A monoallelic variant in CCN2 causes an autosomal dominant spondyloepimetaphyseal dysplasia with low bone mass.

Cellular communication network factor 2 (CCN2) is a secreted extracellular matrix-associated protein, and its aberrantly increased expression has been implicated in a diversity of diseases involving pathological processes of fibrosis, chronic inflammation, or tissue injury, which has promoted the evaluation of CCN2 as therapeutic targets for multiple disorders. However, human phenotypes associated with CCN2 deficiency have remained enigmatic; variants in CCN2 have not yet been associated with a human phenotype. Here, we collected families diagnosed with spondyloepimetaphyseal dysplasia (SEMD), and screened candidate pathogenic genes for families without known genetic causes using next-generation sequencing. We identified a monoallelic variant in signal peptide of CCN2 (NM_001901.2: c.65 G > C [p.Arg22Pro]) as the cause of SEMD in 14 subjects presenting with different degree of short stature, premature osteoarthritis, and osteoporosis. Affected subjects showed decreased serum CCN2 levels. Cell lines harboring the variant displayed decreased amount of CCN2 proteins in culture medium and an increased intracellular retention, indicating impaired protein secretion. And the variant weakened the stimulation effect of CCN2 on osteogenesis of bone marrow mesenchymal stem cells. Zebrafish ccn2a knockout model and osteoblast lineage-specific Ccn2-deficient mice (Ccn2fl/fl;Prx1Cre) partially recapitulated the phenotypes including low bone mass observed in affected subjects. Pathological mechanism implicated in the skeletal abnormality in Ccn2fl/fl;Prx1Cre mice involved decreased bone formation, increased bone resorption, and abnormal growth plate formation. Collectively, our study indicate that monoallelic variants in CCN2 lead to a human inherited skeletal dysplasia, and highlight the critical role of CCN2 in osteogenesis in human.

Serum ionized magnesium acts as an independent protective factor against bone erosion in patients with gouty arthritis: a cross-sectional study.

Background: Gouty arthritis is a common inflammatory arthritis. The recurrent gout attacks severely damage the joint's function, lead to bone erosion, and affect bone metabolism. The role of magnesium (Mg) ions in bone homeostasis has been recognized, whereas its specific relationship with gouty bone erosion remains unclear. This study examined the association between serum ionized Mg levels and bone erosion in patients with gout arthritis. Methods: A total of 769 patients with gout arthritis were included in the study. Participants were classified into four groups based on the quartiles of the serum ionized Mg level. Logistic regression analysis assessed the association between serum ionized Mg and bone erosion. Results: Compared to patients without bone erosion, serum ionized Mg levels were lower in gout patients with bone erosion (p<0.001). When dividing serum ionized Mg into quartiles, the prevalence rate of bone erosion in group Q1, representing the patients with the lowest serum ionized Mg levels, was notably higher than in Q2, Q3, and Q4 (60.2% vs. 43.6%, 45.6%, 40.3%, p<0.001). Multiple logistic regression analysis revealed that patients in Q2-Q4 had a lower odds ratio (OR) of bone erosion compared to those in Q1 (ORs were 0.520, 0.533, and 0.411 in Q2-Q4, respectively, p<0.001). Conclusion: The incidence of bone erosion is higher in gout arthritis patients with lower serum ionized Mg levels. High serum ionized Mg levels may be an independent protective factor for bone erosion in gout arthritis. Thus, Mg supplementation may be a promising approach to prevent or slow down the development of bone erosion in gouty arthritis.

Association of systemic immune-inflammation index with insulin resistance and prediabetes: a cross-sectional study.

Background and Objective: Previous research suggested a relationship between the Systemic Immune-Inflammation Index (SII) and multiple adverse health conditions. However, the role of SII in prediabetes and insulin resistance (IR) remains poorly understood. Therefore, this study aims to explore the potential relationship between SII and prediabetes and IR, providing data support for effective diabetes prevention by reducing systemic inflammation. Methods: Linear regression models were used to assess the correlation between continuous SII and risk markers for type 2 diabetes (T2D). Subsequently, multivariate logistic regression models and subgroup analyses were employed to evaluate the association between SII tertiles and prediabetes and IR, controlling for various confounding factors. Finally, restricted cubic spline graphs were used to analyze the nonlinear relationship between SII and IR and prediabetes. Results: After controlling for multiple potential confounders, SII was positively correlated with fasting blood glucose (FBG) (ß: 0.100; 95% CI: 0.040 to 0.160), fasting serum insulin (FSI) (ß: 1.042; 95% CI: 0.200 to 1.885), and homeostasis model assessment of insulin resistance (HOMA-IR) (ß: 0.273; 95% CI: 0.022 to 0.523). Compared to participants with lower SII, those in the highest tertile had increased odds of prediabetes (OR: 1.17; 95% CI: 1.02-1.34; p for trend < 0.05) and IR (OR: 1.35; 95% CI: 1.18 to 1.51; p for trend<0.001). Conclusions: Our study results demonstrate an elevated association between SII levels and both IR and prediabetes, indicating SII as a straightforward and cost-effective method identifying individuals with IR and prediabetes.

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. METHODS: We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. RESULTS: The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. CONCLUSIONS/INTERPRETATION: Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. DATA AVAILABILITY: RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

The Emerging Role of Interleukin-(IL)-11/IL-11R in Bone Metabolism and Homeostasis: From Cytokine to Osteokine.

Interleukin-(IL)-11 is a cytokine involved in hematopoiesis, cancer metastasis, and inflammation. IL-11 belongs to the IL-6 cytokine family, binding to the complex of receptors glycoprotein gp130 and the ligand-specific-receptor subunits (IL-11Rα or their soluble counterpart sIL-11R). IL-11/IL-11R signaling enhances osteoblast differentiation and bone formation and mitigates osteoclast-induced bone resorption and cancer bone metastasis. Recent studies have shown that systemic and osteoblast/osteocyte-specific IL-11 deficiency leads to reduced bone mass and formation, but also adiposity, glucose intolerance, and insulin resistance. In humans, mutations of IL-11 and the receptor IL-11RA genes are associated with height reduction, osteoarthritis, and craniosynostosis. In this review, we describe the emerging role of IL-11/IL-11R signaling in bone metabolism by targeting osteoblasts, osteoclasts, osteocytes, and bone mineralization. Furthermore, IL-11 promotes osteogenesis and suppresses adipogenesis, thereby influencing the fate of osteoblast/adipocyte differentiation derived from pluripotent mesenchymal stem cells. We have newly identified IL-11 as a bone-derived cytokine that regulates bone metabolism and the link between bone and other organs. Thus, IL-11 is vital in bone homeostasis and could be considered a potential therapeutic strategy.

Type 1 Diabetes Mellitus-Related circRNAs Regulate CD4+ T Cell Functions.

Circular RNAs (circRNAs) participate in development of malignancies through its active role as a "miRNA sponge." Their roles in type 1 diabetes mellitus (T1DM) pathogenesis are elusive. Here, the important role of circRNAs in T1DM was explored. circRNA profiling was performed for isolated CD4+ T cells from blood of T1DM and healthy volunteers. There were 257 differentially expressed circRNAs. Only three upregulated DEcircRNAs (hsa_circ_0000324, hsa_circ_0001853, and hsa_circ_0068797) were consistent with the GEO database. Through KEGG analyses, it was found that the three DEcircRNAs were associated with 11 miRNAs and 8 immune-related target genes (mRNA). Further analysis found that four miRNAs, two circRNAs, and four mRNAs were associated with nine circRNA-miRNA-mRNA networks. This confirmed the requirements of sponge mechanisms. The qRT-PCR analysis revealed that circRNA000324/miRNA675-5p/MAPK14 and circRNA000324/miRNA-675-5p/SYK may be potential mechanisms in regulation of differentiation and proliferation of CD4+ T cell in patients with T1DM. Therefore, targeting circRNA to regulate cellular immune responses by regulating CD4+ T cell differentiation may be a new strategy for the treatment of T1DM.

Nanofiber-Enhanced "Lucky-Bag" Triboelectric Nanogenerator for Efficient Wave Energy Harvesting by Soft-Contact Structure.

Developing clean and renewable ocean wave energy is a top priority and an effective way to achieve carbon neutrality. Triboelectric nanogenerators (TENGs) have emerged as promising green and clean energy-harvesting devices. To harvest low-frequency wave energy efficiently, much effort has been made on the modification of the contact surface, which leads to a higher fabrication cost. In this work, we designed a novel "Lucky-Bag" core (LBC) for spherical TENGs with a low-cost and easy fabricating process. The nanofiber/silicone hybrid porous outer layer of the LBC can switch freely from plane to surface and improve the output performance of both the plane and spherical TENGs. Several factors, such as the input frequency, direction, and resistive load, together with the thickness were systematically investigated; the unique porous soft-contact structure increased the triboelectric contact area, and the working mechanism was studied by using the COMSOL software. The experimental results showed that the peak-to-peak open-circuit voltage (Voc) and short-circuit current (Isc) could reach 580 V and 23.5 µA at 1.5 Hz, even under 2D linear motion. Besides, the maximum output power of the spherical TENGs reached 9.10 mW, which can fully power electronic devices such as capacitors and LEDs under water wave triggering. These findings provide useful guidance for optimizing the performance of spherical TENGs for practical applications in harvesting water wave energy.

Mutation of the novel acetylation site at K414R of BECN1 is involved in adipocyte differentiation and lipolysis.

BECN1, a protein essential for autophagy, is involved in adipocyte differentiation, lipolysis and insulin resistance. The discovery of new mechanisms for modifying BECN1 in adipocytes may provide novel therapeutic targets for obesity. This study aimed to investigate the impact of mutations at the acetylation sites of BECN1 on adipocyte differentiation and lipolysis. We found that Ace-BECN1 levels were increased in 3T3-L1 adipocyte differentiation and isoproterenol-/TNF-α-stimulated lipolysis and in subcutaneous and visceral adipose tissues of high-fat diet mice. K414 was identified as an acetylation site of BECN1, which affects the stability of the BECN1 protein. Mutation at K414 of BECN1 affected autophagy, differentiation and lipolysis in 3T3-L1 adipocytes. These data indicated the potential of BECN1 K414 as a key molecule and a drug target for regulating autophagy and lipid metabolism in adipocytes.

Gene silencing of ZnT8 attenuates inflammation and protects pancreatic tissue injury in T1D.

T lymphocyte mediated inflammation contributes to the development of T1D. Zinc Transporter 8 (ZnT8) has emerged as a target of autoreactive T cells in human T1D in recent years. However, the regulating of ZnT8 in T1D has not been identified. We make a hypothesis that whether alternation of ZnT8 level could attenuate inflammation and protect pancreatic tissue injury in T1D. In this study, we utilized ZnT8 shRNA to inhibit ZnT8 expression, and detected inflammation, glucose tolerance and pancreatic tissue of NOD mice. We found that ZnT8 shRNA attenuated specific CD8+ T cell activation and cytotoxicity. In addition, ZnT8 shRNA protected glucose tolerance and pancreatic tissue injury via down-regulation of ZnT8 in NOD mice. Therefore, the results suggest that RNAi represents a promising target reducing ZnT8 mediated inflammation, and provides a novel therapeutical clue in T1D.

Identification of HLA-A2-restricted immunogenic peptides derived from Vitamin D-Binding Protein.

T-cell-mediated destruction of pancreatic ß cells leads to Type 1 diabetes (TID). Vitamin D-Binding Protein (VDBP) has been identified as an autoantigen and T cell reactivity against VDBP increases in the development of T1D. Autoreactive cytotoxic T lymphocytes (CTLs) recognize ß-cell-derived peptides in the context of major histocompatibility complex class I molecules. However, little is known about the VDBP-derived immunogenic peptides that are presented in the context of human HLA molecules. Here, we predicted and identified VDBP derived immunogenic peptides that were presented in association with human HLA-A2 molecule. The VDBP derived peptides binding to HLA-A∗0201 were predicted by using a computer-assisted algorithm. The candidate peptides were synthesized, then affinity between peptides and HLA-A∗0201 were analyzed. In addition, the CTL activity of the peptides was detected by cytotoxicity assay and ELISPOT assay in vitro. Furthermore, HLA-A∗0201-transgenic mice were immunized with peptides to induce the CTL activity in vivo. The results demonstrated that peptides of VDBP containing residues 211-219 and 235-243 had high affinity with HLA-A∗0201. In addition, these peptides elicited potent CTL responses in vitro, and induced T1D in vivo. Therefore, this experiment identified immunogenic HLA-A∗0201-restricted epitopes derived from VDBP, and provided pathogenesis theory of T1D.

miR-330-5p/Tim-3 axis regulates macrophage M2 polarization and insulin resistance in diabetes mice.

Obesity is associated with a state of low-grade inflammatory response in adipose tissue, and contributes to the development of type 2 diabetes. Immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Therefore, adipose tissue promotes macrophage infiltration, resulting in local inflammation and insulin resistance. Tim-3 negatively regulates IFN-γ secretion and influences the ability to induce T cell tolerance in diabetes. MicroRNA contributes to the development of immunological tolerance and involves in macrophage polarization. However, the potential of Tim-3 to regulate macrophage polarization and the related microRNA has not been reported. In this experiment, 8-week-old C57BL/6 mice were fed a high-fat diet for 8 weeks. The adipose tissue macrophages were isolated, miR-330-5p and Tim-3 levels, and M1/M2 polarization were analyzed. In addition, insulin tolerance tests was detected. The results demonstrated that miR-330-5p levels increased but Tim-3 levels decreased, leading to M1 polarization and insulin tolerance in diabetes mice. In addition, inhibition of miR-330-5p enhanced Tim-3 levels, leading to M2 polarization and insulin tolerance attenuation in diabetes mice. Furthermore, we detected the inverse relationship between miR-330-5p and Tim-3. We found that Tim-3 mRNA contained conserved miR-330-5p binding sites in its 3'UTR, and miR-330-5p could directly regulate Tim-3 expression through these 3'UTR sites. Our study demonstrated that miR-330-5p served as a regulator of the M2 polarization and miR-330-5p/Tim-3 axis potentially down-regulated insulin resistance in diabetes, probably through enhancing the M2 polarization of macrophage.

The draft genome assembly of Rhododendron delavayi Franch. var. delavayi.

Rhododendron delavayi Franch. is globally famous as an ornamental plant. Its distribution in southwest China covers several different habitats and environments. However, not much research had been conducted on Rhododendron spp. at the molecular level, which hinders understanding of its evolution, speciation, and synthesis of secondary metabolites, as well as its wide adaptability to different environments. Here, we report the genome assembly and gene annotation of R. delavayi var. delavayi (the second genome sequenced in the Ericaceae), which will facilitate the study of the family. The genome assembly will have further applications in genome-assisted cultivar breeding. The final size of the assembled R. delavayi var. delavayi genome (695.09 Mb) was close to the 697.94 Mb, estimated by k-mer analysis. A total of 336.83 gigabases (Gb) of raw Illumina HiSeq 2000 reads were generated from 9 libraries (with insert sizes ranging from 170 bp to 40 kb), achieving a raw sequencing depth of ×482.6. After quality filtering, 246.06 Gb of clean reads were obtained, giving ×352.55 coverage depth. Assembly using Platanus gave a total scaffold length of 695.09 Mb, with a contig N50 of 61.8 kb and a scaffold N50 of 637.83 kb. Gene prediction resulted in the annotation of 32 938 protein-coding genes. The genome completeness was evaluated by CEGMA and BUSCO and reached 95.97% and 92.8%, respectively. The gene annotation completeness was also evaluated by CEGMA and BUSCO and reached 97.01% and 87.4%, respectively. Genome annotation revealed that 51.77% of the R. delavayi genome is composed of transposable elements, and 37.48% of long terminal repeat elements (LTRs). The de novo assembled genome of R. delavayi var. delavayi (hereinafter referred to as R. delavayi) is the second genomic resource of the family Ericaceae and will provide a valuable resource for research on future comparative genomic studies in Rhododendron species. The availability of the R. delavayi genome sequence will hopefully provide a tool for scientists to tackle open questions regarding molecular mechanisms underlying environmental interactions in the genus Rhododendron, more accurately understand the evolutionary processes and systematics of the genus, facilitate the identification of genes encoding pharmaceutically important compounds, and accelerate molecular breeding to release elite varieties.

A novel mimovirus encoding ChgA10-19 peptide with PD-L1 induces T cell tolerance and ameliorates the severity of diabetes.

Related studies demonstrate that type 1 diabetes (T1D) is caused by ß-cell antigen specific autoreactive CD8+ T cells. ChgA has recently been identified as the autoantigen in NOD mice and T1D patients. Therefore, attenuating the activation of ChgA specific CD8+ T cells might be a promising target for T1D therapy. The negative co-stimulatory PD-L1 inhibits T cell mediated alloimmunity and induces tolerance. In this experiment, a novel mimovirus encoding ChgA10-19 peptide with PD-L1 was constructed. The NOD.ß2m null HHD mice were administrated with mimovirus transduced DCs. After immunization, the activation and proliferation of CD8+ T cells were detected, diabetes incidence and pancreatic tissue destruction were also analyzed. The results demonstrated that transduced DCs attenuated CD8+ T cell activation and proliferation. In addition, transduced DCs inhibited CD8+ T response to ChgA stimulation, and ameliorated the severity of diabetes. These data suggested that mimovirus transduced DCs might provide novel clues for T1D therapy.

The water-water cycle is a major electron sink in Camellia species when CO2 assimilation is restricted.

The water-water cycle (WWC) is thought to dissipate excess excitation energy and balance the ATP/NADPH energy budget under some conditions. However, the importance of the WWC in photosynthetic regulation remains controversy. We observed that three Camellia cultivars exhibited high rates of photosynthetic electron flow under high light when photosynthesis was restricted. We thus tested the hypothesis that the WWC is a major electron sink in the three Camellia cultivars when CO2 assimilation is restricted. Light response curves indicated that the WWC was strongly increased with photorespiration and was positively correlated with extra ATP supplied from other flexible mechanisms excluding linear electron flow, implying that the WWC is an important alternative electron sink to balance ATP/NADPH energy demand for sustaining photorespiration in Camellia cultivars. Interestingly, when photosynthesis was depressed by the decreases in stomatal and mesophyll conductance, the rates of photosynthetic electron flow through photosystem II declined slightly and the rates of WWC was enhanced. Furthermore, the increased electron flow of WWC was positively correlated with the ratio of Rubisco oxygenation to carboxylation, supporting the involvement of alternative electron flow in balancing the ATP/NADPH energy budget. We propose that the WWC is a crucial electron sink to regulate ATP/NADPH energy budget and dissipate excess energy excitation in Camellia species when CO2 assimilation is restricted.

Simultaneous laser excitation of backward volume and perpendicular standing spin waves in full-Heusler Co2FeAl0.5Si0.5 films.

Spin-wave dynamics in full-Heusler Co2FeAl0.5Si0.5 films are studied using all-optical pump-probe magneto-optical polar Kerr spectroscopy. Backward volume magnetostatic spin-wave (BVMSW) mode is observed in films with thickness ranging from 20 to 100 nm besides perpendicular standing spin-wave (PSSW) mode, and found to be excited more efficiently than the PSSW mode. The field dependence of the effective Gilbert damping parameter appears especial extrinsic origin. The relationship between the lifetime and the group velocity of BVMSW mode is revealed. The frequency of BVMSW mode does not obviously depend on the film thickness, but the lifetime and the effective damping appear to do so. The simultaneous excitation of BVMSW and PSSW in Heusler alloy films as well as the characterization of their dynamic behaviors may be of interest for magnonic and spintronic applications.

ZnT8107-115/HLA-A2 dimers attenuate the severity of diabetes by inducing CD8+ T cell tolerance.

Recent studies demonstrated that activated CD8+ T cells contributed to the development of T1D, and Zinc Transporter 8 (ZnT8) has emerged as a target of autoreactive T cells in human T1D in recent years. In the previous work, we identified that ZnT8107-115 peptide as a candidate to generate CD8+ T cells and induce diabetes in mice. In addition, MHC-peptide complexes that interact with autoreactive T cells can induce immune tolerance. In the current study, we constructed ZnT8107-115/HLA-A2 dimers, and utilized them to immunize diabetes mice. The proliferation, cytotoxicity, and inflammatory cytokine of CD8+ T were analyzed, and the incidence and severity of diabetes were detected. We found that ZnT8107-115/HLA-A2 dimers inhibited proliferation, cytotoxicity, and inflammatory cytokine of CD8+ T. Additionally, ZnT8107-115/HLA-A2 dimers ameliorated the incidence and severity of diabetes mice. Our findings suggested that ZnT8107-115/HLA-A2 dimers abrogate pathogenic CD8+ T cells in diabetes, and the strategies represented promising way in T1D and other autoimmune diseases.

MiR-130b promotes obesity associated adipose tissue inflammation and insulin resistance in diabetes mice through alleviating M2 macrophage polarization via repression of PPAR-γ.

Inflammatory pathways play an important role in impaired glucose metabolism and insulin production. Adipose tissue inflammation is characterized by infiltration and expansion of macrophages, leading to type 2 diabetes (T2D). Macrophage polarization contributes to various inflammatory responses and cytokine production profiles. MiR-130b is involved in regulating immune response and metabolism. However, the specific role in macrophage polarization and glucose metabolism of T2D has not been reported. In this study, C57BL/6 mice were fed a high-fat diet to induce T2D mice model. The peritoneal macrophages were isolated, miR-130b and M1/M2 polarization was analyzed. Glucose tolerance was also detected. In addition, the relationship between miR-130b and the target gene was identified. We showed that mice fed on high-fat diet demonstrated significantly higher body weight and impaired glucose tolerance. In addition, the miR-130b level was up-regulated in macrophage of high-fat diet mice, which regulated M1/M2 polarization, adipose tissue inflammation and glucose tolerance. Furthermore, we identified PPAR-γ as a miR-130b target gene and regulated macrophage polarization. In summary, our findings demonstrated that miR-130b was a novel regulator of macrophage polarization and contributed to adipose tissue inflammation and insulin tolerance via repression of PPAR-γ. Furthermore, miR-130b represented a promising target for T2D therapy in the clinic.

Loss of Heterozygosity of 9p Is Associated with Poorer Survival in Patients with Gliomas.

The prognostic factors associated with the survival of glioma patients have not been well established. Loss of heterozygosity (LOH) of 9p was known to be a typical molecular signature of gliomas, but it was still unclear whether LOH of 9p was associated with poorer survival in patients with gliomas. We searched PubMed and Embase databases from the earliest records to May 2015 to identify studies that met the inclusion criteria. Either a fixed- or a random-effects model was used to calculate the pooled hazard ratio (HR) according to the between-study heterogeneity. Thirteen eligible studies involving 1465 cases of gliomas were included in the meta-analysis. There was little between-study heterogeneity (I 2 = 15 %), and the fixed-effects model was used to calculate the pooled HR. Meta-analysis of total 13 studies showed that LOH of 9p was significantly associated with poorer prognosis of glioma patients (HR = 1.39, 95%CI 1.17-1.64, P = 0.0002). Meta-analysis of eight studies reporting adjusted estimates showed that LOH of 9p was independently associated with poorer prognosis of glioma patients (HR = 1.40, 95%CI 1.14-1.72, P = 0.001). Subgroup analysis by types of gliomas showed that LOH of 9p was significantly associated with poorer prognosis in patients with glioblastoma (HR = 1.34, 95%CI 1.01-1.78, P = 0.04). There was no obvious risk of publication bias shown in the funnel plot. LOH of 9p is significantly associated with poorer prognosis of glioma patients, which is a useful biomarker in predicting patients' survival.

Microinjection of calcitonin in midbrain periaqueductal gray attenuates hyperalgesia in a chronic constriction injury rat model.

OBJECTIVES: As heat, pain is one of the most common clinical symptoms. Generally, calcitonin (CT) is prescribed as an analgesic agent for the treatment of pain, especially for the pain caused by osteoporosis or primary and metastatic bone tumor. However, the detailed mechanism remains unknown. MATERIALS AND METHODS: In this study, chronic constriction injury (CCI) rat model was created, and hot plate test and von frey filaments test were employed to evaluate thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT), respectively. Immunohistochemistry staining and western blot analyses were used to assess the distribution and expression of calcitonin receptor (CT-R) in the midbrain periaqueductal gray (PAG), which was a pivotal site in the modulatory system for the endogenous pain. RESULTS: The TWL and MWT before the surgery (19.6±1.19 sec) were significantly longer than that at day 2 (12.5±1.60 sec), and day 14 (7.75±0.89 sec) (P< 0.01; P< 0.01), respectively. The TWL and MWT at day 14 were significantly increased compared to that at day 7 after microinjection of salmon calcitonin (sCT) with different doses. Interestingly, the expression of CT-R was up-regulated in neuropathic pain. Furthermore, the expression of CT-R was significantly up-regulated and algesia was remarkably relieved when CT was microinjected into PAG. CONCLUSION: These results suggested that an increased CT-R might be associated with hyperalgesia in CCI rat, and CT had a potent antinociceptive effect by the up-regulation of CT-R in the PAG. Thus, it might provide a potential approach for the treatment of bone pain.