Insights From New Age Constraints and Sediment Volumes From the Austrian Northern Alpine Foreland Basin

Detailed characterization of variations in sediment architecture, flux, and transport processes in peri-orogenic basins offers insights into external climatic or tectonic forcings. We tested how four well-known tectonic/erosional events in the Oligocene/Miocene Alpine source area are recorded in the sediment-accumulation rates (SARs) of the deep marine sink in the Northern Alpine Foreland Basin (NAFB): exhumation of the Lepontine Dome (starting at 30 Ma) and the Tauern Window (23-21 Ma), erosion of the Augenstein Formation (∼21 Ma), and the visco-elastic relaxation of the European Plate. The Upper Austrian NAFB offers a unique opportunity to investigate external forcings on sedimentary infill due to the large amount of data on the Alpine hinterland and foreland. Deep-marine sedimentation, forming the Puchkirchen Group and the basal Hall Formation, was controlled by a basin-axial submarine channel (3–5 km wide, >100 km length). Two basin-wide unconformities were recognized in seismic-reflection data: the Northern Slope Unconformity (NSU) and the Base Hall Unconformity (BHU). We combine biostratigraphic and chemostratigraphic analyses of 316 drill-cutting samples from three wells with a large 3D-seismic-reflection data set (3300 km2, >5 km depth) to determine age and duration of the unconformities and to calculate spatially averaged SARs for the submarine channel and its overbanks, separately. Deepening of the basin, recorded by the NSU, occurred between 28.1 and 26.9 Ma. The Puchkirchen Group (26.9–19.6 Ma) is characterized by constant SARs (within standard deviation) in the channel [432–623 (t/m2/Ma)] and on the overbanks [240–340 (t/m2/Ma)]. The visco-elastic relaxation of the European Plate results in low SARs on the overbanks [186 (t/m2/Ma)], a decrease in sediment grain size in channel deposits and a decrease in sea level at the BHU (19.6–19.0 Ma). In the upper Hall Formation (19.0–18.1 Ma), clinoforms prograding from the south filled up the basin [1497 (t/m2/Ma)] within 1 Myrs. We conclude that only two of the tectonic signals are recorded in this part of the deep-marine sink, erosion of Augenstein Formation and visco-elastic relaxation of the European Plate; the exhumation of the Tauern Window and Lepontine Dome remain unrecorded

Post-rift sequence architecture and stratigraphy in the Oligo-Miocene Sardinia rift (Western Mediterranean Sea)

Rift basins provide important sedimentary archives to reconstruct past tectonic and climatic conditions. Understanding their sedimentary history is, however, largely hampered by the competing influence of tectonic versus climatic forcing. The aim of this study is to comprehend the effects of local to regional tectonic and global climatic/eustatic changes on shallow marine depositional systems in the Sardinia Rift (Western Mediterranean Sea). For this purpose the stratigraphic and depositional relations of a mixed siliciclastic-carbonate ramp at the Porto Torres Basin margin were studied along extensive proximal to distal transects. Three depositional sequences (DS1 to DS3) of late Burdigalian to early Serravallian age have been identified, which are separated by erosional unconformities. Each contains a lower trans- gressive part and an upper regressive part. The former includes shoreface sandstone (DS2) or coral reef (DS3) deposits on the proximal ramp and channelized sheet sandstone (DS1) or basinal mudstone (DS2, DS3) deposits on the distal ramp, typically recording an upsection trend of sediment starvation. The latter is represented by basinward-prograding coralline red algal carbonate wedges due to enhanced shallow water carbonate production rates. In the long term, the depositional evolution from DS1 to DS3 reveals basin margin progradation associated with decreasing siliciclastic supply. Integrated calcareous nannoplankton-foraminiferal-pectinid biostratigraphy links the depositional sequences to third-order sea-level cycles and allows to correlate the erosional unconformities at the top of DS1 and DS2 with the Bur 5/Lan 1 and Lan 2/Ser 1 sequence boundaries. The improved sequence stratigraphic framework enables better regional and global correlations. This shows that rhodalgal carbonate slopes started prograding in the western branch of the Sardinia Rift during the late Burdigalian because (1) of a worldwide bloom of rhodalgal facies, and (2) decreasing tectonic activity at the transition from the syn- rift to the post-rift stage caused a continuous reduction of the siliciclastic sediment input

Vitamin D deficiency as a risk factor for dementia: a systematic review and meta-analysis

Abstract Background Sunlight exposure and high vitamin D status have been hypothesised to reduce the risk of developing dementia. The objective of our research was to determine whether lack of sunlight and hypovitaminosis D over time are associated with dementia. Methods We systematically searched MEDLINE (via PubMed), Cochrane Library, EMBASE, SCOPUS, Web of Science, ICONDA, and reference lists of pertinent review articles from 1990 to October 2015. We conducted random effects meta-analyses of published and unpublished data to evaluate the influence of sunlight exposure or vitamin D as a surrogate marker on dementia risk. Results We could not identify a single study investigating the association between sunlight exposure and dementia risk. Six cohort studies provided data on the effect of serum vitamin D concentration on dementia risk. A meta-analysis of five studies showed a higher risk for persons with serious vitamin D deficiency (<25\ua0nmol/L or 7\u201328\ua0nmol/L) compared to persons with sufficient vitamin D supply (\u226550\ua0nmol/L or 54\u2013159\ua0nmol/L) (point estimate 1.54; 95% CI 1.19\u20131.99, I 2 \u2009=\u200920%). The strength of evidence that serious vitamin D deficiency increases the risk of developing dementia, however, is very low due to the observational nature of included studies and their lack of adjustment for residual or important confounders (e.g. ApoE \u3b54 genotype), as well as the indirect relationship between Vitamin D concentrations as a surrogate for sunlight exposure and dementia risk. Conclusions The results of this systematic review show that low vitamin D levels might contribute to the development of dementia. Further research examining the direct and indirect relationship between sunlight exposure and dementia risk is needed. Such research should involve large-scale cohort studies with homogeneous and repeated assessment of vitamin D concentrations or sunlight exposure and dementia outcomes

Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer

Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyse 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP and SHQ1) and driver amplifications (AR and MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5–52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumour genome, most consistent with subclonal diversification of the tumour. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression

Epigenetic regulation of gene expression in response to a changing environment in CHO cell batch culture

Chinese Hamster Ovary (CHO) cells have been the workhorse for industrial production of recombinant therapeutic proteins since 1987. Variations in cellular environment and phenotypes that occur throughout the bioprocess can bring about significant changes in productivity and quality of recombinant proteins. This can potentially lead to rejection of the production lot. Hence, there is interest in an in-depth understanding of cell-line behavior and control to achieve more predictable and reliable process performance. Biological systems undergo dynamic changes over time, where individual genes are turned “on”, “off” or “paused” as and when required. So far, there is very little information available for CHO cell lines, that elucidates the effect of dynamic epigenetic regulation on temporal expression of genes in response to altered substrate availability and culture conditions. While DNA methylation levels around TSS induce either expression or silencing of genes, transcriptional regulation is primarily considered to be an interplay of transcription factors and chromatin modifiers. On top of these, there is a rapid increase in indications that connects phase-specific long non-coding RNAs (lncRNAs) in transcriptional and post-transcriptional gene regulation. Unfortunately, the mechanism of interaction of these lncRNAs with coding genes have not been studied extensively. In this study, the gene transcription dynamics throughout a batch culture of CHO cells was examined by analyzing expression profiles and histone modifications in regular 12-24 hour intervals. Chromatin states and differential methylation profiles were used to understand the role of epigenetic modifiers in the regulation of gene expression. A good correlation between expression level and absence of DNA-methylation in the promoter regions was observed. Genes having all essential active chromatin marks - specific for promoter activity, genic enhancer and active transcription, also showed significantly high positive correlation between the changes in expression levels and histone marks. Both transcription and chromatin modifications during different growth phases were found to be highly dynamic. Clusters of genes showing similar trends of expression depict gradual and continuous adaptation to the changing substrate concentrations. Less narrowly spaced temporal analyses would have prevented detection of critical regulators involved in transient changes during the batch culture. Here, we also report a plausible mode of interaction of lncRNAs with the coding genes mediated by RNA-DNA-DNA triplex formations. Based on the identified interactions, we could predict possible gene targets and the target sites for the expressed lncRNAs and show high level of correlation of expression levels between interacting pairs. To the best of our knowledge this is the first and most comprehensive report of genome wide transcriptional regulation by epigenetic modifiers for CHO. Please click Additional Files below to see the full abstract

Timing and Pacing of Indonesian Throughflow Restriction and Its Connection to Late Pliocene Climate Shifts

drier conditions. This shift fundamentally reorganized Earth\u27s climate from the Miocene state toward conditions similar to the present. During the Pliocene, the progressive restriction of the Indonesian Throughflow (ITF) is suggested to have enhanced this shift toward stronger meridional thermal gradients. Reduced ITF, caused by the northward movement of Australia and uplift of Indonesia, impeded global thermohaline circulation, also contributing to late Pliocene Northern Hemisphere cooling via atmospheric and oceanographic teleconnections. Here we present an orbitally tuned high‐resolution sediment geochemistry, calcareous nannofossil, and X‐ray fluorescence record between 3.65 and 2.97 Ma from the northwest shelf of Australia within the Leeuwin Current. International Ocean Discovery Program Site U1463 provides a record of local surface water conditions and Australian climate in relation to changing ITF connectivity. Modern analogue‐based interpretations of nannofossil assemblages indicate that ITF configuration culminated ~3.54 Ma. A decrease in warm, oligotrophic taxa such as Umbilicosphaera sibogae, with a shift from Gephyrocapsa sp. to Reticulofenestra sp., and an increase of mesotrophic taxa (e.g., Umbilicosphaera jafari and Helicosphaera spp.) suggest that tropical Pacific ITF sources were replaced by cooler, fresher, northern Pacific waters. This initial tectonic reorganization enhanced the Indian Oceans sensitivity to orbitally forced cooling in the southern high latitudes culminating in the M2 glacial event (~3.3 Ma). After 3.3 Ma the restructured ITF established the boundary conditions for the inception of the Sahul‐Indian Ocean Bjerknes mechanism and increased the response to glacio‐eustatic variability

Indonesian Throughflow drove Australian climate from humid Pliocene to arid Pleistocene

Late Miocene to mid-Pleistocene sedimentary proxy records reveal that northwest Australia underwent an abrupt transition from dry to humid climate conditions at 5.5 million years (Ma), likely receiving year-round rainfall, but after ~3.3 Ma, climate shifted toward an increasingly seasonal precipitation regime. The progressive constriction of the Indonesian Throughflow likely decreased continental humidity and transferred control of northwest Australian climate from the Pacific to the Indian Ocean, leading to drier conditions punctuated by monsoonal precipitation. The northwest dust pathway and fully established seasonal and orbitally controlled precipitation were in place by ~2.4 Ma, well after the intensification of Northern Hemisphere glaciation. The transition from humid to arid conditions was driven by changes in Pacific and Indian Ocean circulation and regional atmospheric moisture transport, influenced by the emerging Maritime Continent. We conclude that the Maritime Continent is the switchboard modulating teleconnections between tropical and high-latitude climate systems

Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing

Background Patients with prostate cancer may present with metastatic or recurrent disease despite initial curative treatment. The propensity of metastatic prostate cancer to spread to the bone has limited repeated sampling of tumor deposits. Hence, considerably less is understood about this lethal metastatic disease, as it is not commonly studied. Here we explored whole-genome sequencing of plasma DNA to scan the tumor genomes of these patients non-invasively. Methods We wanted to make whole-genome analysis from plasma DNA amenable to clinical routine applications and developed an approach based on a benchtop high-throughput platform, that is, Illuminas MiSeq instrument. We performed whole-genome sequencing from plasma at a shallow sequencing depth to establish a genome-wide copy number profile of the tumor at low costs within 2 days. In parallel, we sequenced a panel of 55 high-interest genes and 38 introns with frequent fusion breakpoints such as the TMPRSS2-ERG fusion with high coverage. After intensive testing of our approach with samples from 25 individuals without cancer we analyzed 13 plasma samples derived from five patients with castration resistant (CRPC) and four patients with castration sensitive prostate cancer (CSPC). Results The genome-wide profiling in the plasma of our patients revealed multiple copy number aberrations including those previously reported in prostate tumors, such as losses in 8p and gains in 8q. High-level copy number gains in the AR locus were observed in patients with CRPC but not with CSPC disease. We identified the TMPRSS2-ERG rearrangement associated 3-Mbp deletion on chromosome 21 and found corresponding fusion plasma fragments in these cases. In an index case multiregional sequencing of the primary tumor identified different copy number changes in each sector, suggesting multifocal disease. Our plasma analyses of this index case, performed 13 years after resection of the primary tumor, revealed novel chromosomal rearrangements, which were stable in serial plasma analyses over a 9-month period, which is consistent with the presence of one metastatic clone. Conclusions The genomic landscape of prostate cancer can be established by non-invasive means from plasma DNA. Our approach provides specific genomic signatures within 2 days which may therefore serve as 'liquid biopsy'