Smart technologies for effective reconfiguration: the FASTER approach

Current and future computing systems increasingly require that their functionality stays flexible after the system is operational, in order to cope with changing user requirements and improvements in system features, i.e. changing protocols and data-coding standards, evolving demands for support of different user applications, and newly emerging applications in communication, computing and consumer electronics. Therefore, extending the functionality and the lifetime of products requires the addition of new functionality to track and satisfy the customers needs and market and technology trends. Many contemporary products along with the software part incorporate hardware accelerators for reasons of performance and power efficiency. While adaptivity of software is straightforward, adaptation of the hardware to changing requirements constitutes a challenging problem requiring delicate solutions. The FASTER (Facilitating Analysis and Synthesis Technologies for Effective Reconfiguration) project aims at introducing a complete methodology to allow designers to easily implement a system specification on a platform which includes a general purpose processor combined with multiple accelerators running on an FPGA, taking as input a high-level description and fully exploiting, both at design time and at run time, the capabilities of partial dynamic reconfiguration. The goal is that for selected application domains, the FASTER toolchain will be able to reduce the design and verification time of complex reconfigurable systems providing additional novel verification features that are not available in existing tool flows

Explanting Is an Ex Vivo Model of Renal Epithelial-Mesenchymal Transition

Recognised by their de novo expression of alpha-smooth muscle actin (SMA), recruitment of myofibroblasts is key to the pathogenesis of fibrosis in chronic kidney disease. Increasingly, we realise that epithelial-mesenchymal transition (EMT) may be an important source of these cells. In this study we describe a novel model of renal EMT. Rat kidney explants were finely diced on gelatin-coated Petri dishes and cultured in serum-supplemented media. Morphology and immunocytochemistry were used to identify mesenchymal (vimentin+, α-smooth muscle actin (SMA)+, desmin+), epithelial (cytokeratin+), and endothelial (RECA+) cells at various time points. Cell outgrowths were all epithelial in origin (cytokeratin+) at day 3. By day 10, 50 ± 12% (mean ± SE) of cytokeratin+ cells double-labelled for SMA, indicating EMT. Lectin staining established a proximal tubule origin. By day 17, cultures consisted only of myofibroblasts (SMA+/cytokeratin−). Explanting is a reproducible ex vivo model of EMT. The ability to modify this change in phenotype provides a useful tool to study the regulation and mechanisms of renal tubulointerstitial fibrosis

Generation of Human Antigen-Specific Monoclonal IgM Antibodies Using Vaccinated “Human Immune System” Mice

Passive transfer of antibodies not only provides immediate short-term protection against disease, but also can be exploited as a therapeutic tool. However, the 'humanization' of murine monoclonal antibodies (mAbs) is a time-consuming and expensive process that has the inherent drawback of potentially altering antigenic specificity and/or affinity. The immortalization of human B cells represents an alternative for obtaining human mAbs, but relies on the availability of biological samples from vaccinated individuals or convalescent patients. In this work we describe a novel approach to generate fully human mAbs by combining a humanized mouse model with a new B cell immortalization technique. After transplantation with CD34+CD38⁻ human hematopoietic progenitor cells, BALB/c Rag2⁻/⁻IL-2Rγc⁻/⁻ mice acquire a human immune system and harbor B cells with a diverse IgM repertoire. "Human Immune System" mice were then immunized with two commercial vaccine antigens, tetanus toxoid and hepatitis B surface antigen. Sorted human CD19+CD27+ B cells were retrovirally transduced with the human B cell lymphoma (BCL)-6 and BCL-XL genes, and subsequently cultured in the presence of CD40-ligand and IL-21. This procedure allows generating stable B cell receptor-positive B cells that secrete immunoglobulins. We recovered stable B cell clones that produced IgM specific for tetanus toxoid and the hepatitis B surface antigen, respectively. This work provides the proof-of-concept for the usefulness of this novel method based on the immunization of humanized mice for the rapid generation of human mAbs against a wide range of antigen

Design, construction, and characterization of a compact DD neutron generator designed for 40Ar/39Ar geochronology

A next-generation, high-flux DD neutron generator has been designed, commissioned, and characterized, and is now operational in a new facility at the University of California Berkeley. The generator, originally designed for 40Ar/39Ar dating of geological materials, has since served numerous additional applications, including medical isotope production studies, with others planned for the near future. In this work, we present an overview of the High Flux Neutron Generator (HFNG) which includes a variety of simulations, analytical models, and experimental validation of results. Extensive analysis was performed in order to characterize the neutron yield, flux, and energy distribution at specific locations where samples may be loaded for irradiation. A notable design feature of the HFNG is the possibility for sample irradiation internal to the cathode, just 8 mm away from the neutron production site, thus maximizing the neutron flux (n/cm2/s). The generator's maximum neutron flux at this irradiation position is 2.58e7 n/cm2/s +/- 5% (approximately 3e8 n/s total yield) as measured via activation of small natural indium foils. However, future development is aimed at achieving an order of magnitude increase in flux. Additionally, the deuterium ion beam optics were optimized by simulations for various extraction configurations in order to achieve a uniform neutron flux distribution and an acceptable heat load. Finally, experiments were performed in order to benchmark the modeling and characterization of the HFNG.Comment: 31 pages, 20 figure

An association study on contrasting cystic fibrosis endophenotypes recognizes KRT8 but not KRT18 as a modifier of cystic fibrosis disease severity and CFTR mediated residual chloride secretion

<p>Abstract</p> <p>Background</p> <p>F508del-CFTR, the most frequent disease-causing mutation among Caucasian cystic fibrosis (CF) patients, has been characterised as a mutant defective in protein folding, processing and trafficking. We have investigated the two neighbouring cytokeratin genes <it>KRT8 </it>and <it>KRT18 </it>in a candidate gene approach to ask whether variants in <it>KRT8 </it>and/or <it>KRT18 </it>modify the impaired ion conductance known as the CF basic defect, and whether they are associated with correct trafficking of mutant CFTR and disease severity of CF.</p> <p>Methods</p> <p>We have selected contrasting F508del-<it>CFTR </it>homozygous patient subpopulations stratified for disease severity, comparing 13 concordant mildly affected sib pairs vs. 12 concordant severely affected sib pairs, or manifestation of the CF basic defect in intestinal epithelium, comparing 22 individuals who exhibit CFTR-mediated residual chloride secretion vs. 14 individuals who do not express any chloride secretion, for an association. The <it>KRT8</it>/<it>KRT18 </it>locus was initially interrogated with one informative microsatellite marker. Subsequently, a low density SNP map with four SNPs in KRT8 and two SNPs in KRT18, each selected for high polymorphism content, was used to localize the association signal.</p> <p>Results</p> <p><it>KRT8</it>, but not <it>KRT18</it>, showed an association with CF disease severity (P_best= 0.00131; P_corr= 0.0185) and CFTR mediated residual chloride secretion (P_best= 0.0004; P_corr= 0.0069). Two major four-marker-haplotypes spanning 13 kb including the entire <it>KRT8 </it>gene accounted for 90% of chromosomes, demonstrating strong linkage disequilibrium at that locus. Absence of chloride secretion was associated with the recessive haplotype 1122 at rs1907671, rs4300473, rs2035878 and rs2035875. The contrasting haplotype 2211 was dominant for the presence of CFTR mediated residual chloride secretion. In consistency, the <it>KRT8 </it>haplotype 2211 was associated with mild CF disease while 1122 was observed as risk haplotype. Analysis of microsatellite allele distributions on the SNP background suggests that the mild <it>KRT8 </it>haplotype 2211 is phylogenetically older than its severe counterpart.</p> <p>Conclusions</p> <p>The two opposing <it>KRT8 </it>alleles which have been identified as a benign and as a risk allele in this work are likely effective in the context of epithelial cell differentiation. As the mild <it>KRT8 </it>allele is associated with CFTR mediated residual chloride secretion among F508del-<it>CFTR </it>homozygotes, the KRT8/KRT18 heterodimeric intermediary filaments of the cytoskeleton apparently are an essential component for the proper targeting of CFTR to the apical membrane in epithelial cells.</p

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: Assessment of environmental exposures

The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3–4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set

Predicting compound activity from phenotypic profiles and chemical structures

Predicting assay results for compounds virtually using chemical structures and phenotypic profiles has the potential to reduce the time and resources of screens for drug discovery. Here, we evaluate the relative strength of three high-throughput data sources—chemical structures, imaging (Cell Painting), and gene-expression profiles (L1000)—to predict compound bioactivity using a historical collection of 16,170 compounds tested in 270 assays for a total of 585,439 readouts. All three data modalities can predict compound activity for 6–10% of assays, and in combination they predict 21% of assays with high accuracy, which is a 2 to 3 times higher success rate than using a single modality alone. In practice, the accuracy of predictors could be lower and still be useful, increasing the assays that can be predicted from 37% with chemical structures alone up to 64% when combined with phenotypic data. Our study shows that unbiased phenotypic profiling can be leveraged to enhance compound bioactivity prediction to accelerate the early stages of the drug-discovery process

A Normalized Tree Index for identification of correlated clinical parameters in microarray experiments

Martin C, Tauchen A, Becker A, Nattkemper TW. A Normalized Tree Index for identification of correlated clinical parameters in microarray data. BioData Mining. 2011;4(1): 2.BACKGROUND: Measurements on gene level are widely used to gain new insights in complex diseases e.g. cancer. A promising approach to understand basic biological mechanisms is to combine gene expression profiles and classical clinical parameters. However, the computation of a correlation coefficient between high-dimensional data and such parameters is not covered by traditional statistical methods. METHODS: We propose a novel index, the Normalized Tree Index (NTI), to compute a correlation coefficient between the clustering result of high-dimensional microarray data and nominal clinical parameters. The NTI detects correlations between hierarchically clustered microarray data and nominal clinical parameters (labels) and gives a measurement of significance in terms of an empiric p-value of the identified correlations. Therefore, the microarray data is clustered by hierarchical agglomerative clustering using standard settings. In a second step, the computed cluster tree is evaluated. For each label, a NTI is computed measuring the correlation between that label and the clustered microarray data. RESULTS: The NTI successfully identifies correlated clinical parameters at different levels of significance when applied on two real-world microarray breast cancer data sets. Some of the identified highly correlated labels confirm the actual state of knowledge whereas others help to identify new risk factors and provide a good basis to formulate new hypothesis. CONCLUSIONS: The NTI is a valuable tool in the domain of biomedical data analysis. It allows the identification of correlations between high-dimensional data and nominal labels, while at the same time a p-value measures the level of significance of the detected correlations

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes