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Identification of somatic driver mutations in the noncoding genome remains challenging. To comprehensively characterize noncoding driver mutations for pancreatic ductal adenocarcinoma (PDAC), we first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreatic acinar and duct cells. Integration with whole-genome mutation calls from 506 PDACs revealed 314 ACRs/HMMs significantly enriched with 3,614 noncoding somatic mutations (NCSMs). Functional assessment using massively parallel reporter assays (MPRA) identified 178 NCSMs impacting reporter activity (19.45% of those tested). Focused luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near CDKN2A and ZFP36L2 . For the latter, CRISPR interference (CRISPRi) further identified ZFP36L2 as a target gene (16.0 - 24.0% reduced expression, P = 0.023-0.0047) with disrupted KLF9 binding likely mediating the effect. Our integrative approach provides a catalog of potentially functional noncoding driver mutations and nominates ZFP36L2 as a PDAC driver gene., Competing Interests: Competing Interests statement The authors declare no competing interests.

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at 1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine-mapped SNPs, rs13303160 (r 2 =0.93 in 1000G EUR samples, OR=1.23, P value=2.74x10 -9 ) demonstrated allele-preferential gene regulatory activity in vitro and allele-preferential binding of JunB and JunD in vitro and in vivo . Expression Quantitative Trait Locus (eQTL) analysis identified KLHL17 as a likely target gene underlying the signal. Proteomic analysis identified KLHL17 as a member of the Cullin-E3 ubiquitin ligase complex in PDAC-derived cells. In silico differential gene expression analysis of the GTExv8 pancreas data suggested an association between lower KLHL17 (risk associated) and pro-inflammatory pathways. We hypothesize that KLHL17 may mitigate inflammation by recruiting pro-inflammatory proteins for ubiquitination and degradation thereby influencing PDAC risk., Competing Interests: Competing Interests statement The authors declare no competing interests.

Host restriction factors play key roles in innate antiviral defense, but it remains poorly understood which of them restricts HIV-1 in vivo. Here, we used single-cell transcriptomic analysis to identify host factors associated with HIV-1 control during acute infection by correlating host gene expression with viral RNA abundance within individual cells. Wide sequencing of cells from one participant with the highest plasma viral load revealed that intracellular viral RNA transcription correlates inversely with expression of the gene PTMA , which encodes prothymosin α. This association was genome-wide significant ( P adjusted < 0.05) and was validated in 28 additional participants from Thailand and the Americas with HIV-1 CRF01&#95;AE and subtype B infections, respectively. Overexpression of prothymosin α in vitro confirmed that this cellular factor inhibits HIV-1 transcription and infectious virus production. Our results identify prothymosin α as a host factor that restricts HIV-1 infection in vivo, which has implications for viral transmission and cure strategies.

Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10 -17 , OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (p GTEx = 1.40 × 10 -69 , β GTEx = 1.99; p LTG = 1.02 × 10 -30 , β LTG = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10 -16 , OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Following Brexit (the withdrawal of the UK from the EU and the European Atomic Energy Community at the end of 31 January 2020), the British government stated that it hoped to reach a new trade agreement with Canada to be modelled after the Canada-EU Comprehensive Economic and Trade Agreement, the first free-trade deal for which Canadian provinces were directly involved at every stage of negotiations. In the UK, while there are mechanisms for the involvement of devolved regions in European policy, there is no clear constitutional doctrine as to the roles they should play in elaborating trade policy more generally. Moreover, the asymmetric nature of the UK's devolution system complicates the involvement of its devolved governments in trade negotiations. By providing a specific focus on the cases of Quebec and Scotland, this article provides a comparison of substate governments' roles in trade negotiation and trade promotion. It concludes that, while there seems to be only limited scope for substate governments' formal input into future trade negotiations, their trade and investment promotion organizations allow them to pursue different objectives over trade outcomes within a unified national framework., (© The Author(s) 2021.)