Detailed DEM analysis of a rockslide scar to characterize the basal sliding surface of active rockslides

The basal sliding surfaces in large rockslides are often composed of several surfaces and possess a complex geometry. The exact morphology and location in three dimensions of the sliding surface remains generally unknown, in spite of extensive field and subsurface investigations, such as those at the Åknes rockslide (western Norway). This knowledge is crucial for volume estimations, failure mechanisms, and numerical slope stability modeling. This paper focuses on the geomorphologic characterization of the basal sliding surface of a postglacial rockslide scar in the vicinity of Åknes. This scar displays a stepped basal sliding surface formed by dip slopes of the gneiss foliation linked together by steeply dipping fractures. A detailed characterization of the rockslide scar by means of high-resolution digital elevation models permits statistical parameters of dip angle, spacing, persistence, and roughness of foliation surfaces and step fractures to be obtained. The characteristics are used for stochastic simulations of stepped basal sliding surfaces at the Åknes rockslide. These findings are compared with previous models based on geophysical investigations. This study discusses the investigation of rockslide scars and rock outcrops for a better understanding of potential rockslides. This work identifies possible basal sliding surface locations, which is a valuable input for volume estimates, design and location of monitoring instrumentation, and numerical slope stability modeling.

Analysis of stop-gain and frameshift variants in human innate immunity genes.

Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.

Bone anabolic potential of soy isoflavones and plant extracts and genomic changes during differentiation of hPOB-tert osteoblast-like cells

Summary For the nutritional management of bone health and the prevention of osteoporosis it is important to identify nutrients that positively influence the bone remodeling process at the cellular level. Soy isoflavones show promising osteoprotective effects in animals and humans but their mechanism of action in bone cells is yet poorly understood. Firstly, soy tissue cultures were characterized as a new and optimized source of isoflavones. A large variability in the isoflavone content was observed and high-producing strains (46.3 mg/g dry wt isoflavones) were identified. In the Ishikawa cells bioassay, the estrogenicity of isoflavones was confirmed to be 1000 to 10000 less than 17Mestradiol and that of the malonyl forms was shown for the first time (EC50 of 350 nM and 1880 nM for malonylgenistin and malonyldaidzin, respectively). The estrogenic activity of soya tissue culture extracts correlated to their isoflavone content. Secondly, the effects of phytonutrients on BMP-2 gene expression and on the mevalonate synthesis pathway, as key mediators of bone formation, were investigated. Dietary achievable concentrations of genistein and daidzein (10vM), and statins (4xM) but not 17M estradiol (10nM), induced BMP-2 gene expression (by up to 3-fold) and inhibited the cholesterol biosynthetic pathway (by up to 50%) in the human osteoblastic cell line hP0B¬tert. In addition, several plant extracts (Cyperus rotundus, Lindera benzoin and Cnidium monnieri) induced BMP-2 gene expression but this induction was not restricted to the inhibition of the cholesterol synthesis pathway neither to the estrogenicity. Finally, the gene expression profiles during hP0B-tert differentiation induced by vitamin D and dexamethasone were analyzed with the Affymetrix human GeneChip. 1665 different genes and 98 ESTs were significantly regulated. The expression profiles of bone-related genes was largely in agreement with previously documented patterns, supporting the physiological relevance of the genomic results and the hP0B-tert cell line as a valid model of human osteoblast differentiation. The expression of alternative differentiation markers during the osteogenic treatment of hP0B-tert cells indicated that the adipocyte and myoblast differentiation pathways were repressed, confirming that these culture conditions allowed only osteoblast differentiation. The gene ontology analysis identified further sub-groups of genes that may be involved in the bone formation process. Aims of the thesis In order to define new strategies for the nutritional management of bone health and for the prevention of osteoporosis the major goal of the present work was to investigate the potential of phytonutrients to positively modulate the bone formation process at the cellular level and, in particular: 1.To select and optimise alternative plant sources containing high levels of isoflavones with estrogenic activity (Chapter 3). 2.To compare the effects of statins and phytonutrients on BMP-2 gene expression and on the mevalonate synthesis pathway and to select new plant extracts with a bone anabolic potential (Chapter 4). 3.To further characterize the new human periosteal cell line, hP0B-tert, as a bone- formation model, by elucidating its gene expression profile during differentiation induced by vitamin D and dexamethasone (Chapter 5).

Use of antibiotics in pediatric intensive care and potential savings.

OBJECTIVE: Minimizing unwarranted prescription of antibiotics remains an important objective. Because of the heterogeneity between units regarding patient mix and other characteristics, site-specific targets for reduction must be identified. Here we present a model to address the issue by means of an observational cohort study. SETTING: A tertiary, multidisciplinary, neonatal, and pediatric intensive care unit of a university teaching hospital. PATIENTS: All newborns and children present in the unit (n = 456) between September 1998 and March 1999. Reasons for admission included postoperative care after cardiac surgery, major neonatal or pediatric surgery, severe trauma, and medical conditions requiring critical care. METHODS: Daily recording of antibiotics given and of indications for initiation. After discontinuation, each treatment episode was assessed as to the presence or absence of infection. RESULTS: Of the 456 patients 258 (56.6%) received systemic antibiotics, amounting to 1815 exposure days (54.6%) during 3322 hospitalization days. Of these, 512 (28%) were prescribed as prophylaxis and 1303 for suspected infection. Treatment for suspected ventilator-associated pneumonia accounted for 616 (47%) of 1303 treatment days and suspected sepsis for 255 days (20%). Patients were classified as having no infection or viral infection during 552 (40%) treatment days. The average weekly exposure rate in the unit varied considerably during the 29-week study period (range: 40-77/100 hospitalization days). Patient characteristics did not explain this variation. CONCLUSION: In this unit the largest reduction in antibiotic treatment would result from measures assisting suspected ventilator-associated pneumonia to be ruled out and from curtailing extended prophylaxis.

Conceptual models for designing information systems supporting the strategic analysis of technology environments

1 6 STRUCTURE OF THIS THESIS -Chapter I presents the motivations of this dissertation by illustrating two gaps in the current body of knowledge that are worth filling, describes the research problem addressed by this thesis and presents the research methodology used to achieve this goal. -Chapter 2 shows a review of the existing literature showing that environment analysis is a vital strategic task, that it shall be supported by adapted information systems, and that there is thus a need for developing a conceptual model of the environment that provides a reference framework for better integrating the various existing methods and a more formal definition of the various aspect to support the development of suitable tools. -Chapter 3 proposes a conceptual model that specifies the various enviromnental aspects that are relevant for strategic decision making, how they relate to each other, and ,defines them in a more formal way that is more suited for information systems development. -Chapter 4 is dedicated to the evaluation of the proposed model on the basis of its application to a concrete environment to evaluate its suitability to describe the current conditions and potential evolution of a real environment and get an idea of its usefulness. -Chapter 5 goes a step further by assembling a toolbox describing a set of methods that can be used to analyze the various environmental aspects put forward by the model and by providing more detailed specifications for a number of them to show how our model can be used to facilitate their implementation as software tools. -Chapter 6 describes a prototype of a strategic decision support tool that allow the analysis of some of the aspects of the environment that are not well supported by existing tools and namely to analyze the relationship between multiple actors and issues. The usefulness of this prototype is evaluated on the basis of its application to a concrete environment. -Chapter 7 finally concludes this thesis by making a summary of its various contributions and by proposing further interesting research directions.

Genetic analysis of phenoxyalkanoic acid degradation in Sphingomonas herbicidovorans MH.

Phenoxyalkanoic acid degradation is well studied in Beta- and Gammaproteobacteria, but the genetic background has not been elucidated so far in Alphaproteobacteria. We report the isolation of several genes involved in dichlor- and mecoprop degradation from the alphaproteobacterium Sphingomonas herbicidovorans MH and propose that the degradation proceeds analogously to that previously reported for 2,4-dichlorophenoxyacetic acid (2,4-D). Two genes for alpha-ketoglutarate-dependent dioxygenases, sdpA(MH) and rdpA(MH), were found, both of which were adjacent to sequences with potential insertion elements. Furthermore, a gene for a dichlorophenol hydroxylase (tfdB), a putative regulatory gene (cadR), two genes for dichlorocatechol 1,2-dioxygenases (dccA(I/II)), two for dienelactone hydrolases (dccD(I/II)), part of a gene for maleylacetate reductase (dccE), and one gene for a potential phenoxyalkanoic acid permease were isolated. In contrast to other 2,4-D degraders, the sdp, rdp, and dcc genes were scattered over the genome and their expression was not tightly regulated. No coherent pattern was derived on the possible origin of the sdp, rdp, and dcc pathway genes. rdpA(MH) was 99% identical to rdpA(MC1), an (R)-dichlorprop/alpha-ketoglutarate dioxygenase from Delftia acidovorans MC1, which is evidence for a recent gene exchange between Alpha- and Betaproteobacteria. Conversely, DccA(I) and DccA(II) did not group within the known chlorocatechol 1,2-dioxygenases, but formed a separate branch in clustering analysis. This suggests a different reservoir and reduced transfer for the genes of the modified ortho-cleavage pathway in Alphaproteobacteria compared with the ones in Beta- and Gammaproteobacteria.

The occurrence of intra-operative hypotension varies between hospitals: observational analysis of over 147000 anaesthesia

Background: Hypotension, a common intra-operative incident, bears an important potential for morbidity. It is most often manageable and sometimes preventable, which renders its study important. Therefore, we aimed at examining hospital variations in the occurrence of intraoperative hypotension and its predictors. As secondary endpoints, we determined to what extent hypotension relates to the risk of postoperative incidents and death. Methods: We used the Anaesthesia Databank Switzerland, built on routinely and prospectively collected data on all anaesthesias in 21 hospitals. The three outcomes were assessed using multi-level logistic regression models. Results: Among 147573 anaesthesia, hypotension ranged from 0.6 to 5.2% in participating hospitals, and from 0.3 up to 12% in different surgical specialties. Most (73.4%) were minor single events. Age, ASA status, combined general and regional anaesthesia techniques, duration of surgery, and hospitalization were significantly associated to hypotension. Although significantly associated, the emergency status of the surgery had a weaker effect. Hospitals' Odds Ratios for hypotension varied between 0.12 to 2.50 (p ≤0.001) with respect to the mean prevalence of 3.1%, even after adjusting for patient and anaesthesia factors, and for type of surgery. At least one postoperative incident occurred in 9.7% of the interventions, including 0.03% deaths. Intra-operative hypotension was associated with higher risk of post-operative incidents and death. Conclusions: Wide variations in the occurrence of hypotension amongst hospitals remain after adjustment for risk factors. Although differential reporting from hospitals may exist, variations in anesthesia techniques and blood pressure maintenance could have also contributed. Intra-operative hypotension is associated with morbidities and sometimes death, and constant vigilance must thus be advocated.

Modular analysis of gene expression data with R.

SUMMARY: Large sets of data, such as expression profiles from many samples, require analytic tools to reduce their complexity. The Iterative Signature Algorithm (ISA) is a biclustering algorithm. It was designed to decompose a large set of data into so-called 'modules'. In the context of gene expression data, these modules consist of subsets of genes that exhibit a coherent expression profile only over a subset of microarray experiments. Genes and arrays may be attributed to multiple modules and the level of required coherence can be varied resulting in different 'resolutions' of the modular mapping. In this short note, we introduce two BioConductor software packages written in GNU R: The isa2 package includes an optimized implementation of the ISA and the eisa package provides a convenient interface to run the ISA, visualize its output and put the biclusters into biological context. Potential users of these packages are all R and BioConductor users dealing with tabular (e.g. gene expression) data. AVAILABILITY: http://www.unil.ch/cbg/ISA CONTACT: sven.bergmann@unil.ch

DIP-STR: Highly Sensitive Markers for the Analysis of Unbalanced Genomic Mixtures.

Samples containing highly unbalanced DNA mixtures from two individuals commonly occur both in forensic mixed stains and in peripheral blood DNA microchimerism induced by pregnancy or following organ transplant. Because of PCR amplification bias, the genetic identification of a DNA that contributes trace amounts to a mixed sample represents a tremendous challenge. This means that standard genetic markers, namely microsatellites, also referred as short tandem repeats (STR), and single-nucleotide polymorphism (SNP) have limited power in addressing common questions of forensic and medical genetics. To address this issue, we developed a molecular marker, named DIP-STR that relies on pairing deletion-insertion polymorphisms (DIP) with STR. This novel analytical approach allows for the unambiguous genotyping of a minor component in the presence of a major component, where DIP-STR genotypes of the minor were successfully procured at ratios up to 1:1,000. The compound nature of this marker generates a high level of polymorphism that is suitable for identity testing. Here, we demonstrate the power of the DIP-STR approach on an initial set of nine markers surveyed in a Swiss population. Finally, we discuss the limitations and potential applications of our new system including preliminary tests on clinical samples and estimates of their performance on simulated DNA mixtures.

A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues

Tobacco consumption is a global epidemic responsible for a vast burden of disease. With pharmacological properties sought-after by consumers and responsible for addiction issues, nicotine is the main reason of this phenomenon. Accordingly, smokeless tobacco products are of growing popularity in sport owing to potential performance enhancing properties and absence of adverse effects on the respiratory system. Nevertheless, nicotine does not appear on the 2011 World Anti-Doping Agency (WADA) Prohibited List or Monitoring Program by lack of a comprehensive large-scale prevalence survey. Thus, this work describes a one-year monitoring study on urine specimens from professional athletes of different disciplines covering 2010 and 2011. A method for the detection and quantification of nicotine, its major metabolites (cotinine, trans-3-hydroxycotinine, nicotine-N′-oxide and cotinine-N-oxide) and minor tobacco alkaloids (anabasine, anatabine and nornicotine) was developed, relying on ultra-high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-TQ-MS/MS). A simple and fast dilute-and-shoot sample treatment was performed, followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. After method validation, assessing the prevalence of nicotine consumption in sport involved analysis of 2185 urine samples, accounting for 43 different sports. Concentrations distribution of major nicotine metabolites, minor nicotine metabolites and tobacco alkaloids ranged from 10 (LLOQ) to 32,223, 6670 and 538 ng/mL, respectively. Compounds of interest were detected in trace levels in 23.0% of urine specimens, with concentration levels corresponding to an exposure within the last three days for 18.3% of samples. Likewise, hypothesizing conservative concentration limits for active nicotine consumption prior and/or during sport practice (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N′-oxide, cotinine-N-oxide, anabasine, anatabine and nornicotine) revealed a prevalence of 15.3% amongst athletes. While this number may appear lower than the worldwide smoking prevalence of around 25%, focusing the study on selected sports highlighted more alarming findings. Indeed, active nicotine consumption in ice hockey, skiing, biathlon, bobsleigh, skating, football, basketball, volleyball, rugby, American football, wrestling and gymnastics was found to range between 19.0 and 55.6%. Therefore, considering the adverse effects of smoking on the respiratory tract and numerous health threats detrimental to sport practice at top level, likelihood of smokeless tobacco consumption for performance enhancement is greatly supported.

Embolic strokes of undetermined source in the athens stroke registry: a descriptive analysis.

BACKGROUND AND PURPOSE: A new clinical construct termed embolic stroke of undetermined source (ESUS) was recently introduced, but no such population has been described yet. Our aim is to provide a detailed descriptive analysis of an ESUS population derived from a large prospective ischemic stroke registry using the proposed diagnostic criteria. METHODS: The criteria proposed by the Cryptogenic Stroke/ESUS International Working Group were applied to the Athens Stroke Registry to identify all ESUS patients. ESUS was defined as a radiologically confirmed nonlacunar brain infarct in the absence of (a) extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the ischemic area, (b) major-risk cardioembolic source, and (c) any other specific cause of stroke. RESULTS: Among 2735 patients admitted between 1992 and 2011, 275 (10.0%) were classified as ESUS. In the majority of ESUS (74.2%), symptoms were maximal at onset. ESUS were of moderate severity (median National Institute Health Stroke Scale score, 5). The most prevalent risk factor was arterial hypertension (64.7%), and 50.9% of patients were dyslipidemic. Among potential causes of the ESUS, covert atrial fibrillation (AF) was the most prevalent: in 30 (10.9%) patients, AF was diagnosed during hospitalization for stroke recurrence, whereas in 50 (18.2%) patients AF was detected after repeated ECG monitoring during follow-up. Also, covert AF was strongly suggested in 38 patients (13.8%) but never recorded. CONCLUSIONS: About 10% of patients with first-ever ischemic stroke met criteria for ESUS; covert paroxysmal AF seems to be a frequent cause of ESUS.

Statistical evaluation of the reproducibility and the influence of paper on the analysis of black gel pen ink using laser desorption ionisation mass spectrometry

Laser desorption ionisation mass spectrometry (LDI-MS) has demonstrated to be an excellent analytical method for the forensic analysis of inks on a questioned document. The ink can be analysed directly on its substrate (paper) and hence offers a fast method of analysis as sample preparation is kept to a minimum and more importantly, damage to the document is minimised. LDI-MS has also previously been reported to provide a high power of discrimination in the statistical comparison of ink samples and has the potential to be introduced as part of routine ink analysis. This paper looks into the methodology further and evaluates statistically the reproducibility and the influence of paper on black gel pen ink LDI-MS spectra; by comparing spectra of three different black gel pen inks on three different paper substrates. Although generally minimal, the influences of sample homogeneity and paper type were found to be sample dependent. This should be taken into account to avoid the risk of false differentiation of black gel pen ink samples. Other statistical approaches such as principal component analysis (PCA) proved to be a good alternative to correlation coefficients for the comparison of whole mass spectra.

Large-scale gene-centric analysis identifies novel variants for coronary artery disease.

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

SNARE protein expression in synaptic terminals and astrocytes in the adult hippocampus: a comparative analysis.

Several evidences suggest that astrocytes release small transmitter molecules, peptides, and protein factors via regulated exocytosis, implying that they function as specialized neurosecretory cells. However, very little is known about the molecular and functional properties of regulated secretion in astrocytes in the adult brain. Establishing these properties is central to the understanding of the communication mode(s) of these cells and their role(s) in the control of synaptic functions and of cerebral blood flow. In this study, we have set-up a high-resolution confocal microscopy approach to distinguish protein expression in astrocytic structures and neighboring synaptic terminals in adult brain tissue. This approach was applied to investigate the expression pattern of core SNARE proteins for vesicle fusion in the dentate gyrus and CA1 regions of the mouse hippocampus. Our comparative analysis shows that astrocytes abundantly express, in their cell body and main processes, all three protein partners necessary to form an operational SNARE complex but not in the same isoforms expressed in neighbouring synaptic terminals. Thus, SNAP25 and VAMP2 are absent from astrocytic processes and typically concentrated in terminals, while SNAP23 and VAMP3 have the opposite expression pattern. Syntaxin 1 is present in both synaptic terminals and astrocytes. These data support the view that astrocytes in the adult hippocampus can communicate via regulated exocytosis and also indicates that astrocytic exocytosis may differ in its properties from action potential-dependent exocytosis at neuronal synapses, as it relies on a distinctive set of SNARE proteins.

Preparation and analysis of fetal liver extracts.

The aim of this work is to describe the techniques that have been used for preparation and analysis of whole fetal liver extracts destined for in utero transplantation. Nine fetal livers between 12 and 17 weeks of gestation were prepared: cell counts and assessment of the hematopoietic cell viability were performed on cell suspensions. Hepatocytes represented 40 to 80% of the whole cell population. The remaining cells were constituted by hematopoietic cells (mainly erythroblasts), as well as by endothelial cells. The latter expressed CD34 on their surface, interfering with the assessment of CD34+ hematopoietic cells by flow cytometry. Direct visual morphologic control using alkaline phosphatase anti-alkaline phosphatase techniques was needed to differentiate hematopoietic from extra-hematopoietic CD34+ cells. Between 3.0 and 34.6 x 10(6) CD34+ viable hematopoietic cells were collected per fetal liver. Adequate differentiation of these cells into burst-forming units erythroid (BFU-E), colony-forming units granulocyte-macrophage (CFU-GM), and colony-forming units granulocyte erythroid macrophage megakaryocyte (CFU-GEMM) has been shown for each sample in clonogeneic cultures. In conclusion, fetal liver is a potential source of hematopoietic stem cells. Their numeration, based on the presence of CD34, is hampered by the expression of this antigen on other cells contained in the liver cell extract, in particular endothelial cells.