Ancient valleys buried beneath the UK

Buried palaeo‐valleys have significant and often unexpected implications for groundwater, geothermal resources and can provide detailed archives of palaeoenvironmental and landscape change. The BGS has embarked on a program of work as part of the Quaternary Heterogeneities Project to study the applied and palaeoenvironmental significance of these features. In the Midland Valley of Scotland, numerous palaeo‐valleys have been identified historically although their age and genesis was poorly understood. This study utilized a digital data set of over 100,000 borehole records that penetrate the full thickness of Quaternary deposits. In total, the study identified 18 buried palaeo‐valleys, which range between 4-36 km length and 24-162 m depth. Geometric analysis using the borehole dataset has revealed four distinct valley morphologies, which were formed by a combination of subglacial and subaerial processes. In the Midland Valley, some palaeo‐valleys cross‐cut each other with the deepest features aligning east–west. These east–west features align with the reconstructed ice‐flow direction under maximum ice sheet conditions. The shallower features appear more aligned to ice‐flow direction during ice‐sheet retreat, and were therefore probably incised under more restricted ice‐sheet configurations. The infills of these palaeovalleys are equally variable ranging from less than 10% to over 50% sand and gravel and appear largely unrelated to the processes that formed them. Instead, infilling occurred predominantly during deglaciation in response to fluvial capture and/or sea-level change (drowning). Further work is being undertaken to characterise their geometry and infill and to identify and characterise other features elsewhere in the UK

Mucosal antibodies to the C terminus of toxin A prevent colonization of Clostridium difficile

Mucosal immunity is considered important for protection against Clostridium difficile infection (CDI). We show that in hamsters immunized with Bacillus subtilis spores expressing a carboxy-terminal segment (TcdA26-39) of C. difficile toxin A, no colonization occurs in protected animals when challenged with C. difficile strain 630. In contrast, animals immunized with toxoids showed no protection and remained fully colonized. Along with neutralizing toxins, antibodies to TcdA26-39 (but not to toxoids), whether raised to the recombinant protein or to TcdA26-39 expressed on the B. subtilis spore surface, cross-react with a number of seemingly unrelated proteins expressed on the vegetative cell surface or spore coat of C. difficile. These include two dehydrogenases, AdhE1 and LdhA, as well as the CdeC protein that is present on the spore. Anti-TcdA26-39 mucosal antibodies obtained following immunization with recombinant B. subtilis spores were able to reduce the adhesion of C. difficile to mucus-producing intestinal cells. This cross-reaction is intriguing yet important since it illustrates the importance of mucosal immunity for complete protection against CDI

Pre-replication complex proteins assemble at regions of low nucleosome occupancy within the Chinese hamster dihydrofolate reductase initiation zone

Genome-scale mapping of pre-replication complex proteins has not been reported in mammalian cells. Poor enrichment of these proteins at specific sites may be due to dispersed binding, poor epitope availability or cell cycle stage-specific binding. Here, we have mapped sites of biotin-tagged ORC and MCM protein binding in G1-synchronized populations of Chinese hamster cells harboring amplified copies of the dihydrofolate reductase (DHFR) locus, using avidin-affinity purification of biotinylated chromatin followed by high-density microarray analysis across the DHFR locus. We have identified several sites of significant enrichment for both complexes distributed throughout the previously identified initiation zone. Analysis of the frequency of initiations across stretched DNA fibers from the DHFR locus confirmed a broad zone of de-localized initiation activity surrounding the sites of ORC and MCM enrichment. Mapping positions of mononucleosomal DNA empirically and computing nucleosome-positioning information in silico revealed that ORC and MCM map to regions of low measured and predicted nucleosome occupancy. Our results demonstrate that specific sites of ORC and MCM enrichment can be detected within a mammalian intitiation zone, and suggest that initiation zones may be regions of generally low nucleosome occupancy where flexible nucleosome positioning permits flexible pre-RC assembly sites

Plio‐Pleistocene fault reactivation within the Crag Basin, eastern UK : implications for structural controls of landscape development within an intraplate setting

This study examines the long‐term neotectonic evolution of the Crag Basin of eastern England during the Plio‐Pleistocene (c. 4.0–0.48 Ma) and the influence of neotectonics on coastal and drainage development. The Crag Basin was situated within the western margins of the southern North Sea with palaeogeography influenced by changes in global sea‐level and longer‐term regional‐scale neotectonic uplift and subsidence. This study identifies an additional local‐scale neotectonic control on basin development with localized crustal displacement occurring along normal faults. Plio‐Pleistocene movement along these faults was accommodated by partial dip‐slip (normal) reactivation of an Oligocene‐age (Pyrenean) dextral strike‐slip shear zone, which in turn was inherited from much older Caledonian orogenic crustal structure. Fault displacement was driven by sediment‐loading reflecting enhanced landscape denudation under progressively deteriorating climates and increased rates of erosion/sedimentation. Faulting acted to regulate accommodation space, controlling sedimentation patterns and the courses of major preglacial drainage systems including the Kesgrave Thames and Bytham rivers. The lower reaches of both river systems are considered to have been confluent in the Crag Basin during much of the Early Pleistocene with their lower reaches structurally controlled. Divergence occurred at c. 0.9 Ma with the lower reaches of the Bytham utilizing the former Bytham‐Thames valley and the Kesgrave Thames adopting progressively more southern routes, aligned to the axis of subsidence within the London Basin. The study highlights the significance of tectonic inheritance in driving recent neotectonic crustal deformation and its influence on sedimentation patterns and drainage development within an intraplate setting

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain

Anticancer activity of VDR-coregulator inhibitor PS121912

PURPOSE: PS121912 has been developed as selective vitamin D receptor (VDR)–coregulator inhibitor starting from a high throughput screening campaign to identify new agents that modulate VDR without causing hypercalcemia. Initial antiproliferative effects of PS121912 were observed that are characterized herein to enable future in vivo investigation with this molecule. METHODS: Antiproliferation and apoptosis was determined using four different cancer cell lines (DU145, Caco2, HL-60, and SKOV3) in the presence of PS121912, 1,25-(OH)(2)D(3), or a combination of 1,25-(OH)(2)D(3) and PS121912. VDR si-RNA was used to identify the role of VDR during this process. The application of ChIP enabled us to determine the involvement of coregulator recruitment during transcription, which was investigated by rt-PCR with VDR target genes and those affiliated with cell cycle progression. Translational changes of apoptotic proteins were determined with an antibody array. The preclinical characterization of PS121912 include the determination of metabolic stability and CYP3A4 inhibition. RESULTS: PS121912 induced apoptosis in all four cancer cells, with HL-60 cells being the most sensitive. At sub-micromolar concentrations, PS121912 amplified the growth inhibition of cancer cells caused by 1,25-(OH)(2)D(3) without being antiproliferative by itself. A knockout study with VDR si-RNA confirmed the mediating role of VDR. VDR target genes induced by 1,25-(OH)(2)D(3) were down-regulated with the co-treatment of PS121912. This process was highly dependent on the recruitment of coregulators that in case of CYP24A1 was SRC2. The combination of PS121912 and 1,25-(OH)(2)D(3) reduced the presence of SRC2 and enriched the occupancy of corepressor NCoR at the promoter site. E2F transcription factor 1 and 4 were down-regulated in the presence of PS121912 and 1,25-(OH)(2)D(3) that in turn reduced the transcription levels of cyclin A and D thus arresting HL-60 cells in the S or G2/M phase. In addition, proteins with hematopietic functions such as cyclin-dependent kinase 6, histone deacetylase 9 and transforming growth factor beta 2 and 3 were down-regulated as well. Elevated levels of P21 and GADD45, in concert with cyclin D1 also mediated the antiproliferative response of HL-60 in the presence of 1,25-(OH)(2)D(3) and PS121912. Studies at higher concentration of P121912 identified a VDR-independent pathway of antiproliferation that included the enzymatic and transcriptional activation of caspase 3/7. CONCLUSION: Overall, we conclude that PS121912 behaves like a VDR antagonist at low concentrations but interacts with more targets at higher concentrations leading to apoptosis mediated by caspase 3/7 activation. In addition, PS121912 showed an acceptable metabolic stability to enable in vivo cancer studies