Human immunoglobulin G (IgG) agonistic antibodies targeting costimulatory immunoreceptors represent promising cancer immunotherapies yet to be developed. Whether, and how, human IgG hinge and Fc impact on their agonistic functions have been disputed. Here, we show that different natural human IgGs confer divergent agonistic anti-CD40 immunostimulatory and antitumour activities in FcγR-humanized mice, including inactive IgG3 and superior IgG2. This divergence is primarily due to their CH1-hinges despite all human IgGs requiring Fc-FcγR binding for optimal agonistic activities. Unexpectedly, biophysical flexibility of these CH1-hinges inversely correlates with, and can modulate, their agonistic potency. Furthermore, IgG Fcs optimized for selective FcγR binding synergize with and still require IgG hinge, selected for rigidity, to confer improved anti-CD40 immunostimulatory and antitumour activities. These findings highlight the importance of both hinge rigidity and selective FcγR binding in antibody agonistic function, and the need for newer strategies to modulate antibody agonism for improved clinical application.

Understanding the mechanisms that lead to autoimmunity is critical for defining potential therapeutic pathways. In this regard there have been considerable efforts in investigating the interacting roles of TGF-β and IL-2 on the function regulatory T cells. We have taken advantage of dnTGF-βRII Il2ra−/− (abbreviated as Il2ra−/−Tg) mouse model, which allows a direct mechanistic approach to define the relative roles of TGF-β and IL-2 on Treg development. Il2ra−/−Tg mice spontaneously developed multi-organ autoimmune diseases with expansion of pathogenic T cells and enhanced germinal center response at 3–4 weeks of age. Importantly, peripheral Treg cells from Il2ra−/−Tg mice demonstrated an activated Th1-like stable phenotype and normal in vitro suppressive function, while thymus Treg increased but manifested decreased suppressive function. Interestingly, neither thymus nor peripheral Treg cells of Il2ra−/−Tg mice contained Neuropilin-1+ or PD-1hi phenotype, resulting in defective follicular regulatory T (Tfr) cell development. Such defective Tfr development led to elevated follicular T helper cells, enhanced germinal center responses and increased plasma cell infiltration. These data demonstrate an important synergetic role of TGF-β and IL-2 in the generation, activation and stability of Treg cells, as well as their subsequent development into Tfr cells.

Governance of South China Sea (SCS) fisheries remains weak despite acknowledgement of their widespread overexploitation for the past few decades. This review incorporates unreported fish catches to provide an improved baseline of the current status and societal contribution of SCS marine fisheries, so that the socio-economic and ecological consequences of continued fisheries unsustainability may be understood. Potential fisheries contribution to food and livelihoods include 11-17 million t in fisheries catch and USD 12-22 9 10 9 in fisheries landed value annually in the 2000s, and close to 3 million jobs. However, overfishing has resulted in biodiversity and habitat loss, and altered ecosystem trophic structures to a 'fished down' state. The present situation reiterates the urgency for fisheries policies that simultaneously address multiple political, social, economic, and biological dimensions at regional, national, and local scales. Importantly, improved cooperation between SCS nations, particularly in overcoming territorial disputes, is essential for effective regional fisheries governance.

Structural data are available in the PDB under accession numbers 5GPP and 5GPQ.

Our study demonstrated that both recombinant MBP expression vectors significantly enhanced production. In addition, MBP tagged recombinant proteins can sometimes produce crystals. This strategy may be applied to other challenging proteins.

Abstract. Hepatic encephalopathy (HE) is a severe complication of liver cirrhosis and its pathogenesis has yet to be fully elucidated. Previous studies have demonstrated that heme oxygenase-1 (HO-1) is important in the induction of liver cirrhosis. The present study aimed to investigate the role of HO-1 in the pathogenesis of HE. Rats were divided into 5 treatment groups; sham, bile duct ligation (BDL), HE, zinc protoporphyrin (ZnPP) and cobalt protoporphyrin (CoPP). The levels of HO-1 were examined by western blotting and quantitative real-time PCR (qRT-PCR). Serum levels of carboxyhemoglobin (COHb), ammonia levels in the plasma and brain, brain water content and portal vein pressure (PVP) were also quantified. Aquaporin-4 expression levels were measured by immunohistochemistry and qRT-PCR. The results demonstrated that the levels of HO-1 in the brain and the serum levels of COHb were significantly increased in the HE group compared with the BDL group. Brain water content, PVP and ammonia levels in the plasma and brain were increased in the HE and CoPP groups; however, these were reduced following the treatment with ZnPP. The levels of AQP-4 expression and oxidative stress in the brain were reduced following treatment with ZnPP and increased following treatment with CoPP. In conclusion, following the inhibition of HO-1 expression, treatment with ZnPP improved HE due to reducing the expression levels of AQP-4 and oxidative stress. Therefore, ZnPP treatment may represent a novel therapeutic approach for HE.

SUMMARYSalt rocks are commonly used as geologic host rocks for storage of gas and crude oil, and are being considered for the disposal of radioactive waste. Different from the salt rock domes in many countries, the salt rock formations in China are usually laminar with many alternating layers, i.e. rock salt, anhydrite, and/or mudstone. Considering the unique stratigraphic characteristics of these salt rocks, a new Cosseratlike medium constitutive model is proposed in order to facilitate efficient modeling of the mechanical behavior of these formations. In this model, a new representative volume element, containing two different layers, is employed to simulate the compatibility of the meso-displacement between two different layers and also the bending effect. A new method for the deformation and failure analysis of bedded salt rocks is derived therefrom. Having the macro-average stresses, the conventional stresses in the different layers can be obtained in sequence. The conventional stresses can then be utilized in a routine way for the strength and failure analysis. For the initial numerical modeling, the new Cosserat-like medium is reduced to a transversely isotropic one. The simplified constitutive model for layered media is then implemented into FLAC3D codes. A test sample validates that the results by using the numerical model are in good agreement with that by using the built-in model, and the mesh size for the new model is reduced greatly. Finally, an application for the stability of oil storage caverns in deep thinly bedded salt rocks is carried out. The effects on convergence of storage caverns and on the failure of surrounding rock due to the presence of the mudstone interlayers (hard phase) are discussed in detail.

Murine caspase-11 is the centerpiece of the non-canonical inflammasome pathway that can respond to intracellular LPS and induce pyroptosis. Caspase-11 contains two components, an N-terminal caspase recruitment domain (CARD) and a C-terminal catalytic domain. The aggregation of caspase-11 is thought to promote the auto-processing and activation of caspase-11. However, the activation mechanism of caspase-11 remains unclear. In this study, we purified the caspase-11 CARD fused to an MBP tag and found it tetramerizes in solution. Crystallographic analysis reveals an extensive hydrophobic interface formed by the H1–2 helix mediating homotypic CARD interactions. Importantly, mutations of the helix H1–2 hydrophobic residues abolished the tetramerization of MBP-tagged CARD in solution and failed to induce pyroptosis in cells. Our study provides the first evidence of the homotypic interaction mode for an inflammatory caspase by crystal model. This finding demonstrates that the tetramerization of the N-terminal CARD can promote releasing of the catalytic domain auto-inhibition, leading to the caspase-11 activation.