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Abstract Because nickel-titanium (NiTi) alloys have unique functions, such as superelasticity, shape memory, and hysteresis similar to bone in the loading-unloading cycles of their recoverable deformations. They likely offer good bone integration, a low loosening rate, individual customization, and ease of insertion. Due to the poor processability of NITI, traditional methods cannot manufacture NiTi products with complex shapes. Orthopedic NiTi implants need to show an adequate fracture elongation of at least 8%. Additive manufacturing can be used to prepare NiTi implants with complex structures and tunable porosity. However, as previously reported, additively manufactured NiTi alloys could only exhibit a maximum tensile fracture strain of 7%. In new reports, a selective laser melting (SLM)–NiTi alloy has shown greater tensile strain (15.6%). Nevertheless, due to the unique microstructure of additive manufacturing NiTi that differs from traditional NITI, the biocompatibility of SLM-NITI manufactured by this new process requires further evaluation In this study, the effects of the improved NiTi alloy on bone marrow mesenchymal stem cell (BMSC) proliferation, adhesion, and cell viability were investigated via in vitro studies. A commercial Ti-6Al-4V alloy was studied side-by-side for comparison. Like the Ti-6Al-4V alloy, the SLM-NiTi alloy exhibited low cytotoxicity toward BMSCs and similar effect on cell adhesion or cell viability. This study demonstrates that the new SLM-NiTi alloy, which has exhibited improved mechanical properties, also displays excellent biocompatibility. Therefore, this alloy may be a superior implant material in biomedical implantation. Graphical Abstract

In order to elucidate the basic properties of Vigna radiata 7S (Vr7S) globulin genes and their expression patterns during seed growth and development, the physicochemical properties, structural characteristics, protein tertiary structures, phylogenetic relationship and expression profiles of 10 Vr7S globulin genes were studied using bioinformatics and reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the proteins encoded by the Vr7S globulin genes consisted of 246 to 594 amino acid residues, with isoelectric point (pI) ranging from 5.02 to 6.40, and molecular mass ranging from 27.82 to 70.02 kDa. All Vr7S globulin genes contained 3–7 exons, 2–6 introns, and 5–8 conserved motifs. Vr7S B1 had one conserved cupin domain, while the other nine genes contained two cupin domains. Vr7S globulin had four types of tertiary structures including α-helix and β-chain. In the conserved cupin domain, 67 conserved amino acid residues were shared by mung bean and other species, and mung bean 7S globulin genes had the closest homology adzuki bean 7S globulin genes followed by those of French bean, pigeon pea and soybean. The RNA sequencing (RNA-Seq) and RT-PCR expression profiles of mung bean seeds at different development stages showed that the expression level of the Vr7S globulin genes increased with the maturity of mung bean seeds, which was consistent with the expression pattern of 7S globulin genes in other legume species. These results indicated that the Vr7S globulin genes played a positive role in regulating the generation of mung bean seed storage protein. This study may lay a foundation for further analyzing the biological function of the Vr7S globulin genes in the seed development of mung bean.

BackgroundPaeoniae Radix Rubra (PRR) has been used widely to promote blood circulation and eliminate blood stasis in China clinical practice owing to its extensive pharmacological effects. However, the “quality markers” (Q-markers) of the antioxidant effects remains unknown.ObjectTo explore the Q-markers of antioxidant activity based on multiple strategies, which would provide reference for the quality evaluation of PRR based on specific pharmacodynamic-oriented.MethodsFirstly, the “fingerprint” profiles of 15 batches of PRR were acquired and identified by ultrahigh performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF MS/MS) and the common peaks extracted. Meanwhile, the MTT assay was used to evaluate the effect of 15 batches of PRR on H2O2-induced oxidative stress in HT-22 cells. The antioxidant activity of PRR was investigated simultaneously by superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) commercial kits. The relationship between common peaks and antioxidant indexes were constructed by grey relational analysis (GRA) and partial least squares-discriminant analysis (PLS-DA) for the identification of preselected Q-markers. Secondly, experimental verification was conducted to investigate the protective effect of the preliminary components on HT-22 cells undergoing oxidative stress. Finally, for the further validation of effectiveness of antioxidant Q-markers, network pharmacology was applied to explore potential targets, and the molecular docking technology was used to value the binding ability of the potential active components of PRR to the antioxidant targets.ResultsThirty-seven common peaks from 15 batches of PRR were identified qualitatively by UHPLC-Q-TOF MS/MS. The MTT assay showed that PRR could reduce the oxidative damage induced by H2O2 upon HT-22 cells according to the index of MDA, SOD and GSH. Eight potential antioxidant components were screened by spectrum-effect correlation analysis: paeoniflorin, galloylpaeoniflorin, albiflorin, 1,2,3,4,6-o-pentagalloylglucose, benzoylpaeoniflorin, pinocembrin, oleanic acid, and isorhamnetin-3-o-nehesperidine. Each of these preliminary components showed significant protections on cellular oxidative stress (P < 0.05). Interleukin-6 (IL-6), protein kinase B (AKT1), and tumor necrosis factor (TNF) were predicted to be the major potential targets of PRR, and the good binding ability were presented between the potential active components of PRR and each target as a whole.ConclusionEight components were identified as the antioxidant Q-markers of PRR based on an integrated multimodal strategy.

Objective: To construct a traditional Chinese medicine (TCM) knowledge base using knowledge graph based on deep learning methods, and to explore the application of joint models in intelligent question answering systems for TCM. Methods: Textbooks Prescriptions of Chinese Materia Medica and Chinese Materia Medica were applied to construct a comprehensive knowledge graph serving as the foundation for the intelligent question answering system. In the study, a BERT+Slot-Gated (BSG) deep learning model was applied for the identification of TCM entities and question intentions presented by users in their questions. Answers retrieved from the knowledge graph based on the identified entities and intentions were then returned to the user. The Flask framework and BSG model were utilized to develop the intelligent question answering system of TCM. Results: A TCM knowledge map encompassing 3 149 entities and 6 891 relational triples based on the prescriptions and Chinese materia medica was drawn. In the question answering test assisted by a question corpus, the F1 value for recognizing entities when answering 20 types of TCM questions was 0.996 9, and the accuracy rate for identifying intentions was 99.75%. This indicates that the system is both feasible and practical. Users can interact with the system through the WeChat Official Account platform. Conclusion: The BSG model proposed in this paper achieved good results in experiments by increasing the vector dimension, indicating the effectiveness of the joint model method and providing new research ideas for the implementation of intelligent question answering systems in TCM.

Abstract Background Correlations between mitochondrial DNA (mtDNA) and allergic rhinitis (AR) have not been reported before. This study aimed to better understand the mitochondrial genome profile with AR and to investigate the associations between AR in China and the mitochondrial genome at a single variant and gene level. Methods Mitochondrial sequencing was conducted on a total of 134 unrelated individual subjects (68 patients with AR, 66 healthy controls) at discovery stage. Heteroplasmy was analyzed using the Mann-Whitney U test. Sequence kernel association tests (SKAT) were conducted to study the association between mitochondrial genes and AR. Single-variant analysis was performed using logistic regression analysis and further validated in 120 subjects (69 patients with AR, 51 healthy controls). Candidate genes were further explored based on differences in mRNA and protein abundance in nasal mucosal tissue. Results In the discovery stage, 886 variants, including 836 SNV and 50 indels, were identified with mitochondrial sequencing. No statistically significant differences were identified for the mitochondrial heteroplasmy or SKAT analysis between these two groups after applying a Boferroni correction. One nonsynonymous variants, rs3135028 (MT8584.G/A) in ATP6, was related to a reduced risk of AR in both the discovery and validation cohorts. Furthermore, mRNA levels of MT-ATP6 in nasal mucosal tissue were significantly lower in AR individuals than in controls (P

ABSTRACTThe increasing availability of global observational data has sparked a demand for deep learning algorithms on spherical grids to enable intelligent analysis at a global scale. However, a spherical surface cannot be subdivided into completely identical grid cells through recursive division, and its nonuniformity and irregular deformations lead to uncertainties in the spherical convolutional neural network (SCNN). This paper proposes a multimetric evaluation method to assess the impact of the icosahedral diamond grid quality on the performance of the SCNN by introducing the random forest algorithm to establish nonlinear relationships between multiple grid quality metrics and the SCNN performance and using feature importance analysis to assign impact weights to each grid quality metric considering the SCNN performance. The results show an R2 score of 0.80 for the evaluation method, with four indicators having different weights: cell wall midpoint ratio (0.47), distance between grid points and neighbouring points (0.29), zone standardized compactness (0.13), and angle between a grid point and its two neighbours (0.11). The cell wall midpoint ratio indicator has the most significant impact on the SCNN performance among all grid indicators.

The conjunctiva of primary open angle glaucoma patients showed high level of oxidized low-density lipoprotein (ox-LDL), which is associated with the inflammatory response. Microglia and macrophages are the immune cells involved in retinal ganglion cell survival regulation; yet, their roles of the ox-LDL-induced inflammation in glaucoma remain elusive. Here we aimed to investigate the lipid uptake, inflammatory cytokine expression, and metabolomics profiles of human and murine-derived microglial and macrophage cell lines treated with ox-LDL. Under the same ox-LDL concentration, macrophages exhibited higher lipid uptake and expression of pro-inflammatory cytokines as compared to microglia. The ox-LDL increased the levels of fatty acid metabolites in macrophages and sphingomyelin metabolites in microglia. In summary, this study revealed the heterogeneity in the inflammatory capacity and metabolic profiles of macrophages and microglia under the stimulation of ox-LDL.

Groundwater drought is distinctive comparing with other droughts, featuring high concealment, long duration, and obvious hysteresis. It may have significant negative effects on agriculture, eco-environment, and social economy sectors. Therefore, investigating the temporal and spatial characteristics of groundwater drought and its driving factors is meaningful for monitoring and assessing the risks of groundwater shortage. In this study, a groundwater drought index based on groundwater storage anomalies (GWSAs) derived from GRACE satellites was developed to detect and analyze drought events. The spatiotemporal variations and trends of historical groundwater droughts from 2002 to 2021 in the North China Plain were evaluated. In addition, the correlations between groundwater drought and meteorological and agricultural drought were analyzed by the detrended cross-correlation analysis. The results indicated that (1) the standardized groundwater storage anomaly index (SGSAI) could better identify and characterize groundwater drought by eliminating the spatial heterogeneity of GWSAs; (2) from 2002 to 2021, the intensity, frequency, duration, and area of groundwater drought showed an increasing trend; (3) groundwater drought had an obvious hysteresis (>9 months) to meteorological drought and the correlation between groundwater drought and meteorological drought increased, while the relationship with agricultural drought decreased; (4) long-term overexploitation of groundwater resources might be the main driving factor for the exacerbating groundwater drought in this area.

Abstract Aims Diabetic retinopathy (DR) is a significant global public health concern. Alternative, safe, and cost‐effective pharmacologic approaches are warranted. We aimed to investigate the therapeutic potential of nattokinase (NK) for early DR and the underlying molecular mechanism. Methods A mouse model of diabetes induced by streptozotocin was utilized and NK was administered via intravitreal injection. Microvascular abnormities were evaluated by examining the leakage from blood–retinal barrier dysfunction and loss of pericytes. Retinal neuroinflammation was examined through the assessment of glial activation and leukostasis. The level of high mobility group box 1 (HMGB1) and its downstream signaling molecules was evaluated following NK treatment. Results NK administration significantly improved the blood–retinal barrier function and rescued pericyte loss in the diabetic retinas. Additionally, NK treatment inhibited diabetes‐induced gliosis and inflammatory response and protected retinal neurons from diabetes‐induced injury. NK also improved high glucose‐induced dysfunction in cultured human retinal micrangium endothelial cells. Mechanistically, NK regulated diabetes‐induced inflammation partially by modulating HMGB1 signaling in the activated microglia. Conclusions This study demonstrated the protective effects of NK against microvascular damages and neuroinflammation in the streptozotocin‐induced DR model, suggesting that NK could be a potential pharmaceutical agent for the treatment of DR.

Additive manufactured bimetallic structures provide site-specific functions by joining two metallic materials in the designed area, offering customized solutions for biomedical and engineering applications. However, cracking, delamination, or cross-contamination frequently occurs at the joint between two dissimilar metallic materials due to their different thermal properties. In the paper, porous bimetallic structures made of biomedical materials (Fe, Ti6Al4V, and Inconel 718) for bone implants are fabricated via direct ink writing (DIW) with a dual syringe system. After subsequent heat treatment, the original shapes of the bimetallic structures are well-preserved, and the shrinkages of the two materials are equalized by adjusting the sintering temperature. All joints are free of cracks and delamination, and the material deposition sequence has no impact on them, according to microstructural analyses of the interface. The pores created by binder pyrolysis and metallic powder sintering are necessary for bone growth, cell migration, body fluid flow, etc. The Fe–Ti6Al4V and Fe-Inconel 718 bimetallic structures have better mechanical properties than the Fe structures and can perform multiple functions that are challenging for monometallic implants.

Existing research suggested 300∼600 μm as the optimal pore size range for metallic bone implants. The human bones, however, have numerous pores smaller than 300 μm for bone ingrowth, cell growth and migration, fluid flow, and so forth. The bone implant with such small-sized pores has been rarely manufactured and its property is unclear. In the paper, biodegradable Fe scaffolds of different pore sizes (50 μm, 100 μm, 150 μm, 200 μm, and 300 μm) were fabricated by direct ink writing (DIW) with subsequent sintering. The interconnected pores of all scaffolds are highly precise and have no residual powders. The in-vitro degradation and compression tests were conducted on the scaffolds to evaluate the effect of pore size on degradation and mechanical behaviors, respectively. The results indicate that a decrease in pore size leads to an increase in degradation rate, from 0.0423 ± 0.0014 to 0.0433 ± 0.0035 mm/year, with the exception of the 50 μm scaffolds which exhibit the lowest value of 0.0052 ± 0.0018 mm/year due to clogging by degradation products; meanwhile, both elastic modulus and yield strength rise from 344.8 ± 18.6 MPa to 625.0 ± 52.5 MPa and from 9.5 ± 0.9 MPa to 15.1 ± 0.8 MPa, respectively. The pore size of 100 μm shows the most significant potential for use in Fe bone implants regarding its good degradation and mechanical behaviors. Our work provides new insight into the preferable pore size of metallic bone implants produced by additive manufacturing.

The Voronoi diagram on the Earth’s surface is a significant data model, characterized by natural proximity and dynamic stability, which has emerged as one of the most promising solutions for global spatial dynamic management and analysis. However, traditional algorithms for generating spherical raster Voronoi diagrams find it challenging to dynamically adjust the Voronoi diagram while maintaining precision and efficiency. The efficient and accurate construction of the spherical Voronoi diagram has become one of the bottleneck issues limiting its further large-scale application. To this end, this paper proposes a dynamic construction scheme for the spherical Voronoi diagram based on the QTM (Quaternary Triangular Mesh) system, with the aim of enabling efficient generation, local updates, and multi-scale visualization of the spherical Voronoi diagrams. In this paper, canonical ordering is introduced. Tailored for the properties of the spherical triangular grid, it constructs a unified and standardized sorting strategy for the dilation of the spherical grids. The construction and updating of the spherical Voronoi diagram are achieved through the ordered dilation of sites. Furthermore, the multi-scale visualization of the spherical Voronoi diagram is realized through the hierarchical structure of the QTM. The paper presents our algorithm intuitively through pseudocode, conducts comparative experiments on the feasibility and efficiency, and designs an experiment for the dynamic navigation and management of ocean-going vessels based on the global multi-resolution Voronoi diagram. The experimental results demonstrate that our algorithm effectively controls the error of the generation of the raster Voronoi diagram and has a significant efficiency advantage when processing dynamic environments.

To investigate the plasma lipoprotein subclasses in patients with primary open-angle glaucoma (POAG), a total of 20 Chinese POAG patients on intraocular pressure (IOP)-lowering treatment and 20 age-matched control subjects were recruited. Based on the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), the study subjects were divided into elevated- and normal-level subgroups. The plasma lipoprotein, lipoprotein subclasses, and oxidized LDL (oxLDL) levels were quantitatively measured. The discrimination potential of the lipoproteins was evaluated using the area under the receiver operating characteristic curve (AUC), and their correlation with clinical parameters was also evaluated. Compared to the control subjects with elevated TC and/or LDL-C levels, the levels of TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL), LDL subclass LDL3 and small dense LDL (sdLDL), and oxLDL were significantly higher in POAG patients with elevated TC and/or LDL-C levels. No differences in any lipoproteins or the subclasses were found between the POAG patients and control subjects with normal TC and LDL-C levels. Moderate-to-good performance of TC, LDL-C, non-HDL, LDL3, sdLDL, and oxLDL was found in discriminating between the POAG patients and control subjects with elevated TC and/or LDL-C levels (AUC: 0.710–0.950). Significant negative correlations between LDL3 and sdLDL with retinal nerve fiber layer (RNFL) thickness in the superior quadrant and between LDL3 and average RNFL thickness were observed in POAG patients with elevated TC and/or LDL-C levels. This study revealed a significant elevation of plasma lipoproteins, especially the LDL subclasses, in POAG patients with elevated TC and/or LDL-C levels, providing insights on monitoring specific lipoproteins in POAG patients with elevated TC and/or LDL-C.

The dome shaped structures of natural organisms can provide design inspiration for impact resistant structural materials. Most of the existing biomimetic dome shaped impact resistant materials are directly formed using 3D printing technology, and the samples cannot dynamically adjust the impact resistance properties in the various applications. Herein, 4D printing of fused filament fabrication is employed to form flat structures with different structural patterns via programming the printing process parameters, which can be deformed into biomimetic dome structures with dynamic thermal stimulation treatment. The thermal stimulation treatment can drive the dynamic transformation of 2D planar structures into 3D structures, and the higher the thermal stimulation temperature, the greater the degree of eminence and the denser the structure under the same experimental conditions. The thermal stimulation temperature and the mechanical properties of the structural samples show a certain positive correlation. In addition, different design structural patterns have different compressive mechanical properties. The more the number of circular units, the more obvious the energy absorption characteristics. The impact-resistant biomimetic structures can be applied to the surface strengthening and cushioning of various weapons, vehicles, heavy equipment, and launch structure.

Abstract Background The triglyceride-glucose (TyG) index, a simple measure of insulin resistance, is associated with intracranial atherosclerosis (ICAS) and stroke. In hypertensive populations, this association may be pronounced. The aim was to investigate the relationship between TyG and symptomatic intracranial atherosclerosis (sICAS) and recurrence risk in ischemic stroke patients with hypertension. Methods This prospective, multicenter cohort study included patients with acute minor ischemic stroke with a preadmission diagnosis of hypertension from September 2019 to November 2021 with a 3-month follow-up. The presence of sICAS was determined by a combination of clinical manifestations, the location of the infarction, and the corresponding artery with moderate-to-severe stenosis. ICAS burden was determined by the degree and number of ICAS occurrences. Fasting blood glucose (FBG) and triglyceride (TG) were measured to calculate TyG. The main outcome was ischemic stroke recurrence during the 90-day follow-up. Multivariate regression models were used to explore the association of TyG, sICAS, and ICAS burden with stroke recurrence. Results There were 1281 patients with a mean age of 61.6 ± 11.6 years; 70.1% were male, and 26.4% were diagnosed with sICAS. There were 117 patients who experienced stroke recurrence during follow-up. Patients were categorized according to quartiles of TyG. After adjusting for confounders, the risk of sICAS was greater (OR 1.59, 95% CI 1.04–2.43, p = 0.033) and the risk of stroke recurrence was significantly higher (HR 2.02, 95% CI 1.07–3.84, p = 0.025) in the fourth TyG quartile than in the first quartile. The restricted cubic spline (RCS) plot revealed a linear relationship between TyG and sICAS, and the threshold value for TyG was 8.4. Patients were then dichotomized into low and high TyG groups by the threshold. Patients with high TyG combined with sICAS had a higher risk of recurrence (HR 2.54, 95% CI 1.39–4.65) than patients with low TyG without sICAS. An interaction effect on stroke recurrence between TyG and sICAS was found (p = 0.043). Conclusion TyG is a significant risk factor for sICAS in hypertensive patients, and there is a synergistic effect of sICAS and higher TyG on ischemic stroke recurrence. Trial registration number: The study was registered on 16 August 2019 at https://www.chictr.org.cn/showprojen.aspx?proj=41160 (No. ChiCTR1900025214).

Abstract Diabetic retinopathy (DR) is a leading cause of blindness that poses significant public health concerns worldwide. Increasing evidence suggests that neuroinflammation plays a key role in the early stages of DR. Microglia, long-lived immune cells in the central nervous system, can become activated in response to pathological insults and contribute to retinal neuroinflammation. However, the molecular mechanisms of microglial activation during the early stages of DR are not fully understood. In this study, we used in vivo and in vitro assays to investigate the role of microglial activation in the early pathogenesis of DR. We found that activated microglia triggered an inflammatory cascade through a process called necroptosis, a newly discovered pathway of regulated cell death. In the diabetic retina, key components of the necroptotic machinery, including RIP1, RIP3, and MLKL, were highly expressed and mainly localized in activated microglia. Knockdown of RIP3 in DR mice reduced microglial necroptosis and decreased pro-inflammatory cytokines. Additionally, blocking necroptosis with the specific inhibitor GSK-872 improved retinal neuroinflammation and neurodegeneration, as well as visual function in diabetic mice. RIP3-mediated necroptosis was activated and contributed to inflammation in BV2 microglia under hyperglycaemic conditions. Our data demonstrate the importance of microglial necroptosis in retinal neuroinflammation related to diabetes and suggest that targeting necroptosis in microglia may be a promising therapeutic strategy for the early stages of DR.

Purpose: to determine the metabolomics profiles in the plasma samples of primary open-angle glaucoma (POAG) patients. Methods: The plasma samples from 20 POAG patients under intraocular pressure (IOP)-lowering medication treatment and 20 control subjects were subjected to the untargeted metabolomics analysis, among which 10 POAG patients and 10 control subjects were further subjected to the oxylipin-targeted metabolomics analysis by liquid chromatography–mass spectrometry analysis. The prediction accuracy of the differentially abundant metabolites was assessed by the receiver operating characteristic curves. Pathway analysis and correlation analysis on the differentially abundant metabolites and clinical and biochemical parameters were also conducted. Results: Untargeted metabolomics profiling identified 33 differentially abundant metabolites in the POAG patients, in which the metabolism of linoleic acid, α-linolenic acid, phenylalanine, and tricarboxylic acid cycle were enriched. The correlation analysis indicated that the differentially abundant metabolites were associated with central corneal thickness, peripapillary retinal nerve fiber layer thickness, visual field defects, and lymphocytes. The oxylipin-targeted metabolomics analysis identified 15-keto-Prostaglandin F2 alpha, 13,14-Dihydro-15-keto-prostaglandin D2, 11-Dehydro-thromboxane B2, 8,9-Epoxyeicosatrienoic acid, and arachidonic acid to be significantly decreased in the POAG patients and enriched in the arachidonic acid (AA) pathway. Conclusions: This study revealed that the metabolites in the arachidonic acid metabolism pathway are differentially abundant, suggesting high IOP may not be the only detrimental factor for optic nerve cell damage in this group of POAG patients. Lipid metabolism instability-mediated alterations in oxylipins and AA pathways may be important in POAG, suggesting that oxidative stress and immune-related inflammation could be valuable directions for future therapeutic strategies.

Osseointegration is the basic condition for orthopedic implants to maintain long-term stability. In order to achieve osseointegration, a low elastic modulus is the most important performance indicator. It is difficult for traditional titanium alloys to meet this requirement. A novel β-titanium alloy (Ti–35Nb–7Zr–5Ta)98Si2 was designed, which had excellent strength (a yield strength of 1296 MPa and a breaking strength 3263 MPa), an extremely low elastic modulus (37 GPa), and did not contain toxic elements. In previous in vitro studies, we confirmed the good biocompatibility of this alloy and similar bioactivity to Ti-6Al-4V, but no in vivo study was performed. In this study, Ti-6Al-4V and (Ti–35Nb–7Zr–5Ta)98Si2 were implanted into rabbit femurs. Imaging evaluation and histological morphology were performed, and the bonding strength and bone contact ratio of the two alloys were measured and compared. The results showed that both alloys remained in their original positions 3 months after implantation, and neither imaging nor histological observations found inflammatory reactions in the surrounding bone. The bone–implant contact ratio and bonding strength of (Ti–35Nb–7Zr–5Ta)98Si2 were significantly higher than those of Ti-6Al-4V. The results confirmed that (Ti–35Nb–7Zr–5Ta)98Si2 has a better osseointegration ability than Ti-6Al-4V and is a promising material for orthopedic implants.

Carbon fiber reinforced aluminum composites with ordered architectures of shear-induced aligned carbon fibers were fabricated by 3D printing. The microstructures of the printed and sintered samples and mechanical properties of the composites were investigated. Carbon fibers and aluminum powder were bonded together with resin. The spatial arrangement of the carbon fibers was fixed in the aluminum matrix by shear-induced alignment in the 3D printing process. As a result, the elongation of the composites with a parallel arrangement of aligned fibers and the impact toughness of the composites with an orthogonal arrangement were 0.82% and 0.41 ​J/cm2, respectively, about 0.4 and 0.8 times higher than that of the random arrangement.

Abstract With the growth of the market and the number of wearers, contact lenses have been widely used for vision correction and cosmetic purposes for a few years. The current study opens up a new path for their applications. On the one hand, contact lenses are ideal sensing platforms due to advances in the monitoring of relevant indicators in tears such as glucose and intraocular pressure. Aside from detecting a single analyte at a time, multifunctional contact lens sensors were proposed to monitor two or more indicators at the same time. Contact lenses, on the other hand, are also suitable drug delivery platforms due to their good biocompatibility and long contact duration with the cornea. Different drug delivery approaches are being investigated to increase drug duration and bioavailability. In addition, the integration of these novel drug delivery methods into wearable sensors has become a topic for a complete closed‐loop program for disease management. We began this review by summarizing the categories and properties of current contact lenses. Then, innovative applications of contact lenses such as biosensors and drug delivery systems were also summarized. In general, the current progress in the applications of contact lenses provides a new possibility for noninvasive diagnosis and therapy of ocular diseases.

Background: Diabetic retinopathy (DR) is the microvascular ocular complication of diabetes mellitus (DM), which can lead to irreversible blindness and visual impairment if not properly treated. Tears can be collected non-invasively, and the compositions of tears could be the potential biomarkers for ocular diseases. Here we aimed to delineate the metabolomics signature in tears collected from Chinese type-2 DM patients with DR. Methods: The metabolomics profiles of tear samples from 41 Chinese type-2 DM patients with DR and 21 non-diabetic subjects were determined by the untargeted liquid chromatography-mass spectrometry. The associated pathways of the differentially abundant metabolites were delineated, and the receiver operating characteristic curve analysis was conducted to identify the metabolites differentiating non-proliferative DR (NPDR) from proliferative DR (PDR). Results: Total 14 differentially abundant metabolites were identified between total DR and non-diabetic subjects, and 17 differentially abundant metabolites were found between the NPDR and PDR subjects. Moreover, total 18 differentially abundant metabolites were identified between the NPDR and PDR subjects with stratification in DR duration and blood glucose level. d-Glutamine and d-glutamate metabolism was significantly highlighted in the PDR group as compared to the non-diabetic group. For the predictive performance, azelaic acid combined with guanosine achieved the area under receiver operating characteristic curve of 0.855 in the comparison between NPDR and PDR groups. Conclusion: This study revealed the metabolomics changes in tear samples of DR patients. The metabolites in tears could be the potential biomarkers in the DR analysis.

Abstract 4D printing of metallic shape‐morphing systems can be applied in many fields, including aerospace, smart manufacturing, naval equipment, and biomedical engineering. The existing forming materials for metallic 4D printing are still very limited except shape memory alloys. Herein, a 4D printing method to endow non‐shape‐memory metallic materials with active properties is presented, which could overcome the shape‐forming limitation of traditional material processing technologies. The thermal stress spatial control of 316L stainless steel forming parts is achieved by programming the processing parameters during a laser powder bed fusion (LPBF) process. The printed parts can realize the shape changing of selected areas during or after forming process owing to stress release generated. It is demonstrated that complex metallic shape‐morphing structures can be manufactured by this method. The principles of printing parameters programmed and thermal stress pre‐set are also applicable to other thermoforming materials and additive manufacturing processes, which can expand not only the materials used for 4D printing but also the applications of 4D printing technologies.

Through the synergy of nervous system and the self-regulation of muscle stiffness, living organisms are capable of quickly adjusting movements and actively adapting to dynamic environments. Likewise, the stiffness-changing and self-sensing functionalities are critical to empower soft robots with adjustable load capacity and agile movement. This work presents a paradigm for the design and fabrication of soft actuators with stiffness tunability and intrinsic self-sensing feedback through 4D printing method. The integration of 4D printed conductive composite into soft actuator body allows for stiffness adjustment within three orders of magnitude and ensures real-time stiffness-sensing, bending-sensing and pressure-sensing feedback. By constructing the theoretical deformation models and decoupling the resistance signals by machine learning methods, information on the stiffness, deformation and pressure of the material at different temperatures can be obtained. Cardiac-mimicking actuator and active therapeutic insoles are fabricated as proof-of-concept demonstrations, among which the active therapeutic insoles can perceive plantar pressure changes and conduct pressure-releasing actuation to ease the pain of patient at walk. It demonstrates the potential of this design approach for versatile applications such as medical assistive devices, artificial muscles, soft robotics, etc.

It has been reported that particulate matter with an aerodynamic diameter of

Deep neural network-based programs can be applied to protein structure modeling by inputting amino acid sequences. Here, we aimed to evaluate the AlphaFold2-modeled myocilin wild-type and variant protein structures and compare to the experimentally determined protein structures. Molecular dynamic and ligand binding properties of the experimentally determined and AlphaFold2-modeled protein structures were also analyzed. AlphaFold2-modeled myocilin variant protein structures showed high similarities in overall structure to the experimentally determined mutant protein structures, but the orientations and geometries of amino acid side chains were slightly different. The olfactomedin-like domain of the modeled missense variant protein structures showed fewer folding changes than the nonsense variant when compared to the predicted wild-type protein structure. Differences were also observed in molecular dynamics and ligand binding sites between the AlphaFold2-modeled and experimentally determined structures as well as between the wild-type and variant structures. In summary, the folding of the AlphaFold2-modeled MYOC variant protein structures could be similar to that determined by the experiments but with differences in amino acid side chain orientations and geometries. Careful comparisons with experimentally determined structures are needed before the applications of the in silico modeled variant protein structures.

A porous anodic alumina film is proposed to construct an optical fiber temperature and humidity sensor. In the sensor structure, a fiber Bragg grating is used to detect the environment temperature, and the porous film is used to detect the environment humidity. The proposed porous anodic alumina film was fabricated by anodic oxidation reaction, and it is suitable for the use of humidity detection due to its porous structure. Experimental results show the temperature sensitivity of the proposed sensor was 10.4 pm/°C and the humidity sensitivity of the proposed sensor was 185 pm/%RH.

Plastics in the environment can break down into nanoplastics (NPs), which pose a potential threat to public health. Studies have shown that the nervous system constitutes a significant target for nanoplastics. However, the potential mechanism behind nanoplastics’ neurotoxicity remains unknown. This study aimed to investigate the role of lncRNA in the depressive-like responses induced by exposure to 25 nm polystyrene nanoplastics (PS NPs). Forty mice were divided into four groups administered doses of 0, 10, 25, and 50 mg/kg via gavage for 6 months. After conducting behavioral tests, RNA sequencing was used to detect changes in mRNAs, miRNAs, and lncRNAs in the prefrontal cortex of the mice in the 0 and 50 mg/kg PS NPs groups. The results revealed that mice exposed to chronic PS NPs developed depressive-like responses in a dose-dependent manner. It was demonstrated that 987 mRNAs, 29 miRNAs, and 116 lncRNAs were significantly different between the two groups. Then, a competing endogenous RNA (ceRNA) network containing 6 lncRNAs, 18 miRNAs, and 750 mRNAs was constructed. Enrichment results suggested that PS NPs may contribute to the onset of depression-like responses through the activation of axon guidance, neurotrophin-signaling pathways, and dopaminergic synapses. This study provided evidence of the molecular relationship between PS NPs and depression-like responses.

Additive manufacturing of metallic glass has attracted great attentions from researchers owing to the prospect of free-form fabricating high-performance bulk amorphous alloy parts. The characteristics of additive manufacturing from points to tracks, tracks to layers, and layers to parts are suitable for forming complex bulk metallic glass parts, which are difficult to achieve with other processing technologies. Herein, the forming principles used in metallic glass additive manufacturing are reviewed, with an emphasis on the manufacturing processes, material systems, forming part properties and potential applications. The properties of forming bulk metallic glass via selective laser melting, laser-directed energy deposition, and laser foil printing technologies are summarized. In addition, certain newly explored metallic glass additive manufacturing technologies, such as fused filament fabrication, ultrasonic consolidation, thermal spraying, and pneumatic injection, are briefly introduced. Finally, the trends in metallic glass additive manufacturing and perspectives for this emerging field are discussed.

The porosity and degradation rate are critical properties of biodegradable bone implants, as they facilitate the regeneration of bone tissues and ensure a gradual load transfer. Herein, porous iron-hydroxyapatite (Fe-HA) metal-matrix composites (MMCs) with independently adjustable porosity and degradation rate are fabricated through a 3D printing technique, i.e., direct ink writing (DIW). HA micro powders exhibit a significant acceleration effect on the degradation rate, which act as a variable that is independent of the porosity to regulate the degradation rate. The mass losses of Fe-HA MMCs with the porosities of 30%, 50%, and 70% after 21d in-vitro immersion increased by 26%, 38%, and 93%, respectively, with the rising of HA content from 0 to 7.5 wt%. The novel porous Fe-HA MMCs have an adjustable and wide porosity-degradation rate range, yielding great potential to match with varied porosity and regeneration rate among various bones of different people.

Exposure to fine particulate matter (PM2.5) has significant effects on human skin health, mainly disrupting skin homeostasis and accelerating aging. To date, the effects of PM2.5 on psoriasis (PSO) have not been elucidated. An ambient particulate matter exposed and well characterized imiquimod (IMQ)-induced psoriasis mouse model was established. Thirty male C57BL/6 mice aged 8 weeks were randomly divided into three groups: filtered air (FA) group (Control group), PSO+ FA group and PSO + PM2.5 group. A KRT17 knockdown (KRT17-KD) mouse model was simultaneously established by subcutaneously injecting KRT17-KD lentivirus. Forty male C57BL/6 mice were randomly divided into four groups: PSO + FA + KRT17-RNAi negative control lentivirus (KRT17-NC) group, PSO+ FA+ KRT17-KD group, PSO + PM2.5 + KRT17-NC group and PSO + PM2.5 + KRT17-KD group. PM2.5 exposure continued for 8 weeks. Psoriasis was induced by topically applying IMQ on the dorsal skin of the mice for 6 days during week 8. Morphometric and histological analyses were performed to investigate the changes in psoriatic lesions. Differentially expressed genes and enriched pathways were explored using bioinformatics analysis and showed that KRT17 gene and the vascular endothelial growth factor receptor signaling pathway were associated with psoriasis. HaCaT cells were stimulated with interleukin-17A and infected with KRT17-KD lentivirus to establish an in vitro KRT17 knockdown psoriasis cell model. Notably, PM2.5 exposure increased the expression of KRT17 protein and activated AKT/mTOR/HIF-1α signaling pathway in vivo. Moreover, specific agonist of AKT (740Y-P) reversed the decreased neovascularization induced by KRT17 knockdown through AKT/mTOR/HIF-1α signaling pathway in vitro. Consequently, PM2.5 exposure could promote the development and progression of psoriasis through KRT17-dependent activation of AKT/mTOR/HIF-1α signaling pathway.

Plastics breaking down of larger plastics into smaller ones (microplastics and nanoplastic) as potential threats to the ecosystem. Previous studies demonstrate that the central nervous system (CNS) is a vulnerable target of nanoplastics. However, the potentially epigenetic biomarkers of nanoplastic neurotoxicity in rodent models are still unknown. The present research aimed to determine the role of competing endogenous RNA (ceRNA) in the process of polystyrene nanoplastics (PS NPs) exposure-induced nerve injury. The study was designed to investigate whether 25 nm PS NPs could cause learning dysfunction and to elucidate the underlying mechanisms in mice. A total of 40 mice were divided into 4 groups and were exposed to PS NPs (0, 10, 25, 50 mg/kg). Chronic toxicity was introduced in mice by administration of oral gavage for 6 months. The evaluation included assessment of their behavior, pathological investigation and determination of the levels of reactive oxygen species (ROS) and DNA damage. RNA-Seq was performed to detect the expression levels of circRNAs, miRNAs and mRNAs in PFC samples of mice treated with 0 and 50 mg/kg PS NPs. The results indicated that exposure of mice to PS NPs caused a dose-dependent cognitive decline. ROS levels and DNA damage were increased in the PFC following exposure of the mice to PS NPs. A total of 987 mRNAs, 29 miRNAs and 67 circRNAs demonstrated significant differences between the 0 and 50 mg/kg PS NPs groups. Functional enrichment analyses indicated that PS NPs may induce major injury in the synaptic function. A total of 96 mRNAs, which were associated with synaptic dysfunction were identified. A competing endogenous RNA (ceRNA) network containing 27 circRNAs, 19 miRNAs and 35 synaptic dysfunction-related mRNAs was constructed. The present study provided insight into the molecular events associated with nanoplastic toxicity and induction of cognitive dysfunction.

Fine particulate matter (PM2.5) is well known to impair lung function. Strategies protecting against PM2.5-exerted lung dysfunction have been less investigated. Qianjinweijing decoction (QJWJ), a decoction of a herbal medicine of natural origin, has been used to treat lung disorders as it inhibits oxidation and inflammation. However, no clinical trial has yet evaluated the role of QJWJ in PM2.5-induced lung dysfunction. Therefore, we conducted a randomized, double-blind, placebo-controlled trial to assess whether QJWJ provided lung benefits against the adverse effects of PM2.5 exposure among adults. Eligible participants (n = 65) were recruited and randomized to receive QJWJ decoction (n = 32) or placebo (n = 33) for 4 weeks. The restrictive ventilatory defect (RVD), lung function parameters, and induced sputum were analyzed. The PM2.5 exposure concentration was significantly associated with the vital capacity (VC), peak expiratory flow (PEF), and forced expiratory flow at 75% of the forced vital capacity (FEF75). The negative associations between PM2.5 and the lung function parameters were eliminated in response to the QJWJ intervention. Additionally, the percentage of RVD (P = 0.018) and the proportion of eosinophils (Eo%) in induced sputum (P = 0.014) in the QJWJ group was significantly lower than that in the placebo group. This study demonstrated that QJWJ could alleviated PM2.5-induced lung dysfunction and could be a potential treatment for air pollution-related chronic respiratory disease.

Background and AimEvidence about recently proposed data-driven clusters of type 2 diabetes (T2D) is mainly about its prognostic effects and Western populations. We tested the applicability of this clustering approach among the Chinese population. We further investigated the cardiorenal risk profiles among different T2D sub-phenotypes cross-sectionally and before diabetes diagnosis.MethodsWith the use of data from the China Health and Nutrition Survey (1989–2009), 6,728 participants with available fasting blood samples and completed questionnaires in the 2009 survey were included. Glycemic statuses (normoglycemia, prediabetes, and new-onset T2D) were defined according to the 2020 American Diabetes Association criteria. Data-driven cluster analysis was conducted among new-onset T2D based on five variables: age at onset, body mass index (BMI), hemoglobin A1c, homeostasis model estimates of β-cell function, and insulin resistance. Linear regression models were used to cross-sectionally examine the differences of cardiorenal risk factors (body fat distribution, blood pressure, lipid profiles, and kidney function) between glycemic statuses. Mixed-effects models were used to explore a maximum of 20-year trajectories of cardiovascular risk factors (body fat distribution and blood pressure) before diabetes diagnosis.ResultsAmong 557 (8.3%) new-onset T2D, four sub-phenotypes were found, with 57 (10.2%) assigned to the severe insulin-resistant diabetes (SIRD), 72 (12.9%) to the severe insulin-deficient diabetes (SIDD), 167 (30.0%) to the mild obesity-related diabetes (MOD), and 261 (46.9%) to the mild age-related diabetes (MARD). People clustered within different T2D sub-phenotypes had different cardiorenal risk profiles. Three T2D sub-phenotypes (SIRD, SIDD, and MOD) had worse cardiorenal abnormalities, while the risk burden in the MARD sub-phenotype was similar to that in prediabetes. Compared with people with other T2D sub-phenotypes, people in the MOD sub-phenotype had a faster increment in BMI, waist, upper arm circumference, and triceps skinfold up to 10 years before diagnosis. Blood pressure was less distinct in different T2D sub-phenotypes; however, SIDD and MOD clusters had higher blood pressure levels before diabetes diagnosis.ConclusionsData-driven T2D sub-phenotyping is applicable in the Chinese population. Certain sub-phenotypes such as MARD only have a minor cardiorenal risk burden, and distinct cardiovascular risk development occurs long before diabetes diagnosis. Our findings can help improve early prevention and targeted treatment for diabetes.

Cardiac hypertrophy could be induced by ambient fine particulate matter (PM2.5) exposure. Since cardiac hypertrophy represents an early event leading to heart dysfunction, it is necessary to explore the molecular mechanisms, which are largely unknown. In the present study, an ambient particulate matter exposure mice model was established to explore its adverse effects related to the heart and the potential mechanisms. Forty-eight male C57BL/6 mice were randomly subjected to three groups: filtered air group, unfiltered air group and concentrated air group, and were exposed for 8 and 16 weeks, 6 h/day, respectively. In vitro experiments, the cardiac muscle cell line (HL-1) was treated with PM2.5 (0, 25, 50 and 100 μg/mL) for 24 h. In the present study, cardiac hypertrophy was occurred in vivo and vitro after exposure to PM2.5. Mechanistically, circ_0001859 could sponge miR-29b-3p, which could interact with 3′UTRs of Ctnnb1 (gene name of β-catenin). And Ctnnb1 expression was transcriptionally inhibited by si-circ_0001859 or miR-29b-3p mimic in HL-1 cells. Additionally, miR-29b-3p inhibitor could also make a reversion about the inhibition effect of circ_0001859 silencing on Ctnnb1 mRNA level in HL-1 cells. Functionally, knockout of circ_0001859 or overexpression of miR-29b-3p could inhibit LEF1/IGF-2R pathway and alleviate the progress of hypertrophy induced by PM2.5 in HL-1 cells. And miR-29b-3p inhibitor could reverse the inhibition effect of circ_0001859 silencing on hypertrophic response induced by PM2.5 in HL-1 cells. Consequently, the data demonstrated that circRNA_0001859 promoted the process of cardiac hypertrophy through suppressing miR-29b-3p leading to enhance Ctnnb1 level, and activated downstream pathway molecules LEF1/IGF-2R.

Cluster of differentiation 36 (CD36) belongs to the B2 receptors of the scavenger receptor class B family, which is comprised of single-chain secondary transmembrane glycoproteins. It is present in a variety of cell types, including monocytes, macrophages, microvascular endothelial cells, adipocytes, hepatocytes, platelets, skeletal muscle cells, kidney cells, cardiomyocytes, taste bud cells, and a variety of other cell types. CD36 can be localized on the cell surface, mitochondria, endoplasmic reticulum, and endosomes, playing a role in lipid accumulation, oxidative stress injury, apoptosis, and inflammatory signaling. Recent studies have found that CD36 is expressed in a variety of ocular cells, including retinal pigment epithelium (RPE), retinal microvascular endothelial cells, retinal ganglion cells (RGC), Müller cells, and photoreceptor cells, playing an important role in eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Therefore, a comprehensive understanding of CD36 function and downstream signaling pathways is of great significance for the prevention and treatment of eye diseases. This article reviews the molecular characteristics, distribution, and function of scavenger receptor CD36 and its role in ophthalmology in order to deepen the understanding of CD36 in eye diseases and provide new ideas for treatment strategies.

Summary: Organisms in nature grow with senses, nervous, and actuation systems coordinated in ingenious ways to sustain metabolism and other essential life activities. The understanding of biological structures and functions guide the construction of soft robotics with unprecedented performances. However, despite the progress in soft robotics, there still remains a big gap between man-made soft robotics and natural lives in terms of autonomy, adaptability, self-repair, durability, energy efficiency, etc. Here, the actuation and sensing strategies in the natural biological world are summarized along with their man-made counterparts applied in soft robotics. The development trends of bioinspired soft robotics toward closed loop and embodiment are proposed. Challenges for obtaining autonomous soft robotics similar to natural organisms are outlined to provide a perspective in this field.