Functions and mechanisms of circular RNAs in regulating stem cell differentiation.

Stem cells are a class of undifferentiated cells with great self-renewal and differentiation capabilities that can differentiate into mature cells in specific tissue types. Stem cell differentiation plays critical roles in body homoeostasis, injury repair and tissue generation. The important functions of stem cell differentiation have resulted in numerous studies focusing on the complex molecular mechanisms and various signalling pathways controlling stem cell differentiation. Circular RNAs (circRNAs) are a novel class of noncoding RNAs with a covalently closed structure present in eukaryotes. Numerous studies have highlighted important biological functions of circRNAs, and they play multiple regulatory roles in various physiological and pathological processes. Importantly, multiple lines of evidence have shown the abnormal expression of numerous circRNAs during stem cell differentiation, and some play a role in regulating stem cell differentiation, highlighting the role of circRNAs as novel biomarkers of stem cell differentiation and novel targets for stem cell-based therapy. In this review, we systematically summarize and discuss recent advances in our understanding of the roles and underlying mechanisms of circRNAs in modulating stem cell differentiation, thus providing guidance for future studies to investigate stem cell differentiation and stem cell-based therapy.Abbreviations: CircRNAs: circular RNAs; ESCs: embryonic stem cells; ADSCs: adipose-derived mesenchymal stem cells; ecircRNAs: exonic circRNAs; EIciRNAs: exon-intron circRNAs; eiRNAs: circular intronic RNAs; tricRNAs: tRNA intronic circRNAs; pol II: polymerase II; snRNP: small nuclear ribonucleoprotein; m6A: N6-methyladenosine; AGO2: Argonaute 2; RBPs: RNA-binding proteins; MBNL: muscleblind-like protein 1; MSCs: mesenchymal stem cells; hiPSCs: human induced pluripotent stem cells; hiPSC-CMs: hiPSC-derived cardiomyocytes; hBMSCs: human bone marrow mesenchymal stem cells; hADSCs: human adipose-derived mesenchymal stem cells; hDPSCs: human dental pulp stem cells; RNA-seq: high-throughput RNA sequencing; HSCs: haematopoietic stem cells; NSCs: neural stem cells; EpSCs: epidermal stem cells; hESCs: human embryonic stem cells; mESCs: murine embryonic stem cells; MNs: motor neurons; SSUP: small subunit processome; BMSCs: bone marrow-derived mesenchymal stem cells; OGN: osteoglycin; GIOP: glucocorticoid­induced osteoporosis; CDR1as: cerebellar degeneration-related protein 1 transcript; SONFH: steroid-induced osteogenesis of the femoral head; rBMSCs: rat bone marrow-derived mesenchymal stem cells; QUE: quercetin; AcvR1b: activin A receptor type 1B; BSP: bone sialoprotein; mADSCs: mouse ADSCs; PTBP1: polypyrimidine tract-binding protein; ER: endoplasmic reticulum; hUCMSCs: MSCs derived from human umbilical cord; MSMSCs: maxillary sinus membrane stem cells; SCAPs: stem cells from the apical papilla; MyoD: myogenic differentiation protein 1; MSTN: myostatin; MEF2C: myocyte enhancer factor 2C; BCLAF1: BCL2-associated transcription factor 1; EpSCs: epidermal stem cells; ISCs: intestinal stem cells; NSCs: neural stem cells; Lgr5+ ISCs: crypt base columnar cells; ILCs: innate lymphoid cells.

Partial Component-Retained 2-Stage Reconstruction in the Treatment of Infected Hip Arthroplasty.

BACKGROUND: It is considered the gold standard treatment for infected hip arthroplasty to remove and reimplant the corresponding whole set of implant components before and after infection control, but it usually causes substantial bone loss to remove the well-fixed cup or stem, which may increase the difficulty in reconstruction. We would like to determine whether infected hip arthroplasty can be treated without removal of a well-fixed cup or stem. METHODS: Patients with infected hip arthroplasty and a radiographically well-fixed, cementless cup or stem were selected. During the first surgical stage, we retained the stem or cup if these cannot be removed using a stem or cup extractor. We performed the reimplantation surgery after control of infection. RESULTS: From January 2008 to December 2016, 26 patients underwent partial component-retained 2-stage reconstruction. All the patients were free of infection with a mean follow-up time of 43.85 months. CONCLUSION: Partial component-retained 2-stage reconstruction may be a treatment option for infected total hip arthroplasty with a well-fixed component in patients.

Biodegradable NIR-II Pseudo Conjugate Polymeric Nanoparticles Amplify Photodynamic Immunotherapy via Alleviation of Tumor Hypoxia and Tumor-Associated Macrophage Reprogramming.

Photodynamic therapy (PDT) has achieved great success in cancer treatment. Despite its great promise, the efficacy of photodynamic immunotherapy can be limited by the hypoxia in solid tumors which is closely related to the abnormal tumor vasculature. These abnormal vasculatures are a hallmark of most solid tumors and facilitate immune evasion. Therefore, tumor vascular normalization is developed as a promising strategy to overcome tumor hypoxia, resulting in improved cancer therapy. Here, a NIR-II bio-degradable pseudo-conjugate polymer (PSP)-based photodynamic polymer is designed to deliver a vascular normalization agent, i.e., regorafenib (Reg) in nanoparticles (NP-PDT@Reg). NP-PDT@Reg under 808 nm laser irradiation (NP-PDT@Reg + L) can efficiently release Reg to improve the tumor hypoxia via vascular normalization, making more NP-PDT@Reg and oxygen enter the tumors. Moreover, NP-PDT@Reg + L can further result in generation of more reactive oxygen species (ROS) to eradicate tumor cells while inducing immunogenic cell death (ICD) to activate anti-tumor immune responses. In addition, Reg can reprogram TAM from a pro-tumor M2 phenotype to a tumor-killing M1 phenotype as well, thereby reversing the immunosuppressive tumor microenvironment. Taken together, the current study provides an innovative perspective on the development of novel nanomaterials to overcome the limitations in photodynamic immunotherapy.

Targeting Bone Tumor and Subcellular Endoplasmic Reticulum via Near Infrared II Fluorescent Polymer for Photodynamic-Immunotherapy to Break the Step-Reduction Delivery Dilemma.

Specific localization of photosensitizers (PSs) to a certain organelle could result in targeted attack to cause greater trauma to cancer cells, eventually maximizing photodynamic therapy (PDT). However, currently, efficient and precise transportation of PSs via drug delivery to tumor cells and subcellular organelles is still challenging, due to a so-called step-reduction delivery dilemma (SRDD) which also threatens anticancer drug delivery to exert their efficacy. Herein, a cascade targeting near infrared II (NIR II) fluorescent nanoparticles (NPER/BO-PDT ) is designed that can target bone tumor first and then target the subcellular organelle of endoplasmic reticulum (ER). It is found that NPER/BO-PDT achieves the targeted accumulation of the bone tumor and then ER. NPER/BO-PDT generates reactive oxygen species (ROS) in the subcellular organelles of ER under near infrared light irradiation. The continuous ER stress by ROS promotes the release of more damage-associated molecular patterns, induces immunogenic cell death, stimulates the adaptive immune response, and further synergistically inhibits tumor growth, achieving the so-called photodynamic-immunotherapy. Overall, this study exemplifies a safe and efficient nano-drug delivery system for a bone and ER cascade targeting via delivery of PSs to break the SRDD and highlights potential clinical translation.

One-step metallization of weft-knitted fabrics for wearable biaxial strain sensors.

One-step direct patterning of high definition conductive tracks in textiles is realized through laser direct writing in combination with a silver organometallic ink developed in-house. Photoreduction, nano-crystallization, and sintering are accomplished in one pass under the irradiation of a CW green laser light (λ = 532 nm) at moderate intensities (I ≥ 95 mW/mm2). By tailoring the surface tension and viscosity of the ink, high-definition conductive tracks are formed in weft-knitted polyester-Spandex composite fabrics, well-following the laser's profile with negligible coffee stain effect. Length resistance as low as 4 Ω/cm is measured and anisotropy of the gauge factor as high as 25 is achieved. The metallized fabric exhibits reversible and hysteresis-free electromechanical responses subject to high strains. Durability assessment qualifies that the as-metallized strain sensors are able to sustain their performance for over 5000 stretch/release cycles, demonstrating its potential applications in biaxial strain sensing and interactive smart textiles.

Preparing Sr-containing nano-structures on micro-structured titanium alloy surface fabricated by additively manufacturing to enhance the anti-inflammation and osteogenesis.

The development of additive manufacturing technology has made it possible to customize joint implants. However, the fibrous tissue caused by long-term chronic inflammation delays bone regeneration. Moreover, the discovery of micro/nano-structure on the natural bone makes the study of implant surface morphology meaningful. In this study, a Sr-containing nano-structure on micro-structured titanium alloy surface was fabricated to enhanced the anti-inflammatory and osteogenic properties of implants. Ti6Al4V (TC4) alloys with micro-structured surface prepared by additive manufacturing were used as the material base model. Subsequently, spherical SrTiO3 particles were fabricated on the TC4 surfaces by hydrothermal treatment. The anti-inflammatory and osteogenic performance of smooth surface, micro-structured surface, Sr-containing nano-structured surface and Sr-containing micro/nano-structured surface were investigated. In vitro results exhibited that the macrophages cultured on micro/nano-structured surface were polarized to anti-inflammatory M2 phenotype and enhanced the expression of osteogenic growth factors. The Sr-containing micro/nano-structured surface effectively upgraded the proliferation and differentiation of SaOS-2 cells compared with other surfaces. Sr2+ and micro/nano-structure effectively enhanced the anti-inflammatory and osteogenic properties of titanium alloys. This finding suggested that the micro/nano-structured surface doped with bioactive elements is expected to broaden the horizons of biomedical materials. DATA AVAILABILITY: The raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

Stimulation of in vitro and in vivo osteogenesis by Ti-Mg alloys with the sustained-release function of magnesium ions.

Magnesium (Mg) is well-known for its bioactivity and degradability. However, due to its low evaporation temperature and limited solubility in titanium (Ti), the fabrication of Ti-Mg alloys remains a huge challenge. In this study, Ti-xMg (x = 0.312, 0.625, 1.25 and 2.5 wt.%) alloys were fabricated by the combination of mechanical alloying (MA) and spark plasma sintering (SPS). Mg mainly existed as a solid solute element in the Ti matrix, while it also existed as second-phase particles due to its precipitation and dispersion during the SPS process. At a low content of 0.625 wt.%, Mg could increase the mechanical strength of Ti by the solid solution strengthening. However, it was detrimental to material mechanical properties when the Mg content increased to 1.25 wt.%. Being immersed in phosphate buffered solution (PBS), Ti-Mg alloys exhibited a burst Mg2+ release behavior within the first day, and then the rates of Mg2+ release gradually decreased within the following 27 days. The results suggested that the cell viability was dependent on the content of Mg in the Ti-Mg alloys. The high Mg content (2.5 wt.%) in the Ti-Mg alloys could lead to significant cytotoxicity. However, appropriate Mg content (0.312∼0.625 wt.%) could promote cell attachment, proliferation and differentiation. The Ti-0.625Mg alloy exhibited the best in vitro biological performance among all groups. In vivo results obtained by implanting the Ti-0.625Mg alloy in the femurs of rats further revealed its enhanced regenerative potential and osteointegration compared to pure Ti implants.

Genetic evaluations of Chinese patients with odontohypophosphatasia resulting from heterozygosity for mutations in the tissue-non-specific alkaline phosphatase gene.

BACKGROUND: Hypophosphatasia is a rare heritable metabolic disorder characterized by defective bone and tooth mineralization accompanied by a deficiency of tissue-non-specific (liver/bone/kidney) isoenzyme of alkaline phosphatase activity, caused by a number of loss-of-function mutations in the alkaline phosphatase liver type gene. We seek to explore the clinical manifestations and identify the mutations associated with the disease in a Chinese odonto- hypophosphatasia family. RESULTS: The proband and his younger brother affected with premature loss of primary teeth at their 2-year-old. They have mild abnormal serum alkaline phosphatase and 25-hydroxy vitamin D values, but the serum alkaline phosphatase activity of their father, mother and grandmother, who showed no clinical symptoms of hypophosphatasia, was exhibited significant decreased. In addition to premature loss of primary teeth, the proband and his younger brother showed low bone mineral density, X-rays showed that they had slight metaphyseal osteoporosis changes, but no additional skeletal abnormalities. Deoxyribonucleic acid sequencing and analysis revealed a single nucleotide polymorphism c.787T>C (p.Y263H) in exon 7 and/or a novel mutation c.-92C>T located at 5'UTR were found in the affected individuals. MATERIALS AND METHODS: We examined all individuals of an odonto- hypophosphatasia family by clinical and radiographic examinations as well as laboratory assays. Furthermore, all 12 exons and the exon-intron boundaries of the alkaline phosphatase liver type gene were amplified and directly sequenced for further analysis and screened for mutations. CONCLUSION: Our present findings suggest the single nucleotide polymorphism c.787T>C and c.-92C>T should be responsible for the odonto- hypophosphatasia disorders in this family.

The role of titanium in the altered endotoxin-induced nitric oxide synthase expression in alveolar macrophages from titanium-alloy-implanted rats.

We have found that the concentration of titanium (Ti) in the blood of patients with loosened Ti-alloy prostheses is elevated. An increase in the levels of elemental Ti in the blood and lung tissues of rats with an alloyed-Ti implant also has been found. The cellular reaction to elevated elemental Ti in the circulation remains unclear. We further performed experiments to examine the changes of inducible nitric oxide synthase (iNOS) expression in alveolar macrophages from alloyed-Ti-implanted rats. The elevation of nitrite and iNOS expression induced by lipopolysaccharide (LPS) was suppressed. The in vitro effect of a soluble form of Ti was further investigated. Ti (0.01-0.06 mM) inhibited the LPS-induced nitrite production and iNOS expression in alveolar macrophages from normal rats without any cytotoxic effects. LPS induced protein tyrosine phosphorylation, tyrosine-phosphorylation of lyn (a CD14-receptor-associated-tyrosine kinase), and degradation of IkappaB-alpha protein (inhibitor of NF-kappaB) in alveolar macrophages. These events were inhibited by co-incubation with Ti. These results indicate that elemental Ti may impair iNOS expression in alveolar macrophages through the alteration of protein tyrosine phosphorylation and NF-kappaB activation. The inhibitory action of Ti on cellular responses of alveolar macrophages may be anti-inflammatory and thus may depress local defense mechanisms related to microbial killing.

[Electrical acupoint stimulation increases athletes' rapid strength].

OBJECTIVE: To search for a stimulation method for increasing athletes' performance. METHODS: One hundred and fifty athletes were randomly divided into a trial group and a control group, 75 athletes in each group. Acupoints were stimulated with audio frequency pulse modulated wave and multi-blind method were used to investigate effects of the electric stimulation of acupoints on 30-meter running, standing long jumping and Cybex isokinetic testing index. RESULTS: The acupoint electric stimulation method could significantly increase athlete's performance (P < 0.05), and the biomechanical indexes, maximal peak moment of force (P < 0.05), force moment accelerating energy (P < 0.05) and average power (P < 0.05). CONCLUSION: Electrical acupoint stimulation can enhance athlete's rapid strength.