812 research outputs found

    Versatility of MicroRNA Biogenesis

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    MicroRNAs (miRNAs) are short single-stranded RNA molecules that regulate gene expression. MiRNAs originate from large primary (pri) and precursor (pre) transcripts that undergo various processing steps along their biogenesis pathway till they reach their mature and functional form. It is not clear, however, whether all miRNAs are processed similarly. Here we show that the ratio between pre-miRNA and mature miRNA forms varies between different miRNAs. Moreover, over-expression of several factors involved in miRNA biogenesis, including Exportin-5, Drosha, NF90a, NF45 and KSRP, displayed bidirectional effects on pre/mature miRNA ratios, suggesting their intricate biogenesis sensitivity. In an attempt to identify additional factors that might explain the versatility in miRNA biogenesis we have analyzed the contribution of two hnRNP family members, hnRNPH1 and hnRNPR. Knock-down or over-expression of these genes suggested that hnRNPR inhibits, whereas hnRNPH1 facilitates, miRNA processing. Overall, our results emphasize that miRNA biogenesis is versatile

    MicroRNAs in pulmonary arterial remodeling

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    Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

    Natural Strain Variation and Antibody Neutralization of Dengue Serotype 3 Viruses

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    Dengue viruses (DENVs) are emerging, mosquito-borne flaviviruses which cause dengue fever and dengue hemorrhagic fever. The DENV complex consists of 4 serotypes designated DENV1-DENV4. Following natural infection with DENV, individuals develop serotype specific, neutralizing antibody responses. Monoclonal antibodies (MAbs) have been used to map neutralizing epitopes on dengue and other flaviviruses. Most serotype-specific, neutralizing MAbs bind to the lateral ridge of domain III of E protein (EDIII). It has been widely assumed that the EDIII lateral ridge epitope is conserved within each DENV serotype and a good target for vaccines. Using phylogenetic methods, we compared the amino acid sequence of 175 E proteins representing the different genotypes of DENV3 and identified a panel of surface exposed amino acids, including residues in EDIII, that are highly variant across the four DENV3 genotypes. The variable amino acids include six residues at the lateral ridge of EDIII. We used a panel of DENV3 mouse MAbs to assess the functional significance of naturally occurring amino acid variation. From the panel of antibodies, we identified three neutralizing MAbs that bound to EDIII of DENV3. Recombinant proteins and naturally occurring variant viruses were used to map the binding sites of the three MAbs. The three MAbs bound to overlapping but distinct epitopes on EDIII. Our empirical studies clearly demonstrate that the antibody binding and neutralization capacity of two MAbs was strongly influenced by naturally occurring mutations in DENV3. Our data demonstrate that the lateral ridge “type specific” epitope is not conserved between strains of DENV3. This variability should be considered when designing and evaluating DENV vaccines, especially those targeting EDIII

    Developing a dynamic digital twin at a building level: Using Cambridge campus as case study

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    A Digital Twin (DT) refers to a digital replica of physical assets, processes and systems. DTs integrate artificial intelligence, machine learning and data analytics to create dynamic digital models that are able to learn and update the status of the physical counterpart from multiple sources. A DT, if equipped with appropriate algorithms will represent and predict future condition and performance of their physical counterparts. Current developments related to DTs are still at an early stage with respect to buildings and other infrastructure assets. Most of these developments focus on the architectural and engineering/construction point of view. Less attention has been paid to the operation & maintenance (O&M) phase, where the value potential is immense. A systematic and clear architecture verified with practical use cases for constructing a DT is the foremost step for effective operation and maintenance of assets. This paper presents a system architecture for developing dynamic DTs in building levels for integrating heterogeneous data sources, support intelligent data query, and provide smarter decision-making processes. This will further bridge the gaps between human relationships with buildings/regions via a more intelligent, visual and sustainable channels. This architecture is brought to life through the development of a dynamic DT demonstrator of the West Cambridge site of the University of Cambridge. Specifically, this demonstrator integrates an as-is multi-layered IFC Building Information Model (BIM), building management system data, space management data, real-time Internet of Things (IoT)-based sensor data, asset registry data, and an asset tagging platform. The demonstrator also includes two applications: (1) improving asset maintenance and asset tracking using Augmented Reality (AR); and (2) equipment failure prediction. The long-term goals of this demonstrator are also discussed in this paper

    U.S. Billion-ton Update: Biomass Supply for a Bioenergy and Bioproducts Industry

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    The Report, Biomass as Feedstock for a Bioenergy and Bioproducts Industry: The Technical Feasibility of a Billion-Ton Annual Supply (generally referred to as the Billion-Ton Study or 2005 BTS), was an estimate of “potential” biomass within the contiguous United States based on numerous assumptions about current and future inventory and production capacity, availability, and technology. In the 2005 BTS, a strategic analysis was undertaken to determine if U.S. agriculture and forest resources have the capability to potentially produce at least one billion dry tons of biomass annually, in a sustainable manner—enough to displace approximately 30% of the country’s present petroleum consumption. To ensure reasonable confidence in the study results, an effort was made to use relatively conservative assumptions. However, for both agriculture and forestry, the resource potential was not restricted by price. That is, all identified biomass was potentially available, even though some potential feedstock would more than likely be too expensive to actually be economically available. In addition to updating the 2005 study, this report attempts to address a number of its shortcoming

    Observation and study of baryonic B decays: B -> D(*) p pbar, D(*) p pbar pi, and D(*) p pbar pi pi

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    We present a study of ten B-meson decays to a D(*), a proton-antiproton pair, and a system of up to two pions using BaBar's data set of 455x10^6 BBbar pairs. Four of the modes (B0bar -> D0 p anti-p, B0bar -> D*0 p anti-p, B0bar -> D+ p anti-p pi-, B0bar -> D*+ p anti-p pi-) are studied with improved statistics compared to previous measurements; six of the modes (B- -> D0 p anti-p pi-, B- -> D*0 p anti-p pi-, B0bar -> D0 p anti-p pi- pi+, B0bar -> D*0 p anti-p pi- pi+, B- -> D+ p anti-p pi- pi-, B- -> D*+ p anti-p pi- pi-) are first observations. The branching fractions for 3- and 5-body decays are suppressed compared to 4-body decays. Kinematic distributions for 3-body decays show non-overlapping threshold enhancements in m(p anti-p) and m(D(*)0 p) in the Dalitz plots. For 4-body decays, m(p pi-) mass projections show a narrow peak with mass and full width of (1497.4 +- 3.0 +- 0.9) MeV/c2, and (47 +- 12 +- 4) MeV/c2, respectively, where the first (second) errors are statistical (systematic). For 5-body decays, mass projections are similar to phase space expectations. All results are preliminary.Comment: 28 pages, 90 postscript figures, submitted to LP0

    An Initial Look at the Far Infrared-Radio Correlation within Nearby Star-forming Galaxies using the Spitzer Space Telescope

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    (Abridged) We present an initial look at the far infrared-radio correlation within the star-forming disks of four nearby, nearly face-on galaxies (NGC 2403, NGC 3031, NGC 5194, and NGC 6946). Using Spitzer MIPS imaging and WSRT radio continuum data, observed as part of the Spitzer Infrared Nearby Galaxies Survey (SINGS), we are able to probe variations in the logarithmic 24mu/22cm (q_24) and 70mu/22cm (q_70) surface brightness ratios across each disk at sub-kpc scales. We find general trends of decreasing q_24 and q_70 with declining surface brightness and with increasing radius. The residual dispersion around the trend of q_24 and q_70 versus surface brightness is smaller than the residual dispersion around the trend of q_24 and q_70 versus radius, on average by ~0.1 dex, indicating that the distribution of star formation sites is more important in determining the infrared/radio disk appearance than the exponential profiles of disks. We have also performed preliminary phenomenological modeling of cosmic ray electron (CRe^-) diffusion using an image-smearing technique, and find that smoothing the infrared maps improves their correlation with the radio maps. Exponential kernels tend to work better than Gaussian kernels which suggests that additional processes besides simple random-walk diffusion in three dimensions must affect the evolution of CRe^-s. The best fit smoothing kernels for the two less active star-forming galaxies (NGC 2403 and NGC 3031) have much larger scale-lengths than those of the more active star-forming galaxies (NGC 5194 and NGC 6946). This difference may be due to the relative deficit of recent CRe^- injection into the interstellar medium (ISM) for the galaxies having largely quiescent disks.Comment: 41 pages including 6 tables and 12 figures; accepted for publication in the Astrophysical Journal. A full-resolution color version can be found at http://www.astro.yale.edu/murphy/a-ph/murphy_FIR-radio.pdf ; Corrected typo

    Quality assurance in pathology in colorectal cancer screening and diagnosis—European recommendations

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    In Europe, colorectal cancer is the most common newly diagnosed cancer and the second most common cause of cancer deaths, accounting for approximately 436,000 incident cases and 212,000 deaths in 2008. The potential of high-quality screening to improve control of the disease has been recognized by the Council of the European Union who issued a recommendation on cancer screening in 2003. Multidisciplinary, evidence-based European Guidelines for quality assurance in colorectal cancer screening and diagnosis have recently been developed by experts in a pan-European project coordinated by the International Agency for Research on Cancer. The full guideline document consists of ten chapters and an extensive evidence base. The content of the chapter dealing with pathology in colorectal cancer screening and diagnosis is presented here in order to promote international discussion and collaboration leading to improvements in colorectal cancer screening and diagnosis by making the principles and standards recommended in the new EU Guidelines known to a wider scientific community

    An instrument to determine the technological literacy levels of upper secondary school students

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    In this article, an instrument for assessing upper secondary school students’ levels of technological literacy is presented. The items making up the instrument emerged from a previous study that employed a phenomenographic research approach to explore students’ conceptions of technology in terms of their understanding of the nature of technology and their interaction with technological artefacts. The instrument was validated through administration to 1,245 students on completion of their 12 years of formal schooling. A factor analysis was conducted on the data and Cronbach alpha reliability coefficients determined. The results show that a five-dimension factor structure (namely, artefact, process, direction/instruction, tinkering, and engagement) strongly supported the dimensions as developed during the original phenomenographic study. The Cronbach alpha reliability co-efficient of each dimension was satisfactory. Based on these findings, the instrument has been shown to be valid and reliable and can be used with confidence

    Annex to Quirke et al. Quality assurance in pathology in colorectal cancer screening and diagnosis: annotations of colorectal lesions

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    Multidisciplinary, evidence-based European Guidelines for quality assurance in colorectal cancer screening and diagnosis have recently been developed by experts in a pan-European project coordinated by the International Agency for Research on Cancer. The full guideline document includes a chapter on pathology with pan-European recommendations which take into account the diversity and heterogeneity of health care systems across the EU. The present paper is based on the annex to the pathology chapter which attempts to describe in greater depth some of the issues raised in the chapter in greater depth, particularly details of special interest to pathologists. It is presented here to make the relevant discussion known to a wider scientific audience
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