Rdesign: A data dictionary with relational database design capabilities in Ada

Data Dictionary is defined to be the set of all data attributes, which describe data objects in terms of their intrinsic attributes, such as name, type, size, format and definition. It is recognized as the data base for the Information Resource Management, to facilitate understanding and communication about the relationship between systems applications and systems data usage and to help assist in achieving data independence by permitting systems applications to access data knowledge of the location or storage characteristics of the data in the system. A research and development effort to use Ada has produced a data dictionary with data base design capabilities. This project supports data specification and analysis and offers a choice of the relational, network, and hierarchical model for logical data based design. It provides a highly integrated set of analysis and design transformation tools which range from templates for data element definition, spreadsheet for defining functional dependencies, normalization, to logical design generator

Multiple mechanisms of growth hormone-regulated gene transcription

Diverse physiological actions of growth hormone (GH) are mediated by changes in gene transcription. Transcription can be regulated at several levels, including post-translational modification of transcription factors, and formation of multiprotein complexes involving transcription factors, co-regulators and additional nuclear proteins; these serve as targets for regulation by hormones and signaling pathways. Evidence that GH regulates transcription at multiple levels is exemplified by analysis of the proto-oncogene c-fos. Among the GH-regulated transcription factors on c-fos, C/EBPbeta appears to be key, since depletion of C/EBPbeta by RNA interference blocks the stimulation of c-fos by GH. The phosphorylation state of C/EBPbeta and its ability to activate transcription are regulated by GH through MAPK and PI3K/Akt-mediated signaling cascades. The acetylation of C/EBPbeta also contributes to its ability to activate c-fos transcription. These and other post-translational modifications of C/EBPbeta appear to be integrated for regulation of transcription by GH. The formation of nuclear proteins into complexes associated with DNA-bound transcription factors is also regulated by GH. Both C/EBPbeta and the co-activator p300 are recruited to c-fos in response to GH, altering c-fos promoter activation. In addition, GH rapidly induces spatio-temporal re-localization of C/EBPbeta within the nucleus. Thus, GH-regulated gene transcription mediated by C/EBPbeta reflects the integration of diverse mechanisms including post-translational modifications, modulation of protein complexes associated with DNA and re-localization of gene regulatory proteins. Similar integration involving other transcription factors, including Stats, appears to be a feature of regulation by GH of other gene targets.Fil: Ceseña, Teresa I.. University of Michigan; Estados UnidosFil: Cui, Tracy Xiao. University of Michigan; Estados UnidosFil: Piwien Pilipuk, Graciela. Fundación Instituto Leloir; ArgentinaFil: Kaplani, Julianne. University of Michigan; Estados UnidosFil: Calinescu, Anda Alexandra. Michigan State University; Estados UnidosFil: Huo, Jeffrey S.. University of Michigan; Estados UnidosFil: Iñiguez Lluhí, Jorge A.. University of Michigan; Estados UnidosFil: Kwok, Roland. University of Michigan; Estados UnidosFil: Schwartz, Jessica. University of Michigan; Estados Unido

Proteasome Nuclear Activity Affects Chromosome Stability by Controlling the Turnover of Mms22, a Protein Important for DNA Repair

To expand the known spectrum of genes that maintain genome stability, we screened a recently released collection of temperature sensitive (Ts) yeast mutants for a chromosome instability (CIN) phenotype. Proteasome subunit genes represented a major functional group, and subsequent analysis demonstrated an evolutionarily conserved role in CIN. Analysis of individual proteasome core and lid subunit mutations showed that the CIN phenotype at semi-permissive temperature is associated with failure of subunit localization to the nucleus. The resultant proteasome dysfunction affects chromosome stability by impairing the kinetics of double strand break (DSB) repair. We show that the DNA repair protein Mms22 is required for DSB repair, and recruited to chromatin in a ubiquitin-dependent manner as a result of DNA damage. Moreover, subsequent proteasome-mediated degradation of Mms22 is necessary and sufficient for cell cycle progression through the G2/M arrest induced by DNA damage. Our results demonstrate for the first time that a double strand break repair protein is a proteasome target, and thus link nuclear proteasomal activity and DSB repair

CanadiEM: Accessing a Virtual Community of Practice to Create a Canadian National Medical Education Institution

Background: The rise of free open-access medical education (FOAM) has led to a wide range of online resources in emergency medicine. Canadian physicians have been active contributors to FOAM. Objectives: We aimed to create a virtual community of practice that would serve as a national platform for collaboration, learning, and knowledge dissemination. Methods: CanadiEM was formed in 2016 from the merger of two Canadian websites and a podcast. Using a community-of-practice model, we introduced two training programs to support junior community members in becoming core editorial team members and employed asynchronous Web technologies to facilitate collaboration. We also introduced a coached peer review process and formed strategic alliances that aim to ensure a high quality of publication. Results: CanadiEM has become a portal for readers to access a broad range of FOAM content. The website has published 782 articles. Of these, 71 have undergone a coached peer review process. The website has received over 2.5 million page views from 217 countries, and the associated CRACKCast podcast has been downloaded over 750,000 times. Conclusions: CanadiEM has succeeded in building a national multi-interface dissemination network that fosters collaboration and knowledge sharing in emergency medicine while fostering junior digital scholars. The construction of a community of practice has been facilitated by quality assurance, training programs, and the use of asynchronous Web technologies. Ongoing challenges in sustainability include a volunteer workforce with high turnover

Prioritizing causal disease genes using unbiased genomic features

Background: Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits. Results: To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM. Conclusion: Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0534-8) contains supplementary material, which is available to authorized users

Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe

SN 2019ewu: A Peculiar Supernova with Early Strong Carbon and Weak Oxygen Features from a New Sample of Young SN Ic Spectra

With the advent of high cadence, all-sky automated surveys, supernovae (SNe) are now discovered closer than ever to their dates of explosion. However, young pre-maximum light follow-up spectra of Type Ic supernovae (SNe Ic), probably arising from the most stripped massive stars, remain rare despite their importance. In this paper we present a set of 49 optical spectra observed with the Las Cumbres Observatory through the Global Supernova Project for 6 SNe Ic, including a total of 17 pre-maximum spectra, of which 8 are observed more than a week before V-band maximum light. This dataset increases the total number of publicly available pre-maximum light SN Ic spectra by 25% and we provide publicly available SNID templates that will significantly aid in the fast identification of young SNe Ic in the future. We present detailed analysis of these spectra, including Fe II 5169 velocity measurements, O I 7774 line strengths, and continuum shapes. We compare our results to published samples of stripped supernovae in the literature and find one SN in our sample that stands out. SN 2019ewu has a unique combination of features for a SN Ic: an extremely blue continuum, high absorption velocities, a P-cygni shaped feature almost 2 weeks before maximum light that TARDIS radiative transfer modeling attributes to C II rather than H$\alpha$, and weak or non-existent O I 7774 absorption feature until maximum light.Comment: Submitted to the Astrophysical Journal. 15 pages, 6 figure

Gas-phase and particulate products from the atmospheric degradation of the organothiophosphorus insecticide chlorpyrifos-methyl

The phosphorothioate structure is highly present in several organophosphorus pesticides. However, there is insufficient information about its degradation process after the release to the atmosphere and the secondary pollutants formed. Herein, the atmospheric reaction of chlorpyrifos-methyl (o,o-dimethyl o-(3,5,6-trichloropyridin-2-yl) phosphorothioate), is described for semi-urban or rural locations. The photo-oxidation under low NOx conditions (5-55 ppbV) was reproduced in a large outdoor simulation chamber, observing a rapid degradation (lifetime<3.5 h). The formation of gaseous products and particulate matter (aerosol yield 2-8%) was monitored. The chemical composition of minor products (gaseous and particulate) was studied, identifying 15 multi-oxygenated derivatives. The most abundant products were ring-retaining molecules such as o,o-dimethyl o-(3,5,6-trichloropyridin-2-yl) phosphorothioate, dimethyl 3,5,6-trichloropyridin-2-yl phosphate, o-methyl o-(3,5,6-trichloropyridin-2-yl) hydrogen phosphorothioate, 3,5,6-trichloropyridin-2-yl dihydrogen phosphate, 3,5,6-trichloropyridin-2-ol, and 3,5,6-trichloropyridine-2,4-diol. An atmospheric degradation mechanism has been proposed based on an oxidation started with OH-nucleophilic attack to P=S bond. The results have been extrapolated to other organothiophosphorus molecules, such as malathion, parathion, diazinon and methidathion, among many others, to estimate their photo-oxidative degradation and the expected products.The authors wish to thank the EUPHORE staff and J.T.B. The authors wish to acknowledge Ministerio de Economia y Competitividad for IMPLACAVELES (CGL2013-49093-C2-1-R) and IMPESTAT (CGL2010-18474/CLI) projects, and Generalitat Valenciana for the DESESTRES- Prometeo II project. The Fundacion CEAM is partly supported by Generalitat Valenciana - Spain. EUPHORE instrumentation is partly funded by MINECO - Spain, through INNPLANTA Project: PCT-440000-2010-003 and the projects FEDER CEAM10-3E-1301 and CEAM10-3E-1302.Borrás García, EM.; Tortajada-Genaro, LA.; Ródenas, M.; Vera, T.; Coscollá, C.; Yusá, V.; Muñoz, A. (2015). Gas-phase and particulate products from the atmospheric degradation of the organothiophosphorus insecticide chlorpyrifos-methyl. Chemosphere. 138:888-894. https://doi.org/10.1016/j.chemosphere.2014.11.067S88889413

Antibody targeting of Cathepsin S induces antibody-dependent cellular cytotoxicity

<p>Abstract</p> <p>Background</p> <p>Proteolytic enzymes have been implicated in driving tumor progression by means of their cancer cell microenvironment activity where they promote proliferation, differentiation, apoptosis, migration, and invasion. Therapeutic strategies have focused on attenuating their activity using small molecule inhibitors, but the association of proteases with the cell surface during cancer progression opens up the possibility of targeting these using antibody dependent cellular cytotoxicity (ADCC). Cathepsin S is a lysosomal cysteine protease that promotes the growth and invasion of tumour and endothelial cells during cancer progression. Our analysis of colorectal cancer patient biopsies shows that cathepsin S associates with the cell membrane indicating a potential for ADCC targeting.</p> <p>Results</p> <p>Here we report the cell surface characterization of cathepsin S and the development of a humanized antibody (Fsn0503h) with immune effector function and a stable <it>in vivo </it>half-life of 274 hours. Cathepsin S is expressed on the surface of tumor cells representative of colorectal and pancreatic cancer (23%-79% positive expression). Furthermore the binding of Fsn0503h to surface associated cathepsin S results in natural killer (NK) cell targeted tumor killing. In a colorectal cancer model Fsn0503h elicits a 22% cytotoxic effect.</p> <p>Conclusions</p> <p>This data highlights the potential to target cell surface associated enzymes, such as cathepsin S, as therapeutic targets using antibodies capable of elicitingADCC in tumor cells.</p