Moderate mutation rate in the SARS coronavirus genome and its implications

BACKGROUND: The outbreak of severe acute respiratory syndrome (SARS) caused a severe global epidemic in 2003 which led to hundreds of deaths and many thousands of hospitalizations. The virus causing SARS was identified as a novel coronavirus (SARS-CoV) and multiple genomic sequences have been revealed since mid-April, 2003. After a quiet summer and fall in 2003, the newly emerged SARS cases in Asia, particularly the latest cases in China, are reinforcing a wide-spread belief that the SARS epidemic would strike back. With the understanding that SARS-CoV might be with humans for years to come, knowledge of the evolutionary mechanism of the SARS-CoV, including its mutation rate and emergence time, is fundamental to battle this deadly pathogen. To date, the speed at which the deadly virus evolved in nature and the elapsed time before it was transmitted to humans remains poorly understood. RESULTS: Sixteen complete genomic sequences with available clinical histories during the SARS outbreak were analyzed. After careful examination of multiple-sequence alignment, 114 single nucleotide variations were identified. To minimize the effects of sequencing errors and additional mutations during the cell culture, three strategies were applied to estimate the mutation rate by 1) using the closely related sequences as background controls; 2) adjusting the divergence time for cell culture; or 3) using the common variants only. The mutation rate in the SARS-CoV genome was estimated to be 0.80 – 2.38 × 10(-3 )nucleotide substitution per site per year which is in the same order of magnitude as other RNA viruses. The non-synonymous and synonymous substitution rates were estimated to be 1.16 – 3.30 × 10(-3 )and 1.67 – 4.67 × 10(-3 )per site per year, respectively. The most recent common ancestor of the 16 sequences was inferred to be present as early as the spring of 2002. CONCLUSIONS: The estimated mutation rates in the SARS-CoV using multiple strategies were not unusual among coronaviruses and moderate compared to those in other RNA viruses. All estimates of mutation rates led to the inference that the SARS-CoV could have been with humans in the spring of 2002 without causing a severe epidemic

Preparation of reducing sugars from corncob by solid acid catalytic pretreatment combined with in situ enzymatic hydrolysis

The efficient conversion of hemicellulose and cellulose into reducing sugars remains as one major challenge for biorefinery of lignocellulosic biomass. In this work, saccharification of corncob in the aqueous phase was effectively realized via pretreatment by magnetic carbon-based solid acid (MMCSA) catalyst, combined with the subsequent in situ enzymatic hydrolysis (occurring in the same pretreatment system after separation of MMCSA). Through the combined two-step hydrolysis of corncob, the total sugar (xylose and glucose) yield of 90.03% was obtained, including a xylose yield of 86.99% and an enzymatic digestibility of pretreatment residue of 91.24% (cellulase loading of 20 FPU/g, 24 h). Compared with the traditional enzymatic hydrolysis of pretreated residue, the presented in situ enzymatic hydrolysis system can reach a comparable enzymatic digestibility in one-third reacting time with a half cellulase loading and save about 31% water consumption, which provides a more sustainable and low-cost method for the saccharification of lignocellulose

The Transcription Factor IRF4 Determines the Anti-tumor Immunity of CD8+ T cells

Understanding the factors that regulate T cell infiltration and functional states in solid tumors is crucial for advancing cancer immunotherapies. Here, we discovered that the expression of interferon regulatory factor 4 (IRF4) was a critical T cell intrinsic requirement for effective anti-tumor immunity. Mice with T-cell-specific ablation of IRF4 showed significantly reduced T cell tumor infiltration and function, resulting in accelerated growth of subcutaneous syngeneic tumors and allowing the growth of allogeneic tumors. Additionally, engineered overexpression of IRF4 in anti-tumor CD8+ T cells that were adoptively transferred significantly promoted their tumor infiltration and transition from a naive/memory-like cell state into effector T cell states. As a result, IRF4-engineered anti-tumor T cells exhibited significantly improved anti-tumor efficacy, and inhibited tumor growth either alone or in combination with PD-L1 blockade. These findings identify IRF4 as a crucial cell-intrinsic driver of T cell infiltration and function in tumors, emphasizing the potential of IRF4-engineering as an immunotherapeutic approach

Role of redox centre in charge transport investigated by novel self-assembled conjugated polymer molecular junctions

Molecular electronics describes a field that seeks to implement electronic components made of molecular building blocks. To date, few studies have used conjugated polymers in molecular junctions despite the fact that they potentially transport charge more efficiently than the extensively investigated small-molecular systems. Here we report a novel type of molecular tunnelling junction exploring the use of conjugated polymers, which are self-assembled into ultrathin films in a distinguishable ‘planar' manner from the traditional vertically oriented small-molecule monolayers. Electrical measurements on the junctions reveal molecular-specific characteristics of the polymeric molecules in comparison with less conjugated small molecules. More significantly, we decorate redox-active functionality into polymeric backbones, demonstrating a key role of redox centre in the modulation of charge transport behaviour via energy level engineering and external stimuli, and implying the potential of employing tailor-made polymeric components as alternatives to small molecules for future molecular-scale electronics

Large-Scale Pathway-Based Analysis of Bladder Cancer Genome-Wide Association Data from Five Studies of European Background

Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways (‘Aromatic amine metabolism’ [PGSEA = 0.0100, PARTP = 0.0020], ‘NAD biosynthesis’ [PGSEA = 0.0018, PARTP = 0.0086], ‘NAD salvage’ [PARTP = 0.0068], ‘Clathrin derived vesicle budding’ [PARTP = 0.0018], ‘Lysosome vesicle biogenesis’ [PGSEA = 0.0023, PARTP<0.00012], ’Retrograde neurotrophin signaling’ [PGSEA = 0.00840], and ‘Mitotic metaphase/anaphase transition’ [PGSEA = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis

Social Support, Social Comparison, and Career Adaptability: A Moderated Mediation Model

Our aim in this study was to identify the social factors that underpin the career adaptability of college graduates in China by examining the effects of social support and career self-efficacy on career adaptability among a sample of 879 Chinese college graduates. We also emphasized the moderating role of social comparison in influencing this relationship. The results showed that, (a) social support enhanced career adaptability, (b) career self-efficacy played a mediating role in the relationship between social support and career adaptability, and (c) social comparison orientation moderated the mediation model; specifically, a high social comparison orientation weakened the enhancing effect of social support on career self-efficacy and career adaptability. Theoretical and practical implications of these findings are discussed.</jats:p

Authentic Leadership and Taking Charge Behavior: A Moderated Mediation Model of Psychological Capital and Occupational Calling

To achieve sustainable development goals, it is necessary to establish a positive organization so that employees can pay attention to their strengths and talents and engage in more proactive behaviors, such as taking charge behavior. Taking charge behavior involves the voluntary and constructive effort of employees to make organizationally functional change, which may consume more scarce resources of employees. Previous studies have shown that support from leaders can promote employees’ taking charge behavior, but most of them are from the perspective of social exchange. By drawing on the conservation of resources theory, we develop a theoretical model in which authentic leadership can provide employees with more positive resources and guide them into gain spiral of resources. We conducted two-wave questionnaire surveys to collect data from 199 employees and their supervisors at 16 companies in China. The results showed that authentic leadership was positively associated with employee taking charge via the mediation role of psychological capital. Furthermore, the direct and indirect relationship between authentic leadership and employee taking charge was demonstrated to be stronger when employees have a higher stage of occupational calling. This study provides a new explanation for the mechanism of authentic leadership and clarifies the boundary conditions of authentic leadership effectiveness.</jats:p