Alteration of Thyroid Hormones in Mouse Models of Alzheimer's Disease and Aging.

INTRODUCTION: Aging is characterized by the deterioration of a wide range of functions in tissues and organs, and Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Hypothyroidism occurs when there is insufficient production of thyroid hormones (THs) by the thyroid. The relationship between hypothyroidism and aging as well as AD is controversial at present. METHODS: We established an animal model of AD (FAD4T) with mutations in the APP and PSEN1 genes, and we performed a thyroid function test and RNA sequencing (RNA-Seq) of the thyroid from FAD4T and naturally aging mice. We also studied gene perturbation correlation in the FAD4T mouse thyroid, bone marrow, and brain by further single-cell RNA sequencing (scRNA-seq) data of the bone marrow and brain. RESULTS: In this study, we found alterations in THs in both AD and aging mice. RNA-seq data showed significant upregulation of T-cell infiltration- and cell proliferation-related genes in FAD4T mouse thyroid. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that upregulated genes were enriched in the functional gene modules of activation of immune cells. Downregulated energy metabolism-related genes were prominent in aging thyroids, which reflected the reduction in THs. GSEA showed a similar enrichment tendency in both mouse thyroids, suggesting their analogous inflammation state. In addition, the regulation of leukocyte activation and migration was a common signature between the thyroid, brain, and bone marrow of FAD4T mice. CONCLUSIONS: Our findings identified immune cell infiltration of the thyroid as the potential underlying mechanism of the alteration of THs in AD and aging.

Gentiopicroside promotes the osteogenesis of bone mesenchymal stem cells by modulation of ß-catenin-BMP2 signalling pathway.

Osteoporosis is characterized by increased bone fragility, and the drugs used at present to treat osteoporosis can cause adverse reactions. Gentiopicroside (GEN), a class of natural compounds with numerous biological activities such as anti-resorptive properties and protective effects against bone loss. Therefore, the aim of this work was to explore the effect of GEN on bone mesenchymal stem cells (BMSCs) osteogenesis for a potential osteoporosis therapy. In vitro, BMSCs were exposed to GEN at different doses for 2 weeks, whereas in vivo, ovariectomized osteoporosis was established in mice and the therapeutic effect of GEN was evaluated for 3 months. Our results in vitro showed that GEN promoted the activity of alkaline phosphatase, increased the calcified nodules in BMSCs and up-regulated the osteogenic factors (Runx2, OSX, OCN, OPN and BMP2). In vivo, GEN promoted the expression of Runx2, OCN and BMP2, increased the level of osteogenic parameters, and accelerated the osteogenesis of BMSCs by activating the BMP pathway and Wnt/ß-catenin pathway, effect that was inhibited using the BMP inhibitor Noggin and Wnt/ß-catenin inhibitor DKK1. Silencing the ß-catenin gene and BMP2 gene blocked the osteogenic differentiation induced by GEN in BMSCs. This block was also observed when only ß-catenin was silenced, although the knockout of BMP2 did not affect ß-catenin expression induced by GEN. Therefore, GEN promotes BMSC osteogenesis by regulating ß-catenin-BMP signalling, providing a novel strategy in the treatment of osteoporosis.

Three-dimensional printing of patient-specific plates for the treatment of acetabular fractures involving quadrilateral plate disruption.

BACKGROUND: Complicated acetabular fractures comprise the most challenging field for orthopedists. The purpose of this study was to develop three-dimensional printed patient-specific (3DPPS) Ti-6Al-4 V plates to treat complicated acetabular fractures involving quadrilateral plate (QLP) disruption and to evaluate their efficacy. METHODS: Fifty patients with acetabular fractures involving QLP disruption were selected between January 2016 and June 2017. Patients were divided into a control group (Group A, 35 patients) and an experimental group (Group B, 15 patients), and were treated by the conventional method of shaping reconstruction plates or with 3DPPS Ti-6AL-4 V plates, respectively. The efficacy of Ti-6AL-4 V plates was evaluated by blood loss, operative time, reduction quality, postoperative residual displacement, and complications. RESULTS: The operative time and blood loss in Group B were reduced compared to Group A, and the difference was statistically significant (P < 0.05). There was no significant difference in reduction quality between the two groups (P > 0.05). Reduction quality in Group B was anatomic in 10 (66.7%), satisfactory in four (26.7%), and poor in one (6.7%). In Group A, they were anatomic in 18 (51.4%), satisfactory in 13 (37.1%), and poor in four (11.4%). Residual displacement in Group B was less than that in Group A, and the difference was statistically significant (P < 0.05). In Group B, one case exhibited loosening of the pubic screw postoperatively. In Group A, there was one case of wound infection, one of deep vein thrombosis (DVT) in the ipsilateral lower limb, one case of traumatic arthritis and two obturator nerve injuries. CONCLUSIONS: The 3DPPS Ti-6AL-4 V plate is a feasible, accurate and effective implant for acetabular fracture treatment.

Long non-coding RNA TUG1 alleviates LPS-induced injury of PC-12 cells by down-regulating microRNA-127.

The limited therapeutic strategies and the unsatisfied prognosis for spinal cord injury (SCI) make the identification of innovative therapeutic targets for SCI become very urgent. Herein, we explored the role of long non-cording RNA taurine up-regulated gene 1 (lncRNA TUG1) in lipopolysaccharide (LPS)-treated PC-12 cells and studied the downstream effector and signaling cascades. We found that LPS-induced decrease of cell viability, increase of apoptosis and release of IL-6 and TNF-α were mitigated by TUG1 overexpression. MicroRNA (miR-127) was negatively regulated by TUG1. Effects of TUG1 on LPS-treated PC-12 cells were reversed by miR-127 overexpression. Besides, TUG1 inactivated NF-κB and p38MAPK pathways in LPS-treated PC-12 cells via down-regulating miR-127. Dynactin 4 and protein tyrosine phosphatase (PTP) were the target genes of miR-127. miR-127 regulated the NF-κB and p38MAPK pathways in PC-12 cells at least by targeting dynactin 4 and PTP. In conclusion, we discovered that TUG1 alleviated LPS-induced PC-12 cell inflammatory injury might be through down-regulating miR-127, influencing dynactin 4 and PTP, and then inactivating NF-κB and p38MAPK pathways.

Unexpected Self-Assembly of Nanographene Oxide Membranes upon Electron Beam Irradiation for Ultrafast Ion Sieving.

Nanographene oxide (nGO) flakes-graphene oxide with a lateral size of ≈100 nm or less-hold great promise for superior flux and energy-efficient nanofiltration membranes for desalination and precise ionic sieving owing to their unique high-density water channels with less tortuousness. However, their potential usage is currently limited by several challenges, including the tricky self-assembly of nano-sized flakes on substrates with micron-sized pores, severe swelling in aqueous solutions, and mechanical instability. Herein, the successful fabrication of a robust membrane stacked with nGO flakes on a substrate with a pore size of 0.22 µm by vacuum filtration is reported. This membrane achieved an unprecedented water permeance above 819.1 LMH bar-1, with a high rejection rate of 99.7% for multivalent metal ions. The nGO flakes prepared using an electron beam irradiation method, have uniquely pure hydroxyl groups and abundant aromatic regions. The calculations revealed the strong hydrogen bonds between two nGO flakes, which arise from hydroxyl groups, coupled with hydrophobic aromatic regions, greatly enhance the stability of stacked flakes in aqueous solutions and increase their effective lateral size. The research presents a simple yet effective approach toward the fabrication of advanced 2D nanographene membranes with superior performance for ion sieving applications.

Single-cell transcriptomics identifies premature aging features of TERC-deficient mouse brain and bone marrow.

Aging is a progressive loss of physiological function and increased susceptibility to major pathologies. Degenerative diseases in both brain and bone including Alzheimer disease (AD) and osteoporosis are common in aging groups. TERC is RNA component of telomerase, and its deficiency accelerates aging-related phenotypes including impaired life span, organ failure, bone loss, and brain dysfunction. In this study, we investigated the traits of bone marrow-brain cross-tissue communications in young mice, natural aging mice, and premature aging (TERC deficient, TERC-KO) mice by single-cell transcriptome sequencing. Differentially expressed gene analysis of brain as well as bone marrow between premature aging mouse and young mouse demonstrated aging-related inflammatory response and suppression of neuron development. Further analysis of senescence-associated secretory phenotype (SASP) landscape indicated that TERC-KO perturbation was enriched in oligodendrocyte progenitor cells (OPCs) and hematopoietic stem and progenitor cells (HSPC). Series of inflammatory associated myeloid cells was activated in premature aging mice brain and bone marrow. Cross-tissue comparison of TERC-KO mice brain and bone marrow illustrated obvious ligand-receptor communications between brain glia cells, macrophages, and bone marrow myeloid cells in premature aging-induced inflammation. Enrichment of co-regulation modules between brain and bone marrow identified premature aging response genes such as Dusp1 and Ifitm3. Our study provides a rich resource for understanding premature aging-associated perturbation in brain and bone marrow and supporting myeloid cells and endothelial cells as promising therapy targeting for age-related brain-bone diseases.

Population-Based Survival Analysis of Patients With Limb Rhabdomyosarcoma and Metastasis at Diagnosis.

Purpose: Given the poor prognosis and the relative rarity of patients diagnosed with limb rhabdomyosarcoma (LRMS) and metastasis at diagnosis, we performed this study to reveal distinctive clinical features and evaluated prognostic factors of this special population in order to provide appropriate treatment. Patients and Methods: We carried out retrospective research of patients diagnosed with LRMS and metastasis from 1975 to 2016 using the Surveillance, Epidemiology, and End Results (SEER) program database. Survival curves were generated by applying the Kaplan-Meier method. In terms of evaluating and determining independent predictors of survival, we conducted univariate and multivariate survival analyses using the Cox proportional hazard regression model. Results: This retrospective analysis contained a series of 245 patients with metastatic LRMS, with male predominance (male vs. female, 1.6:1). Nearly half of the patients were diagnosed with alveolar rhabdomyosarcoma (44.9%). According to the results of the univariate and multivariate analyses, younger age, tumor subtype, and radiotherapy were found to be significantly associated with improved overall survival (OS) and cause-specific survival (CSS). Conclusions: Patients with LRMS and metastasis at diagnosis experienced a quite poor prognosis. Age at diagnosis, tumor subtype, and radiotherapy can help clinicians to better estimate the prognosis. This study indicated that local radiotherapy can provide a survival benefit.

Enhanced BMP signalling causes growth plate cartilage dysrepair in rats.

Growth plate cartilage injuries often result in bony repair at the injury site and premature mineralisation at the uninjured region causing bone growth defects, for which underlying mechanisms are unclear. With the prior microarray study showing upregulated bone morphogenetic protein (BMP) signalling during the injury site bony repair and with the known roles of BMP signalling in bone healing and growth plate endochondral ossification, this study used a rat tibial growth plate drill-hole injury model with or without systemic infusion of BMP antagonist noggin to investigate roles of BMP signalling in injury repair responses within the injury site and in the adjacent "uninjured" cartilage. At days 8, 14 and 35 post-injury, increased expression of BMP members and receptors and enhanced BMP signalling (increased levels of phosphorylated (p)-Smad1/5/8) were found during injury site bony repair. After noggin treatment, injury site bony repair at days 8 and 14 was reduced as shown by micro-CT and histological analyses and lower mRNA expression of osteogenesis-related genes Runx2 and osteocalcin (by RT-PCR). At the adjacent uninjured cartilage, the injury caused increases in the hypertrophic zone/proliferative zone height ratio and in mRNA expression of hypertrophy marker collagen-10, but a decrease in chondrogenesis marker Sox9 at days 14 and/or 35, which were accompanied by increased BMP signalling (increased levels of pSmad1/5/8 protein and BMP7, BMPR1a and target gene Dlx5 mRNA). Noggin treatment reduced the hypertrophic zone/proliferative zone height ratio and collagen-10 mRNA expression, but increased collagen-2 mRNA levels at the adjacent growth plate. This study has identified critical roles of BMP signalling in the injury site bony repair and in the hypertrophic degeneration of the adjacent growth plate in a growth plate drill-hole repair model. Moreover, suppressing BMP signalling can potentially attenuate the undesirable bony repair at injury site and suppress the premature hypertrophy but potentially rescue chondrogenesis at the adjacent growth plate.

[Experimental study on internal fixation with screws through femoral epiphyseal plate].

OBJECTIVE: To explore the effect of internal fixation with screw through femoral epiphyseal plate on growth in- hibition via an experimental study. METHODS: Forty New Zealand rabbits were randomly divided into 4 groups and 10 rabbits in each group. Epiphyseal plate was injured by penetrating of screws, and the size of damage area was controlled by changing the number of threads. Group A: blank group; group B: injury area accounted for 4% of the epiphyseal plate; group C: injury area accounted for 6%; group D: injury area accounted for 8%. The internal fixation was removed after 2 weeks, and the results were observed with X-ray film for 4 groups to judge the complications such as early closure of epiphyseal. RESULTS: In each group, there were no statistical differences in the length of the femoral neck, the diameter of femoral neck, the diameter of the femoral head, and the epiphyseal plate closure time. The growth speed of the length and diameter of the femoral neck, as well as the diameter of femoral head, were quicker on the early phase, and the speed was slowest when the epiphyseal plate was being closed. CONCLUSION: The injury area of epiphyseal plate under 8% is safe for its growth. Because no evidences demonstrate the growth inhibition of epiphyseal plate, the screws can be used for rabbit epiphyseal plates.

[Treatment of radial neck fracture in children with elastic stable intramedullary nails].

OBJECTIVE: To investigate effects of elastic stable intramedullary nails for the treatment of radial neck fracture in children. METHODS: From July 2006 to December 2011, 25 children with radical neck fractures, which included 16 males and 9 females aged from 7 to 15 years old (means 10.7), were treated with elastic stable intramedullary nails. According to Judet classification, 6 cases were type II, 17 cases were type III and 2 cases were type IV (including 1 case with type IVa and 1 case with type IVb). The fracture healing, pain, deformity and range of motion of elbow were recorded. RESULTS: All patients were followed up for 6 to 24 months with an average of 14 months. Twenty-five patients were obtained bone healing. According to Tibone and Stoltz evaluation standard, 18 cases got excellet results, 4 cases in good and 3 cases in moderate. CONCLUSION: Elastic stable intramedullary nails for the treatment of radial neck fracture in children has advantages of simple operation,less trauma and good results.

[Analysis on complications of elastic nail treating children's long bone fractures].

OBJECTIVE: To analyze the reasons on complications of treatment with elastic nail in children's long bone fracture. METHODS: Sixty-six cases (75 parts of long bone fratures) were treated by elastic nail including 49 male and 17 female. The age ranged from 3 to 17 years, mean 7.8 years. There were 35 femur fractures (2 cases were hibateral), 20 tibia and fibula fractures (12 cases were tibia fractures), 8 radial fractures (1 case was ulna fracture) and 3 humerus fractures. The cases included 4 open fractures and 62 closed fractures. All cases were fresh fractures, no multi-segmental fractures. Three cases associated with brain and chest injuries. These cases were treated by open or closed reduction and internal fixaion with elastic nail. A cast or brace had been used after operation for a month. Following-up included the function of the joint,the bottom of the nail and the callus. Complications were timely recorded. RESULTS: All the patients were followed-up for 12 to 29 months, averaged 17 months. The cases occurrenced compilications including 2 cases of nonunion, 2 of new fracture, 1 of displacment, 4 of joint dysfunction, 3 of irritation of the bottom of the nail and 1 malunion. CONCLUSION: Strict indication, well design,canonical operation is a good way to avoid compliacations. At the same time,early treatment can reduce the sequela.

[Distribution of hepatitis B virus genotype in 5 cities of Fujian province and the clinical implications of HBV genotype].

OBJECTIVE: To study the prevalence of hepatitis B virus (HBV) genotype in 5 cities of Fujian province and the clinical implications of distinct genotypes in HBV-related liver diseases. METHODS: HBV genotype was determined by the restriction fragment length polymorphism analysis in patients with chronic HBV infection in 5 cities of Fujian province. The relationship between HBV genotype and its clinical implications was studied by multinomal logistic regression and correspondence analysis. RESULTS: Of the 431 HBV DNA positive patients detected by PCR, 275 (63.8%) belonged to HBV genotype B, 100 (23.2%) to genotype C, 51 (11.8%) to genotype D and D-mixed genotype. Genotype A, E and F were not found. Multinomal logistic regression showed that genotype B was more prevalent in Quanzhou and Sanming cities than in Fuzhou (P = 0.002, P = 0.006), and genotype B appeared significantly more common in asymptomatic carriers (ASC), chronic hepatitis B (CHB) and severe hepatitis (SH). Genotype C was most prevalent in patients with liver cirrhosis (LC) (47.0%) than in those with ASC (14.5%) and SH (14.7%) (P = 0.009, P < 0.001). The positive rate of hepatitis B e antigen was higher in patients with genotype C than in those with genotype B and genotype D (56.0% vs. 52.4%, P = 0.008, and 56.0% vs. 30.8%, P = 0.051, respectively). By correspondence analysis, genotype D and D-mixed genotype seemed to be correlated with hepatocellular carcinoma (HCC). CONCLUSIONS: (1) The major popular genotypes of HBV were B, C and D in Fujian. (2) Data of our study suggested that the geographic distribution of genotype B and C might be different in some cities of Fujian. (3) Genotype B might have a tendency to lead to SH in younger patients with chronic hepatitis B and the development of LC might be associated with genotype C among the elder patients. (4) Genotype D appeared to associate with development of HCC, which called for further study to confirm.