A Conserved Role for Syndecan Family Members in the Regulation of Whole-Body Energy Metabolism

Syndecans are a family of type-I transmembrane proteins that are involved in cell-matrix adhesion, migration, neuronal development, and inflammation. Previous quantitative genetic studies pinpointed Drosophila Syndecan (dSdc) as a positional candidate gene affecting variation in fat storage between two Drosophila melanogaster strains. Here, we first used quantitative complementation tests with dSdc mutants to confirm that natural variation in this gene affects variability in Drosophila fat storage. Next, we examined the effects of a viable dSdc mutant on Drosophila whole-body energy metabolism and associated traits. We observed that young flies homozygous for the dSdc mutation had reduced fat storage and slept longer than homozygous wild-type flies. They also displayed significantly reduced metabolic rate, lower expression of spargel (the Drosophila homologue of PGC-1), and reduced mitochondrial respiration. Compared to control flies, dSdc mutants had lower expression of brain insulin-like peptides, were less fecund, more sensitive to starvation, and had reduced life span. Finally, we tested for association between single nucleotide polymorphisms (SNPs) in the human SDC4 gene and variation in body composition, metabolism, glucose homeostasis, and sleep traits in a cohort of healthy early pubertal children. We found that SNP rs4599 was significantly associated with resting energy expenditure (P = 0.001 after Bonferroni correction) and nominally associated with fasting glucose levels (P = 0.01) and sleep duration (P = 0.044). On average, children homozygous for the minor allele had lower levels of glucose, higher resting energy expenditure, and slept shorter than children homozygous for the common allele. We also observed that SNP rs1981429 was nominally associated with lean tissue mass (P = 0.035) and intra-abdominal fat (P = 0.049), and SNP rs2267871 with insulin sensitivity (P = 0.037). Collectively, our results in Drosophila and humans argue that syndecan family members play a key role in the regulation of body metabolism

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Fire behavior in nonuniform fuels /

no.23

Modelling the impact of shutdowns on resurging SARS-CoV-2 transmission in Canada

Background: Shutdowns are enacted when alternative public health measures are insufficient to control the epidemic and the population is largely susceptible. An age-stratified agent-based model was developed to explore the impact of shutdowns to control SARS-CoV-2 transmission in Canada under the assumption that current efforts to control the epidemic remains insufficient and in the absence of a vaccine. Methods: We estimated the current levels of interventions in Canada to generate a baseline scenario from 7 February to 7 September 2020. Four aspects of shutdowns were explored in scenarios that ran from 8 September 2020 to 7 January 2022, these included the impact of how quickly shutdowns are implemented, the duration of shutdowns, the minimum break (delays) between shutdowns and the types of sectors to shutdown. Comparisons among scenarios were made using cases, hospitalizations, deaths and shutdown days during the 700-day model runs. Results: We found a negative relationship between reducing SARS-CoV-2 transmission and the number of shutdown days. However, we also found that for shutdowns to be optimally effective, they need to be implemented fast with minimal delay, initiated when community transmission is low, sustained for an adequate period and be stringent and target multiple sectors, particularly those driving transmission. By applying shutdowns in this manner, the total number of shutdown days could be reduced compared to delaying the shutdowns until further into the epidemic when transmission is higher and/or implementing short insufficient shutdowns that would require frequent re-implementation. This paper contrasts a range of shutdown strategies and trade-offs between health outcomes and economic metrics that need to be considered within the local context. Interpretation: Given the immense socioeconomic impact of shutdowns, they should be avoided where possible and used only when other public health measures are insufficient to control the epidemic. If used, the time it buys to delay the epidemic should be used to enhance other equally effective, but less disruptive, public health measures