Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization

Background and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.The European Union’s Horizon 2020/Marie Sklodowska-Curie grant agreement No 722609 (INTRICARE);Swedish Heart and Lung FoundationSwedish Research Council (K2009-65X-2233-01-3, K2013- 65X-06816-30-4, 349-2007-8703)Uppdrag Besegra Stroke (P581/ 2011-123)Stockholm County Council (ALF2011-0260, ALF-2011- 0279)Swedish Society for Medical ResearchTore Nilsson’s FoundationMagnus Bergvall’s FoundationKarolinska Institutet FoundationEuropean Commission (722609)Publishe

Game Theory of Social Distancing in Response to an Epidemic

Social distancing practices are changes in behavior that prevent disease transmission by reducing contact rates between susceptible individuals and infected individuals who may transmit the disease. Social distancing practices can reduce the severity of an epidemic, but the benefits of social distancing depend on the extent to which it is used by individuals. Individuals are sometimes reluctant to pay the costs inherent in social distancing, and this can limit its effectiveness as a control measure. This paper formulates a differential-game to identify how individuals would best use social distancing and related self-protective behaviors during an epidemic. The epidemic is described by a simple, well-mixed ordinary differential equation model. We use the differential game to study potential value of social distancing as a mitigation measure by calculating the equilibrium behaviors under a variety of cost-functions. Numerical methods are used to calculate the total costs of an epidemic under equilibrium behaviors as a function of the time to mass vaccination, following epidemic identification. The key parameters in the analysis are the basic reproduction number and the baseline efficiency of social distancing. The results show that social distancing is most beneficial to individuals for basic reproduction numbers around 2. In the absence of vaccination or other intervention measures, optimal social distancing never recovers more than 30% of the cost of infection. We also show how the window of opportunity for vaccine development lengthens as the efficiency of social distancing and detection improve

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace.

The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR's PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition

Phylogeny Disambiguates the Evolution of Heat-Shock cis-Regulatory Elements in Drosophila

Heat-shock genes have a well-studied control mechanism for their expression that is mediated through cis-regulatory motifs known as heat-shock elements (HSEs). The evolution of important features of this control mechanism has not been investigated in detail, however. Here we exploit the genome sequencing of multiple Drosophila species, combined with a wealth of available information on the structure and function of HSEs in D. melanogaster, to undertake this investigation. We find that in single-copy heat shock genes, entire HSEs have evolved or disappeared 14 times, and the phylogenetic approach bounds the timing and direction of these evolutionary events in relation to speciation. In contrast, in the multi-copy gene Hsp70, the number of HSEs is nearly constant across species. HSEs evolve in size, position, and sequence within heat-shock promoters. In turn, functional significance of certain features is implicated by preservation despite this evolutionary change; these features include tail-to-tail arrangements of HSEs, gapped HSEs, and the presence or absence of entire HSEs. The variation among Drosophila species indicates that the cis-regulatory encoding of responsiveness to heat and other stresses is diverse. The broad dimensions of variation uncovered are particularly important as they suggest a substantial challenge for functional studies

Whole-Genome Analysis Reveals That Active Heat Shock Factor Binding Sites Are Mostly Associated with Non-Heat Shock Genes in Drosophila melanogaster

During heat shock (HS) and other stresses, HS gene transcription in eukaryotes is up-regulated by the transcription factor heat shock factor (HSF). While the identities of the major HS genes have been known for more than 30 years, it has been suspected that HSF binds to numerous other genes and potentially regulates their transcription. In this study, we have used a chromatin immunoprecipitation and microarray (ChIP-chip) approach to identify 434 regions in the Drosophila genome that are bound by HSF. We have also performed a transcript analysis of heat shocked Kc167 cells and third instar larvae and compared them to HSF binding sites. The heat-induced transcription profiles were quite different between cells and larvae and surprisingly only about 10% of the genes associated with HSF binding sites show changed transcription. There were also genes that showed changes in transcript levels that did not appear to correlate with HSF binding sites. Analysis of the locations of the HSF binding sites revealed that 57% were contained within genes with approximately 2/3rds of these sites being in introns. We also found that the insulator protein, BEAF, has enriched binding prior to HS to promoters of genes that are bound by HSF upon HS but that are not transcriptionally induced during HS. When the genes associated with HSF binding sites in promoters were analyzed for gene ontology terms, categories such as stress response and transferase activity were enriched whereas analysis of genes having HSF binding sites in introns identified those categories plus ones related to developmental processes and reproduction. These results suggest that Drosophila HSF may be regulating many genes besides the known HS genes and that some of these genes may be regulated during non-stress conditions

Modulation of Heat Shock Transcription Factor 1 as a Therapeutic Target for Small Molecule Intervention in Neurodegenerative Disease

A yeast-based small molecule screen identifies a novel activator of human HSF1 and protein chaperone expression and which appears to alleviate the toxicity of protein misfolding diseases

Group IV Phospholipase A2α Controls the Formation of Inter-Cisternal Continuities Involved in Intra-Golgi Transport

The enzyme phospholipase A2 (cPLA2α) is involved in the formation of intercisternal tubules that mediate transport of proteins within the Golgi complex