Palaeoseismicity studies on end-Pleistocene and Holocene lake deposits around Basle, Switzerland

Palaeoseismological investigations in the lakes of Seewen and Bergsee in the Basle region, Switzerland and southern Germany, revealed characteristic event horizons in an otherwise uniform background sedimentary record. Dated and correlated based on radiocarbon ages, palynostratigraphy and sedimentation rates, some of these event horizons show soft-sediment deformation features and fractures that can be interpretated as being the result of earthquake shaking. Two of the event horizons with clear indications for earthquake deformation were detected in both lakes, showing approximately the same age as indicated by radiocarbon dating. A third event horizon with fractures of apparent seismogenic origin, was detected at several drill sites in only one lake (Bergsee). Three further event horizons, two in the Bergsee and one in Lake Seewen, are of uncertain origin, though they show some characteristics that could well be caused by earthquakes. Based on the observations in both lakes, five events were detected of which three are most probably related to earthquakes which occurred between 180 BC-1160 BC, 8260 BC-9040 BC and 10 720 BC-11 200 BC, respectively. The Basle region is well known for the strongest historical earthquake north of the Alps, the AD 1356 Basle earthquake. Based on combined historical and palaeoseismological data, it has been inferred that earthquakes with size comparable to the AD 1356 Basle earthquake have occurred several times within the last 12 000 yr and that the recurrence time for such strong earthquakes are in the range of 1500-3000 y

The role of osteoprotegerin and receptor activator of nuclear factor kappa-betta ligand in vascular calcification and the influence of insulin and liraglutide on this process in type 2 diabetes mellitus.

Background: The process of vascular calcification (VC) appears to involve certain vascular cell populations assuming an osteoblastic phenotype. Osteoprotegerin (OPG) has been proposed as an inhibitor of VC, potentially via blockade of either receptor activator of nuclear factor kappa-beta ligand (RANKL) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Treatments for type 2 diabetes mellitus (T2DM) such as insulin analogues and liraglutide are known to affect OPG, and may also affect VC. The aims of this thesis were to characterise the roles of OPG/RANKL/TRAIL in VC,and to measure how insulin and liraglutide affect coronary artery calcification (CAC) in T2DM. Methods: Production and secretion of OPG/RANKL/TRAIL was measured in human aortic endothelial and smooth muscle cells (HAECs \u26 HASMCs). RANKL, TRAIL, insulin glargine and liraglutide were added to HAECs and HASMCs, and osteoblastic transformation of HASMCs was measured via alkaline phosphatise activity in the cell media and messenger ribonucleic acid (mRNA) markers of osteoblastic activity. In a clinical study, patients with T2DM who were commencing either insulin analgoues or liraglutide had CAC scans at 0 and 16 months of treatment. Results: OPG, but not TRAIL or RANKL was secreted in large amounts by HASMCs, and to a lesser extent by HAECs. The direct application of RANKL or TRAIL did not induce osteoblastic transformation of HASMCs, but application of RANKL to HAECs led to increased production of bone morphogenetic protein 2 (BMP-2), which in turn led to increased osteoblastic activity in HASMCs. Insulin glargine, but not liraglutide, decreased OPG production and increased osteoblastic activity in HASMCs in vitro, and insulin analogues, but not liraglutide, was associated with a trend towards accelerated CAC in the T2DM population. Conclusions: OPG inhibits osteoblastic transformation of HASMCs via prevention of RANKL-induced BMP-2 release from HAECs. Insulin analogues increase VC in vitro and are associated with increased CAC in vivo in T2DM

Abundant Oligonucleotides Common to Most Bacteria

BACKGROUND: Bacteria show a bias in their genomic oligonucleotide composition far beyond that dictated by G+C content. Patterns of over- and underrepresented oligonucleotides carry a phylogenetic signal and are thus diagnostic for individual species. Patterns of short oligomers have been investigated by multiple groups in large numbers of bacteria genomes. However, global distributions of the most highly overrepresented mid-sized oligomers have not been assessed across all prokaryotes to date. We surveyed overrepresented mid-length oligomers across all prokaryotes and normalised for base composition and embedded oligomers using zero and second order Markov models. PRINCIPAL FINDINGS: Here we report a presumably ancient set of oligomers conserved and overrepresented in nearly all branches of prokaryotic life, including Archaea. These oligomers are either adenine rich homopurines with one to three guanine nucleosides, or homopyridimines with one to four cytosine nucleosides. They do not show a consistent preference for coding or non-coding regions or aggregate in any coding frame, implying a role in DNA structure and as polypeptide binding sites. Structural parameters indicate these oligonucleotides to be an extreme and rigid form of B-DNA prone to forming triple stranded helices under common physiological conditions. Moreover, the narrow minor grooves of these structures are recognised by DNA binding and nucleoid associated proteins such as HU. CONCLUSION: Homopurine and homopyrimidine oligomers exhibit distinct and unusual structural features and are present at high copy number in nearly all prokaryotic lineages. This fact suggests a non-neutral role of these oligonucleotides for bacterial genome organization that has been maintained throughout evolution

Mechanistic Study of the Effect of Endothelin SNPs in Microvascular Angina – protocol of the PRIZE Endothelin Sub-Study

Introduction Microvascular angina (MVA) is a common cause of ischemia with non-obstructive coronary arteries (INOCA) and limited therapeutic options are available to those affected. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathophysiology of MVA. A large randomised, double blinded, placebo controlled crossover trial, the PRecIsion medicine with ZibotEntan in microvascular angina (PRIZE) trial is currently underway, investigating an endothelin receptor antagonist – Zibotentan, as a new drug treatment for microvascular angina. The trial uses a 'precision medicine' approach by preferential selection of those with higher ET-1 expression conferred by the PHACTR1 minor G allele single nucleotide polymorphism (SNP). The incidence of this SNP occurs in approximately one third of the population therefore a considerable number of screened patients will be ineligible for randomisation and the treatment phase of the trial. Methods In the PRIZE Endothelin (ET) Sub-Study, patients screened out of the PRIZE trial will be genotyped for other genetic variants in the ET-1 pathway. These will be correlated with phenotypic characteristics including exercise tolerance, angina severity and quantitative measures of microvascular function on cardiovascular MRI as well as mechanistic data on endothelin pathway signalling. Conclusions The study will provide a comprehensive genotype and phenotype bio-resource identifying novel ET-1 genotypes to inform the potential wider use of endothelin receptor antagonists for this indication.Wellcome Trust [WT107715/Z/15/Z, APD], British Heart Foundation [CB, RE/18/6134217], Medical Research Council [CB, MR/S018905/1], ].Jon Moulton Charity Trust [GRA, SPH

Pseudomonas aeruginosa Genomic Structure and Diversity

The Pseudomonas aeruginosa genome (G + C content 65–67%, size 5.5–7 Mbp) is made up of a single circular chromosome and a variable number of plasmids. Sequencing of complete genomes or blocks of the accessory genome has revealed that the genome encodes a large repertoire of transporters, transcriptional regulators, and two-component regulatory systems which reflects its metabolic diversity to utilize a broad range of nutrients. The conserved core component of the genome is largely collinear among P. aeruginosa strains and exhibits an interclonal sequence diversity of 0.5–0.7%. Only a few loci of the core genome are subject to diversifying selection. Genome diversity is mainly caused by accessory DNA elements located in 79 regions of genome plasticity that are scattered around the genome and show an anomalous usage of mono- to tetradecanucleotides. Genomic islands of the pKLC102/PAGI-2 family that integrate into tRNALys or tRNAGly genes represent hotspots of inter- and intraclonal genomic diversity. The individual islands differ in their repertoire of metabolic genes that make a large contribution to the pangenome. In order to unravel intraclonal diversity of P. aeruginosa, the genomes of two members of the PA14 clonal complex from diverse habitats and geographic origin were compared. The genome sequences differed by less than 0.01% from each other. One hundred ninety-eight of the 231 single nucleotide substitutions (SNPs) were non-randomly distributed in the genome. Non-synonymous SNPs were mainly found in an integrated Pf1-like phage and in genes involved in transcriptional regulation, membrane and extracellular constituents, transport, and secretion. In summary, P. aeruginosa is endowed with a highly conserved core genome of low sequence diversity and a highly variable accessory genome that communicates with other pseudomonads and genera via horizontal gene transfer

Intraclonal genome diversity of Pseudomonas aeruginosa clones CHA and TB.

International audienceBACKGROUND: Adaptation of Pseudomonas aeruginosa to different living conditions is accompanied by microevolution resulting in genomic diversity between strains of the same clonal lineage. In order to detect the impact of colonized habitats on P. aeruginosa microevolution we determined the genomic diversity between the highly virulent cystic fibrosis (CF) isolate CHA and two temporally and geographically unrelated clonal variants. The outcome was compared with the intraclonal genome diversity between three more closely related isolates of another clonal complex. RESULTS: The three clone CHA isolates differed in their core genome in several dozen strain specific nucleotide exchanges and small deletions from each other. Loss of function mutations and non-conservative amino acid replacements affected several habitat- and lifestyle-associated traits, for example, the key regulator GacS of the switch between acute and chronic disease phenotypes was disrupted in strain CHA. Intraclonal genome diversity manifested in an individual composition of the respective accessory genome whereby the highest number of accessory DNA elements was observed for isolate PT22 from a polluted aquatic habitat. Little intraclonal diversity was observed between three spatiotemporally related outbreak isolates of clone TB. Although phenotypically different, only a few individual SNPs and deletions were detected in the clone TB isolates. Their accessory genome mainly differed in prophage-like DNA elements taken up by one of the strains. CONCLUSIONS: The higher geographical and temporal distance of the clone CHA isolates was associated with an increased intraclonal genome diversity compared to the more closely related clone TB isolates derived from a common source demonstrating the impact of habitat adaptation on the microevolution of P. aeruginosa. However, even short-term habitat differentiation can cause major phenotypic diversification driven by single genomic variation events and uptake of phage DNA

The SeqWord Genome Browser: an online tool for the identification and visualization of atypical regions of bacterial genomes through oligonucleotide usage

<p>Abstract</p> <p>Background</p> <p>Data mining in large DNA sequences is a major challenge in microbial genomics and bioinformatics. Oligonucleotide usage (OU) patterns provide a wealth of information for large scale sequence analysis and visualization. The purpose of this research was to make OU statistical analysis available as a novel web-based tool for functional genomics and annotation. The tool is also available as a downloadable package.</p> <p>Results</p> <p>The SeqWord Genome Browser (SWGB) was developed to visualize the natural compositional variation of DNA sequences. The applet is also used for identification of divergent genomic regions both in annotated sequences of bacterial chromosomes, plasmids, phages and viruses, and in raw DNA sequences prior to annotation by comparing local and global OU patterns. The applet allows fast and reliable identification of clusters of horizontally transferred genomic islands, large multi-domain genes and genes for ribosomal RNA. Within the majority of genomic fragments (also termed genomic core sequence), regions enriched with housekeeping genes, ribosomal proteins and the regions rich in pseudogenes or genetic vestiges may be contrasted.</p> <p>Conclusion</p> <p>The SWGB applet presents a range of comprehensive OU statistical parameters calculated for a range of bacterial species, plasmids and phages. It is available on the Internet at <url>http://www.bi.up.ac.za/SeqWord/mhhapplet.php</url>.</p

Sputum metagenomics of people with bronchiectasis

BACKGROUND: The microbiota in the sputum of people with bronchiectasis has repeatedly been investigated in cohorts of different geographic origin, but so far has not been studied to the species level in comparison to control populations including healthy adults and smokers without lung disease.METHODS: The microbial metagenome from sputa of 101 European Bronchiectasis Registry (EMBARC) study participants was examined by using whole-genome shotgun sequencing.RESULTS: Our analysis of the metagenome of people with bronchiectasis revealed four clusters characterised by a predominance of Haemophilus influenzae, Pseudomonas aeruginosa or polymicrobial communities with varying compositions of nonpathogenic commensals and opportunistic pathogens. The metagenomes of the severely affected patients showed individual profiles characterised by low alpha diversity. Importantly, nearly 50% of patients with severe disease were grouped in a cluster characterised by commensals. Comparisons with the sputum metagenomes of healthy smokers and healthy nonsmokers revealed a gradient of depletion of taxa in bronchiectasis, most often Neisseria subflava, Fusobacterium periodonticum and Eubacterium sulci.CONCLUSION: The gradient of depletion of commensal taxa found in healthy airways is a key feature of bronchiectasis associated with disease severity.</p

Sputum metagenomics of people with bronchiectasis

BACKGROUND: The microbiota in the sputum of people with bronchiectasis has repeatedly been investigated in cohorts of different geographic origin, but so far has not been studied to the species level in comparison to control populations including healthy adults and smokers without lung disease.METHODS: The microbial metagenome from sputa of 101 European Bronchiectasis Registry (EMBARC) study participants was examined by using whole-genome shotgun sequencing.RESULTS: Our analysis of the metagenome of people with bronchiectasis revealed four clusters characterised by a predominance of Haemophilus influenzae, Pseudomonas aeruginosa or polymicrobial communities with varying compositions of nonpathogenic commensals and opportunistic pathogens. The metagenomes of the severely affected patients showed individual profiles characterised by low alpha diversity. Importantly, nearly 50% of patients with severe disease were grouped in a cluster characterised by commensals. Comparisons with the sputum metagenomes of healthy smokers and healthy nonsmokers revealed a gradient of depletion of taxa in bronchiectasis, most often Neisseria subflava, Fusobacterium periodonticum and Eubacterium sulci.CONCLUSION: The gradient of depletion of commensal taxa found in healthy airways is a key feature of bronchiectasis associated with disease severity.</p

Seismic imaging of the metamorphism of young sediment into new crystalline crust in the actively rifting Imperial Valley, California

Plate-boundary rifting between transform faults is opening the Imperial Valley of southern California and the rift is rapidly filling with sediment from the Colorado River. Three 65–90 km long seismic refraction profiles across and along the valley, acquired as part of the 2011 Salton Seismic Imaging Project, were analyzed to constrain upper crustal structure and the transition from sediment to underlying crystalline rock. Both first arrival travel-time tomography and frequency-domain full-waveform inversion were applied to provide P-wave velocity models down to ∼7 km depth. The valley margins are fault-bounded, beyond which thinner sediment has been deposited on preexisting crystalline rocks. Within the central basin, seismic velocity increases continuously from ∼1.8 km/s sediment at the surface to >6 km/s crystalline rock with no sharp discontinuity. Borehole data show young sediment is progressively metamorphosed into crystalline rock. The seismic velocity gradient with depth decreases approximately at the 4 km/s contour, which coincides with changes in the porosity and density gradient in borehole core samples. This change occurs at ∼3 km depth in most of the valley, but at only ∼1.5 km depth in the Salton Sea geothermal field. We interpret progressive metamorphism caused by high heat flow to be creating new crystalline crust throughout the valley at a rate comparable to the ≥2 km/Myr sedimentation rate. The newly formed crystalline crust extends to at least 7–8 km depth, and it is shallower and faster where heat flow is higher. Most of the active seismicity occurs within this new crust