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The intricate dynamic feedback mechanisms involved in bone homeostasis provide valuable inspiration for the design of smart biomaterial scaffolds to enhance in situ bone regeneration. In this work, we assembled a biomimetic hyaluronic acid nanocomposite hydrogel (HA-BP hydrogel) by coordination bonds with bisphosphonates (BPs), which are antiosteoclastic drugs. The HA-BP hydrogel exhibited expedited release of the loaded BP in response to an acidic environment. Our in vitro studies showed that the HA-BP hydrogel inhibits mature osteoclastic differentiation of macrophage-like RAW264.7 cells via the released BP. Furthermore, the HA-BP hydrogel can support the initial differentiation of primary macrophages to preosteoclasts, which are considered essential during bone regeneration, whereas further differentiation to mature osteoclasts is effectively inhibited by the HA-BP hydrogel via the released BP. The in vivo evaluation showed that the HA-BP hydrogel can enhance the in situ regeneration of bone. Our work demonstrates a promising strategy to design biomimetic biomaterial scaffolds capable of regulating bone homeostasis to promote bone regeneration.

The potential translation of bio-inert polymer scaffolds as bone substitutes is limited by the lack of neovascularization upon implantation and subsequently diminished ingrowth of host bone, most likely resulted from the inability to replicate appropriate endogenous crosstalk between cells. Human umbilical vein endothelial cell-derived decellularized extracellular matrix (HdECM), which contains a collection of angiocrine biomolecules, has recently been demonstrated to mediate endothelial cells(ECs) – osteoprogenitors(OPs) crosstalk. We employed the HdECM to create a PCL (polycaprolactone)/fibrin/HdECM (PFE) hybrid scaffold. We hypothesized PFE scaffold could reconstitute a bio-instructive microenvironment that reintroduces the crosstalk, resulting in vascularized bone regeneration. Following implantation in a rat femoral bone defect, the PFE scaffold demonstrated early vascular infiltration and enhanced bone regeneration by microangiography (μ-AG) and micro-computational tomography (μ-CT). Based on the immunofluorescence studies, PFE mediated the endogenous angiogenesis and osteogenesis with a substantial number of type H vessels and osteoprogenitors. In addition, superior osseointegration was observed by a direct host bone-PCL interface, which was likely attributed to the formation of type H vessels. The bio-instructive microenvironment created by our innovative PFE scaffold made possible superior osseointegration and type H vessel-related bone regeneration. It could become an alternative solution of improving the osseointegration of bone substitutes with the help of induced type H vessels, which could compensate for the inherent biological inertness of synthetic polymers., Graphical abstract Human umbilical vein endothelial cell-derived decellularized extracellular matrix (HdECM), which contains a collection of angiocrine biomolecules, were employed to create a PCL (polycaprolactone)/fibrin/HdECM (PFE) hybrid scaffold. Following implantation in a rat femoral bone defect, the PFE scaffold demonstrated early vascular infiltration and enhanced bone regeneration by microangiography (μ-AG) and micro-computational tomography (μ-CT). PFE mediated the endogenous angiogenesis and osteogenesis with a substantial number of type H vessels and osteoprogenitors. In addition, superior osseointegration was observed by a direct host bone-PCL interface, which was likely attributed to the formation of type H vessels. The bio-instructive microenvironment created by our innovative PFE scaffold made possible superior osseointegration and type H vessel-related bone regeneration.Image 1, Highlights • We present a 3D-printed PCL scaffold incorporated with HdECM/fibrin gel for accelerated vascularized bone regeneration. • The PFE scaffold mediated the formation of type H vessels, coupled with the osterix-positive osteoprogenitor cells. • Optimal osseointegration was seen with a presence of direct host bone-PCL connection without fibrous encapsulation. • It might provide a clue for future research that type H vessel-targeted biomaterials could improve implant osseointegration.

Background Synovial sarcoma (SS) is a highly malignant tumor of unknown histological origin. This tumor can occur in various parts of the body, including those without synovial structures, but mainly in and around the joints, mostly in the lower extremities. Primary intracranial SSs are remarkably rare. This paper aims to report a case of primary intracranial SS with hemorrhage. Case summary A 35-year-old male patient suffered a headache and slurred speech during manual labor and was sent to the emergency department. Through imaging examination, the patient was considered to have high-grade glioma complicated with hemorrhage and was treated with craniotomy. Postoperative pathology revealed SS. positron emission tomography/computed tomography was performed, which ruled out the possibility of metastasis to the intracranial from other parts of the body. Postoperative radiotherapy was given to the patient, during which radiation necrosis occurred. Sixteen months after craniotomy, cranial magnetic resonance imaging revealed recurrence of the tumor. Conclusion Primary intracranial SS is a rare malignant tumor. Primary intracranial SS with hemorrhage and radiation necrosis should be carefully monitored during postoperative radiotherapy. Surgical resection of the tumor combined with postoperative radiotherapy and chemotherapy is currently used, but the prognosis is poor.

OBJECTIVES: With implementation of mass immunization and improvements in sanitation, China is moving rapidly from high to low endemicity of hepatitis A (HA). To prevent a resurgence after intense vaccination, a comprehensive and systematic assessment of long-term protection against HA conferred by vaccine was thus performed. METHODS: In 1996, 3,515 susceptible children aged one to 12 years were recruited in a randomized, open trial to assess the efficacy of a live-attenuated HA vaccine. During a 17-year follow-up period, children were tested for antibody persistence and long-term protection against both hepatitis A virus (HAV) disease and infection. Case finding was conducted using the China National Notifiable Infectious Disease Reporting System. Serum anti-HAV antibody levels were evaluated by the ELISA method to ascertain antibody persistence and protection against infection. RESULTS: During the 17-year follow-up, 2,132 (61%) children from the initial cohort were available for analysis. After calibrating the sensitivity of assay, excluding natural infection and vaccine booster, the sero-positive rate and the geometric mean concentrations declined from 94.9% and 131.3 mIU/mL (91.5-188.4mIU/mL) at the peak to 55.6% and 41.1 mIU/mL (95% CI: 27.8-61.0 mIU/mL) respectively, with a similar natural infection rate in both groups. CONCLUSIONS: This study demonstrates that long-term protection against hepatitis A persists at least for 17 years after administration of a single dose of a live-attenuated HA vaccine and suggests that a booster dose is currently not necessary. FUNDING STATEMENT: This work was supported by grants from National Natural Science Foundation (China) (81072346), National Science and Technology Project of Major Infectious Diseases (2008ZX10002-003, 2012ZX10002002004) DECLARATION OF INTERESTS: The authors declare that they have no competing interests. ETHICS APPROVAL STATEMENT: This study was reviewed and approved by the Institutional Review Board of the Institutes of Biomedical Sciences, Fudan University. Written inform consent was obtained from each participant.

Zhi-Yong Zhang, Ming-Xu Li, Hai Yu, Jun Zhao, Feng-Lin Xiao, Fang Xuan, Yi-Xin Zhao Department of Nephrology, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Ming-Xu LiDepartment of Nephrology, The Sixth Medical Center of PLA General Hospital, No. 6 Fucheng Road, Haidian District, Beijing 100048, People’s Republic of ChinaTel +86-18600310159Email lmx1964bw@sina.comPurpose: Chronic renal failure has become a major public health concern and treatment strategies are urgently needed. We aimed to investigate whether combination of hemodialysis modes was superior to regular hemodialysis for patients under maintenance hemodialysis.Patients and Methods: A total of 144 patients with end-stage renal failure (ESRF) were enrolled in this single-center retrospective study. Patients received regular hemodialysis (HD) were included in HD group (n=52), patients received regular HD plus hemodiafiltration (HDF) in HD/HDF group (n=47), patients received the combination of regular HD, HDF and hemoperfusion (HP) in HD/HDF/HP group (n=45). After 1-month and 24-months treatment, therapeutic effects were assessed in terms of nutritional status, control of complications, dialysis adequacy, mean arterial pressure (MAP), infection rate and living quality.Results: When patients received 1-month treatment, there were no statistically significant differences among three groups. After 24-months treatment, patients in HD/HDF and HD/HDF/HP group presented with better dialysis adequacy, lower MAP and infection rate, higher serum albumin, hemoglobin and calcium levels, lower serum phosphorus and intact parathyroid hormone levels, lower incidence of malnutrition and the Hamilton Depression Scale score, higher the Barthel Index score than HD group (P< 0.05). The levels of calcium, phosphorus and intact parathyroid hormone in HD/HDF/HP group were lower than those in HD/HDF group (P< 0.05).Conclusion: Our finding highly indicated that combination of hemodialysis modes was superior to regular HD for patients with ESRF in nutritional status, control of complications, dialysis adequacy, and living quality.Keywords: maintenance hemodialysis, hemodialysis, hemodiafiltration, hemoperfusion, end-stage renal failure

Background Dexamethasone intravitreal implants (0.7 mg) (Ozurdex®, Allergan Inc., Madison, NJ) are FDA approved for managing macular oedema (ME) of retinal vein occlusion (RVO). The major complications associated with intravitreal Ozurdex® implant include increased intraocular pressure and cataract progression. In regard to the occurrence of retinal complications, we report an unusual intravitreal Ozurdex® implantation-related acute retinal necrosis (ARN). Case presentation A 45-year-old immunocompetent woman with a history of encephalitis presented with photophobia, redness, floaters, and rapidly decreased vision in her left eye. Three and six months ago, she received two doses of intravitreal Ozurdex® implant for ME of RVO. Clinical evaluation, including slit-lamp biomicroscopy, retinal photography, and fluorescein angiography, revealed anterior chamber cells, granulomatous keratic precipitates, cells in the vitreous, optic disc oedema, occlusive retinal vasculitis, scattered retinal haemorrhages, one quadrant of peripheral white areas with retinal necrosis, optic disc and vessels fluorescein staining, and retinal nonperfusion zones. All the above clinical manifestations showed an ARN. Herpes simplex virus was detected in the aqueous and vitreous humour by quantitative polymerase chain reaction testing. Intravenous acyclovir 500 mg tid for 7 days followed by oral valcyclovir was immediately performed for ARN. At 4 months, the patient’s condition improved without retinal detachment, and the best-corrected visual acuity remained stable at 0.3. Conclusions ARN might represent a risk of Ozurdex® administration.

Activated PI3Kδ syndrome 1 is a primary immunodeficiency disease, usually caused by heterozygous mutations in PIK3CD. We aimed to identify the cause of homozygous mutation at c.G3061A (p.E1021K) in a patient and the effect of allele dose in this mutation. Genomic DNA from the parent-child trio was analyzed by next-generation sequencing. We performed phenotypic analyses in the patient and in Pik3cdE1024K+/+ mice. The patient was a girl harboring a homozygous mutation for p.E1021K in PIK3CD. At the age of 2 months, she began experiencing respiratory tract infections and lymphoproliferation, accompanied by bronchiectasis and extensive atelectasis in the lungs. She suffered from Haemophilus influenzae and Cytomegalovirus infections and experienced restricted growth and development. Whole-exome sequencing showed a region that included PIK3CD, with loss of heterozygosity (LOH) in chromosome 1 of the patient. The patient had not inherited any allele from her father in the LOH region. Copy number variation analysis showed no changes in the patient’s father and the patient. Ultra-deep sequencing of genomic DNA from the patient’s mother showed that the mutant allele frequency for c.G3061A was 1.64%. Thus, the presence of segmental maternal uniparental disomy and maternal gonosomal mosaicism resulted in the homozygous mutation. Lymphadenopathy, differentiation of activated T cells, and follicular B cells lymphopenia were found to be more prominent in Pik3cdE1024+/+ mice than in Pik3cdE1024+/− mice. This report showed the coexistence of uniparental disomy and mosaicism in PIK3CD. Some immunological features were seen to be allele dose-dependent in the presence of p.E1021K mutation.

Tumor-derived exosomal miRNAs may have important functions in the onset and progression of cancers and are potential biomarkers for early diagnosis and prognosis monitoring. Yet, simple, sensitive, and label-free detection of exosomal miRNAs remains challenging. Herein, an ultrasensitive, label-free, and stable field-effect transistor (FET) biosensor based on a polymer-sorted high-purity semiconducting carbon nanotube (CNT) film is reported to detect exosomal miRNA. Different from conventional CNT FETs, the CNT FET biosensors employed a floating gate structure using an ultrathin Y2O3 as an insulating layer, and assembled Au nanoparticles (AuNPs) on Y2O3 as linkers to anchor probe molecules. A thiolated oligonucleotide probe was immobilized on the AuNP surface of the sensing area, after which miRNA21 was detectable by monitoring the current change before and after hybridization between the immobilized DNA probe and target miRNA. This method achieved both high sensitivity (LOD: 0.87 aM) and high specificity. Furthermore, the FET biosensor was employed to test clinical plasma samples, showing significant differences between healthy people and breast cancer patients. The CNT FET biosensor shows the potential applications in the clinical diagnosis of breast cancer.

Background The precise etiology of anterior inferior cerebellar artery (AICA) infarction is difficult to identify because of the high anatomic variability of vertebrobasilar arteries and the limitations of conventional vascular examinations. Basi-parallel anatomic scanning magnetic resonance imaging (BPAS-MRI) can reveal the outer contour of the intracranial vertebrobasilar arteries, which may be helpful to distinguish the arteriosclerosis from congenital dysplasia and dissection. Case presentation In this study, we reported 3 cases of AICA infarction and discussed the diagnostic value of BPAS-MRI in the evaluation of vascular etiology. Conclusions The BPAS-MRI could be considered as an important supplementary in the diagnosis of vascular etiology of infarction in AICA territory.

Objective To analyze the levels of high mobility group box 1 (HMGB1) protein on different courses of juvenile idiopathic arthritis (JIA). Methods In our prospective longitudinal study, children with JIA were included with their blood samples collected at the first visit, 1-month, 3-month, and 6-month follow-up, respectively. Samples were also collected from healthy controls and children with reactive arthritis at the first visit. Levels of HMGB1 were determined using enzyme-linked immunosorbent assays. Clinical disease characteristics and routine laboratory findings were analyzed as well. Results A total of 64 children were enrolled, of whom 31 (48.4%) were female. The median age at the first visit for participants with JIA was 9.25 years (range, 1.42–15.42) and the median duration of disease was 2.38 months (range, 1.53–49.31). Serum HMGB1 levels at the first visit were significantly elevated in children with systemic JIA compared with other groups, and so were in enthesitis-related arthritis versus healthy controls. Significant correlations were established at the first visit between HMGB1 levels and duration of disease, C-reactive protein, percentage of neutrophils, and ferritin. Data from all samples revealed that serum HMGB1 levels in JIA were significantly associated with erythrocyte sedimentation rates, C-reactive protein, percentage of neutrophils, and disease activity scores. Conclusions Serum HMGB1 may be associated with clinical disease activity of JIA and specifically increased at the first visit in children with systemic JIA, suggesting its function as a sensitive inflammatory marker. Further large-scale studies are warranted to explore its spectrum in JIA.

Purpose To explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms. Methods and Materials Rho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial. Results RhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors. Conclusions RhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.

In order to study the molecular differences between type 2 diabetes mellitus (T2DM) and T2DM with depression (DD), we aimed to screen the differential expression of lncRNA, mRNA, and circRNA in the blood of patients with T2DM and DD. Based on the self-rating depression scale (SDS), patient health questionnaire 9 (PHQ9), blood glucose and HbA1c, we divided the patients into T2DM and DD group. Peripheral blood was collected from the two groups of patients to perform lncRNA, mRNA, and circRNA expression profiling and screening DD-related specific molecules. Subsequently, bioinformatics analysis was performed to investigate the functions of differentially expressed genes (DEgenes). Finally, RT-PCR and lncRNA-mRNA regulatory network was performed to verify the expressions of lncRNAs and mRNAs related to the occurrence and development of DD. 28 lncRNAs, 107 circRNAs, and 89 mRNAs were identified in DD differential expression profiles. GO and pathway analysis found that 20 biological process (BP) related entities and 20 pathways associated with DD. The analysis shows that the genes that are differentially expressed in the DD group involved in the development of the neuropsychiatric system, immunity, and inflammation. Then, we screening for the important DElncRNA and mRNA associated with DD were verified by RT-PCR experiments and the results of RT-PCR were consistent with the sequencing results. LncRNA, circRNA, and mRNA differential expression profiles exist in DD patients compared with T2DM. The lncRNA-mRNA regulatory network analysis confirmed the crosslinking and complex regulation patterns of lncRNA and mRNA expression and verified the authenticity of the regulatory network.

To develop a more effective and safer drug for the treatment of type 2 diabetes mellitus (T2DM)-induced liver damage, we investigated the protective effects of punicalagin, a major component in pomegranate peel, on the liver of mice with T2DM. After five weeks of punicalagin treatment, blood and liver samples were obtained for the subsequent analyses. Western blotting, reverse transcription polymerase chain reaction, and immunohistochemical staining were performed to determine the expression of endoplasmic reticulum (ER) stress markers in the liver tissue. The results showed that punicalagin alleviated glucose and insulin resistance, increased insulin sensitivity, and reduced serum free fatty acids levels and hepatic steatosis in the mice with T2DM. Furthermore, punicalagin down-regulated the elevated mRNA expression of the ER stress markers eIF2α, GRP78, ATF4, and CHOP in the liver of mice with T2DM. Our results suggest that punicalagin is a potential natural agent for the prevention of T2DM-induced liver damage.

This paper aims to determine the role of miR-520e in the replication of hepatitis B virus (HBV) and the growth of hepatocellular carcinoma (HCC) cells. MiR-520e and EphA2 in HBV-positive HCC tissues and cells were detected. HepG2.2.15 and Huh7 cells transfected with pHBV1.2 were divided into Mock, NC, miR-520e mimic, miR-520e inhibitor, si-EphA2, and miR-520e inhibitor + si-EphA2 groups. MiR-520e, HBV DNA content, HBsAg and HBeAg levels, cell proliferation, apoptosis and protein expression of EphA2 and MAPK pathways were evaluated. Furthermore, rAAV81.3HBV infected-mouse model was established to detect HBV-DNA levels. MiR-520e was up-regulated and EphA2 was down-regulated in HBV-positive HCC tissues and cells (HepG2.2.15 and HepAD38). MiR-520e was decreased in Huh7-X and HepG2-X cells in which HBx was stably expressed, but miR-520e was dose-dependently elevated in Huh7-X, HepG2-X, and HepG2.2.15 cells after interfering HBx. Additionally, miR-520e mimic and si-EphA2 groups were apparently reduced in HBV DNA content, HBsAg and HBeAg levels, cell proliferation, and were enhanced in the expressions of EphA2, MAPK pathways and cell apoptosis. Furthermore, si-EphA2 can reverse the promotion effect of miR-520e inhibitor on the HBV replication and tumor cell growth Up-regulating miR-520e in rAAV81.3HBV infected-mouse resulted in the reduced EphA2 in liver tissues and HBV DNA content in serum. MiR-520e was found to be decreased in HBV-positive HCC tissues and cells, while over-expression of miR-520e blocked MAPK pathways via inhibiting EphA2, ultimately reducing HBV replication and inhibiting tumor cell growth.

Natural pollen traps have been known for many years. This study analyzed the palynological characteristics of 12 ant nests on branches and 12 surface soil samples, collected from tropical areas of ...

In the initiation and evolution of human cancers, circular RNAs (circRNAs) act as crucial regulators. The aim of this report was to ascertain the functional mechanisms of circRNA plasmacytoma variant translocation 1 (circPVT1) in the metastasis and chemoresistance of non-small cell lung cancer (NSCLC). The levels of circPVT1, microRNA-181a-5p (miR-181a-5p) and non-inherited maternal antigens-related kinase 7 (NEK7) were examined via quantitative real-time polymerase chain reaction (qRT-PCR). The levels of the associated proteins were determined through western blot. Cell counting kit-8 (CCK-8) and flow cytometry were used to assess the half inhibitory concentration (IC50) of cisplatin and cell apoptosis, respectively. Cell invasion was detected by transwell assay. A dual-luciferase reporter assay and RNA immunoprecipitation (RIP) were used to confirm the target relation. The impact of circPVT1 on cisplatin chemoresistance in vivo was investigated using xenograft experiments. CircPVT1 and NEK7 were up-regulated and miR-181a-5p was down-regulated in NSCLC. CircPVT1 knockdown refrained the cisplatin chemoresistance and metastasis of NSCLC cells. MiR-181a-5p was a target of circPVT1 and circPVT1 inhibition alleviated the effects of a miR-181a-5p inhibitor on NSCLC cells. The decrease of circPVT1 accentuated the si-NEK7-inhibited metastasis by the miR-181a-5p/NEK7 axis and relieved the 3-methyladenine (3-MA)-promoted cisplatin chemoresistance by miR-181a-5p-mediated autophagy. Down-regulation of circPVT1 facilitated the cisplatin sensitivity of NSCLC cells in vivo. Due to the modulation of cell metastasis via the miR-181a-5p/NEK7 axis and cisplatin chemoresistance by miR-181a-5p-mediated autophagy in NSCLC, circPVT1 might act as an appreciable therapeutic marker for NSCLC.

We conducted a systematic review and network meta-analysis to compare the efficacy and safety of nine non-steroidal antiinflammatory drugs (NSAIDs) in treating patients with juvenile idiopathic arthritis (JIA). Randomized controlled trials (RCTs) of NSAIDs for the treatment in children with JIA were searched systematically by using MEDLINE, EMBASE, and the Cochrane Library for available literature up to January 1, 2019. Bayesian network meta-analysis was used to combine direct and indirect evidence on treatment effectiveness and safety. Eight eligible RCTs involving 1112 patients with JIA were identified, addressing 9 interventions. The ranking probability plot based on the surface under the cumulative ranking curve (SUCRA) indicated that celecoxib (6 mg/kg twice-a-day) had the highest probability of being most effective (SUCRA = 76.4%) among four NSAIDs (celecoxib, rofecoxib, meloxicam, and naproxen). Also, rofecoxib (0.3 mg/kg once-a-day) and piroxicam demonstrated a higher probability of safety in treating children with JIA (SUCRA = 33.0% and 35.5%, respectively), compared with other interventions. The quality of available evidence limits the formation of powerful conclusions regarding the comparative efficacy or safety of NSAIDs used to treat JIA.

Regardless of the advancement of synthetic bone substitutes, allograft-derived bone substitutes still dominate in the orthopaedic circle in the treatments of bone diseases. Nevertheless, the stringent devitalization process jeopardizes their osseointegration with host bone and therefore prone to long-term failure. Hence, improving osseointegration and transplantation efficiency remains important. The alteration of bone tissue microenvironment (TME) to facilitate osseointegration has been generally recognized. However, the concept of exerting metal ionic cue in bone TME without compromising the mechanical properties of bone allograft is challenging. To address this concern, an interfacial tissue microenvironment with magnesium cationc cue was tailored onto the gamma-irradiated allograft bone using a customized magnesium-plasma surface treatment. The formation of the Mg cationic cue enriched interfacial tissue microenvironment on allograft bone was verified by the scanning ion-selective electrode technique. The cellular activities of human TERT-immortalized mesenchymal stem cells on the Mg-enriched grafts were notably upregulated. In the animal test, superior osseointegration between Mg-enriched graft and host bone was found, whereas poor integration was observed in the gamma-irradiated controls at 28 days post-operation. Furthermore, the bony in-growth appeared on magnesium-enriched allograft bone was significant higher. The mechanism possibly correlates to the up-regulation of integrin receptors in mesenchymal stem cells under modified bone TME that directly orchestrate the initial cell attachment and osteogenic differentiation of mesenchymal stem cells. Lastly, our findings demonstrate the significance of magnesium cation modified bone allograft that can potentially translate to various orthopaedic procedures requiring bone augmentation., Graphical abstract Graphical Abstract. Schematic illustration of the interaction of cells and magnesium cationic cue enriched interfacial tissue microenvironment over the surface of gamma-irradiated allograft bone and the orchestrated effect on osseointegration. The magnesium cationic cue enriched interfacial TME has been exerted on gamma-irradiated allograft bone without compromising the mechanical properties, and the ability of this interfacial tissue microenvironment to facilitate fracture healing and osseointegration has been recognized. More importantly, the up-regulation of integrin receptors induced by this interfacial tissue microenvironment is found to be pivotal for orchestrated cellular activity and promotes early osseointegration between the allograft and the host bone.Image 1, Highlights • A modified interfacial Mg TME was tailored onto the GI allograft bone matrix without compromising the mechanical properties. • The SIET were applied to recognize the Mg2+-cue enriched interfacial TME on the surface of the Mg-treated bone allograft. • The rodent model that is analogous to the clinical use of allograft bone were applied to charaterize the osseointegration. • The boundary of the Mg-enriched allograft bone was already unable to be identified and become homogeneous at D28 post-op. • The Mg2+-cue enriched interfacial TME is able to convince the upregulation of several integrin receptors of MSCs.

Ethnopharmacological relevance Salvianolic acid B (SalB) is a polyphenolic compound in Salvia miltiorrhiza Bunge (“Danshen”), which has been largely used in Traditional Chinese Medicine for the treatment of metabolic syndrome, obesity, diabetes, among others. Aim of study This study was to investigate the effects of Salvianolic acid B (SalB) on mRNA, lncRNA and circRNA's expression profile in brown adipose tissue (BAT) of obese mice. Materials and methods High-fat-diet induced obese C57BL/6J mice were treated with SalB (100 mg/kg/day) for 8 weeks. Then, BAT was harvested for RNA-Seq analysis. Differentially expressed mRNAs, lncRNAs and circRNAs were analyzed using the Illumina Hiseq 4000. Following this procedure, bioinformatic tools including Gene ontology (GO), KEGG pathway and lncRNA-mRNA co-network analysis were utilized. Finally, RT-qPCR was performed to validate the differentially expressed RNAs. Results Compared with control group, 2532 mRNAs, 774 lncRNAs and 25 circRNAs were differentially expressed in SalB group. Additionally, 40 upregulated and 109 downregulated gene-related pathways were identified in the SalB group. Among them, metabolic pathways showed the highest enrichment coefficient in upregulated genes. Moreover, 54 up-regulated and 626 down-regulated coding mRNAs associated with lncRNA-Hsd11b1 and lncRNA-Vmp1. Conclusions SalB may play an anti-obesity role by adjusting the expression of mRNAs correlated with inflammatory response and energy metabolism through regulating the expression of lncRNA-Hsd11b1. The findings of this research provide new directions to study the mechanisms of SalB, and would open therapeutic avenues for the treatment of obesity.

Successful wound healing relies on reconstructing proper tissue homeostasis, particularly the post-traumatic inflammatory tissue microenvironment. Nevertheless, diabetes jeopardizes tissue’s immune homeostasis of cutaneous wounds, characterized by the accumulation of reactive oxygen species (ROS), causing persistent chronic inflammation and cytokine dysfunction. Previously, we have developed an autologous regeneration factors (ARFs) technology to extract the cytokine composite from autologous tissue to restore the immune homeostasis and promote wound healing. However, treatment efficacy was significantly compromised in diabetic conditions. Therefore, we proposed the combinational use of melatonin and ARF could be an effective treatment for diabetic wounds, considering the melatonin can scavenge ROS, which is beneficial for the proper immune homeostasis reconstruction. Our research showed that the utilization of melatonin-mediated ARF biogel (AM gel) promoted diabetic wound regeneration at a more rapid healing rate. Furthermore, RNA-seq analysis showed that the AM gel treatment could restore more favorable immune tissue homeostasis with unique inflammatory patterning by the dramatically diminished intensity of acute and chronic inflammation. Currently, AM gel could be a novel and promising therapeutic strategy for diabetic wounds in clinical scenarios by reconstructing more favorable immune homeostasis in tissue microenvironment by orchestrating a proper post-traumatic inflammation patterning.# Funding: This work was supported by the National Natural Science Foundation of China (NSFC) (Nos. 81772354, 81902189, 82072409), Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR0201001), Science Technology Project of Guangzhou City (201804010185), Natural Science Foundation of Guangdong Province (2019A1515012020), Science and Technology Innovation Project of Foshan City (1920001000025), and National Young Thousand-Talent Scheme to Zhang Zhi-Yong. Declaration of Interest: The authors declare that they have no potential conflict of interest in relation to the study in this paper. Ethical Approval: All animal experiments were approved by the Animal Ethics Committee of Guangdong Medical Laboratory Animal Center.

Objective To comprehensively review the literature and summarize the results from human and animal studies related to the possible causes and pathogenesis of traumatic temporomandibular joint ankylosis (TMJA). Materials and Methods The Google Scholar, Embase, and Web of Science databases were used to search for articles related to traumatic TMJA from 2011 to 2020. All articles were screened according to the inclusion and exclusion criteria, collected, and analyzed. Results Nineteen relevant articles were collected. These articles were classified into three groups: predisposing and etiological factors, cellular studies, and molecular studies. Conclusion The pathological mechanisms are similar between TMJA and nonunion hypertrophy. Aberrant structural and etiological factors as well as disordered cellular and molecular mechanisms might contribute to TMJA formation. Although preclinical and clinical data have provided new evidence on the pathogenesis of traumatic TMJA, the molecular mechanisms and biological events require further exploration.

Cancerous microvesicles (MVs), which are heterogeneous membrane-bound nanovesicles shed from the surfaces of cancer cells into the extracellular environment, have been widely recognized as promising "biofingerprints" for various cancers. High-performance identification of cancerous MVs plays a vital role in the early diagnosis of cancer, yet it is still technically challenging. Herein, we report a gold nanoparticle (AuNP)-decorated, dual-aptamer modified reduced graphene oxide (RGO) field-effect transistor (AAP-GFET) nanosensor for the label-free, specific, and sensitive quantification of HepG2 cell-derived MVs (HepG2-MVs). After GFET chips were fabricated, AuNPs were then decorated on the RGO surface. For specific capture and detection of HepG2-MVs, both sulfhydrylated HepG2 cell specific TLS11a aptamer (AptTLS11a) and epithelial cell adhesion molecule aptamer (AptEpCAM) were immobilized on the AuNP surface through an Au-S bond. This developed nanosensor delivered a broad linear dynamic range from 6 × 105 to 6 × 109 particles/mL and achieved a high sensitivity of 84 particles/μL for HepG2-MVs detection. Moreover, this AAP-GFET platform was able to distinguish HepG2-MVs from other liver cancer-related serum proteins (such as AFP and CEA) and MVs derived from human normal cells and other cancer cells of lung, pancreas, and prostate, suggesting its excellent method specificity. Compared with those modified with a single type of aptamer alone (AptTLS11a or AptEpCAM), such an AAP-GFET nanosensor showed greatly enhanced signals, suggesting that the dual-aptamer-based bio-nano interface was uniquely designed and could realize more sensitive quantification of HepG2-MVs. Using this platform to detect HepG2-MVs in clinical blood samples, we found that there were significant differences between healthy controls and hepatocellular carcinoma (HCC) patients, indicating its great potential in early HCC diagnosis.

Activated phosphoinositide 3-kinase δ syndrome 1 (APDS1) is a primary immunodeficiency disease caused by gain-of-function mutations in PIK3CD. Clinical features of autoimmune disease have been reported in patients with APDS1. In this study, we reported three patients with APDS1 presenting with systemic lupus erythematosus (SLE) phenotype. The clinical manifestations included recurrent respiratory tract infection, lymphoproliferation, Coombs-positive hemolytic anemia, decreased complement fractions, positive antinuclear antibodies, renal complications related to SLE associated diseases, which met the clinical spectrum of APDS1 and the classification criteria of SLE. The immunological phenotype included an inversion in the CD4:CD8 ratio, an increase in both non-circulating Tfh CD4+ memory T and circulating Tfh populations, a low level of recent thymic emigrant T cells, overexpression of CD57 on T cells, and a decrease in B cells with fewer antibody class switch recombination. These phenotypes detected in patients with APDS1 presenting with SLE were resemble that in patients with APDS1 presenting without SLE. Meanwhile, we described the effect of glucocorticoids and rapamycin therapy on patients with APDS1. The phosphorylation of S6 at Ser235/236 was inhibited in patients with APDS1 who underwent glucocorticoids therapy, including two who presented with SLE phenotype. The phosphorylation of AKT at Ser473 and phosphorylation of S6 at Ser235/236 were inhibited in other patients with APDS1 who underwent rapamycin therapy. Here, we showed the coexistence of immunodeficiency and SLE phenotype in APDS1, and the inhibition of rapamycin in activated Akt-mTOR signaling pathway.

In many countries, assessment of legal age, also known as age of majority, has become increasingly important over the years. In China, individuals older than 18 years of age have full capacity regarding civil conduct and can be tried as an adult for criminal charges. Therefore, from a legal point of view, it is crucial to determine whether an individual is an adult. The developmental degree of the third molar is widely recognized as a suitable site for age estimation in late adolescence. This article uses the third molar maturity index (I3M) with a cutoff value of I3M = 0.08, which was established by Cameriere et al. in 2008, to distinguish whether an individual is a minor or an adult (≥ 18 years of age) in a northern Chinese population. A total of 840 digital orthopantomograms (OPTs) from 420 male and 420 female northern Chinese subjects aged 12 to 25 years were evaluated. It was found that an increase in I3M corresponded to a decrease in chronological age. In our study, I3M = 0.10 showed better accuracy in age discrimination in both men and women. This threshold also resulted in high sensitivity (0.929 and 0.809) and specificity (0.940 and 0.973) in males and females, respectively. The proportion of correctly classified subjects was 0.917 (95% CI, 0.898 to 0.935) in total, 0.938 (95% CI, 0.915 to 0.961) in male and 0.895 (95% CI, 0.866 to 0.925) in female subjects. Bayes post-test probabilities were 0.967 (95% CI, 0.947 to 0.986) in males and 0.983 (95% CI, 0.966 to 0.998) in females. These differences in threshold values between Chinese and Caucasian populations might be because the development of third molars is delayed in the Chinese population compared to the Caucasian population. In conclusion, I3M might be a useful method in legal and forensic practices to determine ages in late adolescence in northern Chinese individuals. However, a specific population should be tested before I3M is used for legal age estimation.

Great effort has been spent to promote the vascularization of tissue engineering bone grafts (TEBG) for improved therapeutic outcome. However, the thorough vascularization especially in the central region still remained as a major challenge for the clinical translation of TEBG. Here, we developed a new strategy to construct a centrally vascularized TEBG (CV-TEBG) with unique core-shell composite structure, which is consisted of an angiogenic core and an osteogenic shell. The in vivo evaluation in rabbit critical sized femoral defect was conducted to meticulously compare CV-TEBG to other TEBG designs (TEBG with osteogenic shell alone, or angiogenic core alone or angiogenic core+shell). Microfil-enhanced micro-CT analysis has been shown that CV-TEBG could outperform TEBG with pure osteogenic or angiogenic component for neo-vascularization. CV-TEBG achieved a much higher and more homogenous vascularization throughout the whole scaffold (1.52-38.91 folds, p < 0.01), and generated a unique burrito-like vascular network structure to perfuse both the central and peripheral regions of TEBG, indicating a potential synergistic effect between the osteogenic shell and angiogenic core in CV-TEBG to enhance neo-vascularization. Moreover, CV-TEBG has generated more new bone tissue than other groups (1.99-83.50 folds, p < 0.01), achieved successful bridging defect with the formation of both cortical bone like tissue externally and cancellous bone like tissue internally, and restored approximately 80% of the stiffness of the defected femur (benchmarked to the intact femur). It has been further observed that different bone regeneration patterns occurred in different TEBG implants and closely related to their vascularization patterns, revealing the potential profound influence of vascularization patterns on the osteogenesis pattern during defect healing.

Physalis alkekengi L. var. franchetii (Solanaceae) has been widely used in Chinese folk medicine due to its wide distribution throughout the country, for the treatment of a wide range of diseases including heat and cold, sore throat, fever, fungal infection, inflammation, toothache, rheumatism, burn, analgesic, ulcer and urinary diseases. However, the effect of P. alkekengi var. franchetii on ulcer and Helicobacter pylori infection has not been reported to date.This study was designed to investigate the anti-inflammatory, anti-ulcer, anti-Helicobacter pylori and analgesic properties of ethyl acetate fraction of the crude aqueous methanolic extract from the aerial parts of the plant P. alkekengi L. var. franchetii in rodents.Acute toxicity of the crude extract of P. alkekengi L. var. franchetii (PAF) was evaluated in rats. The petroleum ether fraction (PEF), butanol fraction (BF), ethyl acetate fraction (EAF) and aqueous fraction (AF) of crude aqueous methanolic extract from PAF were screened for anti-inflammatory and anti-ulcer potential at doses of 100, 250 and 500mg/kg (p.o.), using carrageenin-induced hind paw edema and ethanol-induced gastric lesions test in rats. In vitro anti-Helicobacter pylori activity of EAF was assayed subsequently. In addition, three doses of EAF were evaluated for analgesic activity using hot plate and writhing tests, respectively. Finally, we performed a phytochemical analysis of EAF.Four fractions of crude extract from PAF significantly reduced the paw volume in carrageenin-induced hind paw edema model at different doses (100, 250 and 500mg/kg, p.o.). The fraction EAF at a dose of 500mg/kg exhibited the highest (75.92%) (0.150 ± 0.045***, ***p0.001) anti-inflammatory potential, which is similar to indomethacin (***P0.001)（0.120 ± 0.014***, 80.74% inhibition of inflammation） at 5mg/kg. Pretreatment with EAF (500mg/kg, p.o.) significantly reduced the intensity of gastric mucosal damage and showed higher gastroprotective activity (90.6%) when compared to the standard drug famotidine (84.6%). In addition, EAF fraction also showed a moderate (P0.05) anti-Helicobacter pylori activity with a minimal inhibition concentration (MIC) of 500μg/ml. Furthermore, pain sensation was effectively inhibited at 500mg/kg, p.o. of EAF as manifested by an increase (p0.001) of latency time in hot plate from 30 to 90min and a decrease (p0.001) in count of writhing induced by acetic acid. By HPLC, we determined some steroid, terpenoid and flavonoids (four compounds): kaempferol, quercetin, Blumenol A and physalindicanols A, which were isolated from the ethyl acetate fraction and identified usingThis study demonstrated the anti-inflammatory, anti-ulcer, anti-Helicobacter pylori and analgesic properties of EAF of the crude extract from PAF thus justifying its traditional usage.

The distribution pattern of vegetation on Qinghai–Tibetan Plateau is fundamentally influenced by the plateau climate, which is mainly controlled by Indian monsoon during summer. The long distance transportation of pollen (mostly anemophilous taxa) produced by trees on the plateau has been recorded by modern pollen samples in previous studies, and hypothesized to be a good indicator of monsoon dynamics. Here we use 270 surface pollen samples from Qinghai–Tibetan Plateau to test the distribution patterns of the anemophilous tree pollen. Meanwhile factors related to Indian monsoon affecting pollen transportation are simulated and analyzed. Results show that depositional patterns of anemophilous tree pollen, especially Abies , Pinus , Quercus and Betula are completely controlled by the pathways of Indian monsoon. This is reflected by climatic indicators of the atmospheric pressure pattern over June–July–August, by the precipitation pattern over June–July–August and by the topographic feature of the plateau. The spatial interpolation of thin plate spline results also display two depositional centers ( ca . 30°N, 95°E and 30°N, 105°E) of the anemophilous tree pollen. In contrast to previous conclusion that pollen distributional pattern is determined by mean annual precipitation, we argue that Indian monsoon is the essential controller because of the synchronization between timing of monsoon wind and timing of plants flowering. Our finding strongly suggests that distributional pattern of anemophilous tree pollen on the plateau is a good proxy of Indian monsoon.

In humans, the complete lack of tyrosine kinase ZAP70 function results in combined immunodeficiency (CID), with abnormal thymic development and defective T cell receptor (TCR) signaling of peripheral T cells, characterized by the selective absence of CD8+ T cells. So far, 15 unique ZAP70 mutations have been identified in approximately 20 patients with CID, with variable clinical presentations. Herein, we report the first case from China of novel compound heterozygous mutations in ZAP70 (c.598-599delCT, p.L200fsX28; c.847 C>T, R283H). The patient suffered from early-onset and recurrent infections, but showed normal growth and development without signs of failure to thrive, thus presenting as leaky SCID. The patient also had clinical manifestations of autoimmunity, such as eczematous skin lesion, inflammatory bowel disease (IBD), and intractable diarrhea, suggesting compromised T cell tolerogenic functions. Residual ZAP70 expression was identified. Immunological analysis revealed the selective absence of CD8+ T cells in the periphery and the presence of CD4+ T cells that failed to respond to phytohemagglutinin. Stimulation with lectin from pokeweed mitogen also failed to stimulate B cell proliferation in the patient. The frequency of Tfhs and Tregs in the patient was lower compared with the normal reference. Compared with the age-matched healthy control, the level of IL-17 was higher and the levels of IFN-γ, IL-4, and IL-21 were lower. Infants with selected CD8 deficiency and severe autoimmune disorders or exaggerated inflammation should be screened for ZAP70 deficiency.

The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA.

Bone augmentation is increasingly important in implantology. Bone substitute materials exert essential roles during bone augmentation process. However, accelerating bone substitute materials remodeling and acquiring high bone architecture quality was still the challenges of bone augmentation. Accumulated studies had suggested osteoclasts is the key cell type to resorb bone or bone substitute materials. Our previous study and other studies suggested osteoclasts contributed to bone formation by promoting osteoblast function and facilitate angiogenesis. We hypothesized that bone substitute materials loaded osteoclastogenic cytokines or osteoclast progenitors will help to bone substitute materials rapid remodeling and subsequent bone formation. Our hypothesis could help to lessen long-term post-bone augmentation period and acquire better bone quality for osseointegration.

The authors describe a field effect transistor (FET) based immunoassay for the detection of inactivated ebola virus (EBOV). An equine antibody against the EBOV glycoprotein was immobilized on the surface of the FET that was previously modified with reduced graphene oxide (RGO). The antibody against EBOV was immobilized on the modified FET, and the response to EBOV was measured as a function of the shift of Dirac voltage. The method can detect the EBOV over the concentration range from 2.4 × 10−12 g·mL−1 to 1.2 × 10−7 g·mL−1 and with a limit of detection as low as 2.4 pg·mL−1. The assay has satisfactory specificity and was applied to the quantitation of inactivated EBOV in spiked serum.

In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells (HSCs) transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency diseases (PIDs). Despite of some pitfalls at early stage clinical trials, the field of gene therapy has advanced significantly in the last decade with improvements in viral vector safety, preparatory regime for manufacturing high quality virus, automated CD34 cell purification. Hence, the overall outcome from the clinical trials for the different PIDs has been very encouraging. In addition to the viral vector based gene therapy, the recent fast moving forward developments in genome editing using engineered nucleases in HSCs has provided a new promising platform for the treatment of PIDs. This review provides an overall outcome and progress in gene therapy clinical trials for SCID-X, ADA-SCID, WAS, X- CGD, and the recent developments in genome editing technology applied in HSCs for developing potential therapy, particular in the key studies for PIDs. Keywords: Adenosine deaminase deficient, Chronic granulomatous disease, Gene therapy, Genome editing, Hematopoietic progenitor stem cells, Primary immunodeficiency diseases, Wiskott-Aldrich syndrome, X-liked severe combined immunodeficiency

Background: Osteoarthritis (OA) is a complex and heterogeneous condition, and one of the most common degenerative joint diseases. A standardized OA classification based on molecular criteria has yet to be defined. We performed transcriptomic profiling to determine the different molecular signatures associated with knee OA phenotypes. Methods: Five centres clinical research with next-generation sequencing was carried out using 201 samples from patients with knee osteoarthritis. Transcriptomic analysis and unsupervised clustering methods were performed on 131 cartilage samples. To investigate tissue crosstalk of the whole knee microenvironment, transcriptomic analysis was performed in 60 synovia and 65 subchondral bone samples. Findings: We identified four OA subgroups with distinct biological signatures: 1) the glycosaminoglycan metabolic disorder subgroup highly expressed ACAN, lowly expressed VCAN, and was enriched with glycosaminoglycan metabolic functions; 2) the collagen metabolic disorder subgroup presented with osteophyte formation, highly expressed COL1A1 and COL6A1, and was enriched with collagen catabolic functions; 3) the sensory neurons activated subgroup highly expressed GRIK2 and GRM7, and was enriched with synapse assembly functions; and 4) the immunogenic subgroup presented with high inflammation and narrow joint space, highly expressed IL1AŸ and CD34, and was enriched with immune responses. We also explored immune cell composition and tissue crosstalk for three identified metabolic disorder subgroups. Interpretation: These findings challenge the classical diagnosis model based on medical imaging, revealing distinct molecular subgroups in knee OA patients, and opening the door to precision diagnosis and treatment of OA. Funding Statement: This work was financially supported by the National Key R&D Program of China (2017YFA0104902), the National Natural Science Foundation of China (81630065, 31830029, 81802195) grants and China Postdoctoral Science Foundation (2017M621913). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Informed consent was obtained from all the participants. The study was approved by the local clinical ethics committees of Zhejiang University School of Medicine and the affiliated hospital of Wenzhou Medical University (2017KYLL11).

Hydrogels stabilized by dynamic reversible crosslinks provide a more permissive three-dimensional (3D) microenvironment to support various behaviors of encapsulated cells. Compared with hydrogels based on dynamic covalent crosslinks, supramolecular hydrogels based on host–guest interactions generally possess higher structural dynamics but lower elasticity due to the highly dynamic nature of the host–guest interactions. Herein, we first preassemble thiolated β-cyclodextrin (CD-SH) with adamantane-grafted hyaluronic acid (HA-Ada) before reacting with maleimide-grafted HA (HA-Mal) via the thiol–ene click reaction to fabricate host–guest hydrogels (HAHG) with a highly dynamic network. Furthermore, a minor fraction of covalent crosslinking can be easily incorporated into the hydrogel network by using multivalent CD-SH as the crosslinker to produce HAHG hydrogels with varying residual elasticity (RE) while keeping the hydrogel chemical composition unchanged. We demonstrated that HAHG hydrogels with a moderate level of RE best support the 3D spreading and intercellular interactions of encapsulated stem cells. This work provides an easy strategy to prepare cell-adaptable dynamic hydrogels with tunable network elasticity to study the effects of biophysical properties of hydrogel networks on cellular behavior in 3D environments.