Osteocyte ferroptosis induced by ATF3/TFR1 contributes to cortical bone loss during ageing.

Cortical bone loss is intricately associated with ageing and coincides with iron accumulation. The precise role of ferroptosis, characterized by iron overload and lipid peroxidation, in senescent osteocytes remains elusive. We found that ferroptosis was a crucial mode of osteocyte death in cortical bone during ageing. Using a single-cell transcriptome analysis, we identified activating transcription factor 3 (ATF3) as a critical driver of osteocyte ferroptosis. Elevated ATF3 expression in senescent osteocytes promotes iron uptake by upregulating transferrin receptor 1 while simultaneously inhibiting solute carrier family 7-member 11-mediated cystine import. This process leads to an iron overload and lipid peroxidation, culminating in ferroptosis. Importantly, ATF3 inhibition in aged mice effectively alleviated ferroptosis in the cortical bone and mitigated cortical bone mass loss. Taken together, our findings establish a pivotal role of ferroptosis in cortical bone loss in older adults, providing promising prevention and treatment strategies for osteoporosis and fractures.

The role of photobiomodulation in accelerating bone repair.

Bone repair is faced with obstacles such as slow repair rates and limited bone regeneration capacity. Delayed healing even nonunion could occur in bone defects, influencing the life quality of patients severely. Photobiomodulation (PBM) utilizes different light sources to derive beneficial therapeutic effects with the advantage of being non-invasive and painless, providing a promising strategy for accelerating bone repair. In this review, we summarize the parameters, mechanisms, and effects of PBM regulating bone repair, and further conclude the current clinical application of PBM devices in bone repair. The wavelength of 635-980 nm, the output power of 40-100 mW, and the energy density of less than 100 J/cm2 are the most commonly used parameters. New technologies, including needle systems and biocompatible and implantable optical fibers, offer references to realize an efficient and safe strategy for bone repair. Further research is required to establish the reliability of outcomes from in vivo and in vitro studies and to standardize clinical trial protocols.

Porphyrin-Thiophene Based Conjugated Polymer Cathode with High Capacity for Lithium-Organic Batteries.

Organic electrode materials are promising for next-generation energy storage materials due to their environmental friendliness and sustainable renewability. However, problems such as their high solubility in electrolytes and low intrinsic conductivity have always plagued their further application. Polymerization to form conjugated organic polymers can not only inhibit the dissolution of organic electrodes in the electrolyte, but also enhance the intrinsic conductivity of organic molecules. Herein, we synthesized a new conjugated organic polymer (COPs) COP500-CuT2TP (poly [5,10,15,20-tetra(2,2'-bithiophen-5-yl) porphyrinato] copper (II)) by electrochemical polymerization method. Due to the self-exfoliation behavior, the porphyrin cathode exhibited a reversible discharge capacity of 420 mAh g-1, and a high specific energy of 900 Wh Kg-1 with a first coulombic efficiency of 96 % at 100 mA g-1. Excellent cycling stability up to 8000 cycles without capacity loss was achieved even at a high current density of 5 A g-1. This highly conjugated structure promotes COP500-CuT2TP combined high energy density, high power density, and good cycling stability, which would open new opportunity for the designable and versatile organic electrodes for electrochemical energy storage.

The osteoclastic activity in apical distal region of molar mesial roots affects orthodontic tooth movement and root resorption in rats.

The utilization of optimal orthodontic force is crucial to prevent undesirable side effects and ensure efficient tooth movement during orthodontic treatment. However, the sensitivity of existing detection techniques is not sufficient, and the criteria for evaluating optimal force have not been yet established. Here, by employing 3D finite element analysis methodology, we found that the apical distal region (A-D region) of mesial roots is particularly sensitive to orthodontic force in rats. Tartrate-resistant acidic phosphatase (TRAP)-positive osteoclasts began accumulating in the A-D region under the force of 40 grams (g), leading to alveolar bone resorption and tooth movement. When the force reached 80 g, TRAP-positive osteoclasts started appearing on the root surface in the A-D region. Additionally, micro-computed tomography revealed a significant root resorption at 80 g. Notably, the A-D region was identified as a major contributor to whole root resorption. It was determined that 40 g is the minimum effective force for tooth movement with minimal side effects according to the analysis of tooth movement, inclination, and hyalinization. These findings suggest that the A-D region with its changes on the root surface is an important consideration and sensitive indicator when evaluating orthodontic forces for a rat model. Collectively, our investigations into this region would aid in offering valuable implications for preventing and minimizing root resorption during patients' orthodontic treatment.

The Effects and Mechanisms of PBM Therapy in Accelerating Orthodontic Tooth Movement.

Malocclusion is one of the three major diseases, the incidence of which could reach 56% of the imperiled oral and systemic health in the world today. Orthodontics is still the primary method to solve the problem. However, it is clear that many orthodontic complications are associated with courses of long-term therapy. Photobiomodulation (PBM) therapy could be used as a popular way to shorten the course of orthodontic treatment by nearly 26% to 40%. In this review, the efficacy in cells and animals, mechanisms, relevant cytokines and signaling, clinical trials and applications, and the future developments of PBM therapy in orthodontics were evaluated to demonstrate its validity. Simultaneously, based on orthodontic mechanisms and present findings, the mechanisms of acceleration of orthodontic tooth movement (OTM) caused by PBM therapy were explored in relation to four aspects, including blood vessels, inflammatory response, collagen and fibers, and mineralized tissues. Also, the cooperative effects and clinical translation of PBM therapy in orthodontics have been explored in a growing numbers of studies. Up to now, PBM therapy has been gaining popularity for its non-invasive nature, easy operation, and painless procedures. However, the validity and exact mechanism of PBM therapy as an adjuvant treatment in orthodontics have not been fully elucidated. Therefore, this review summarizes the efficacy of PBM therapy on the acceleration of OTM comprehensively from various aspects and was designed to provide an evidence-based platform for the research and development of light-related orthodontic tooth movement acceleration devices.

Developmental growth plate cartilage formation suppressed by artificial light at night via inhibiting BMAL1-driven collagen hydroxylation.

Exposure to artificial light at night (LAN) can induce obesity, depressive disorder and osteoporosis, but the pernicious effects of excessive LAN exposure on tissue structure are poorly understood. Here, we demonstrated that artificial LAN can impair developmental growth plate cartilage extracellular matrix (ECM) formation and cause endoplasmic reticulum (ER) dilation, which in turn compromises bone formation. Excessive LAN exposure induces downregulation of the core circadian clock protein BMAL1, which leads to collagen accumulation in the ER. Further investigations suggest that BMAL1 is the direct transcriptional activator of prolyl 4-hydroxylase subunit alpha 1 (P4ha1) in chondrocytes, which orchestrates collagen prolyl hydroxylation and secretion. BMAL1 downregulation induced by LAN markedly inhibits proline hydroxylation and transport of collagen from ER to golgi, thereby inducing ER stress in chondrocytes. Restoration of BMAL1/P4HA1 signaling can effectively rescue the dysregulation of cartilage formation within the developmental growth plate induced by artificial LAN exposure. In summary, our investigations suggested that LAN is a significant risk factor in bone growth and development, and a proposed novel strategy targeting enhancement of BMAL1-mediated collagen hydroxylation could be a potential therapeutic approach to facilitate bone growth.

Sustainable sepiolite-based composites for fast clotting and wound healing.

Uncontrolled bleeding and bacterial coinfection are the major causes of death after an injury. Fast hemostatic capacity, good biocompatibility, and bacterial coinfection inhibition pose great challenges to hemostatic agent development. A prospective sepiolite/Ag nanoparticles (sepiolite@AgNPs) composite has been prepared by using natural clay sepiolite as template. A tail vein hemorrhage mouse model and a rabbit hemorrhage model were used to evaluate the hemostatic properties of the composite. The sepiolite@AgNPs composite can quickly absorb fluid to subsequently stop bleeding due to the natural fibrous crystal structure of sepiolite, and inhibit bacterial growth with the antibacterial ability of AgNPs. Compared with commercially-available zeolite material, the as-prepared composite exhibits competitive hemostatic properties without exothermic reaction in the rabbit model of femoral and carotid artery injury. The rapid hemostatic effect was due to the efficient absorption of erythrocyte and activation of the coagulation cascade factors and platelets. Besides, after heat-treatment, the composites can be recycled without significant reduction of hemostatic performance. Our results also prove that sepiolite@AgNPs nanocomposites can stimulate wound healing. The sustainability, lower-cost, higher bioavailability, and stronger hemostatic efficacy of sepiolite@AgNPs composite render these nanocomposites as more favorable hemostatic agents for hemostasis and wound healing.

Leaching characteristics and pollution risk assessment of potentially harmful elements from coal gangue exposed to weathering for different periods of time.

To explore the leaching behavior and potential degree of pollution that can result from the backfilling of goafs with different types of coal gangue (CG), fresh CG from the Hongqi Coal Mine goaf and surface CG (weathered for 1 year) were selected as the research objects in this study. A series of leaching experiments were carried out using the Ordovician limestone karst waters of the mining areas as the soaking solution. A comparative study on the dissolution characteristics of Fe3+, Mn2+, and SO42- and on the traditional water quality parameters of the two types of CG was conducted. The results showed that the soaked, weathered CG displayed a higher ion dissolution value than fresh CG. The ratio of each ion was as follows: Fe3+ was 1, Mn2+ was 2.86 ~ 68.18, and SO42- was 1.34 ~ 2.09. Over time, the ion concentration of water samples that initially contained high ion concentration values showed a decreasing trend after CG was soaked in these waters, but the values were still in the range of high ion release concentrations. The pH and oxidation‒reduction potential (ORP) values of the leachate of both CG types indicated that the leachates were weakly alkaline and weakly oxidizing, and the overall change in total dissolved solids (TDS) was small and consistent with the SO42- trend. SO42- in the leachate of the weathered CG showed a more significant correlation with the pH and TDS of the soaking solution, and it was the major pollutant. According to the geoaccumulation index evaluation, weathered CG had higher pollution potential than fresh CG. Fe3+ presented a slight and moderate risk for contamination.

Acceleration of Oral Wound Healing under Diabetes Mellitus Conditions Using Bioadhesive Hydrogel.

Oral wounds under diabetic conditions display a significant delay during the healing process, mainly due to oxidative stress-induced inflammatory status and abnormal immune responses. Besides, the wet and complicated dynamic environment of the oral cavity impedes stable treatment of oral wounds. To overcome these, a biomimetic hydrogel adhesive was innovatively developed based on a mussel-inspired multifunctional structure. The adhesive displays efficient adhesion and mechanical harmony on the oral mucosa through enhanced bonding in an acidic proinflammatory environment. The bioadhesive hydrogel exhibits excellent antioxidative properties by mimicking antioxidative enzymatic activities to reverse reactive oxygen species (ROS)-mediated immune disorders. Experiments on oral wounds of diabetic rats showed that this hydrogel adhesive could effectively protect against mucosal wounds and obviously shorten the inflammatory phase, thus promoting the wound-healing process. Therefore, this study offers a promising therapeutic choice with the potential to advance the clinical treatment of diabetic oral wounds.

Circadian clock-A promising scientific target in oral science.

The oral and maxillofacial organs play vital roles in chewing, maintaining facial beauty, and speaking. Almost all physiological processes display circadian rhythms that are driven by the circadian clock, allowing organisms to adapt to the changing environment. In recent years, increasing evidence has shown that the circadian clock system participates in oral and maxillofacial physiological and pathological processes, such as jaw and tooth development, salivary gland function, craniofacial malformations, oral carcinoma and other diseases. However, the roles of the circadian clock in oral science have not yet been comprehensively reviewed. Therefore, This paper provides a systematic and integrated perspective on the function of the circadian clock in the fields of oral science, reviews recent advances in terms of the circadian clock in oral and maxillofacial development and disease, dialectically analyzes the importance of the circadian clock system and circadian rhythm to the activities of oral and maxillofacial tissues, and focuses on analyzing the mechanism of the circadian clock in the maintenance of oral health, affecting the common diseases of the oral and maxillofacial region and the process of oral-related systemic diseases, sums up the chronotherapy and preventive measures for oral-related diseases based on changes in tissue activity circadian rhythms, meanwhile, comes up with a new viewpoint to promote oral health and human health.

Low intensity near-infrared light promotes bone regeneration via circadian clock protein cryptochrome 1.

Bone regeneration remains a great clinical challenge. Low intensity near-infrared (NIR) light showed strong potential to promote tissue regeneration, offering a promising strategy for bone defect regeneration. However, the effect and underlying mechanism of NIR on bone regeneration remain unclear. We demonstrated that bone regeneration in the rat skull defect model was significantly accelerated with low-intensity NIR stimulation. In vitro studies showed that NIR stimulation could promote the osteoblast differentiation in bone mesenchymal stem cells (BMSCs) and MC3T3-E1 cells, which was associated with increased ubiquitination of the core circadian clock protein Cryptochrome 1 (CRY1) in the nucleus. We found that the reduction of CRY1 induced by NIR light activated the bone morphogenetic protein (BMP) signaling pathways, promoting SMAD1/5/9 phosphorylation and increasing the expression levels of Runx2 and Osterix. NIR light treatment may act through sodium voltage-gated channel Scn4a, which may be a potential responder of NIR light to accelerate bone regeneration. Together, these findings suggest that low-intensity NIR light may promote in situ bone regeneration in a CRY1-dependent manner, providing a novel, efficient and non-invasive strategy to promote bone regeneration for clinical bone defects.

Effect of different molecular characteristics on the lubrication behavior of polysaccharide solutions.

Polysaccharides strongly affect the sensorial properties of foods, which is partly related to the lubrication they provide. We investigated the lubrication performance of polysaccharides with different characteristics (i.e. molecular weight, conformation, stiffness, and charge density) to identify the most relevant structural features related to lubrication ability. The effect of viscosity was excluded using isoviscous systems. Conformation resulted to be a key factor in determining lubrication. Rigid rod-like polysaccharides (xanthan) showed higher lubricating capacity and better resistance to changes in pH and ionic strength compared to semi-flexible (pectin and carboxymethyl cellulose) and flexible polysaccharide (guar gum). The friction behavior of flexible polysaccharides was highly dependent on concentration and sliding speed, for which a model including parameters of friction, concentration, and speed was developed. The concentration-dependency of the lubrication was related to the shear-thinning behavior, and possible mechanisms to explain these differences in terms of molecular properties of the polysaccharides are proposed.

Effect of Interlaminar Toughness on the Residual Compressive Capacity of Carbon Fiber Laminates with Different Types of Delamination.

In this paper, the effect of interlaminar properties and the type of delamination defects on the residual compression properties of carbon fiber laminates were experimentally investigated. A new method, which employed magnetic force to guide the arrangement direction of stainless steel particles between layers of laminates, was adopted to improve the interlayer toughness. The digital image correlation, C-scan, and micro-CT were used to measure and identify the compression failure damages. Test results showed that the compressive strength of the intact carbon fiber laminates was 299.37 MPa, and the one of specimens containing the deeply buried delamination, the through-width delamination, and the surface delamination decreased by 55.98 MPa, 58.69 MPa, and 60.23 MPa, respectively. The compressive strength of the specimens containing the deeply buried delamination only decreased by 14.01 MPa when the mode I toughness increased by 81.88%, and the specimen containing the surface delamination only decreased by 30.86 MPa when the mode II fracture toughness increased by 87.72%. However, improving the fracture toughness could not strengthen the specimens containing the through-width delamination. Moreover, a qualitative dynamic damage relationship, which described the relationship between delamination expansion and compression damage vividly, was proposed. The reason the increase of the toughness could improve the residual compression performance of the laminates containing delamination was that the higher fracture toughness hindered the secondary expansion of the delamination during the compression process so that the delamination area could almost remain unchanged.

Construction of Ultrafine Ag2S NPs Anchored onto 3D Network Rodlike Bi2SiO5 and Insight into the Photocatalytic Mechanism.

A novel three-dimensional (3D) network rodlike Ag2S/Bi2SiO5 photocatalyst with a p-n heterostructure composed of ultrafine Ag2S nanoparticles (NPs) and Bi2SiO5 nanosheets was prepared using an anionic self-regulation strategy by a two-step hydrothermal process. The architecture facilitated the efficient transfer and separation of photogenerated electron-hole pairs. The optimal Ag2S/Bi2SiO5 composite (ABSO0.10) exhibited an excellent reduction activity (93.5% Cr(VI) removal in wastewater containing 50 mg·L-1 Cr(VI) within 90 min under visible light), which was about 11.2 and 25.6 times higher than that of the pristine Ag2S and virgin Bi2SiO5, respectively. Assisted by experiments and density functional theory (DFT) calculations, a possible photocatalytic mechanism for Cr(VI) reduction over the Ag2S/Bi2SiO5 composite under visible-light irradiation was proposed.

Identification of a novel immune gene panel in tongue squamous cell carcinoma.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) is one of the most common oral cancers. Immune activity is significantly related to the initiation and progression of TSCC. Systemic analysis of the immunogenomic landscape and identification of crucial immune-related genes (IRGs) would help understanding of TSCC. Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) provide multiple TSCC cases for use in an integrated immunogenomic study. METHODS: Immune landscape of TSCC was depicted by expression microarray data from GSE13601 and GSE34105. Univariate Cox analysis, in combination with survival analysis, was applied to select candidate IRGs with significant survival value. Survival predicting models were constructed by multivariate Cox regression and logistic regression analysis. Unsupervised clustering analysis was used to construct an immune gene panel based on prognostic IRGs to distinguish TSCC subgroups with different prognostic outcomes. Finally, IHC staining was performed to validate the clinical value of this immune-gene panel. RESULTS: Differentially expressed IRGs were identified in two TSCC microarray datasets. Functional enrichment analysis revealed that ontology terms associated with variations in T cell function, were highly enriched. Infiltration status of activated CD8+ T cells, central memory CD4+ T cells and type 17 T helper cells, had great prognostic value for TSCC progression. Unsupervised clustering analysis was further performed to classify TSCC patients into three subgroups. CTSG, CXCL13, and VEGFA were finally combined together to form an immune-gene panel, todistinguish different TSCC subgroups. IHC staining of TSCC sections further validated the clinical efficiency of the immune-gene panel consisting of prognostic IRGs to distinguish TSCC patients. CONCLUSION: VEGFA, CXCL13, and CTSG, correlated with T cell infiltration and prognostic outcome. They were screened to form an immune-gene panel to identify TSCC subgroups with different prognostic outcomes. Clinical IHC further validated the efficacy of this immune-gene panel to evaluate aggressiveness of TSCC development.

Moisture-resistant MXene-sodium alginate sponges with sustained superhydrophobicity for monitoring human activities.

Wearable mechanical sensors are easily influenced by moisture resulting in inaccuracy for monitoring human health and body motions. Though the superhydrophobic barrier has been extensively explored as passive water repel strategy on the sensor surface, the dense superhydrophobic surface not only limits the sensor working under large deformations but also inevitable degradation in high humidity or saturation water vapor environments. This work reports a superhydrophobic MXene-sodium alginate sponge (SMSS) pressure sensor with a low voltage Joule heating effect to provide sustain moisture-insensitive property for both sensing performance and superhydrophobicity by heating-driven water molecules away. Because of the positive temperature coefficient under pressure applied, the Joule heating can provides a stable temperature to the moisture-insensitivity property during the whole dynamic pressure cycled. Therefore, the pressure sensor with a simple spray-coating superhydrophobic coating on the outer layer demonstrates key capabilities even in extreme use scenarios with high humidity or water vapor and also provides stable and reliable bio-signal monitoring.

Aquaporin OsPIP2;2 links the H2O2 signal and a membrane-anchored transcription factor to promote plant defense.

To overcome pathogen infection, plants deploy a highly efficient innate immune system, which often uses hydrogen peroxide (H2O2), a versatile reactive oxygen species, to activate downstream defense responses. H2O2 is a potential substrate of aquaporins (AQPs), the membrane channels that facilitate the transport of small compounds across plasma membranes or organelle membranes. To date, however, the functional relationship between AQPs and H2O2 in plant immunity is largely undissected. Here, we report that the rice (Oryza sativa) AQP OsPIP2;2 transports pathogen-induced apoplastic H2O2 into the cytoplasm to intensify rice resistance against various pathogens. OsPIP2;2-transported H2O2 is required for microbial molecular pattern flg22 to activate the MAPK cascade and to induce the downstream defense responses. In response to flg22, OsPIP2;2 is phosphorylated at the serine residue S125, and therefore gains the ability to transport H2O2. Phosphorylated OsPIP2;2 also triggers the translocation of OsmaMYB, a membrane-anchored MYB transcription factor, into the plant cell nucleus to impart flg22-induced defense responses against pathogen infection. On the contrary, if OsPIP2;2 is not phosphorylated, OsmaMYB remains associated with the plasma membrane, and plant defense responses are no longer induced. These results suggest that OsPIP2;2 positively regulates plant innate immunity by mediating H2O2 transport into the plant cell and mediating the translocation of OsmaMYB from plasma membrane to nucleus.

Recyclable europium functionalized metal-organic fluorescent probe for detection of tryptophan in biological fluids and food products.

An europium functionalized metal-organic fluorescent probe, Eu3+@UiO-66-FDC was constructed by post-synthetic modification through coordination interactions. Eu3+@UiO-66-FDC displayed high selectivity and sensitivity toward Tryptophan (Trp) among all the 20 natural amino acids and other general compounds in food and biological samples, with a wide linear concentration range (0-1000 µM), low detection limit (0.29 µM), and a rapid response (<1 min). Besides, this probe was utilized to detect Trp in rabbit blood serum and milk samples with good recoveries, which were verified by high-performance liquid chromatography (HPLC). Notably, this fluorescent probe proved to be a recyclable material. Hence, this work provides a reliable and recyclable fluorescent probe applicable toward the detection of Trp in biological fluids and/or food products.

Possible Immunotherapeutic Strategies Based on Carcinogen-Dependent Subgroup Classification for Oral Cancer.

The oral cavity serves as an open local organ of the human body, exposed to multiple external factors from the outside environment. Coincidentally, initiation and development of oral cancer are attributed to many external factors, such as smoking and drinking, to a great extent. This phenomenon was partly explained by the genetic abnormalities traditionally induced by carcinogens. However, more and more attention has been attracted to the influence of carcinogens on the local immune status. On the other hand, immune heterogeneity of cancer patients is a huge obstacle for enhancing the clinical efficacy of tumor immunotherapy. Thus, in this review, we try to summarize the current opinions about variant genetic changes and multiple immune alterations induced by different oral cancer carcinogens and discuss the prospects of targeted immunotherapeutic strategies based on specific immune abnormalities caused by different carcinogens, as a predictive way to improve clinical outcomes of immunotherapy-treated oral cancer patients.

Age and gender differences in ACE2 and TMPRSS2 expressions in oral epithelial cells.

BACKGROUND: SARS-CoV-2, which has brought a huge negative impact on the world since the end of 2019, is reported to invade cells using the spike (S) protein to bind to angiotensin-converting enzyme II (ACE2) receptors on human cells while the transmembrane protease serine 2 (TMPRSS2) is the key protease that activates the S protein, which greatly facilitates the entry of SARS-CoV-2 into target cells. In our previous study, it was observed that the positive rate of SARS-CoV-2 nucleic acids in saliva was higher in male and the elderly COVID-19 patients, suggesting that the susceptibility of oral tissues to SARS-CoV-2 may be related to gender and age. This research aimed to further investigate the SARS-CoV-2 susceptibility in oral tissues and influencing factors from the perspective of ACE2 and TMPRSS2, which were two proteins closely associated with SARS-CoV-2 infection. METHODS: Immunofluorescence was used to find the localization of ACE2 and TMPRSS2 in oral mucosal tissues. Transcriptomic sequencing data of several datasets were then collected to analysis the relationship between the expressions of ACE2 and TMPRSS2 with the age and gender of patients. Furthermore, oral tissues from patients with different ages and genders were collected. Immunohistochemistry staining, qRT-PCR and western blot were performed to explore the relationship between expression levels of ACE2 and TMPRSS2 and patient age as well as gender. RESULTS: The results showed that the two proteins were able to be co-expressed in the epithelial cells of oral tissues, and their expression levels were higher in the relatively elderly group than those in relatively younger group. Male oral epithelial cells exhibited higher level of TMPRSS2. CONCLUSIONS: Our findings comprehensively confirmed the existence of ACE2 and TMPRSS2 in oral tissues and clarify the relationship between the expression levels with human age and gender for the first time, providing evidence for possible entry routes of SARS-CoV-2 and the influencing factors of SARS-CoV-2 colonization in oral cavity. Thus, the oral mucosa might be at potential risk of infection by SARS-CoV-2, especially in male or elderly patients. Using saliva to detect the nucleic acids of SARS-CoV-2 may be more accurate for elder male COVID-19 patients.