Aberrant Ca2+ homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity [preprint]

Chronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+ channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposure in vitro or by obesity in vivo lead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+ and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+ is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+ homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity

Direct and indirect effects of climate on richness drive the latitudinal diversity gradient in forest trees

Data accessibility statement: Full census data are available upon reasonable request from the ForestGEO data portal, http://ctfs.si.edu/datarequest/ We thank Margie Mayfield, three anonymous reviewers and Jacob Weiner for constructive comments on the manuscript. This study was financially supported by the National Key R&D Program of China (2017YFC0506100), the National Natural Science Foundation of China (31622014 and 31570426), and the Fundamental Research Funds for the Central Universities (17lgzd24) to CC. XW was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB3103). DS was supported by the Czech Science Foundation (grant no. 16-26369S). Yves Rosseel provided us valuable suggestions on using the lavaan package conducting SEM analyses. Funding and citation information for each forest plot is available in the Supplementary Information Text 1.Peer reviewedPostprin

G12R mutation in Cx26 downregulates the expression levels of TLR2 and its downstream inflammatory factors in keratinocytes

Objective To investigate the effect of G12R mutation in Cx26 on the expression of TLR2 and its downstream inflammatory factors in human keratinocytes. Methods Human keratinocytes (HaCaT) without (WT-Cx26) or with G12R-mutation (G12R-Cx26) were co-cultured with Trichophyton rubrum. Expression levels of TLR2 mRNA and its downstream effector molecules were detected by real-time PCR. The expression levels of TLR2 protein were detected by western blot. Cytokine levels in the culture medium were measured by ELISA. Immunofluorescence was used to determine distribution of Cx26 and TLR2 in G12R-Cx26 HaCaT cells. Results Expression levels of TLR2 mRNA were comparable between WT-Cx26 and G12R-Cx26 cells (t=1.92, P=0.190). However, G12R mutation in Cx26 decreased expression levels of TLR2 protein in cell membrane and cytoplasm (both P<0.01 vs. WT-Cx26) in addition to reductions in expression levels of downstream of TLR2 pathway, including TNF (t=6.91, P<0.05), IL-6 (t=13.03, P<0.01) and antimicrobial peptide LL-37 (t=25.31, P<0.001). Coculture of G12R-Cx26 cells with ikarugamycin increased co-localization of Cx26 and TLR2 on the cell membrane. Conclusion Cx26-G12R mutation down-regulates the expression of TLR2 and downstream inflammatory cytokines, including TNF, IL-6 and antimicrobial peptide LL-37, in keratinocytes

Depression of Vaccinal Immunity to Marek’s Disease by Infection with Chicken Infectious Anemia Virus

Marek’s disease (MD) has been occurring with increasing frequency in chickens in recent years. To our knowledge, however, there has been no report of the very virulent plus (vv+) MD virus (MDV) field isolate in China. Studies have shown that dual infection with immunosuppressive viruses such as chicken infectious anemia virus (CIAV) occurs frequently in chickens developing MD. In this study, we performed a designed set of in vivo experiments, which comprised five different groups of chickens, including the group of CVI988/Rispens-vaccinated chickens, the groups of CVI988/Rispens-vaccinated chickens infected with MDV or CIAV or both viruses (MDV and CIAV), and the group of MDV-challenged chickens. The effects of CIAV dual infection on the immunization of commercial MDV vaccine CVI988/Rispens were evaluated. The results show that infection of the SD15 strain of CIAV significantly reduced the weight and antibody titers to avian influenza virus (AIV)/Newcastle disease virus (NDV) inactivated vaccines of chickens immunized with the CVI988/Rispens, and resulted in the atrophy of thymus/bursa and the enlargement of spleen. The CVI988/Rispens vaccination conferred good immune protection for chickens challenged with 2000 PFU of the GX0101 strain of MDV. However, dual infection with SD15 significantly reduced the body weight, antibody titers induced by AIV/NDV inactivated vaccines and protective index of CVI988/Rispens, and resulted in the aggravation of the immunosuppression, mortality, and viremia of GX0101 in CVI988/Rispens-immunized/GX0101-challenged chickens. Overall, CIAV infection significantly reduced the protective effects of the CVI988/Rispens vaccine against MDV, implying that concurrent infection with CIAV may be a major contributor in the frequent attacks of MD in China in recent years

Additive manufacturing of high-performance 15-5PH stainless steel matrix composites

The consolidation of ceramic particles into the metallic matrix is promising to translate their exceptional properties from the micro-scale to the macro world. Herein, four different 15-5PH stainless steel (SS) matrix composites: 15-5PH/TiB2, 15-5PH/TiN, 15-5PH/TiC and 15-5PH/WC were fabricated by directed energy deposition (DED). The introduction of TiB2 particles substantially refines the martensite grain size, however, fails to achieve the performance improvement due to the elemental segregation of Cr and formation of considerable macro- and micro-cracks. The TiN composite realises a simultaneous enhancement of strength and ductility due to grain refinement, however, fails to enhance the corrosion resistance due to the Cr element segregation. The WC and TiC composites achieve the balance between the improved strength and ductility coupled with simultaneous enhancement of corrosion resistance. This work demonstrates the substantial potential in developing martensitic SS matrix composites with excellent strength-ductility synergy and corrosion resistance

Comparison of daily operation strategies for a fuel cell/battery tram

This paper focuses on describing the daily operation strategy of a tram powered by a hybrid system based on fuel cell stack and a battery pack. The daily operation strategy focusses on the hydrogen refueling and battery recharging timing in one-day operation of 18 h, combined with serval driving cycles and three operation modes. The battery state of charge balanced (SOC-) strategy and the dynamic programming (DP-) strategy are two proposed power allocation methods. For one-cycle operation, the latter save 6.6% hydrogen consumption than the former. As for one-day operation, a simplified DP-strategy is deduced to replace the DP-strategy and accelerate the calculation. It shares equivalent hydrogen consumption with the SOC-strategy but guarantees the durability of the fuel cell and prolongs the driving mileage