Guided Deep V-Network-Based Motion Planning Algorithm for Fixed-Wing Unmanned Aerial Vehicles.

Fixed-wing UAVs have shown great potential in both military and civilian applications. However, achieving safe and collision-free flight in complex obstacle environments is still a challenging problem. This paper proposed a hierarchical two-layer fixed-wing UAV motion planning algorithm based on a global planner and a local reinforcement learning (RL) planner in the presence of static obstacles and other UAVs. Considering the kinematic constraints, a global planner is designed to provide reference guidance for ego-UAV with respect to static obstacles. On this basis, a local RL planner is designed to accomplish kino-dynamic feasible and collision-free motion planning that incorporates dynamic obstacles within the sensing range. Finally, in the simulation training phase, a multi-stage, multi-scenario training strategy is adopted, and the simulation experimental results show that the performance of the proposed algorithm is significantly better than that of the baseline method.

Diagnostic value of curved planar reformation of MRI for lumbosacral nerve roots in the localization of nerve roots for adult lumbar degenerative scoliosis.

PURPOSE: To compare the diagnostic value of curved planar reformation of MRI (MRI-CPR) and 2D MRI in determining the responsible nerve in patients with adult lumbar degenerative scoliosis (ALDS). METHOD: A total of 45 patients diagnosed with ALDS were included in the study. All patients underwent MRI-CPR and 2D MRI and subsequently received surgery. These two diagnostic methods were compared with the results of surgical exploration to assess nerve root compression. RESULTS: The sensitivity and accuracy of MRI-CPR are higher than 2D MRI (93.8% vs 80.0%; 92.8% vs 77.7%, respectively). And the specificity of MRI-CPR is higher than 2D MRI (87.5% vs 68.8%). Besides, the PPV and NPV of MRI-CPR are higher than 2D MRI (96.8% vs 91.2%; 7.8.% vs 45.8%). The area (AUC) under the receiver operating characteristic curve (ROC) for MRI-CPR and 2D MRI was 0.74 and 0.91, respectively. The judgement was made by two independent radiologists, while the consistency tests for 2D MRI and MRI-CPR with Kappa values were 90.6% and 82.2%, respectively. CONCLUSIONS: The clinical diagnostic value of MRI-CPR was better than 2D MRI in the determination of the responsible nerve root. Moreover, MRI-CPR sequence images can clearly show the route of lumbosacral nerve roots and their relationship with adjacent tissues. Therefore, MRI-CPR can be an important complement to conventional 2D MRI in the diagnosis of responsible nerve roots in patients with ALDS.

Dok-1 regulates mast cell degranulation negatively through inhibiting calcium-dependent F-actin disassembly.

In food allergies, antigen-induced aggregation of FcεRI on mast cells initiates highly ordered and sequential signaling events. Dok-1(downstream of tyrosine kinase 1), undergoes intense tyrosine phosphorylation upon FcεRI stimulation, which negatively regulates Ras/Erk signaling and the subsequent cytokine release, but it remains unclear whether Dok-1 regulates Fc-mediated degranulation. In this study, we investigated the role of Dok-1 in FcεRI-mediated degranulation. Dok-1 overexpressing RBL-2H3 cells were established. Degranulation, immunoprecipitation, co-immunoprecipitation, immunoblotting and flow cytometry assay were performed to explore the effects of Dok-1 and its underlying mechanisms. We found that, following FcεRI activation, Dok-1 was recruited to the plasma membrane, leading to tyrosine phosphorylation. Phosphorylated Dok-1 inhibits FcεRI-operated calcium influx, and negatively regulated degranulation by inhibiting calcium-dependent disassembly of actin filaments. Our data revealed that Dok-1 is a negative regulator of FcεRI-mediated mast cell degranulation. These findings contribute to the identification of therapeutic targets for food allergies.

Mimicking Cellular Metabolism in Artificial Cells: Universal Molecule Transport across the Membrane through Vesicle Fusion.

Mass transport across cell membranes is a primary process for cellular metabolism. For this purpose, electrostatically mediated membrane fusion is exploited to transport various small molecules including glucose-6-phosphate, isopropyl ß-D-thiogalactoside, and macromolecules such as DNA plasmids from negatively charged large unilamellar vesicles (LUVs) to positively charged giant unilamellar vesicles (GUVs). After membrane fusion between these oppositely charged vesicles, molecules are transported into GUVs to trigger the NAD+ involved enzyme reaction, bacterial gene expression, and in vitro gene expression of green fluorescent protein from a DNA plasmid. The optimized charged lipid percentages are 10% for both positively charged GUVs and negatively charged LUVs to ensure the fusion process. The experimental results demonstrate a universal way for mass transport into the artificial cells through vesicle fusions, which paves a crucial step for the investigation of complicated cellular metabolism.

N-glycosylation of CD82 at Asn157 is required for suppressing migration and invasion by reversing EMT via Wnt/ß-catenin pathway in colon cancer.

CD82, a tetraspanin superfamily member, has been identified to be glycosylated at three specific residues (Asn129, Asn157, and Asn198). However, CD82 post-translational modification and its effect on colorectal cancer (CRC) metastasis remain unclear. Here, we constructed various deficient mutants of CD82 N-glycosylation in SW620 cells and demonstrated that the Asn157 site is necessary for CD82 glycosylation in CRC cells migration and LN-dependent adhesion in vitro. Furthermore, we found that CD82 N-glycosylation at the Asn157 site leads to lower expression levels of vimentin and claudin-1 but higher expression levels of E-cadherin, which are the EMT markers; also, there are lower expression levels of phospho-GSK3ß and less ß-catenin transportation to the nucleus. These findings suggest that CD82 N-glycosylation at the Asn157 site inhibits EMT by down-regulating the Wnt/ß-catenin pathway. Moreover, we reported that CD82 with N-glycosylation at a single site of the Asn157 reduces lung metastases in vivo. The results indicate that N-glycosylation of CD82 at the Asn157 site regulates CRC metastasis and adhesion. These observations suggest that the N-glycosylation of CD82 might be a potential therapeutic target for CRC.

Associations between Source-Specific Fine Particulate Matter and Mortality and Hospital Admissions in Beijing, China.

The health effects of PM2.5 exposure have become a major public concern in developing countries. Identifying major PM2.5 sources and quantifying the health effects at the population level are essential for controlling PM2.5 pollution and formulating targeted emissions reduction policies. In the current study, we have obtained PM2.5 mass data and used positive matrix factorization to identify the major sources of PM2.5. We evaluated the relationship between short-term exposure to PM2.5 sources and mortality or hospital admissions in Beijing, China, using 441 742 deaths and 9 420 305 hospital admissions from 2013 to 2018. We found positive associations for coal combustion and road dust sources with mortality. Increased hospital admission risks were significantly associated with sources of vehicle exhaust, coal combustion, secondary sulfates, and secondary nitrates. Compared to the cool season, excess mortality risk estimates of coal combustion source were significantly higher in the warm season. Our findings show that reducing more toxic sources of PM2.5, especially coal emissions, and developing clean energy alternatives can have critical implications for improving air quality and protecting public health.

Impact of Heavy PM2.5 Pollution Events on Mortality in 250 Chinese Counties.

We explored the impact of heavy PM2.5 pollution events on the health of residents in 250 counties in China. A time-series approach involving a two-stage analysis was applied to estimate the association between heavy PM2.5 pollution events and mortality from 2013 to 2018. The associations between heavy (PM2.5 ≥75 µg/m3 and <150 µg/m3) and extremely heavy (PM2.5 ≥150 µg/m3) PM2.5 pollution days with mortality were explored. The added effects of the heavy PM2.5 pollution events were evaluated by controlling PM2.5 concentration in the model. From 2013 to 2018, there were 57,279 county days of heavy PM2.5 pollution and 21,248 county days of extremely heavy PM2.5 pollution. The risks of mortality during this period of heavy PM2.5 pollution events increased by 1.22% (95% CI: 0.82-1.63%), 1.14% (95% CI: 0.74-1.53%), 1.09% (95% CI: 0.58-1.60%), and 1.30% (95% CI: 0.40-2.20%), for all-cause, nonaccidental, circulatory, and respiratory mortality, respectively. We also observed that heavy PM2.5 pollution events had an added effect on mortality risk associated with all-cause, nonaccidental, circulatory, and respiratory mortality, evident from an observed increase by 0.77% (95% CI: 0.29-1.24%), 0.73% (95% CI: 0.27-1.19%), 0.96% (95% CI: 0.37-1.55%), and 0.55% (95% CI: -0.52-1.63%), respectively. Heavy PM2.5 pollution events increased mortality risks and caused an independent added effect. The findings serve as a foundation for policymakers in developing early warning systems and policy interventions.

Reciprocal regulation of NRF2 by autophagy and ubiquitin-proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles.

NRF2 is the key antioxidant molecule to maintain redox homeostasis, however the intrinsic mechanisms of NRF2 activation in the context of nanoparticles (NPs) exposure remain unclear. In this study, we revealed that copper oxide NPs (CuONPs) exposure activated NRF2 pathway in vascular endothelial cells. NRF2 knockout remarkably aggravated oxidative stress, which were remarkably mitigated by ROS scavenger. We also demonstrated that KEAP1 (the negative regulator of NRF2) was not primarily involved in NRF2 activation in that KEAP1 knockdown did not significantly affect CuONPs-induced NRF2 activation. Notably, we demonstrated that autophagy promoted NRF2 activation as evidenced by that ATG5 knockout or autophagy inhibitors significantly blocked NRF2 pathway. Mechanically, CuONPs disturbed ubiquitin-proteasome pathway and consequently inhibited the proteasome-dependent degradation of NRF2. However, autophagy deficiency reciprocally promoted proteasome activity, leading to the acceleration of degradation of NRF2 via ubiquitin-proteasome pathway. In addition, the notion that the reciprocal regulation of NRF2 by autophagy and ubiquitin-proteasome was further proven in a CuONPs pulmonary exposure mice model. Together, this study uncovers a novel regulatory mechanism of NRF2 activation by protein degradation machineries in response to CuONPs exposure, which opens a novel intriguing scenario to uncover therapeutic strategies against NPs-induced vascular injury and disease.

Chemical Information Exchange in Organized Protocells and Natural Cell Assemblies with Controllable Spatial Positions.

An ultrasound-based platform is established to prepare homogenous arrays of giant unilamellar vesicles (GUVs) or red blood cell (RBCs), or hybrid assemblies of GUV/RBCs. Due to different responses to the modulation of the acoustic standing wave pressure field between the GUVs and RBCs, various types of protocell/natural cell hybrid assemblies are prepared with the ability to undergo reversible dynamic reconfigurations from vertical to horizontal alignments, or from 1D to 2D arrangements. A two-step enzymatic cascade reaction between transmitter glucose oxidase-containing GUVs and peroxidase-active receiver RBCs is used to implement chemical signal transduction in the different hybrid micro-arrays. Taken together, the obtained results suggest that the ultrasound-based micro-array technology can be used as an alternative platform to explore chemical communication pathways between protocells and natural cells, providing new opportunities for bottom-up synthetic biology.

A novel totivirus isolated from the phytopathogenic fungus Rhodosporidiobolus odoratus strain GZ2017.

To our knowledge, there have been no reports of mycoviruses infecting Rhodosporidiobolus odoratus. Here, we describe the sequence of a novel mycovirus isolated from R. odoratus, which was designated "Rhodosporidiobolus odoratus RNA virus 1" (RoRV1). Sequence analysis revealed that RoRV1 has two discontinuous open reading frames (ORFs), ORF1 and ORF2, potentially encoding a hypothetical protein and an RNA-dependent RNA polymerase (RdRp), respectively. Phylogenetic analysis based on RdRp sequences clearly placed RoRV1 in the genus Totivirus, family Totiviridae. The fungus also contains two additional, smaller dsRNAs, which might represent RoRV1 satellite RNAs.

Gas chromatography-mass spectrometry based metabolomics profile of hippocampus and cerebellum in mice after chronic arsenic exposure.

Intake of arsenic (As) via drinking water has been a serious threat to global public health. Though there are numerous reports of As neurotoxicity, its pathogenesis mechanisms remain vague especially its chronic effects on metabolic network. Hippocampus is a renowned area in relation to learning and memory, whilst recently, cerebellum is argued to be involved with process of cognition. Therefore, the study aimed to explore metabolomics alternations in these two areas after chronic As exposure, with the purpose of further illustrating details of As neurotoxicity. Twelve 3-week-old male C57BL/6J mice were divided into two groups, receiving deionized drinking water (control group) or 50 mg/L of sodium arsenite (via drinking water) for 24 weeks. Learning and memory abilities were tested by Morris water maze (MWM) test. Pathological and morphological changes of hippocampus and cerebellum were captured via transmission electron microscopy (TEM). Metabolic alterations were analyzed by gas chromatography-mass spectrometry (GC-MS). MWM test confirmed impairments of learning and memory abilities of mice after chronic As exposure. Metabolomics identifications indicated that tyrosine increased and aspartic acid (Asp) decreased simultaneously in both hippocampus and cerebellum. Intermediates (succinic acid) and indirect involved components of tricarboxylic acid cycle (proline, cysteine, and alanine) were found declined in cerebellum, indicating disordered energy metabolism. Our findings suggest that these metabolite alterations are related to As-induced disorders of amino acids and energy metabolism, which might therefore, play an important part in mechanisms of As neurotoxicity.

Optimization technique for rolled edge control process based on the acentric tool influence functions.

In the process of computer controlled optical surfacing (CCOS), the uncontrollable rolled edge restricts further improvements of the machining accuracy and efficiency. Two reasons are responsible for the rolled edge problem during small tool polishing. One is that the edge areas cannot be processed because of the orbit movement. The other is that changing the tool influence function (TIF) is difficult to compensate for in algorithms, since pressure step appears in the local pressure distribution at the surface edge. In this paper, an acentric tool influence function (A-TIF) is designed to remove the rolled edge after CCOS polishing. The model of A-TIF is analyzed theoretically, and a control point translation dwell time algorithm is used to verify that the full aperture of the workpiece can be covered by the peak removal point of the tool influence functions. Thus, surface residual error in the full aperture can be effectively corrected. Finally, the experiments are carried out. Two fused silica glass samples of 100 mm×100 mm are polished by traditional CCOS and the A-TIF method, respectively. The rolled edge was clearly produced in the sample polished by the traditional CCOS, while residual errors do not show this problem the sample polished by the A-TIF method. Therefore, the rolled edge caused by the traditional CCOS process is successfully suppressed during the A-TIF process. The ability to suppress the rolled edge of the designed A-TIF has been confirmed.

Global profiling of miRNAs and the hairpin precursors: insights into miRNA processing and novel miRNA discovery.

MicroRNAs (miRNAs) constitute an important class of small regulatory RNAs that are derived from distinct hairpin precursors (pre-miRNAs). In contrast to mature miRNAs, which have been characterized in numerous genome-wide studies of different organisms, research on global profiling of pre-miRNAs is limited. Here, using massive parallel sequencing, we have performed global characterization of both mouse mature and precursor miRNAs. In total, 87 369 704 and 252 003 sequencing reads derived from 887 mature and 281 precursor miRNAs were obtained, respectively. Our analysis revealed new aspects of miRNA/pre-miRNA processing and modification, including eight Ago2-cleaved pre-miRNAs, eight new instances of miRNA editing and exclusively 5' tailed mirtrons. Furthermore, based on the sequences of both mature and precursor miRNAs, we developed a miRNA discovery pipeline, miRGrep, which does not rely on the availability of genome reference sequences. In addition to 239 known mouse pre-miRNAs, miRGrep predicted 41 novel ones with high confidence. Similar as known ones, the mature miRNAs derived from most of these novel loci showed both reduced abundance following Dicer knockdown and the binding with Argonaute2. Evaluation on data sets obtained from Caenorhabditis elegans and Caenorhabditis sp.11 demonstrated that miRGrep could be widely used for miRNA discovery in metazoans, especially in those without genome reference sequences.

Left type I proatlantal artery with bilateral aberrant vertebral arteries and a ruptured aneurysm: a case report and review of the literature.

Persistent proatlantal artery is one rare kind of persistent primitive anastomoses between carotid and basilar vascular system. This case firstly introduces a type I proatlantal artery with complex vascular anomalies of bilateral vertebral arteries and a ruptured aneurysm, which is extremely uncommon. A 43-year-old female was hospitalised for SAH and ventricular hematocele. The subsequent digital subtraction angiography and computed tomography angiography revealed a type I proatlantal artery which arises from left internal carotid artery, associating with a hypoplastic right vertebral artery, an aplastic left vertebral artery and a ruptured left posterior inferior cerebellar artery aneurysm. An interventional procedure was taken later. The present case raises awareness on the incidence of persistent primitive anastomoses which combined other complex vascular anomalies before surgical or interventional procedures, especially in view of unique blood supply to posterior circulation from the primitive vessel.

New phenotypic characteristics of three tmm alleles in Arabidopsis thaliana.

KEY MESSAGE: Three new tmm mutants were isolated and showed differential phenotypes from tmm - 1 , and TMM overexpression led to abnormal leaf trichomes. TOO MANY MOUTH (TMM) plays a significant role in the stomatal signal transduction pathway, which involves in the regulation of stomatal distribution and patterning. Three mutants with clustered stomata were isolated and identified as new alleles of tmm. tmm-4 mutation included a base transversion from adenine to thymidine in position 1,033 of the TMM coding region and resulted in premature termination of translation at position 345 of TMM. tmm-5 had a base transition from cytosine to thymidine in 244 of TMM and translated 82 amino acids before premature termination. tmm-6 mutation took a base transition from guanine to adenine in 463 of TMM and changed a glycine (Gly) to an arginine (Arg) in position 155 of the protein. tmm-6 had an evident reduction of stomatal clusters and fewer stomata in cluster compared with other tmm alleles, possibly due to decreased level of entry divisions in cells next to two stomata or their precursors. tmm-5 and tmm-6 were hypersensitive to abscisic acid (ABA) in seedling growth and seed germination, while tmm-4 was defective in response to ABA during seed dormancy, suggesting that TMM was involved in ABA signaling transduction. Interestingly, overexpression of TMM resulted in the reduction of leaf trichomes and their branches, and this might reveal a new function of TMM in trichome development.

Clinical significance of percutaneous endoscopic gastrostomy for patients with severe craniocerebral injury.

OBJECTIVE: To investigate the application of percutaneous endoscopic gastrostomy (PEG) to patients with severe craniocerebral injury for the purpose of nutritional support therapy and pulmonary infection prevention. METHODS: A total of 43 patients with severe craniocerebral injury admitted to our department from January 2008 to December 2012 received PEG followed by nutritional therapy. There were other 82 patients who were prescribed nasal-feeding nutrition. Nutrition status was evaluated by comparing serum albumin levels, and the incidence of pulmonary infection 1 week before and 2 weeks after operation was identified and compared. RESULTS: Both PEG and nasal-feeding nutrition therapies have significantly elevated serum albumin levels (P<0.05). Serum albumin levels before and after nutritional therapies showed no significant difference between the two groups (P>0.05). The incidence of pulmonary infection in PEG group was significantly decreased compared with that in nasal-feeding nutrition group (P<0.05). CONCLUSION: PEG is an effective method for severe craniocerebral injury patients. It can not only provide enteral nutrition but also prevent pulmonary infection induced by esophageal reflux.

Knee osteoarthritis: A review of animal models and intervention of traditional Chinese medicine.

BACKGROUND: Knee osteoarthritis (KOA) characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults. The pathophysiology of KOA remains poorly understood, as it involves complex mechanisms that result in the same outcome. Consequently, researchers are interested in studying KOA and require appropriate animal models for basic research. Chinese herbal compounds, which consist of multiple herbs with diverse pharmacological properties, possess characteristics such as multicomponent, multipathway, and multitarget effects. The potential benefits in the treatment of KOA continue to attract attention. PURPOSE: This study aims to provide a comprehensive overview of the advantages, limitations, and specific considerations in selecting different species and methods for KOA animal models. This will help researchers make informed decisions when choosing an animal model. METHODS: Online academic databases (e.g., PubMed, Google Scholar, Web of Science, and CNKI) were searched using the search terms "knee osteoarthritis," "animal models," "traditional Chinese medicine," and their combinations, primarily including KOA studies published from 2010 to 2023. RESULTS: Based on literature retrieval, this review provides a comprehensive overview of the methods of establishing KOA animal models; introduces the current status of advantages and disadvantages of various animal models, including mice, rats, rabbits, dogs, and sheep/goats; and presents the current status of methods used to establish KOA animal models. CONCLUSION: This study provides a review of the animal models used in recent KOA research, discusses the common modeling methods, and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Exposure to Concurrent Heatwaves and Ozone Pollution and Associations with Mortality Risk: A Nationwide Study in China.

BACKGROUND: Concurrent extreme events are projected to occur more frequently under a changing climate. Understanding the mortality risk and burden of the concurrent heatwaves and ozone (O3) pollution may support the formulation of adaptation strategies and early warning systems for concurrent events in the context of climate change. OBJECTIVES: We aimed to estimate the mortality risk and excess deaths of concurrent heatwaves and O3 pollution across 250 counties in China. METHODS: We collected daily mortality, meteorological, and air pollution data for the summer (1 June to 30 September) during 2013-2018. We defined heatwaves and high O3 pollution days, then we divided the identified days into three categories: a) days with only heatwaves (heatwave-only event), b) days with only high O3 pollution (high O3 pollution-only event), and c) days with concurrent heatwaves and high O3 pollution (concurrent event). A generalized linear model with a quasi-Poisson regression was used to estimate the risk of mortality associated with extreme events for each county. Then we conducted a random-effects meta-analysis to pool the county-specific estimates to derive the overall effect estimates. We used mixed-effects meta-regression to identify the drivers of the heterogeneity. Finally, we estimated the excess death attributable to extreme events (heatwave-only, high O3 pollution-only, and concurrent events) from 2013 to 2020. RESULTS: A higher all-cause mortality risk was associated with exposure to the concurrent heatwaves and high O3 pollution than exposure to a heatwave-only or a high O3 pollution-only event. The effects of a concurrent event on circulatory and respiratory mortality were higher than all-cause and nonaccidental mortality. Sex and age significantly impacted the association of concurrent events and heatwave-only events with all-cause mortality. We estimated that annual average excess deaths attributed to the concurrent events were 6,249 in China from 2017 to 2020, 5.7 times higher than the annual average excess deaths attributed to the concurrent events from 2013 to 2016. The annual average proportion of excess deaths attributed to the concurrent events in the total excess deaths caused by three types of events (heatwave-only events, high O3 pollution-only events, and concurrent events) increased significantly in 2017-2020 (31.50%; 95% CI: 26.73%, 35.53%) compared with 2013-2016 (9.65%; 95% CI: 5.67%, 10.81%). Relative excess risk due to interaction revealed positive additive interaction considering the concurrent effect of heatwaves and high O3 pollution. DISCUSSION: Our findings may provide scientific basis for establishing a concurrent event early warning system to reduce the adverse health impact of the concurrent heatwaves and high O3 pollution. https://doi.org/10.1289/EHP13790.