Description: Akt and mTOR mediate programmed necrosis in neurons Cell Death and Disease 5, e1084 (February 2014). doi:10.1038/cddis.2014.69 Authors: Q Liu, J Qiu, M Liang, J Golinski, K van Leyen, J E Jung, Z You, E H Lo, A Degterev & M J Whalen

Description: Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1 –/– mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1 –/– bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency–mediated human immunodeficiency syndrome.

Description: MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene Oncogene 32, 3019 (20 June 2013). doi:10.1038/onc.2012.323 Authors: G Ke, L Liang, J M Yang, X Huang, D Han, S Huang, Y Zhao, R Zha, X He & X Wu

Description: Amorphous nickel hydroxide nanospheres with ultrahigh capacitance and energy density as electrochemical pseudocapacitor materials Nature Communications 4, 1894 (2013). doi:10.1038/ncomms2932 Authors: H. B. Li, M. H. Yu, F. X. Wang, P. Liu, Y. Liang, J. Xiao, C. X. Wang, Y. X. Tong & G. W. Yang

Description: Aims The balance between leaf photosynthesis and respiration of terrestrial plants determines the net carbon (C) gain by vegetation and consequently is important to climate–C cycle feedback. This study is to reveal the global patterns of the responses of leaf-level net photosynthesis and dark respiration to elevated temperature. Methods Data for leaf-level net photosynthesis rate ( P n ) and dark respiration rate ( R d ) in natural terrestrial plant species with standard deviation (or standard error or confidence interval) and sample size were collected from searched literatures on Web of Science. Then a meta-analysis was conducted to estimate the effects of experimental warming on leaf-level P n and R d of terrestrial plants. Important findings Across all the plants included in the analysis, warming enhanced P n and R d significantly by 6.13 and 33.14%, respectively. However, the responses were plant functional type (PFT) specific. Specifically, photosynthesis of C 4 herbs responded to experimental warming positively but that of C 3 herbs did not, whereas their respiratory responses were similar, suggesting C 4 plants would benefit more from warming. The photosynthetic response declined linearly with increasing ambient temperature. The respiratory responses linearly enhanced with the increase in warming magnitude. In addition, a thermal acclimation of R d , instead of P n , was observed. Although greater proportion of fixed C was consumed (greater R d / P n ratio), warming significantly enhanced the daily net C balance at the leaf level. This provides an important mechanism for the positive responses of plant biomass and net primary productivity to warming. Overall, the findings, including the contrastive responses of different PFTs and the enhancement in daily leaf net C balance, are important for improving model projection of the climate–C cycle feedback.

Description: TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.

Description: Cancer is associated with a profound perturbation in myelopoiesis that results in the accumulation of myeloid-derived suppressor cells (MDSCs) to promote disease progression. Recent studies in mice suggest that tumor-derived factors could regulate the differentiation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and subsequently contribute to...

Description: Aspergillus fumigatus is an opportunistic fungal pathogen that causes fatal invasive aspergillosis among immunocompromised patients. The cell wall β-1,3-glucan is mainly elongated by β-1,3-glucanosyltransferase Gel family, which is vital for growth and virulence of A. fumigatus . Although seven members of Gels have been annotated, only Gel1, Gel2 and Gel4 were characterized. In this study, the function of Gel7 was analyzed for the first time, by constructing gel7 , gel7 cwh41 and gel1 gel7 cwh41 separately. Disruption of gel7 alone did not result in any obvious phenotype except an abnormality in conidia formation, whereas gel7 cwh41 and gel1 gel7 cwh41 exhibited abnormal conidiogenesis, a heat-induced delay of germination and a severe decrease in β-1,3-glucan content. Our results suggested that the A. fumigatus β-1,3-glucanosyltransferase Gel7 was involved in conidiation and was compensated for the cell wall β-1,3-glucan defects when Gel1 and Gel2 lost their functions, especially at an elevated temperature.

Description: Nanomaterials have the characteristics associated with high surface-to-volume ratios and have been explored for their antiviral activity. Despite some success, cytotoxicity has been an issue in nanomaterial-based antiviral strategies. We previously developed a novel method to fully exfoliate montmorillonite clay to generate the most fundamental units of nanoscale silicate platelet (NSP). We further modified NSP by capping with various surfactants and found that the surfactant-modified NSP (NSQ) was less cytotoxic. In this study, we tested the antiviral potentials of a series of natural-clay-derived nanomaterials. Among the derivatives, NSP modified with anionic sodium dodecyl sulfate (NSQc), but not the pristine clay, unmodified NSP, a silver nanoparticle-NSP hybrid, NSP modified with cationic n -octadecanylamine hydrochloride salt, or NSP modified with nonionic Triton X-100, significantly suppressed the plaque-forming ability of Japanese encephalitis virus (JEV) at noncytotoxic concentrations. NSQc also blocked infection with dengue virus (DEN) and influenza A virus. Regarding the antiviral mechanism, NSQc interfered with viral binding through electrostatic interaction, since its antiviral activity can be neutralized by Polybrene, a cationic polymer. Furthermore, NSQc reduced the lethality of JEV and DEN infection in mouse challenge models. Thus, the surfactant-modified exfoliated nanoclay NSQc may be a novel nanomaterial with broad and potent antiviral activity. IMPORTANCE Nanomaterials have being investigated as antimicrobial agents, yet their antiviral potential is overshadowed by their cytotoxicity. By using a novel method, we fully exfoliated montmorillonite clay to generate the most fundamental units of nanoscale silicate platelet (NSP). Here, we show that the surfactant-modified NSP (NSQ) is less cytotoxic and that NSQc (NSP modified with sodium dodecyl sulfate) could potently block infection by dengue virus (DEN), Japanese encephalitis virus (JEV), and influenza A virus at noncytotoxic concentrations. For the antiviral mechanism, we find that the electrostatic interaction between the negatively charged NSQc and the positively charged virus particles blocks viral binding. Furthermore, we used mouse challenge models of JEV and DEN to demonstrate the in vivo antiviral potential of NSQc. Thus, NSQc may function as a potent and safe antiviral nanohybrid against several viruses, and our success in synthesizing surfactant-modified NSP with antiviral activity may shed some light on future antiviral development.

Description: CC chemokine ligand-2 (CCL2)/monocyte chemoattractant protein (MCP)-1 expression is upregulated during pulmonary inflammation, and the CCL2-CCR2 axis plays a critical role in leukocyte recruitment and promotion of host defense against infection. The role of CCL2 in mediating macrophage subpopulations in the pathobiology of noninfectious lung injury is unknown. The goal of this study was to examine the role of CCL2 in noninfectious acute lung injury. Our results show that lung-specific overexpression of CCL2 protected mice from bleomycin-induced lung injury, characterized by significantly reduced mortality, reduced neutrophil accumulation, and decreased accumulation of the inflammatory mediators IL-6, CXCL2 (macrophage inflammatory protein-2), and CXCL1 (keratinocyte-derived chemokine). There were dramatic increases in the recruitment of myosin heavy chain (MHC) II IA/IE int CD11c int cells, exudative macrophages, and dendritic cells in Ccl2 transgenic mouse lungs both at baseline and after bleomycin treatment compared with levels in wild-type mice. We further demonstrated that MHCII IA/IE int CD11c int cells engulfed apoptotic cells during acute lung injury. Our data suggested a previously undiscovered role for MHCII IA/IE int CD11c int cells in apoptotic cell clearance and inflammation resolution.