Effect of oral administration of microcin Y on growth performance, intestinal barrier function and gut microbiota of chicks challenged with Salmonella Pullorum.

The lasso peptide microcin Y (MccY) effectively inhibits various serotypes of Salmonella in vitro, but the antibacterial effect against S. Pullorum in poultry is still unclear. This study was the first to evaluate the safety and anti-S. Pullorum infection of MccY in specific pathogen-free (SPF) chicks. The safety test showed that the body weight, IgA and IgM levels of serum, and cecal microbiota structure of 3 groups of chicks orally administrated with different doses of MccY (5 mg/kg, 10 mg/kg, 20 mg/kg) for 14 days were not significantly different from those of the control group. Then, the chicks were randomized into 3 groups for the experiment of anti-S. Pullorum infection: (I) negative control group (NC), (II) S. Pullorum-challenged group (SP, 5 × 108 CFU/bird), (III) MccY-treated group (MccY, 20 mg/kg). The results indicated that compared to the SP group, treatment of MccY increased body weight and average daily gain (P < 0.05), reduced S. Pullorum burden in feces, liver, and cecum (P < 0.05), enhanced the thymus, and decreased the spleen and liver index (P < 0.05). Additionally, MccY increased the jejunal villus height, lowered the jejunal and ileal crypt depth (P < 0.05), and upregulated the expression of IL-4, IL-10, ZO-1 in the jejunum and ileum, as well as CLDN-1 in the jejunum (P < 0.05) compared to the SP group. Furthermore, MccY increased probiotic flora (Barnesiella, etc.), while decreasing (P < 0.05) the relative abundance of pathogenic flora (Escherichia and Salmonella, etc.) compared to the SP group.

Defect driven physics-informed neural network framework for fatigue life prediction of additively manufactured materials.

Additive manufacturing (AM) has attracted many attentions because of its design freedom and rapid manufacturing; however, it is still limited in actual application due to the existing defects. In particular, various defect features have been proved to affect the fatigue performance of components and lead to fatigue scatter. In order to properly assess the influences of these defect features, a defect driven physics-informed neural network (PiNN) is developed. By embedding the critical defects information into loss functions, the defect driven PiNN is enhanced to capture physical information during training progress. The results of fatigue life prediction for different AM materials show that the proposed PiNN effectively improves the generalization ability under small samples condition. Compared with the fracture mechanics-based PiNN, the proposed PiNN provides physically consistent and higher accuracy without depending on the choice of fracture mechanics-based model. Moreover, this work provides a scalable framework being able to integrate more prior knowledge into the proposed PiNN. This article is part of the theme issue 'Physics-informed machine learning and its structural integrity applications (Part 1)'.

Physics-informed machine learning and its structural integrity applications: state of the art.

The development of machine learning (ML) provides a promising solution to guarantee the structural integrity of critical components during service period. However, considering the lack of respect for the underlying physical laws, the data hungry nature and poor extrapolation performance, the further application of pure data-driven methods in structural integrity is challenged. An emerging ML paradigm, physics-informed machine learning (PIML), attempts to overcome these limitations by embedding physical information into ML models. This paper discusses different ways of embedding physical information into ML and reviews the developments of PIML in structural integrity including failure mechanism modelling and prognostic and health management (PHM). The exploration of the application of PIML to structural integrity demonstrates the potential of PIML for improving consistency with prior knowledge, extrapolation performance, prediction accuracy, interpretability and computational efficiency and reducing dependence on training data. The analysis and findings of this work outline the limitations at this stage and provide some potential research direction of PIML to develop advanced PIML for ensuring structural integrity of engineering systems/facilities. This article is part of the theme issue 'Physics-informed machine learning and its structural integrity applications (Part 1)'.

Three-dimensional silk fibroin scaffolds enhance the bone formation and angiogenic differentiation of human amniotic mesenchymal stem cells: a biocompatibility analysis.

Silk fibroin (SF) is a fibrous protein with unique mechanical properties, adjustable biodegradation, and the potential to drive differentiation of mesenchymal stem cells (MSCs) along the osteogenic lineage, making SF a promising scaffold material for bone tissue engineering. In this study, hAMSCs were isolated by enzyme digestion and identified by multiple-lineage differentiation. SF scaffold was fabricated by freeze-drying, and the adhesion and proliferation abilities of hAMSCs on scaffolds were determined. Osteoblast differentiation and angiogenesis of hAMSCs on scaffolds were further evaluated, and histological staining of calvarial defects was performed to examine the cocultured scaffolds. We found that hAMSCs expressed the basic surface markers of MSCs. Collagen type I (COL-I) expression was observed on scaffolds cocultured with hAMSCs. The scaffolds potentiated the proliferation of hAMSCs and increased the expression of COL-I in hAMSCs. The scaffolds also enhanced the alkaline phosphatase activity and bone mineralization, and upregulated the expressions of osteogenic-related factors in vitro. The scaffolds also enhanced the angiogenic differentiation of hAMSCs. The cocultured scaffolds increased bone formation in treating critical calvarial defects in mice. This study first demonstrated that the application of 3D SF scaffolds co-cultured with hAMSCs greatly enhanced osteogenic differentiation and angiogenesis of hAMSCs in vitro and in vivo. Thus, 3D SF scaffolds cocultured with hAMSCs may be a better alternative for bone tissue engineering.

Influence of PepF peptidase and sporulation on microcin J25 production in Bacillus subtilis.

The lasso peptide microcin J25 (MccJ25) possesses strong antibacterial properties and is considered a potential effective component of bacterial disease treatment drugs and safe food preservatives. Although MccJ25 can be heterologously expressed in Bacillus subtilis as we have previously reported, its regulation and accumulation are yet to be understood. Here, we investigated the expression level and stability of MccJ25 in B. subtilis strains with disruption in peptidase genes pepA, pepF, and pepT. Oligoendopeptidase F (PepF) was found to be involved in reduction of the production of MccJ25 by degradation of its precursor peptide. In the pepF mutant, the MccJ25 reached a concentration of 1.68 µM after a cultivation time exceeding 60 hours, while the wild-type strain exhibited a concentration of only 0.14 µM. Moreover, the production of MccJ25 in B. subtilis downregulated the genes associated with sporulation, and this may contribute to its accumulation. Finally, this study provides a strategy to improve the stability and production of MccJ25 in B. subtilis. IMPORTANCE: MccJ25 displays significant antibacterial activity, a well-defined mode of action, exceptional safety, and remarkable stability. Hence, it presents itself as a compelling candidate for an optimal antibacterial or anti-endotoxin medication. The successful establishment of exogenous production of MccJ25 in Bacillus subtilis provides a strategy for reducing its production cost and diversifying its utilization. In this study, we have provided evidence indicating that both peptidase PepF and sporulation are significant factors that limit the expression of MccJ25 in B. subtilis. The ΔpepF and ΔsigF mutants of B. subtilis express MccJ25 with higher production yield and enhanced stability. To sum up, this study developed several better engineered strains of B. subtilis, which greatly reduced the consumption of MccJ25 during the nutrient depletion stage of the host strain, improved its production, and elucidated factors that may be involved in reducing MccJ25 accumulation in B. subtilis.

Continuous cryotherapy vs. traditional cryotherapy after total knee arthroplasty: A systematic review and meta-analysis of randomized controlled trials.

Background: Cryotherapy is widely applied to relieve pain and improve functional outcomes after total knee arthroplasty (TKA). New cryotherapy devices have recently been developed to guarantee a fixed temperature for a prolonged time. Therefore, we conducted a systematic review and meta-analysis to compare continuous cryotherapy and traditional cryotherapy (ice bag or gel pack) for patients after TKA. Methods: This study was conducted according to a predefined protocol registered on PROSPERO. Two independent reviewers performed an electronic database search of PubMed, Embase, Cochrane, Web of Science, Google Scholar, and ClinicalTrials.gov. Dichotomous outcomes were reported as risk difference (RD) with 95% confidence intervals (CIs), and continuous outcomes were reported as mean difference (MD), or standardized mean difference (SMD) with 95% CIs. Results: Seven trials enrolling a total of 519 patients were included. There were no differences in pain intensity (MD: -0.54, 95% CI: -1.55 to 0.47; P = 0.30), analgesics consumption (MD: -0.37, 95% CI: -1.28 to 0.55; P = 0.43), postoperative range of motion (MD: 0.47, 95% CI: -4.09 to 5.03; P = 0.84), swelling of the knee joint, blood loss, change in hemoglobin, or transfusion rate. Meanwhile, there were no differences in length of hospital stay (MD: -0.77, 95% CI: -1.62 to 0.08; P = 0.07) and adverse events (RD: 0, 95% CI: -0.02 to 0.03; P = 0.74). In addition, continuous cryotherapy leads to extra costs and resources than traditional cryotherapy. Conclusions: Continuous cryotherapy does not appear to offer significant benefits for TKA when compared with traditional cryotherapy. Based on currently available evidence, traditional cryotherapy is still recommended as continuous cryotherapy is not cost-effective. Further well-designed studies with larger sample sizes are warranted to further confirm these preliminary results. PROSPERO Registration: Identifier [CRD42022308217].

Effect of gelatin nano-coating containing Gardenia pigment on the preservation of pork slices.

The nano-coating composed of gelatin and Gardenia pigment (GP) was successfully prepared and showed strong antioxidant activity. The average particle sizes of the nano-coating containing 0.1% and 0.3% GP were 269.58 and 394.13 nm, respectively. The pork slices uncoated and coated with the nano-coating were preserved at 4 °C for 15 days. The pork slices' pH, total volatile basic nitrogen (TVB-N), total viable counts (TVC), water-binding capacity (WHC), and thiobarbituric acid reactive substances (TBARS) were measured to assess the preservation effect of the nano-coating. The results showed that the pork coated with the nano-coating had lower pH, TVC, TVB-N, TBARS, and higher WHC, significantly different (p < 0.05) than the uncoated pork. It is suggested that the proposed nano-coating can be used to effectively improve the pork's quality and shelf life during refrigeration storage.

Bone mineral density, osteopenia, osteoporosis, and fracture risk in patients with atopic dermatitis: a systematic review and meta-analysis.

BACKGROUND: The relationship between atopic dermatitis (AD) and abnormal bone metabolism remains unclear. We performed a systematic review and meta-analysis to determine whether patients with AD were associated with increased risks of low bone mineral density (BMD), osteopenia, osteoporosis, and related fractures. METHODS: We searched PubMed, Embase, and the Cochrane Library through December 2019 to identify studies that investigated the association between AD and abnormal bone metabolism (including BMD, osteopenia, osteoporosis, and related fractures). The predefined primary outcome was related fractures; secondary outcomes included osteoporosis, osteopenia, and BMD. We calculated the summary odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. RESULTS: Ten studies were included in this systematic review. In children and adolescents, four studies investigated the association between AD and BMD; three studies indicated that children and adolescents with AD were associated with an increased risk of low BMD; one study found similar BMD between AD and control groups. In adults, three studies assessed the risk of fracture and were included in the meta-analysis, comprising 562,405 AD patients among 3,171,268 participants. Adults with AD were associated with an increased risk of fracture (OR 1.13; 95% CI, 1.05-1.22; P=0.001). Three studies investigated the association between AD and osteoporosis, which suggested that patients with AD were associated with an increased risk of osteoporosis (OR 1.95; 95% CI, 1.18-3.23; P=0.009). Further, patients with AD were associated with increased risks of osteopenia (OR 1.90; 95% CI, 1.51-2.38; P<0.001) and low BMD at the femur and spine. CONCLUSIONS: Patients with AD were associated with increased risks of low BMD, osteopenia, osteoporosis, and related fractures. Both clinical studies and basic research are needed to clarify the mechanisms of association between AD and abnormal bone metabolism.

Bone morphogenetic protein 9 enhances osteogenic and angiogenic responses of human amniotic mesenchymal stem cells cocultured with umbilical vein endothelial cells through the PI3K/AKT/m-TOR signaling pathway.

BACKGROUND: Neovascularization plays an essential part in bone fracture and defect healing, constructing tissue engineered bone that targets bone regeneration. Bone morphogenetic protein 9 (BMP9) is a regular indicator that potentiates osteogenic and angiogenic differentiation of MSCs. OBJECTIVES: To investigate the effects of BMP9 on osteogenesis and angiogenesis of human amniotic mesenchymal stem cells (hAMSCs) cocultured with human umbilical vein endothelial cells (HUVECs) and determine the possible underlying molecular mechanism. RESULTS: The isolated hAMSCs expressed surface markers of MSCs. hAMSCs cocultured with HUVECs enhance osteogenic differentiation and upregulate the expression of angiogenic factors. BMP9 not only potentiates angiogenic signaling of hAMSCs cocultured with HUVECs also increases ectopic bone formation and subcutaneous vessel invasion. Mechanically, the coupling effect between osteogenesis and angiogenesis induced by BMP9 was activated by the BMP/Smad and PI3K/AKT/m-TOR signaling pathways. CONCLUSIONS: BMP9-enhanced osteoblastic and angiogenic differentiation in cocultivation with hAMSCs and HUVECs in vitro and in vivo also provide a chance to harness the BMP9-regulated coordinated effect between osteogenic and angiogenic pathways through BMP/Smad and PI3K/AKT/m-TOR signalings. MATERIALS AND METHODS: The ALP and Alizarin Red S staining assay to determine the effects of osteoblastic differentiation. RT-qPCR and western blot was measured the expression of angiogenesis-related factors. Ectopic bone formation was established and retrieved bony masses were subjected to histochemical staining. The angiogenesis ability and vessel invasion were subsequently determined by immunofluorescence staining. Molecular mechanisms such as the BMP/Smad and PI3K/AKT/m-TOR signaling pathways were detected by ELISA and western blot analysis.

Influence of porous tantalum scaffold pore size on osteogenesis and osteointegration: A comprehensive study based on 3D-printing technology.

The emerging role of porous tantalum (Ta) scaffold for bone tissue engineering is noticed due to its outstanding biological properties. However, it is controversial which pore size and porosity are more conducive for bone defect repair. In the present work, porous tantalum scaffolds with pore sizes of 100-200, 200-400, 400-600 and 600-800 µm and corresponding porosities of 25%, 55%, 75%, and 85% were constructed, using computer aided design and 3D printing technologies, then comprehensively studied by in vitro and in vivo studies. We found that Ta scaffold with pore size of 400-600 µm showed stronger ability in facilitating cell adhesion, proliferation, and osteogenic differentiation in vitro. In vivo tests identified that porous tantalum scaffolds with pore size of 400-600 µm showed better performance of bone ingrowth and integration. In mechanism, computational fluid dynamics analysis proved porous tantalum scaffolds with pore size of 400-600 µm hold appropriate permeability and surface area, which facilitated cell adhesion and proliferation. Our results strongly indicate that pore size and porosity are essential for further applications of porous tantalum scaffolds, and porous tantalum scaffolds with pore size 400-600 µm are conducive to osteogenesis and osseointegration. These findings provide new evidence for further application of porous tantalum scaffolds for bone defect repair.

Three-Dimensional, MultiScale, and Interconnected Trabecular Bone Mimic Porous Tantalum Scaffold for Bone Tissue Engineering.

To investigate the biocompatibility and bone ingrowth properties of a novel trabecular bone mimic porous tantalum scaffold which holds potential for bone tissue engineering, a novel three-dimensional, multiscale interconnected porous tantalum scaffold was designed and manufactured. The morphology of the novel scaffold was observed with the use of scanning electron microscopy (SEM) and industrial computerized tomography. Mesenchymal stem cells (MSCs) were cultured with novel porous tantalum powder, SEM was carried out for the observation of cell morphology and adhesion, and cytotoxicity was evaluated by the MTT assay. Canine femoral shaft bone defect models were established, and novel porous tantalum rods were used to repair the bone defect. Repair effects and bone integration were evaluated by hard tissue slice examination and push-out tests at the indicated time. We found that the novel porous tantalum scaffold is a trabecular bone mimic, having the characteristics of being three-dimensional, multiscaled, and interconnected. The MSCs adhered to the surface of tantalum and proliferated with time, the tantalum extract did not have a cytotoxic effect on MSCs. In the bone defect model, porous tantalum rods integrated tightly with the host bone, and new bone formation was found on the scaffold-host bone interface both 3 and 6 months after the implantation. Favorable bone ingrowth was observed in the center of the tantalum rod. The push-out test showed that the strength needed to push out the tantalum rod is comparable for both 3 and 6 months when compared with the normal femoral shaft bone tissue. These findings suggested that the novel trabecular bone mimic porous tantalum scaffold is biocompatible and osteoinductive, which holds potential for bone tissue engineering application.

Protective effects of autophagy and NFE2L2 on reactive oxygen species-induced pyroptosis of human nucleus pulposus cells.

Intervertebral disc degeneration (IDD) is characterized by the decrease of nucleus pulposus cells (NPCs). With the increase of the degree of degeneration, the reactive oxygen species (ROS) in nucleus pulposus tissue increases. Pyroptosis is a newly discovered form of cell death and its relationship with oxidative stress in NPCs remains unclear. This study was performed to investigate the mechanisms of pyroptosis of NPCs under oxidative stress. NPCs were isolated from IDD patients by surgical treatment. Pyroptosis related proteins like NLR family pyrin domain containing 3(NLRP3) and PYD and CARD domain containing (PYCARD) were detected by western blot, and membrane pore formation was observed by hochest33342/PI double staining or scanning electron microscope. The results showed that ROS induced the pyroptosis of NPCs and it depended on the expression of NLRP3 and PYCARD. The increased ROS level also increased transcription factor nuclear factor, erythroid 2 like 2 (NFE2L2, Nrf2) and the autophagy of NPCs, both of which attenuated the pyroptosis. In summary, ROS induces the pyroptosis of NPCs through the NLRP3/ PYCARD pathway, and establishes negative regulation by increasing autophagy and NFE2L2. These findings may provide a better understanding of the mechanism of IDD and potential therapeutic approaches for IDD treatment.

Femoral Stress Changes after Total Hip Arthroplasty with the Ribbed Prosthesis: A Finite Element Analysis.

BACKGROUND: A total hip reconstruction is related to the stress distribution throughout the prosthesis, cement, and femur. Researches on reducing the stress in all components to minimize the risk of failure are of great significance. The objective of our study was to determine the biomechanical variation in overall femoral stress and periprosthetic femoral stress distribution after implantation with the Ribbed anatomic prosthesis. METHODS: Three-dimensional finite element models of intact femur and Ribbed prosthesis were developed according to the morphology, while the hip joint loading and the strength of related muscles were applied in the models. The overall stress changes of the intact femur before and after the implantation were analyzed, and the periprosthetic stress distribution especially in the proximal region of the femur was quantified. RESULTS: As a result, the overall stress pattern of the femur did not change after the implantation compared with the intact femur. The region of peak stress value was located in the middle and lower segments of the full length femur, but the stress value level decreased. The final prosthesis resulted in a significant decrease in the equivalent stress level of the periprosthetic bone tissue, and the most severe area appeared at the endmost posterior quadrant. The stress shielding ratio of the Ribbed prosthesis was 71.6%. The stress value level gradually increased towards the distal part of the prosthesis and recovered to physiological level at the end of the prosthesis. CONCLUSIONS: The Ribbed prosthesis can cause significant stress shielding effect in the proximal femur. These results may help optimize prosthetic design to reduce stress shielding effect and improve clinical outcomes.

Hospital readmission after anterior cruciate ligament reconstruction: protocol for a systematic review and meta-analysis.

INTRODUCTION: Anterior cruciate ligament (ACL) injury is one of the most common injuries of the knee. ACL reconstruction (ACLR) has been widely performed as a safe and effective treatment for ACL injuries. As there is an increasing trend in the incidence of ACL injury, hospital readmission after ACLR has attracted renewed attention for the financial burden to both patients and the healthcare system. However, information about hospital readmission after ACLR remains fragmented. Therefore, we plan to systematically review the literature to investigate the rate of, causes and risk factors for hospital readmission after ACLR, and summarise interventions to reduce hospital readmission. This article is to provide the protocol for an upcoming systematic review and meta-analysis on this important issue. METHODS AND ANALYSIS: Reporting of this protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist. Electronic databases, including PubMed, Embase and the Cochrane Library, will be systematically searched from inception to June 2020. No language restrictions will be applied. Studies will be included if they reported hospital readmission or explored the associated potential causes and risk factors for hospital readmission after ACLR. The primary outcome will be the number and time frame of hospital readmission after ACLR. Secondary outcomes will be reasons for readmission, number and types of complications, risk factors for readmission and preventive measures for readmission after ACLR. Quality assessments will be performed by using the Newcastle-Ottawa Scale (NOS). If possible, study results will be summarised in a forest plot, and heterogeneity will be tested by using the Cochran's Q and I2 statistics. ETHICS AND DISSEMINATION: No ethical approval is required because our study is not related to patients or animals. The results will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020058624.

Efficacy of a three-day prolonged-course of multiple-dose versus a single-dose of tranexamic acid in total hip and knee arthroplasty.

BACKGROUND: The application of tranexamic acid (TXA) in total hip arthroplasty (THA) and total knee arthroplasty (TKA) has brought momentous changes in blood management. However, the optimal regimen of TXA has not yet been identified. This study aimed to compare the efficacy of a three-day prolonged-course of multiple-dose of TXA with a single pre-operative dose of TXA in patients who undergo THA and TKA. METHOD: We retrospectively analyzed two groups of consecutive patients who received primary unilateral THA and TKA from 2015 to 2017. One group received a three-day prolonged-course of multiple-dose of TXA, while another group received a single-dose of TXA. The primary outcomes included the changes in hemoglobin (Hb), estimated total blood loss (TBL), and transfusion rate; the secondary outcomes included the platelet (PLT) counts, inflammatory markers, and fibrinolysis parameters. RESULTS: A total of 193 THA and 166 TKA procedures were included for comparison. Compared with the patients who received a single-dose of TXA, the patients who received a three-day prolonged-course of multiple-dose of TXA had smaller post-operative drops in Hb levels, which led to consistently significantly higher Hb levels in both THA and TKA. Therefore, the use of multiple-dose of TXA was associated with significantly lower maximum Hb drops and estimated TBL in both THA (24.58±11.43 vs. 30.38±11.33 g/L, P=0.001; 685.88±412.02 vs. 968.94±479.9 mL, P<0.0001) and TKA (18.04±9.75 vs. 27.24±10.99 g/L, P<0.0001; 497.35±291.03 vs. 816.51±354.38 mL, P<0.0001), and marginally reduced transfusion requirements (THA: 1/65 vs. 10/128; TKA: 0/70 vs. 2/96). The multiple-dose group also showed higher PLT counts, continuously reduced inflammatory responses, and significantly and durably attenuated fibrinolytic responses. CONCLUSIONS: A three-day prolonged-course of multiple-dose of TXA was consistently effective in reducing post-operative Hb drops, estimated TBL, inflammatory responses, and fibrinolytic responses, which could be recommended for clinical practice. However, these findings need to be confirmed by prospective studies.

Analysis of Mechanical Properties and Mechanical Anisotropy in Canine Bone Tissues of Various Ages.

The effect of age on mechanical behavior and microstructure anisotropy of bone is often ignored by researchers engaged in the study of biomechanics. The objective of our study was to determine the variations in mechanical properties of canine femoral cortical bone with age and the mechanical anisotropy between the longitudinal and transverse directions. Twelve beagles divided into three age groups (6, 12, and 36 months) were sacrificed and all femurs were extracted. The longitudinal and transverse samples of cortical bone were harvested from three regions of diaphysis (proximal, central, and distal). A nanoindentation technique was used for simultaneously measuring force and displacement of a diamond tip pressed 2000nm into the hydrated bone tissue. An elastic modulus was calculated from the unloading curve with an assumed Poisson ratio of 0.3, while hardness was defined as the maximal force divided by the corresponding contact area. The mechanical properties of cortical bone were determined from 852 indents on two orthogonal cross-sectional surfaces. Mean elastic modulus ranged from 7.56±0.32 GPa up to 21.56±2.35 GPa, while mean hardness ranged from 0.28±0.057 GPa up to 0.84±0.072 GPa. Mechanical properties of canine femoral cortical bone tended to increase with age, but the magnitudes of these increase for each region might be different. The longitudinal mechanical properties were significantly higher than that of transverse direction (P<0.01). A significant anisotropy was found in the mechanical properties while there was no significant correlation between the two orthogonal directions in each age group (r 2<0.3). Beyond that, the longitudinal mechanical properties of the distal region in each age group were lower than the proximal and central regions. Hence, mechanical properties in nanostructure of bone tissue must differ mainly among age, sample direction, anatomical sites, and individuals. These results may help a number of researchers develop more accurate constitutive micromechanics models of bone tissue in future studies.