Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism

Hepatic Lipase (HL; EC 3.1.1.3) is an extracellular glycoprotein with phospholipase A1 and triacylglycerol hydrolase activity. The human HL protein is encoded by the LIPC gene on chromosome 15q21. Most of this protein is synthesized in the parenchymal cells of the liver and secreted into the space of Disse where it binds to heparin sulfate proteoglycans. Some synthesis of HL was also observed in macrophages. The HL protein is also present in the steroidogenic adrenal glands, ovaries and, in small amounts, in the testes. By using heparin, HL protein is displaced from its binding site. Human HL protein is a homodimer, the monomer has a molecular weight of 65 kDa. In the metabolism of plasma lipoproteins HL plays an important role; it mediates the conversion of high density lipoprotein subfraction 2 (HDL2) to high density lipoprotein subfraction 3 (HDL3), the conversion of intermediate density lipoprotein (IDL) to low density l

Fermi Surface Properties of Low Concentration Cex_{x}La1−x_{1-x}B6_{6}: dHvA

The de Haas-van Alphen effect is used to study angular dependent extremal areas of the Fermi Surfaces (FS) and effective masses of Ce$_{x}$La$_{1-x}$B$_{6}$ alloys for $x$ between 0 and 0.05. The FS of these alloys was previously observed to be spin polarized at low Ce concentration ($x$ = 0.05). This work gives the details of the initial development of the topology and spin polarization of the FS from that of unpolarized metallic LaB$_{6}$ to that of spin polarized heavy Fermion CeB$_{6}$ .Comment: 7 pages, 9 figures, submitted to PR

Prototyping the Semantics of a DSL using ASF+SDF: Link to Formal Verification of DSL Models

A formal definition of the semantics of a domain-specific language (DSL) is a key prerequisite for the verification of the correctness of models specified using such a DSL and of transformations applied to these models. For this reason, we implemented a prototype of the semantics of a DSL for the specification of systems consisting of concurrent, communicating objects. Using this prototype, models specified in the DSL can be transformed to labeled transition systems (LTS). This approach of transforming models to LTSs allows us to apply existing tools for visualization and verification to models with little or no further effort. The prototype is implemented using the ASF+SDF Meta-Environment, an IDE for the algebraic specification language ASF+SDF, which offers efficient execution of the transformation as well as the ability to read models and produce LTSs without any additional pre or post processing.Comment: In Proceedings AMMSE 2011, arXiv:1106.596

Evaluating the usability of a visual feature modeling notation

International audienceFeature modeling is a popular Software Product Line Engineering (SPLE) technique used to describe variability in a product family. A usable feature modeling tool environment should enable SPLE practitioners to produce good quality models, in particular, models that effectively communicate modeled information. FAMILIAR is a text-based environment for manipulating and composing Feature Models (FMs). In this paper we present extensions we made to FAMILIAR to enhance its usability. The extensions include a visualization of FMs, or more precisely , a feature diagram rendering mechanism that supports the use of a combination of text and graphics to describe FMs, their configurations, and the results of FM analyses. We also present the results of a preliminary evaluation of the environment's usability. The evaluation involves comparing the use of the extended environment with the previous text-based console-driven version. The preliminary experiment provides some evidence that use of the new environment results in increased cognitive effectiveness of novice users and improved quality of new FMs

A systematic review of online resources to support patient decision-making for full-thickness rectal prolapse surgery

BACKGROUND: The internet is becoming an increasingly popular resource to support patient decision-making outside of the clinical encounter. The quality of online health information is variable and largely unregulated. The aim of this study was to assess the quality of online resources to support patient decision-making for full-thickness rectal prolapse surgery. METHODS: This systematic review was registered on the PROSPERO database (CRD42017058319). Searches were performed on Google and specialist decision aid repositories using a pre-defined search strategy. Sources were analysed according to three measures: (1) their readability using the Flesch-Kincaid Reading Ease score, (2) DISCERN score and (3) International Patient Decision Aids Standards (IPDAS) minimum standards criteria score (IPDASi, v4.0). RESULTS: Overall, 95 sources were from Google and the specialist decision aid repositories. There were 53 duplicates removed, and 18 sources did not meet the pre-defined eligibility criteria, leaving 24 sources included in the full-text analysis. The mean Flesch-Kincaid Reading Ease score was higher than recommended for patient education materials (48.8 ± 15.6, range 25.2-85.3). Overall quality of sources supporting patient decision-making for full-thickness rectal prolapse surgery was poor (median DISCERN score 1/5 ± 1.18, range 1-5). No sources met minimum decision-making standards (median IPDASi score 5/12 ± 2.01, range 1-8). CONCLUSIONS: Currently, easily accessible online health information to support patient decision-making for rectal surgery is of poor quality, difficult to read and does not support shared decision-making. It is recommended that professional bodies and medical professionals seek to develop decision aids to support decision-making for full-thickness rectal prolapse surgery

The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.

Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.Funding in the Huntly laboratory comes from Cancer Research UK, Leukemia Lymphoma Research, the Kay Kendal Leukemia Fund, the Leukemia lymphoma Society of America, the Wellcome Trust, The Medical Research Council and an NIHR Cambridge Biomedical Research Centre grant. Patient samples were processed in the Cambridge Blood and Stem Cell Biobank.This is the author accepted manuscript. The final version is available via NPG at http://dx.doi.org/10.1038/onc.2015.9

Automated reasoning on feature models

Software Product Line (SPL) Engineering has proved to be an effective method for software production. However, in the SPL community it is well recognized that variability in SPLs is increasing by the thousands. Hence, an automatic support is needed to deal with variability in SPL. Most of the current proposals for automatic reasoning on SPL are not devised to cope with extra– functional features. In this paper we introduce a proposal to model and reason on an SPL using constraint programming. We take into account functional and extra–functional features, improve current proposals and present a running, yet feasible implementation

On the Effectiveness of Unit Tests in Test-driven Development

Background: Writing unit tests is one of the primary activities in test-driven development. Yet, the existing reviews report few evidence supporting or refuting the effect of this development approach on test case quality. Lack of ability and skills of developers to produce sufficiently good test cases are also reported as limitations of applying test-driven development in industrial practice. Objective: We investigate the impact of test-driven development on the effectiveness of unit test cases compared to an incremental test last development in an industrial context. Method: We conducted an experiment in an industrial setting with 24 professionals. Professionals followed the two development approaches to implement the tasks. We measure unit test effectiveness in terms of mutation score. We also measure branch and method coverage of test suites to compare our results with the literature. Results: In terms of mutation score, we have found that the test cases written for a test-driven development task have a higher defect detection ability than test cases written for an incremental test-last development task. Subjects wrote test cases that cover more branches on a test-driven development task compared to the other task. However, test cases written for an incremental test-last development task cover more methods than those written for the second task. Conclusion: Our findings are different from previous studies conducted at academic settings. Professionals were able to perform more effective unit testing with test-driven development. Furthermore, we observe that the coverage measure preferred in academic studies reveal different aspects of a development approach. Our results need to be validated in larger industrial contexts.Istanbul Technical University Scientific Research Projects (MGA-2017-40712), and the Academy of Finland (Decision No. 278354)

Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed