Design and activity detection of BH3-mimetic peptide based on Bcl-XL binding potency

Communicated by Ramaswamy H. Sarma     

Structural Studies of G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) constitute the largest and the most physiologically important membrane protein family that recognizes a variety of environmental stimuli, and are drug targets in the treatment of numerous diseases. Recent progress on GPCR structural studies shed light on molecular mechanisms of GPCR ligand recognition, activation and allosteric modulation, as well as structural basis of GPCR dimerization. In this review, we will discuss the structural features of GPCRs and structural insights of different aspects of GPCR biological functions.     

Correlations between Clinical Features and Mortality in Patients with Vibrio vulnificus Infection

Vibrio vulnificus is a common gram-negative bacterium, which might cause morbidity and mortality in patients following consumption of seafood or exposure to seawater in Southeast China. We retrospectively analyzed clinical data of patients with laboratory confirmed V. vulnificus infection. Twenty one patients were divided into a survival group and a non-surviving (or death) group according to their clinical outcome. Clinical data and measurements were statistically analyzed. Four patients (19.05%) died and five patients gave positive cultures from bile fluid, and 16 other patients gave positive culture from blood or blisters. Ten patients (47.62%) had an underlying liver disease and marine-related events were found in sixteen patients (76.2%). Patients with heavy drinking habits might be at increased mortality (p = 0.028). Clinical manifestations of cellulitis (47.6%), septic shock (42.9%) and multiple organ failure (28.6%) were statistically significant when comparing survivors and non-survivors (p = 0.035, p = 0.021 and p = 0.003, respectively). The laboratory results, including hemoglobin < 9.0 g/L (p = 0.012), platelets < 2.0×10⁹ /L, prothrombin time activity (PTA) <20%, decreased serum creatinine and increased urea nitrogen were statistically significant (p = 0.012, p = 0.003, p = 0.028 and p = 0.028, respectively). Patients may be at a higher risk of mortality under situations where they have a history of habitual heavy alcoholic drink consumption (p = 0.028, OR = 22.5, 95%CI 1.5–335.3), accompanied with cellulitis, shock, multiple organ failure, and laboratory examinations that are complicated by decreased platelets, hemoglobin and significantly prolonged prothrombin time (PT).     

mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC)

In non-alcoholic fatty liver disease (NAFLD) and insulin resistance, hepatic de novo lipogenesis is often elevated, but the underlying mechanisms remain poorly understood. Recently, we show that CDK8 functions to suppress de novo lipogenesis. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a critical regulator of CDK8 and its activating partner CycC. Using pharmacologic and genetic approaches, we show that increased mTORC1 activation causes the reduction of the CDK8-CycC complex in vitro and in mouse liver in vivo. In addition, mTORC1 is more active in three mouse models of NAFLD, correlated with the lower abundance of the CDK8-CycC complex. Consistent with the inhibitory role of CDK8 on de novo lipogenesis, nuclear SREBP-1c proteins and lipogenic enzymes are accumulated in NAFLD models. Thus, our results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression.     

Determinants of Delphacidae richness and endemism in China

1. Identifying the macro-scale patterns and the underlying mechanisms of species richness are key aspects of biodiversity-related research. In China, previous studies on the mechanisms underlying insect richness have primarily focused on the current ecological conditions. Therefore, the impact of historical climate change on these mechanisms is less well understood. 2. Here, we use members of the Delphacidae family to evaluate the relative impact of the current environmental conditions and that of the Last Glacial Maximum on total species richness and endemism. Total species richness and endemic species richness were summed in 1° × 1° grid cells that the insects occupied. Generalised linear models, simultaneous autoregressive models, and random forest models were used to assess the effects of different environmental factors on total species richness and endemism. 3. The two patterns of species richness are jointly regulated by the current environment and the Last Glacial Maximum, but their key determinants differ. Winter coldness and the temperature annual range strongly affected the total species richness, but temperature variation during the Last Glacial Maximum also played an important role in the development of species richness. The distribution of endemic species was most strongly affected by the Last Glacial Maximum temperature change. 4. The studies confirm that historical climate change contributes to patterns of insect species richness, particularly patterns of endemism. Considering that China was mildly affected by the last glacial period, we propose that the incorporation of historical climate data into such studies will provide a better understanding of the underlying mechanisms.     

Declined miR‐181a‐5p expression is associated with impaired natural killer cell development and function with aging

MicroRNAs (miRNAs) regulate gene expression and thereby influence cell development and function. Numerous studies have shown the significant roles of miRNAs in regulating immune cells including natural killer (NK) cells. However, little is known about the role of miRNAs in NK cells with aging. We previously demonstrated that the aged C57BL/6 mice have significantly decreased proportion of mature (CD27⁻CD11b⁺) NK cells compared with young mice, indicating impaired maturation of NK cells with aging. Here, we performed deep sequencing of CD27⁺ NK cells from young and aged mice. Profiling of the miRNome (global miRNA expression levels) revealed that 49 miRNAs displayed a twofold or greater difference in expression between young and aged NK cells. Among these, 30 miRNAs were upregulated and 19 miRNAs were downregulated in the aged NK cells. We found that the expression level of miR‐l8la‐5p was increased with the maturation of NK cells, and significantly decreased in NK cells from the aged mice. Knockdown of miR‐181a‐5p inhibited NK cell development in vitro and in vivo. Furthermore, miR‐181a‐5p is highly conserved in mice and human. MiR‐181a‐5p promoted the production of IFN‐γ and cytotoxicity in stimulated NK cells from both mice and human. Importantly, miR‐181a‐5p level markedly decreased in NK cells from PBMC of elderly people. Thus, our results demonstrated that the miRNAs profiles in NK cells change with aging, the decreased level of miR‐181a‐5p contributes to the defective NK cell development and function with aging. This opens new strategies to preserve or restore NK cell function in the elderly.     

The role of 14-3-3 proteins in cell signalling pathways and virus infection

14-3-3 proteins are highly conserved in species ranging from yeast to mammals and regulate numerous signalling pathways via direct interactions with proteins carrying phosphorylated 14-3-3–binding motifs. Recent studies have shown that 14-3-3 proteins can also play a role in viral infections. This review summarizes the biological functions of 14-3-3 proteins in protein trafficking, cell-cycle control, apoptosis, autophagy and other cell signal transduction pathways, as well as the associated mechanisms. Recent findings regarding the role of 14-3-3 proteins in viral infection and innate immunity are also reviewed.     

Assessing the contribution of tumor mutational phenotypes to cancer progression risk

Cancer occurs via an accumulation of somatic genomic alterations in a process of clonal evolution. There has been intensive study of potential causal mutations driving cancer development and progression. However, much recent evidence suggests that tumor evolution is normally driven by a variety of mechanisms of somatic hypermutability, which act in different combinations or degrees in different cancers. These variations in mutability phenotypes are predictive of progression outcomes independent of the specific mutations they have produced to date. Here we explore the question of how and to what degree these differences in mutational phenotypes act in a cancer to predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational phenotypes, followed by a machine learning framework to identify key features predictive of progression. Analyses of breast invasive carcinoma and lung carcinoma demonstrate that a large fraction of the risk of future clinical outcomes of cancer progression—overall survival and disease-free survival—can be explained solely from mutational phenotype features derived from the phylogenetic analysis. We further show that mutational phenotypes have additional predictive power even after accounting for traditional clinical and driver gene-centric genomic predictors of progression. These results confirm the importance of mutational phenotypes in contributing to cancer progression risk and suggest strategies for enhancing the predictive power of conventional clinical data or driver-centric biomarkers.