In this paper, we introduce an age-related preferential selection mechanism into the prisoner's dilemma game. Under this mechanism, players can select a source of strategy imitation from their neighbors in a biased way proportional to their ages. Tuned by a selection parameter α, the impact of aging on the evolution of cooperation can be very different. The numerical results show that the cooperation will be effectively promoted by adjusting the value of α. By examining the evolution process and spatial patterns for different values of α, it is found that larger α will effectively promote the formation of large scale of cooperator clusters. In addition, the impact of noise K on the spreading process of cooperation strategy is studied. We find that small K can make cooperation monotonously increase with α, while large K guarantees the optimal existence of cooperation for an intermediate α.
Background:Alzheimer’s disease (AD) is a genetically complex, multifactorial neurodegenerative disease. It affects more than 45 million people worldwide and currently remains untreatable. Although genome-wide association studies (GWAS) have identified many AD-associated common variants, only about 25 genes are currently known to affect the risk of developing AD, despite its highly polygenic nature. Moreover, the causal variants underlying GWAS AD-association signals remain unknown.Methods:We developed a computational pipeline that integrates 936 AD-associated SNPs, linkage disequilibrium and genomic data from multiple sources – e.g., disease genes databases, functional annotation of genetic variants, GTEx, and the 1000 Genomes Project – to predict both AD risk genes and their causal variants.Results:We identified 342 putative AD risk genes in 203 risk regions spanning 502 AD-associated common variants. 246 AD risk genes have not been identified as AD risk genes by previous GWAS, and 115 of them are outside the risk regions, likely under the regulation of transcriptional regulatory elements contained therein. Even more significantly, for 109 AD risk genes, we predicted 150 causal variants, of both coding and regulatory (in promoters or enhancers) types, and 85 (57%)of them are supported by functional annotation. In-depth functional analyses showed that AD risk genes were overrepresented in AD-related pathways or GO terms – e.g., the complement and coagulation cascade andphosphorylation and activation of immune response – and their expression was relatively enriched in microglia, endothelia, and pericytes of the human brain. We found nine AD risk genes – e.g., IL1RAP, PMAIP1, LAMTOR4 – as predictors for the prognosis of AD survival and genes such as ARL6IP5with altered network connectivity between AD patients and normal individuals involved in AD progressionConclusions: Our findings provide novel biological insights into the genetic architecture, expression profiles, functional pathways involved in the AD etiology, and open new strategies for developing therapeutics targeting AD risk genes or causal variants to influence AD pathogenesis.
The precise mechanism by which autophagy affects psoriasis is poorly understood. Here we show that keratinocytes (KCs) autophagy was activated in psoriatic lesions of patients and mice model, positively correlating with psoriatic severity, and could be inhibited by MAPK family (ERK, p38, JNK) inactivation, implying autophagy was associated with psoriatic inflammation. Indeed, impaired autophagy flux, caused by autophagy inhibitors or KC-specific deletion of Atg5, alleviated psoriasisform inflammation, demonstrating autophagy positively regulated psoriatic inflammation. We then found an autophagy-based unconventional secretory pathway (autosecretion), depended on Atg5 and GRASP55, promoted the psoriasiform KCs inflammation. Moreover, alarmin HMGB1 was more effective than other autosecretory proteins, IL-1β and IL-18, to regulate the psoriasiform cutaneous inflammation. HMGB1 neutralization in autophagy-efficient KCs vanished the psoriasiform inflammation differences between autophagy-efficient KCs and autophagy-deficient KCs. Conversely, recombinant HMGB1 almost completely restored the psoriasiform inflammation in autophagy-deficient KCs in vivo. These results suggested that HMGB1-associated autosecretion, not other intracellular autophagy pathways, played a pivotal role in cutaneous inflammation. Finally, we demonstrated that KC-specific HMGB1 deficient mice, but not DC- or myeloid cell-specific HMGB1 deficient mice, displayed attenuated psoriatic inflammation, due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and γδT cells. Thus, we uncover a novel autophagy mechanism in psoriasis pathogenesis, and imply its clinical significance in psoriasis treatment.
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