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Abstract In clinical situations, peripheral blood accessible CD3+CD4+CXCR5+ T-follicular helper (TFH) cells may have to serve as a surrogate indicator for dysregulated germinal center responses in tissues. To determine the heterogeneity of TFH cells in peripheral blood versus tonsils, CD3+CD4+CD45RA–CXCR5+ cells of both origins were sorted. Transcriptomes, TCR repertoires and cell-surface protein expression were analysed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Reassuringly, all blood-circulating CD3+CD4+CXCR5+ T-cell subpopulations also appear in tonsils, there with some supplementary TFH characteristics, while peripheral blood-derived TFH cells display markers of proliferation and migration. Three further subsets of TFH cells, however, with bona fide T-follicular gene expression patterns, are exclusively found in tonsils. One additional, distinct and oligoclonal CD4+CXCR5+ subpopulation presents pronounced cytotoxic properties. Those ‘killer TFH (TFK ) cells’ can be discovered in peripheral blood as well as among tonsillar cells but are located predominantly outside of germinal centers. They appear terminally differentiated and can be distinguished from all other TFH subsets by expression of NKG7 (TIA-1), granzymes, perforin, CCL5, CCR5, EOMES, CRTAM and CX3CR1. All in all, this study provides data for detailed CD4+CXCR5+ T-cell assessment of clinically available blood samples and extrapolation possibilities to their tonsil counterparts.

Abstract Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

Abstract Regulating metabolic disorders has become a promising focus in treating intervertebral disc degeneration (IDD). A few drugs regulating metabolism, such as atorvastatin, metformin, and melatonin, show positive effects in treating IDD. Glutamine participates in multiple metabolic processes, including glutaminolysis and glycolysis; however, its impact on IDD is unclear. The current study reveals that glutamine levels are decreased in severely degenerated human nucleus pulposus (NP) tissues and aging Sprague-Dawley (SD) rat nucleus pulposus tissues, while lactate accumulation and lactylation are increased. Supplementary glutamine suppresses glycolysis and reduces lactate production, which downregulates adenosine-5’-monophosphate-activated protein kinase α (AMPKα) lactylation and upregulates AMPKα phosphorylation. Moreover, glutamine treatment reduces NP cell senescence and enhances autophagy and matrix synthesis via inhibition of glycolysis and AMPK lactylation, and glycolysis inhibition suppresses lactylation. Our results indicate that glutamine could prevent IDD by glycolysis inhibition-decreased AMPKα lactylation, which promotes autophagy and suppresses NP cell senescence.

Abstract The treatment of critical-size bone defects with irregular shapes remains a major challenge in the field of orthopedics. Bone implants with adaptability to complex morphological bone defects, bone-adhesive properties, and potent osteogenic capacity are necessary. Here, a shape-adaptive, highly bone-adhesive, and ultrasound-powered injectable nanocomposite hydrogel is developed via dynamic covalent crosslinking of amine-modified piezoelectric nanoparticles and biopolymer hydrogel networks for electrically accelerated bone healing. Depending on the inorganic-organic interaction between the amino-modified piezoelectric nanoparticles and the bio-adhesive hydrogel network, the bone adhesive strength of the prepared hydrogel exhibited an approximately 3-fold increase. In response to ultrasound radiation, the nanocomposite hydrogel could generate a controllable electrical output (-41.16 to 61.82 mV) to enhance the osteogenic effect in vitro and in vivo significantly. Rat critical-size calvarial defect repair validates accelerated bone healing. In addition, bioinformatics analysis reveals that the ultrasound-responsive nanocomposite hydrogel enhanced the osteogenic differentiation of bone mesenchymal stem cells by increasing calcium ion influx and up-regulating the PI3K/AKT and MEK/ERK signaling pathways. Overall, the present work reveals a novel wireless ultrasound-powered bone-adhesive nanocomposite hydrogel that broadens the therapeutic horizons for irregular bone defects.

Metal implants holds significant promise for diverse fixed prostheses. However, their long-term reliability and broader application are hindered by challenges related to the disequilibrium at the soft-hard tissue interface. By using anti-inflammatory (PDA/IL4) and pro-inflammatory (PDA/LPS/IFNγ) coatings to modulate distinct immune characteristics, we discovered a dynamic bioactive structure at the soft-hard tissue interface around metal implant, which we have named the 'Remodeling Triangle Area' (RTA). We further demonstrate that the RTA can be influenced by the PDA/IL4 coating to favor a phenotype that enhances both innate and adaptive immunity. This leads to stronger epithelial adhesion, the formation of dense connective tissue via IGF1 secretion, and a more balanced soft-hard tissue interface through the OPG/RANKL axis. Conversely, the PDA/LPS/IFNγ coating shifts the RTA towards a phenotype that activates the innate immune response. This results in a less cohesive tissue structure and bone resorption, characterized by reduced IGF1 secretion and an imbalanced OPG/RANKL axis. Over all, our study introduces the novel concept termed the 'Remodeling Triangle Area' (RTA), an immune-rich anatomical region located at the nexus of the implant interface, epithelial, connective, and bone tissue, which becomes highly interactive post-implantation to modulate the soft-hard tissue interface equilibrium. We believe that an RTA-centric, immunomodulatory approach has the potential to revolutionize the design of next-generation metal implants, providing unparalleled soft-hard tissue interface equilibrium properties.

Abstract Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra‐conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory‐polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4‐ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein‐based conduits. Moreover, the NGC can gradually regulate the intra‐conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.

Polyphenol is one of the characteristic physical and chemical indexes of edible plant enzyme, which has the effects of anti-oxidation, reducing fat and anti-tumor. This paper reviews the composition of polyphenols in food plant enzyme products, the factors affecting the formation of polyphenols in food plant enzyme products, the health care effects of polyphenols, and the further research directions of polyphenols in edible plant enzymes are also prospected.

Three humic acids(AHA, YHA, and EHA) from different origin were characterized by elementary analysis, UV-Vis and FTIR spectra, and the functional groups were determined by chemical titration. The effects of pH, time, temperature, and ionic strength on the complexation of three HAs with U(Ⅵ) were investigated systematically. Meanwhile, the interaction of U(Ⅵ) with three HA models in aqueous phase was studied by means of molecular dynamics(MD) simulations, and the dynamics, coordination structures, and interaction mechanism were further explored. The experimental results show that the elemental composition and functional group types of three HAs from different origin are basically similar, with strong aromaticity and conjugated double bonds, but slight differences can be also observed between them. The low H/C atom ratio, high acidity, and high content of functional groups indicate that YHA has high humification degree, high conjugation or aromatic composition, and strong metal complexation ability. The complexation behavior of three HAs with U(Ⅵ) are significantly different, which is substantially affected by pH, time, temperature, and ionic strength. MD simulations demonstrate that the complexation of single HA with U(Ⅵ) can be completed in a short time, and the main binding sites are carboxyl groups. The coordination structures formed by HAs with U(Ⅵ) in aqueous solution have quite differences, and the main driving force is electrostatic interaction. The results reported here are beneficial to further understanding the chemical behavior of uranium in the presence of HA, and provide data and reference for the geological disposal and safety evaluation of radioactive wastes.

Abstract The biological barriers of the body, such as the blood–brain, placental, intestinal, skin, and air‐blood, protect against invading viruses and bacteria while providing necessary physical support. However, these barriers also hinder the delivery of drugs to target tissues, reducing their therapeutic efficacy. Extracellular vesicles (EVs), nanostructures with a diameter ranging from 30 nm to 10 μm secreted by cells, offer a potential solution to this challenge. These natural vesicles can effectively pass through various biological barriers, facilitating intercellular communication. As a result, artificially engineered EVs that mimic or are superior to the natural ones have emerged as a promising drug delivery vehicle, capable of delivering drugs to almost any body part to treat various diseases. This review first provides an overview of the formation and cross‐species uptake of natural EVs from different organisms, including animals, plants, and bacteria. Later, it explores the current clinical applications, perspectives, and challenges associated with using engineered EVs as a drug delivery platform. Finally, it aims to inspire further research to help bioengineered EVs effectively cross biological barriers to treat diseases.

The important factor in the design and realization of tissue engineering is the structure of three-dimensional (3D) synthetic scaffold that functions as synthetic extracellular matrix (ECM) which mimicking natural cell environment and preserve bioactive signal molecules such as growth factors (GFs). In this study, formulation of synthetic three-dimensional (3D) coral matrices was developed, characterized, and screened to obtain the most ideal formulation. Consecutively matrix ability to induce MSCs (mesenchymal stem cells) to differentiate into osteoblast both in vitro and in vivo was investigated. The potential matrix was observed for its capability in enhancing bone regeneration process within various culture conditions involving either standard culture medium or osteogenic medium, with the presence or absence of GFs cocktail in platelet rich plasma (PRP) and MSCs. Expressions of Runx, Osterix, and Osteocalcin markers were measured following the analysis on cell attachment and proliferations. Among several fabricated synthetic 3D coral matrices in various concentrations, SC-05 formulation was found preferable with the lowest degradability rate of 39.31 ± 3.55 % even after 96 h immersion in phosphate buffer saline continued by 6 h in acid solution. The release profile of PRP from the SC-05 matrix was also found preferable at 81.55 ± 1.15 %. The matrix loaded with growth factors cocktail from PRP provided ideal microenvironment for MSCs to attach, proliferate, and differentiate into osteoblast indicated by high expression level of Runx2, Osterix, and Osteocalcin. This verified that engineered microenvironment based on SCM loaded with growth factors can enhance bone tissue regeneration.

Abstract Tendon‐to‐bone interface has a hierarchical structure and gradient component that are conducive to distributing the stresses to achieve movement. Conventional biomaterials lack the capacity to induce synchronous repair of multiple tissues, resulting in the failure of the interface repair. Biomimetic strategies have attracted enormous attention in the field of complex structure regeneration because they can meet the different physiological requirements of multiple tissues. Herein, a biomimetic ink mimicking tendon/bone tissues is developed by combining tendon/bone‐related cells and Mo‐containing silicate (MS) bioceramics. Subsequently, biomimetic multicellular scaffolds are fabricated to achieve the simulation of the hierarchical structure and cellular composition of tendon‐to‐bone interfaces by the spatial distribution of the biomimetic inks via 3D bioprinting, which is of great significance for inducing the regeneration of complex structures in the interface region. In addition, attributed to the desirable ionic microenvironment created by MS bioceramics, the biomimetic scaffolds possess the dual function of inducing tendon/bone‐related cells tenogenic and osteogenic differentiation in vitro, and promote the integrated regeneration of tendon‐to‐bone interfaces in vivo. The study offers a feasible strategy to construct biomimetic multicellular scaffolds with bifunction for inducing multi‐lineage tissue regeneration, especially for regenerating soft‐to‐hard tissue interfaces.

Abstract Periodontitis is an infection‐induced inflammation, evidenced by an increase in inflammatory macrophage infiltration. Recent research has highlighted the role of plasma‐activated medium (PAM) as a regulator of the innate immune system, where macrophages are the main effector cells. This study therefore aims to investigate the immunomodulatory effects of PAM on macrophages and its potential applications for periodontitis management. PAM was generated using an argon jet and applied to culture macrophages. Proinflammatory macrophage markers were significantly reduced after PAM stimulation, and this was correlated with the activation of autophagy via the Akt signaling pathway. Further investigations on the proregenerative effects of PAM‐treated macrophages on periodontal ligament cells (PDLCs) revealed a significant increase in the expression of osteogeneis/cementogenesis‐associated markers as well as mineralization nodule formation. Our findings suggest that PAM is an excellent candidate for periodontal therapeutic applications.

Trunk-like continuum robots have wide applications in manipulation and locomotion. In particular, trunk-like soft arms exhibit high dexterity and adaptability very similar to the creatures of the natural world. However, owing to the continuum and soft bodies, their performance in payload and spatial movements is limited. In this paper, we investigate the influence of key design parameters on robotic performance. It is verified that a larger workspace, lateral stiffness, payload, and bending moment could be achieved with adjustments to soft materials’ hardness, the height of module segments, and arrayed radius of actuators. Especially, a 55% increase in arrayed radius would enhance the lateral stiffness by 25% and a bending moment by 55%. An 80% increase in segment height would enlarge 112% of the elongation range and 70 % of the bending range. Around 200% and 150% increments in the segment’s lateral stiffness and payload forces, respectively, could be obtained by tuning the hardness of soft materials. These relations enable the design customization of trunk-like soft arms, in which this tapering structure ensures stability via the stocky base for an impact reduction of 50% compared to that of the tip and ensures dexterity of the long tip for a relatively larger bending range of over 400% compared to that of the base. The complete methodology of the design concept, analytical models, simulation, and experiments is developed to offer comprehensive guidelines for trunk-like soft robotic design and enable high performance in robotic manipulation.

Objective To investigate the influence of smoking on subgingival flora after periodontitis treatment through microbiological experiments. Methods Fifty-nine patients with periodontitis who completed periodontal treatment in the Department of Stomatology of Nanjing Jiangbei Hospital from 2019 to 2021 were selected and divided into smoking group(30 patients) and non-smoking group(29 patients). The clinical samples of patients's periodontal pockets before and after treatment were collected for detection of Actinobacillus (Aa), Porphyromonas gingivalis (Pg), Plasmobacterium intermedius (PI), Bacteroides forsythiae (Bf), Fusobacterium nucleatum (Fn) and Streptococcus minimus (Pm). Results After treatment, the bleeding index and periodontal attachment of the smoking group were better than those before treatment, while the plaque area index, bleeding index, periodontal pocket depth and periodontal attachment of the non-smoking group were better than those before treatment, and the plaque area index, periodontal pocket depth and periodontal attachment of the non-smoking group were better than those of the smoking group, with statistically significant differences(P＜0.05). After treatment, the positive rate of Pg and Pi in the smoking group was lower than that before treatment, the positive rate of Aa, Pg, Pi, Bf, Fn and Pm in the non-smoking group was lower than that before treatment, and the positive rate of Pg, Bf, Fn and Pm in the non-smoking group was lower than that in the smoking group, with statistically significant differences(P＜0.05). Conclusion Compared with smokers, non-smokers have better periodontal attachment recovery and lower detection rate of periodontal bacteria after periodontal treatment.

Abstract Background Transepithelial medical devices are increasing utilized in clinical practices. However, the damage of continuous natural epithelial barrier has become a major risk factor for the failure of epithelium-penetrating implants. How to increase the “epithelial barrier structures” (focal adhesions, hemidesmosomes, etc.) becomes one key research aim in overcoming this difficulty. Directly targeting the in situ “epithelial barrier structures” related proteins (such as fibronectin) absorption and functionalization can be a promising way to enhance interface-epithelial integration. Methods Herein, we fabricated three plasma polymerized bio-interfaces possessing controllable surface chemistry. Their capacity to adsorb and functionalize fibronectin (FN) from serum protein was compared by Liquid Chromatography-Tandem Mass Spectrometry. The underlying mechanisms were revealed by molecular dynamics simulation. The response of gingival epithelial cells regarding the formation of epithelial barrier structures was tested. Results Plasma polymerized surfaces successfully directed distinguished protein adsorption profiles from serum protein pool, in which plasma polymerized allylamine (ppAA) surface favored adsorbing adhesion related proteins and could promote FN absorption and functionalization via electrostatic interactions and hydrogen bonds, thus subsequently activating the ITG β1-FAK-mTOR signaling and promoting gingival epithelial cells adhesion. Conclusion This study offers an effective perspective to overcome the current dilemma of the inferior interface-epithelial integration by in situ protein absorption and functionalization, which may advance the development of functional transepithelial biointerfaces. Graphical Abstract Tuning the surface chemistry by plasma polymerization can control the adsorption of fibronectin and functionalize it by exposing functional protein domains. The functionalized fibronectin can bind to human gingival epithelial cell membrane integrins to activate epithelial barrier structure related signaling pathway, which eventually enhances the formation of epithelial barrier structure.

Spent nuclear fuel reprocessing is the key step of the nuclear fuel cycle. It also restricts the sustainable development of nuclear power. With the help of external neutron source in an accelerator driven advanced nuclear energy system(ADANES), spent nuclear fuel reprocessing only needs to remove some volatile fission products and neutron poisons, such as rare elements. Moreover, it is not necessary to separate the long-lived minor actinides Np, Am and Cm finely. These minor actinides can be refabricated as new nuclear fuels together with uranium dioxide for burn, transmutation, breeding, and power production in the accelerator driven advanced nuclear energy system. Based on this, our group proposed a technical route for spent nuclear fuel reprocessing and regeneration of accelerator driven advanced nuclear energy system, including high-temperature oxidation pulverization and volatilization, selective dissolution separation, and fuel regeneration. The recent research of our group is summarized, which has a great significance for implementation of accelerator driven advanced nuclear energy system.

Abstract Repeat firing produces uncertainty about stabilizing lithium disilicate glass-ceramic (LDGC) material properties, even though prolonged holding time can enhance the mechanical property of LDGC during a single firing cycle. However, the effect of prolonged holding time and repeat firing on the mechanical property and microstructure of LDGC is not fully understood. In the present study, three groups of LDGC material were created: (i) extension of holding time (7 vs. 14 vs. 28 min) at 780–800 °C; (ii) holding time extension (7 vs. 14 min) and dual sintering at 800–820 °C, respectively; (iii) dual sintering with prolonged holding time (7 vs. 14 min) at 820–840 °C. The nano-indenter test revealed that prolonged holding time (14 and 28 min) promoted the enhancement of LDGC hardness and Young’s modulus. X-ray photoelectron spectroscopy, X-ray diffraction and Fourier transform infrared spectroscopy confirmed that prolonged holding time increased and stabilized LD phase in LDGC, as well as induced residual compressive stress. Scanning electron microscopy showed that prolonged holding time increased LD crystal grains homogeneously and facilitated LDGC to form dense interlocking structure without enlarging crystal size grains significantly. In contrast, LDGC that dual sintered alone at 820–840 °C possessed inferior mechanical properties, coupled with heterogeneous crystal phases, residual tensile stress, and melted crystals grains in the porous microstructure. Interestingly, these deteriorated properties of LDGC caused by dual sintering alone could be counteracted by prolonging the holding time. Nevertheless, the LDGC materials displayed an excellent biocompatibility throughout the study. This study identified that prolonged holding time during repeated firing cycles stabilized LD phase and crystal grain size of LDGC, thus enhanced the mechanical properties, which provided a new insight to extend the repeat fired restoration longevity of LDGC. Graphical abstract

Abstract Background It is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the macrophage-osteocyte interaction, and how their crosstalk could affect bone homeostasis and mineralization. This research therefore aims to investigate the effects of macrophage polarization on osteocyte maturation and mineralization process. Methods A macrophage-derived conditioned medium based osteocyte culture was set up to investigate the impact of macrophages on osteocyte maturation and terminal mineralization. Surgically induced osteoarthritis (OA) rat model was used to further investigate the macrophage-osteocyte interaction in inflammatory bone remodeling, as well as the involvement of the Notch signaling pathway in the mineralization process. Results Our results identified that osteocytes were confined in an immature stage after the M1 macrophage stimulation, showing a more rounded morphology, higher expression of early osteocyte marker E11, and significantly lower expression of mature osteocyte marker DMP1. Immature osteocytes were also found in inflammatory bone remodeling areas, showing altered morphology and mineralized structures similar to those observed under the stimulation of M1 macrophages in vitro, suggesting that M1 macrophages negatively affect osteocyte maturation, leading to abnormal mineralization. The Notch signaling pathway was found to be down regulated in M1 macrophage-stimulated osteocytes as well as osteocytes in inflammatory bone. Overexpression of the Notch signaling pathway in osteocytes showed a significant circumvention on the negative effects from M1 macrophage. Conclusion Taken together, our findings provide valuable insights into the mechanisms involved in abnormal bone mineralization under inflammatory conditions.

An adaptive metamodel-based global approximation (AMGA) method for solving the global approximation problem of black-box models in large design domain is proposed in this study. The method employs the RBF model to compute the Hessian matrix and a heuristic direct search algorithm DIRECT to find the maximum curvature point of the metamodel surface, through which the design domain is split to obtain additional sampling points and to achieve fast update and fast valuation of the metamodel. The initial design domain is split into a series of sub-design domains by continuous iterations, and the metamodels built within the various sub-design domains achieve the global approximate model of the entire design domain. To demonstrate the final effect of the global approximation model and design domain splitting, six common two-dimensional test functions are chosen. The AMGA method is further tested using seven typical test functions and compared to other sampling and metamodel updating methods, with the findings demonstrating the usefulness of the proposed method in the low-dimensional scenario (less than four variables). Finally, the AMGA method is applied to a sophisticated electric car model, yielding good results.

The application of gelatin hydrogels is hampered by their poor mechanical properties, which are unfavorable for debridement and diabetic wound healing. Herein, bovine serum albumin (BSA)-bridged gelatin hydrogels biopotentiated by bone marrow mesenchymal stem cell (BMSC)-derived nanovesicles (NV), named NV@BSA-GEL, were fabricated by reinforcement of gelatin hydrogels with genipin and BSA in a one-pot, low-cost green approach based on amide bonding-guided crosslinking. Genipin introduction endowed the crosslinking of gelatin hydrogels with weak mechanical properties that were reinforced by BSA bridging to realize suitable mechanical properties for wound dressing, including excellent flexibility and appropriate rigidity. The bioactivity of NV released by the hydrogels resulted in efficient ROS scavenging and favorable immunomodulatory activity as well as promoted cell proliferation and migration of fibroblasts and vascular endothelial cells. Proteomic analysis confirmed that NV harbors a variety of growth factors that can promote wound healing. In vivo, the NV@BSA-GEL hydrogel had superior wound healing effects compared to BSA-GEL, including faster wound healing, stimulation of angiogenesis, contributing to an anti-inflammatory extracellular matrix, and promoting skin maturation, with no systemic toxicity. Thus, the combined merits of NV@BSA-GEL suggest that it has high potential as a new hydrogel dressing for the safe and efficient treatment of diabetic wounds.

Targeting macrophages to regulate the immune microenvironment is a new strategy for bone regeneration with nano-drugs. Nano-drugs have achieved surprising anti-inflammatory and bone-regenerative effects, however, their underlying mechanisms in macrophages remain to be clarified. Macrophage polarization, immunomodulation, and osteogenesis are governed by autophagy. Rapamycin, an autophagy inducer, has shown promising results in bone regeneration, but high dose-mediated cytotoxicity and low bioavailability hinder its clinical application. This study aimed to develop rapamycin-loaded virus-like hollow silica nanoparticles (R@HSNs) which are easily phagocytosed by macrophages and translocated to lysosomes. R@HSNs induced macrophage autophagy, promoted M2 polarization, and alleviated the degree of M1 polarization as indicated by the downregulation of inflammatory factors IL-6, IL-1β, TNF-α, and iNOS, and upregulation of anti-inflammatory factors CD163, CD206, IL-1ra, IL-10, and TGF-β. These effects were nullified by cytochalasin B-induced inhibition of R@HSNs uptake in macrophages. The conditioned medium (CM) collected from R@HSNs-treated macrophages promoted osteogenic differentiation of mouse bone marrow mesenchymal stromal cells (mBMSCs). In a mouse calvaria defect model, free rapamycin treatment was inhibited, but R@HSNs robustly promoted bone defect healing. In conclusion, silica nanocarrier-mediated intracellular rapamycin delivery to macrophages effectively triggers autophagy-mediated M2 macrophage polarization, further enhancing bone regeneration by triggering osteogenic differentiation of mBMSCs.

The nonuniform distribution of organic matter in oil shale strata results in different mechanical response and failure mechanism. Uniaxial compression test, digital image correlation method and infrared thermal imaging technology were used to study the deformation field, temperature field and energy evolution characteristics of oil shale during the whole loading process under different organic matter abundances, and to reveal the influence of organic matter abundance on mechanical properties and deformation and failure mechanism of oil shale. The results show that the stress-strain characteristics of oil shale present gradual attenuation as the organic matter abundance increases, while the ductility has improved significantly. The failure mode changes from splitting tensile failure to tension-shear compound failure, which is attributed to the fact that organic matter abundance affects the control degree of bedding planes on the macroscopic crack evolution. Moreover, the deformation field and temperature field exhibit obvious localized features during loading. With the increase of organic matter abundance, the surface deformation and infrared temperature increase, and the degree of differentiation of the two fields also intensifies. In addition, organic matter abundance also affects the energy transformation and distribution of oil shale. With the increase of organic matter abundance, the energy absorption, storage and release properties weaken, while the dissipation property enhances, causing a lower overall energy state. This is the essential reason for the differences in mechanical properties and deformation and failure laws of oil shale with different organic matter abundances.

Abstract Background Due to the advancement of modern societies, the proportion of women who delay childbearing until or beyond 30 years has dramatically increased in the last three decades and has been linked with adverse maternal-neonatal outcomes. Objective To determine the trend in delayed childbearing and its negative impact on pregnancy outcomes. Material and methods A tertiary hospital-based retrospective study was conducted in Wuhan University Renmin Hospital, Hubei Province, China, during the years 2011–2019. The joinpoint regression analysis was used to find a trend in the delayed childbearing and the multiple binary logistic regression model was used to estimate the association between maternal age and pregnancy outcomes. Results Between 2011 and 2019, the trend in advanced maternal age (AMA ≥35 years) increased by 75% [AAPC 7.5% (95% CI: − 10.3, 28.9)]. Based on maternal education and occupation, trend in AMA increased by 130% [AAPC 11.8% (95% CI: 1.1, 23.7)] in women of higher education level, and 112.5% [AAPC 10.1% (95% CI: 9.4, 10.9)] in women of professional services. After adjusting for confounding factors, AMA was significantly associated with increased risk of gestational hypertension (aOR 1.5; 95% CI: 1.2, 2.1), preeclampsia (aOR 1.6; 95% CI: 1.4, 1.9), sever preeclampsia (aOR 1.7; 95% CI: 1.1, 2.6), placenta previa (aOR 1.8; 95% CI: 1.5, 2.2), gestational diabetes mellitus (aOR 2.5; 95% CI: 2.3, 2.9), preterm births (aOR 1.6; 95% CI: 1.4, 1.7), perinatal mortality (aOR 1.8; 95% CI: 1.3, 2.3), and low birth weight (aOR 1.3; 95% CI: 1.2, 1.4) compared with women aged

Micro/nano topographic structures have shown great utility in many biomedical areas including cell therapies, tissue engineering, and implantable devices. Computer-assisted informatics methods hold great promise for the design of topographic structures with targeted properties for a specific medical application. To benefit from these methods, researchers and engineers require a highly reusable “one structural parameter – one set of cell responses” database. However, existing confounding factors in topographic cell culture devices seriously impede the acquisition of this kind of data. Through carefully dissecting the confounding factors and their possible reasons for emergence, we developed corresponding guideline requirements for topographic cell culture device development to remove or control the influence of such factors. Based on these requirements, we then suggested potential strategies to meet them. In this work, we also experimentally demonstrated a topographic cell culture device with controlled confounding factors based on these guideline requirements and corresponding strategies. A “guideline for the development of topographic cell culture devices” was summarized to instruct researchers to develop topographic cell culture devices with the confounding factors removed or well controlled. This guideline aims to promote the establishment of a highly reusable “one structural parameter – one set of cell responses” database that could facilitate the application of informatics methods, such as artificial intelligence, in the rational design of future biotopographic structures with high efficacy.

Gold nanoparticles (AuNPs) with surface-anchored molecules present tremendous potential in tissue regeneration. However, little is known about chiral-modified AuNPs. In this study, we successfully prepared L/D-cysteine-anchored AuNPs (L/D-Cys-AuNPs) and studied the effects of chiral-modified AuNPs on osteogenic differentiation and autophagy of human periodontal ligament cells (hPDLCs) and periodontal tissue regeneration. In vitro, more L-Cys-AuNPs than D-Cys-AuNPs tend to internalize in hPDLCs. L-Cys-AuNPs also significantly increased the expression of alkaline phosphatase, collagen type 1, osteocalcin, runt-related transcription factor 2, and microtubule-associated protein light chain 3 II and decreased the expression of sequestosome 1 in hPDLCs compared to the expression levels in the hPDLCs treated by D-Cys-AuNPs. In vivo tests in a rat periodontal-defect model showed that L-Cys-AuNPs had the greatest effect on periodontal-tissue regeneration. The activation of autophagy in L-Cys-AuNP-treated hPDLCs may be responsible for the cell differentiation and tissue regeneration. Therefore, compared to D-Cys-AuNPs, L-Cys-AuNPs show a better performance in cellular internalization, regulation of autophagy, cell osteogenic differentiation, and periodontal tissue regeneration. This demonstrates the immense potential of L-Cys-AuNPs for periodontal regeneration and provides a new insight into chirally modified bioactive nanomaterials.

Injectable bone cement is especially useful in minimally invasive surgeries to repair small and irregular bone defects. Amongst different kinds of injectable bone cements, bioactive calcium phosphate bone cement (CPC) has been widely studied due to its biological activity. However, its dense structure and poor biodegradability prevent the ingrowth of living tissue, which leads to undesirable bone regeneration and clinical translation. To address this issue, we prepared bone cement based on Magnesium-containing microspheres (MMSs) that can not only be cured into a 3D porous scaffold but also have controllable biodegradability that continuously provides space for desired tissue ingrowth. Interestingly, magnesium ions released from MMSs cement (MMSC) trigger positive immunomodulation via upregulation of the anti-inflammatory genes IL-10 and M2 macrophage polarization with increased expression of CD206, which is beneficial to osteogenesis. Moreover, the physicochemical properties of MMSC, including heat release, rheology and setting time, can be tuned to meet the requirements of injectable bone cement for clinical application. Using a rat model, we have demonstrated that MMSC promoted osteogenesis via mediation of tissue ingrowth and anti-inflammatory immunomodulation. The study provides a paradigm for the design and preparation of injectable bone cements with 3D porous structures, biodegradability and anti-inflammatory immunoregulation to efficiently promote osteogenesis.

Summary: The identification, uptake, and clearance of nanoparticles (NPs) by phagocytes are critical in NP-based therapeutics. The cell membrane coating technique has recently emerged as an ideal surface modification approach to help NP bypass phagocytosis. CD47, a regulatory protein for phagocytosis, is a cell surface glycoprotein expressed on all cell types, including platelets. Herein, we enclosed bioactive glass (BG) with a platelet membrane to bestow BG with unique cell surface functions for immune evasion and immunomodulation. Compared with the uncoated particles, platelet membrane-coated BG shows reduced cellular uptake and can generate an immune environment favorable for osteogenesis. This is evidenced by the triggering of robust osteogenic differentiation in bone mesenchymal stromal cells, suggesting the synergistic effect of platelet membrane and BG in bone regeneration. These collectively indicate that cell membrane coating is a promising approach to enhance the therapeutic efficacy of biomaterials and thus provide new insight into biomaterial-mediated bone regeneration.

Abstract Aims/Introduction Periodontal disease, a chronic inflammation induced by bacteria, is closely linked with diabetes mellitus. Many complications associated with diabetes are related to epigenetic changes. However, the exact epigenetic changes whereby diabetes affects periodontal disease remain largely unknown. Thus, we sought to investigate the role of diabetes‐dependent epigenetic changes of gingival tissue in the susceptibility to periodontal disease. Materials and Methods We studied the effect of streptozotocin‐induced diabetes in minipigs on gingival morphological and epigenetic tissue changes. Accordingly, we randomly divided six minipigs into two groups: streptozotocin‐induced diabetes group, n = 3; and non‐diabetes healthy control group, n = 3. After 85 days, all animals were killed, and gingival tissue was collected for histology, deoxyribonucleic acid methylation analysis and immunohistochemistry. Results A diabetes mellitus model was successfully created, as evidenced by significantly increased blood glucose levels, reduction of pancreatic insulin‐producing β‐cells and histopathological changes in the kidneys. The gingival tissues in the diabetes group presented acanthosis of both gingival squamous epithelium and sulcular/junctional epithelium, and a significant reduction in the number and length of rete pegs. Deoxyribonucleic acid methylation analysis showed a total of 1,163 affected genes, of which 599 and 564 were significantly hypermethylated and hypomethylated, respectively. Immunohistochemistry staining showed that the hypomethylated genes – tumor necrosis factor‐α and interleukin‐6 – were positively expressed under the junctional epithelium area in the diabetes group. Conclusions Diabetes mellitus induces morphological and epigenetic changes in periodontal tissue, which might contribute to the increased susceptibility of periodontal diseases in patients with diabetes.

Objective: This article is aimed to explore the influence of closed/open conditions on the flavor compounds of Maillard reaction. Methods: The species and amounts of flavor compounds produced from Tyrosine-based Maillard reactions under closed/open conditions in different solvents and reaction temperatures were determined by GC-MS. Results: The results showed that the species and contents of flavor products are quite different under closed and open conditions. The amounts of alcohol flavor compounds were higher in closed system, while the amount of esters and ketones were higher inopensystem. Conclusion: The amounts of active oxygen and intermediates produced during the reactions likely result in the difference between closed and opensystems from the proposed mechanisms.

Hydrogels have been widely applied to the fabrication of tissue engineering scaffolds via three-dimensional (3D) bioprinting because of their extracellular matrix-like properties, capacity for living cell encapsulation, and shapeable customization depending on the defect shape. However, the current hydrogel scaffolds show limited regeneration activity, especially in the application of periodontal tissue regeneration. In this study, we attempted to develop a novel multi-component hydrogel that possesses good biological activity, can wrap living cells for 3D bioprinting and can regenerate periodontal soft and hard tissue. The multi-component hydrogel consisted of gelatin methacryloyl (GelMA), sodium alginate (SA) and bioactive glass microsphere (BGM), which was first processed into hydrogel scaffolds by cell-free 3D printing to evaluate its printability and in vitro biological performances. The cell-free 3D-printed scaffolds showed uniform porous structures and good swelling capability. The BGM-loaded scaffold exhibited good biocompatibility, enhanced osteogenic differentiation, apatite formation abilities and desired mechanical strength. The composite hydrogel was further applied as a bio-ink to load with mouse bone marrow mesenchymal stem cells (mBMSCs) and growth factors (BMP2 and PDGF) for the fabrication of a scaffold for periodontal tissue regeneration. The cell wrapped in the hydrogel still maintained good cellular vitality after 3D bioprinting and showed enhanced osteogenic differentiation and soft tissue repair capabilities in BMP2- and PDGF-loaded scaffolds. It was noted that after transplantation of the cell- and growth factor-laden scaffolds in Beagle dog periodontal defects, significant regeneration of gingival tissue, periodontal ligament, and alveolar bone was detected. Importantly, a reconstructed periodontal structure was established in the treatment group eight weeks post-transplantation of the scaffolds containing the cell and growth factors. In conclusion, we developed a bioactive composite bio-ink for the fabrication of scaffolds applicable for the reconstruction and regeneration of periodontal tissue defects.

It is presently difficult to achieve dental pulp vitality maintenance and regeneration in adult teeth. Dentin destruction results in the exposure of the dental pulp tissue to infectious oral environments, thereby triggering continuous severe pulp inflammation that impedes the self-regenerative capacity of the pulp. For these reasons, the regeneration of dentin bridges to block pulp tissue from the oral environment is an indispensable step. Nevertheless, this goal is difficult to achieve using present strategies, because the importance of immunoregulation in the pulp inflammatory microenvironment has been ignored. In our previous study, we found that the nanomaterial dihydrolipoic acid-functionalized gold nanoclusters (DHLA-AuNCs) efficiently regulated inflammatory responses in microglia (resident macrophages in the central nervous system), suggesting that DHLA-AuNCs may induce dentin bridge regeneration by regulating dental pulp macrophage responses. In the present study, we found that DHLA-AuNCs inhibited the M1 phenotype while promoting the M2 phenotype in macrophages in inflammatory conditions in vitro. This regulation of the inflammatory environment in dental pulp enhanced the differentiation of human dental pulp stromal cells (hDPC) toward odontoblasts, a beneficial effect on dentin regeneration. DHLA-AuNCs also had a direct role in the differentiation and mineralization of hDPC. These findings suggest that DHLA-AuNCs facilitate dentin regeneration through both efficient immunomodulation and direct induction of stromal cell differentiation/mineralization, providing a potential therapeutic nanomaterial for dentin bridge regeneration, effects that would be beneficial for dental pulp regeneration.

Abstract Background Growing evidence suggests that the pluripotent state of mesenchymal stem cells (MSCs) relies on specific local microenvironmental cues such as adhesion molecules and growth factors. Fibronectin (FN), fibroblast growth factor 2 (FGF2), and bone morphogenetic protein 4 (BMP4) are the key players in the regulation of stemness and lineage commitment of MSCs. Therefore, this study was designed to investigate the pluripotency and multilineage differentiation of bone marrow-derived MSCs (BMSCs) with the introduction of FN, FGF-2, and BMP4 and to identify the metabolic and proteomic cues involved in stemness maintenance. Methods To elucidate the stemness of BMSCs when treated with FN, FGF-2, and BMP4, the pluripotency markers of OCT4, SOX2, and c-MYC in BMSCs were monitored by real-time PCR and/or western blot. The nuclear translocation of OCT4, SOX2, and c-MYC was investigated by immunofluorescence staining. Multilineage differentiation of the treated BMSCs was determined by relevant differentiation markers. To identify the molecular signatures of BMSC stemness, gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and bioinformatics analysis were utilized to determine the metabolite and protein profiles associated with stem cell maintenance. Results Our results demonstrated that the expression of stemness markers decreased with BMSC passaging, and the manipulation of the microenvironment with fibronectin and growth factors (FGF2 and BMP4) can significantly improve BMSC stemness. Of note, we revealed 7 differentially expressed metabolites, the target genes of these metabolites may have important implications in the maintenance of BMSCs through their effects on metabolic activity, energy production, and potentially protein production. We also identified 21 differentially abundant proteins, which involved in multiple pathways, including metabolic, autophagy-related, and signaling pathways regulating the pluripotency of stem cells. Additionally, bioinformatics analysis comfirned the correlation between metabolic and proteomic profiling, suggesting that the importance of metabolism and proteome networks and their reciprocal communication in the preservation of stemness. Conclusions These results indicate that the culture environment supplemented with the culture cocktail (FN, FGF2, and BMP4) plays an essential role in shaping the pluripotent state of BMSCs. Both the metabolism and proteome networks are involved in this process and the modulation of cell-fate decision making. All these findings may contribute to the application of MSCs for regenerative medicine.

The fuel cell technology is a highly-efficient clean energy technology which can alleviate the power and environmental problems. Proton exchange membrane fuel cell (PEMFC) is an important type of fuel cell, of which proton exchange membrane is the key component which is proton-conductive and electron-insulating. Elevation of the working temperature of PEMFCs can solve the intractable issues for low-temperature PEMFCs. Therefore, proton exchange membrane materials which can work under high temperature and low relative humidity are required. The main types, preparation and modification methods, and proton exchange mechanisms of high temperature proton exchange membranes were summarized in this review. Proton conductor doped polybenzimidazole (PBI) based membrane materials are potential candidates for high temperature low humidity proton exchange membranes. The preparation, types of proton conductors and performance enhancement methods of PBI based high temperature proton exchange membranes were discussed. The challenges and research trends of high temperature proton exchange membranes were pointed out such as synthesis of new types of proton conductor, improvement of PBI anti-oxidation stability, regulation of membrane microstructure to improve the performance and develop novel polymer electrolytes.

To overcome the shortcoming of conventional transarterial chemoembolization (cTACE) like high systemic release, a novel droplet-based flow-focusing microfluidic device was fabricated and the biocompatible poly(lactic-co-glycolic acid) (PLGA) magnetic drug-eluting beads transarterial chemoembolization (TACE) microspheres with tunable size and shell thickness were prepared via this device. Paclitaxel, as a model active, was loaded through O/O/W emulsion method with high efficiency. The size and the shell thickness vary when adjusting the flow velocity and/or solution concentration, which caters for different clinical requirements to have different drug loading and release behavior. Under the designed experimental conditions, the average diameter of the microspheres is 60 ± 2 μm and the drug loading efficiency has reached 6%. The drug release behavior of the microspheres shows the combination of delayed release and smoothly sustained release profiles and the release kinetics differ within different shell thickness. The microspheres also own the potential of magnetic resonance imaging (MRI) visuality because of the loaded magnetic nanoparticles. The microsphere preparation method and device we proposed are simple, feasible, and effective, which have a good application prospect.

Treatment of large bone fractures remains a challenge for orthopedists. Bone regeneration is a complex process that includes skeletal cells such as osteoblasts, osteoclasts, and immune cells to regulate bone formation and resorption. Osteoimmunology, studying this complicated process, has recently been used to develop biomaterials for advanced bone regeneration. Ideally, a biomaterial shall enable a timely switch from early stage inflammatory (to recruit osteogenic progenitor cells) to later-stage anti-inflammatory (to promote differentiation and terminal osteogenic mineralization and model the microstructure of bone tissue) in immune cells, especially the M1-to-M2 phenotype switch in macrophage populations, for bone regeneration. Nanoparticle (NP)-based advanced drug delivery systems can enable the controlled release of therapeutic reagents and the delivery of therapeutics into specific cell types, thereby benefiting bone regeneration through osteoimmunomodulation. In this review, we briefly describe the significance of osteoimmunology in bone regeneration, the advancement of NP-based approaches for bone regeneration, and the application of NPs in macrophage-targeting drug delivery for advanced osteoimmunomodulation.

Bone is capable of adjusting size, shape, and quality to maintain its strength, toughness, and stiffness and to meet different needs of the body through continuous remodeling. The balance of bone homeostasis is orchestrated by interactions among different types of cells (mainly osteoblasts and osteoclasts), extracellular matrix, the surrounding biological milieus, and waste products from cell metabolisms. Inorganic ions liberated into the localized microenvironment during bone matrix degradation not only form apatite crystals as components or enter blood circulation to meet other bodily needs but also alter cellular activities as molecular modulators. The osteoinductive potential of inorganic motifs of bone has been gradually understood since the last century. Still, few have considered the naturally generated ionic microenvironment’s biological roles in bone remodeling. It is believed that a better understanding of the naturally balanced ionic microenvironment during bone remodeling can facilitate future biomaterial design for bone tissue engineering in terms of the modulatory roles of the ionic environment in the regenerative process.

Abstract The immune response of a biomaterial determines its osteoinductive effect. Although the mechanisms by which some immune cells promote regeneration have been revealed, the biomaterial-induced immune response is a dynamic process involving multiple cells. Currently, it is challenging to accurately regulate the innate and adaptive immune responses to promote osteoinduction in biomaterials. Herein, we investigated the roles of macrophages and dendritic cells (DCs) during the osteoinduction of biphasic calcium phosphate (BCP) scaffolds. We found that osteoinductive BCP directed M2 macrophage polarization and inhibited DC maturation, resulting in low T cell response and efficient osteogenesis. Accordingly, a dual-targeting nano-in-micro scaffold (BCP loaded with gold nanocage, BCP-GNC) was designed to regulate the immune responses of macrophages and DCs. Through a dual-wavelength photosensitive switch, BCP-GNC releases interleukin-4 in the early stage of osteoinduction to target M2 macrophages and then releases dexamethasone in the later stage to target immature DCs, creating a desirable inflammatory environment for osteogenesis. This study demonstrates that biomaterials developed to have specific regulatory capacities for immune cells can be used to control the early inflammatory responses of implanted materials and induce osteogenesis.

BackgroundThe clinical benefits of omega-3 fatty acids (FAs) supplementation in preventing and treating coronary heart disease (CHD) remain controversial. Therefore, this study aimed to investigate the clinical benefits of omega-3 FA supplementation, with special attention given to specific subgroups.MethodsRandomized controlled trials (RCTs) that compared the effects of omega-3 FA supplementation for CHD vs. a control group and including at least 1,000 patients were eligible for the inclusion in this meta-analysis. The relative risk (RR) of all-cause death, major adverse cardiovascular events (MACEs), cardiovascular death, myocardial infarction (MI), stroke, and revascularization were estimated. We analyzed the association between cardiovascular risk and omega-3 FA supplementation in the total subjects. We focused on the cardiovascular risk compared to omega-3 FA in subgroups with different development stages of CHD, omega-3 FA supplementation application dose, diabetes, and sex. PROSPERO Registration Number: CRD42021282459.ResultsThis meta-analysis included 14 clinical RCTs, including 1,35,291 subjects. Omega-3 FA supplementation reduced the risk of MACE (RR; 0.95; CI: 0.91–0.99; p for heterogeneity 0.27; I2 = 20%; p = 0.03), cardiovascular death (RR; 0.94; CI: 0.89–0.99; p for heterogeneity 0.21; I2 = 25%; p = 0.02), and MI (RR; 0.86; CI: 0.79–0.93; p for heterogeneity 0.28; I2 = 19%; p < 0.01), but had no significant effect on all-cause death, stroke, and revascularization. In the subgroup analysis, omega-3 FA supplementation decreased the incidence of MACE and cardiovascular death in acute patients with MI, the risk of MI and stroke in patients with CHD, and the risk of MI in patients with high-risk CHD. 0.8–1.2 g omega-3 FA supplementation reduced the risk of MACE, cardiovascular death, and MI. It was revealed that gender and diabetes have no significant association between omega-3 FA supplementation and MACE risk.ConclusionsOmega-3 FA supplementation had a positive effect in reducing the incidence of MACE, cardiovascular death, MI. Regardless of the stage of CHD, omega-3 FA supplementation can prevent the occurrence of MI. The 0.8–1.2 g omega-3 FA supplementation alleviated CHD risk more effectively than lower or higher doses.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42021282459.

CD4+CXCR5+Foxp3+ T-follicular regulatory (TFR) cells control the germinal center responses. Like T-follicular helper cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. As one type of effector Treg, TFR cells express B lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 can directly repress Cxcr5 and NFATc1/αA is necessary to overcome this Blimp-1-mediated repression. Interestingly, Blimp-1 even reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA and preserve the Treg identity. This is because although NFATc1/αA strengthens the follicular development of Tregs, it bears the inherent risk of causing an ex-Treg phenotype.

Intervertebral disc degeneration (IDD) is closely associated with low back pain, but its underlying mechanism remains unclear. Cholesterol is an essential nutrient in mammalian cells. Alterations in cholesterol levels lead to impairments in cell physiology, such as cell proliferation and signal transduction. Previous clinical studies demonstrated that hypercholesterolemia could be a potential risk factor for IDD, but how cholesterol induces IDD remains unknown. The current study aimed to explore the regulatory role of cholesterol in IDD development and the potential underlying mechanisms. It was found that different forms of cholesterol levels were elevated in degenerative nucleus pulposus (NP) tissues in both humans and Sprague–Dawley rats. Rats fed a high cholesterol diet (HCD) exhibited degenerative features in the lumbar intervertebral disc compared with those fed a standard diet. Interestingly, this effect could be abolished by cholesterol-lowering drug atorvastatin. In NP cells treated with TNF-α and IL-1β, a significantly higher level of cholesterol was observed. These results suggested a pivotal role of cholesterol in the progression of IDD. We also observed accelerated pyroptosis in NP cells and extracellular matrix (ECM) degradation in the rat NP cells treated with exogenous cholesterol. We further demonstrated that endoplasmic reticulum stress was responsible for cholesterol-induced pyroptosis and ECM degradation. Moreover, RNA-seq analysis revealed that the mature form of SREBP1 (mSREBP1), an important regulator of lipid metabolism, is involved in regulating endoplasmic reticulum stress in knockdown experiments. In conclusion, this study demonstrated that cholesterol could induce pyroptosis in NP cells and ECM degradation by activating endoplasmic reticulum stress through stimulating mSREBP1 in IDD.

Abstract Cartilage matrix remodelling homeostasis is a crucial factor in maintaining cartilage integrity. Loss of cartilage integrity is a typical characteristic of osteoarthritis (OA). Strategies aimed at maintaining cartilage integrity have attracted considerable attention in the OA research field. Recently, a series of studies have suggested dual functions of microRNA-140 (miR-140) in cartilage matrix remodelling. Here, we discuss the significance of miR-140 in promoting cartilage formation and inhibiting degeneration. Additionally, we focused on the role of miR-140 in the chondrogenesis of mesenchymal stem cells (MSCs). Of note, we carefully reviewed recent advances in MSC exosomes for miRNA delivery in OA treatment.

Osteoarthritis (OA) is a prevalent whole joint disease characterised by cartilage degradation, subchondral bone sclerosis and bone remodelling, and synovium inflammation, leading to pain, deformity, and cartilage dysfunction. Currently, there is no appropriate therapy for OA, and available treatments simply aim to reduce pain and swelling. Exosomes are membrane-bound extracellular vesicles secreted by almost all cells, receiving increasing interest because of their effect in cell-to-cell communication. Increasing evidence suggests that exosomes play an important role in cartilage physiological and pathological effects. This article reviews the potential role of exosomes in OA regenerative medicine. Special attention is given to mesenchymal stem cells-derived exosomes due to the extensive research on their cartilage repair property and their function as miRNA cargo. More investigations are needed for the effects of exosomes from synovial fluid and chondrocytes in joints. A better understanding of the mechanisms will contribute to a novel and promising therapy for OA patients. The translational potential of this article: A better understanding of the role of extracellular vesicles in regenerative medicine will contribute to a novel and promising therapy for OA patients. Keywords: Chondrocytes, Exosomes, Mesenchymal stem cells, MicroRNA, Osteoarthritis, Synovial inflammation

Melt blending method dominated by normal stress for polymer-based composite was realized via a self-developed vane mixer. Effects of mixing sequences and mixing time on the microstructure, rheological properties, thermal properties and tensile strength of PA6/HDPE/CNTs ternary blend were experimentally investigated. SEM results show that the normal stress flow field can realize the uniform dispersion of PA6 and CNTs in a short time. Compared with the other two mixing sequences, the blend of the mixing sequence that HDPE and CNTs are firstly mixed to form the masterbatch, and then the masterbatch is mixed with PA6 (HDPE/CNTs+PA6) has the smallest PA6 particle size; DSC results show that Xc is significantly affected by the mixing sequence; mechanical properties show that the better tensile strength is obtained when the mixing sequence is HDPE/CNTs+PA6 and proper mixing time can further improve the tensile strength of the blend.The results aforementioned indicate that the normal stress flow field provides enough energy for the CNTs to overcome the energy barrier of the HDPE/PA6 two-phase interface and migrate into the PA6 phase, which proves that the normal stress flow field has higher dispersion efficiency.

BackgroundHistiocytic sarcoma (HS) is a rare hematopoietic malignancy with an aggressive clinical presentation associated with a poor overall survival. To date, surgical resection, radiation therapy, and chemotherapy were often utilized for HS, but curative effects are rather disappointing.Case PresentationA 19-year-old female was referred to our hospital with a pathologic diagnosis of HS in December 2017. The patient had a severe airway obstruction resulting from a large mass (6.0 cm × 4.4 cm) arising from the left parapharyngeal space. She did not respond to cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOEP) chemotherapy, then she was switched to radiotherapy and crizotinib according to next-generation sequencing (NGS) results (mutations in MET and MAP2K1). The patient got a partial response after radiotherapy and crizotinib, then she switched to imatinib combined with thalidomide treatment. The patient got a long-term complete response from the treatment and is alive 44 months after initial diagnosis without disease progression. Further KEGG pathway enrichment analysis of NGS results from patient’s tissue revealed that phosphatidylinositol 3′ kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways were activated in this HS patient. We further performed experiments in vitro in a canine histiocytic sarcoma cell line DH82, in order to explore the possible mechanism of imatinib plus thalidomide in HS. Results of cell counting kit-8 (CCK8) assays showed that the proliferation activity of DH82 was significantly inhibited by imatinib but not thalidomide. Combined thalidomide and imatinib treatment did not improve the inhibitory effects of imatinib to DH82. Results of Western blot confirmed the inhibitory effects of imatinib on DH82 by targeting activation of MAPK and PI3K/AKT pathways.ConclusionRadiotherapy combined with targeted therapy guided by NGS may be promising, and further perspective clinical trial is warranted for the localized HS.

The traditional two-dimensional (2D) cell culture methods have a long history of mimicking in vivo cell growth. However, these methods cannot fully represent physiological conditions, which lack two major indexes of the in vivo environment; one is a three-dimensional 3D cell environment, and the other is mechanical stimulation; therefore, they are incapable of replicating the essential cellular communications between cell to cell, cell to the extracellular matrix, and cellular responses to dynamic mechanical stimulation in a physiological condition of body movement and blood flow. To solve these problems and challenges, 3D cell carriers have been gradually developed to provide a 3D matrix-like structure for cell attachment, proliferation, differentiation, and communication in static and dynamic culture conditions. 3D cell carriers in dynamic culture systems could primarily provide different mechanical stimulations which further mimic the real in vivo microenvironment. In this review, the current advances in 3D dynamic cell culture approaches have been introduced, with their advantages and disadvantages being discussed in comparison to traditional 2D cell culture in static conditions.

Juan Cobo, a Spanish Dominican, preached to the Chinese in the Philippines between 1588 and 1592. During this time, he translated Ming Xin Bao Jian 《明心寶鑒》, which was the first Chinese classic translated into a Western language. In addition, he also authored an evangelical work: Bian Zheng Jiao Zhen Chuan Shilu 《辯正教真傳實錄》. His approach was notably different from his contemporary Dominicans’ orthodox inclinations. Juan Cobo’s works show his enthusiastic admiration for the Chinese culture, which is demonstrated in his open attitude towards the Confucian and Daoist doctrines, as well as in his recorded egalitarian discussion with a Mandarin scholar. In this article, based on Juan Cobo’s works, an analysis is undertaken regarding how this missionary adopted Neo-Confucian concepts and ideas, which then occupied a mainstream position in the local academic world, in his evangelical work with the Chinese people. Furthermore, this analysis also investigates how Juan Cobo intended to integrate the Oriental and Western philosophies, despite their theoretical and methodological divergences, in order to achieve the quick acceptance and diffusion of Christianity among the Sangleys. The historical background, the causes, and the results of such practices are also discussed in the present article.

Osteocytes play an important role in bone metabolism. The interactions of osteocytes with the surrounding microenvironment can alter cellular and lacunar morphological changes. However, objective quantification of osteocyte lacunae is challenging due to their deep location in the bone matrix. This project established a novel method for the analytical study of osteocytes/lacunae, which was then used to evaluate the osteocyte morphological changes in diabetic pig mandibular bone. Eight miniature pigs were sourced, and diabetes was randomly induced in four animals using streptozotocin (STZ) administration. The mandibular tissues were collected and processed. The jawbone density was evaluated with micro-CT. Osteocyte lacunae were effectively acquired and identified using backscattered electron scanning microscopy (BSE). A significantly decreased osteocyte lacunae size was found in the diabetic group. Using the acid etching method, it was demonstrated that the area of osteocyte and lacunae, and the pericellular areas were both significantly reduced in the diabetes group. In conclusion, a standard and relatively reliable method for analyzing osteocyte/lacunae morphological changes under compromised conditions has been successfully established. This method demonstrates that diabetes can significantly decrease osteocyte/lacunae size in a pig’s mandibular cancellous bone.

Water recovery is a significant proposition for human survival and sustainable development, and we never stop searching for more efficient, easy-operating, low-cost and environmentally friendly methods to decontaminate water bodies. Herein, we combined the advantages of β-cyclodextrin (β-CD), magnetite nanoparticles (MNs), and two kinds of quaternary ammonium salts to synthesize two porous quaternary ammonium groups capped magnetic β-CD polymers (QMCDP1 and QMCDP2) to remove organic pollutants and eradicate pathogenic microorganisms effectively through a single implementation. In this setting, β-CD polymer (CDP) was utilized as the porous substrate material, while MNs endowed the materials with excellent magnetism enhancing recyclability in practical application scenarios, and the grafting of quaternary ammonium groups was beneficial for the adsorption of anionic dyes and sterilization. Both QMCDPs outperformed uncapped MCDPs in their adsorption ability of anionic pollutants, using methyl blue (MB) and orange G (OG) as model dyes. Additionally, QMCDP2, which was modified with longer alkyl chains than QMCDP1, exhibits superior bactericidal efficacy with a 99.47% removal rate for Staphylococcus aureus. Accordingly, this study provides some insights into designing a well-performed and easily recyclable adsorbent for simultaneous sterilization and adsorption of organic contaminants in wastewater.

Background: As a wound dressing and barrier membrane, surface modification of polycaprolactone (PCL) is needed in order to achieve better biological activities. Exosomes derived from mesenchymal stem cells (MSCs) hold significant tissue regeneration promise. Silver nanoparticles (Ag) have been suggested as the surface modification technique for various medical devices.Materials and Methods: Ag and human bone marrow MSC (hBMSC)-derived exosomes (MSCs-exo) were used to modify the PCL scaffold. The impact of different scaffolds on immune cells and MSC proliferation and differentiation was further evaluated.Results: MSCs-exo exhibited cup-shaped morphology with a diameter around 100 nm. MSCs-exo were enriched with exosome marker CD81 and showed good internalization into recipient cells. 200 ng/ml Ag nanoparticles and MSCs-exo were further used to modify the PCL scaffold. The internalization study further indicated a similar releasing pattern of exosomes from Ag/MSCs-exo hybrid scaffolds into RAW264.7 and hBMSCs at 12 and 24 h, respectively. Macrophages play an important role during different stages of bone regeneration. The MTT and confocal microscopy study demonstrated no significant toxicity of exosome and/or Ag hybrid scaffolds for macrophages and MSCs. Inflammatory macrophages were further used to mimic the inflammatory environment. A mixed population of elongated and round morphology was noted in the exosome and Ag hybrid group, in which the proinflammatory genes and secretion of IL-6 and TNF-α were significantly reduced. In addition, the exosome and Ag hybrid scaffolds could significantly boost the osteogenic differentiation of hBMSCs.Discussion: This study highlights the possibility of using Ag nanoparticles and MSCs-exo to modify the PCL scaffold, thus providing new insight into the development of the novel immunomodulatory biomembrane.