An empirical evaluation of a novel domain-specific language - modelling vehicle routing problems with Athos.

Domain-specific languages (DSLs) are a popular approach among software engineers who demand for a tailored development interface. A DSL-based approach allows to encapsulate the intricacies of the target platform in transformations that turn DSL models into executable software code. Often, DSLs are even claimed to reduce development complexity to a level that allows them to be successfully applied by domain-experts with limited programming knowledge. Recent research has produced some scientifically backed insights on the benefits and limitations of DSLs. Further empirical studies are required to build a sufficient body of knowledge from which support for different claims related to DSLs can be derived. In this research study, we adopt current DSL evaluation approaches to investigate potential gains in terms of effectiveness and efficiency, through the application of our DSL Athos, a language developed for the domain of traffic and transportation simulation and optimisation. We compare Athos to the alternative of using an application library defined within a general-purpose language (GPL). We specified two sets of structurally identical tasks from the domain of vehicle routing problems and asked study groups with differing levels of programming knowledge to solve the tasks with the two approaches. The results show that inexperienced participants achieved considerable gains in effectiveness and efficiency with the usage of Athos DSL. Though hinting at Athos being the more efficient approach, the results were less distinct for more experienced programmers. The vast majority of participants stated to prefer working with Athos over the usage of the presented GPL's API. Supplementary Information: The online version contains supplementary material available at 10.1007/s10664-022-10210-whttps://doi.org/10.1007/s10664-022-10210-w.

A Task Taxonomy for Temporal Graph Visualisation.

By extending and instantiating an existing formal task framework, we define a task taxonomy and task design space for temporal graph visualisation. We discuss the process involved in their generation, and describe how the design space can be 'sliced and diced' into multiple overlapping task categories, requiring distinct visual techniques for their support. The approach addresses deficiencies in the task literature, offering domain independence, greater task coverage, and unambiguous task specification. The taxonomy and design space capture tasks for temporal graphs, and also static graphs, multivariate graphs, and graph comparison, and will be of value in the design and evaluation of temporal graph visualisation systems.

Quantitative proteomic analysis of Burkholderia pseudomallei Bsa type III secretion system effectors using hypersecreting mutants.

Burkholderia pseudomallei is an intracellular pathogen and the causative agent of melioidosis, a severe disease of humans and animals. One of the virulence factors critical for early stages of infection is the Burkholderia secretion apparatus (Bsa) Type 3 Secretion System (T3SS), a molecular syringe that injects bacterial proteins, called effectors, into eukaryotic cells where they subvert cellular functions to the benefit of the bacteria. Although the Bsa T3SS itself is known to be important for invasion, intracellular replication, and virulence, only a few genuine effector proteins have been identified and the complete repertoire of proteins secreted by the system has not yet been fully characterized. We constructed a mutant lacking bsaP, a homolog of the T3SS "gatekeeper" family of proteins that exert control over the timing and magnitude of effector protein secretion. Mutants lacking BsaP, or the T3SS translocon protein BipD, were observed to hypersecrete the known Bsa effector protein BopE, providing evidence of their role in post-translational control of the Bsa T3SS and representing key reagents for the identification of its secreted substrates. Isobaric Tags for Relative and Absolute Quantification (iTRAQ), a gel-free quantitative proteomics technique, was used to compare the secreted protein profiles of the Bsa T3SS hypersecreting mutants of B. pseudomallei with the isogenic parent strain and a bsaZ mutant incapable of effector protein secretion. Our study provides one of the most comprehensive core secretomes of B. pseudomallei described to date and identified 26 putative Bsa-dependent secreted proteins that may be considered candidate effectors. Two of these proteins, BprD and BapA, were validated as novel effector proteins secreted by the Bsa T3SS of B. pseudomallei.

Complement factor D in age-related macular degeneration.

PURPOSE: To examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by analysis of genetic association, copy number variation, and plasma CFD concentrations. METHODS: Single nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy number was analyzed by gene copy number assay. Plasma CFD was measured by an enzyme-linked immunosorbent assay. RESULTS: Genetic association was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-analysis of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the association almost confined to females. Copy number variation in the CFD gene was identified in 13 out of 640 samples examined but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concentration was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest versus lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females. CONCLUSIONS: CFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic association between a CFD gene SNP and AMD and a significant increase in plasma CFD concentration in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis.

Discovery and assessment of conserved Pax6 target genes and enhancers.

The characterization of transcriptional networks (TNs) is essential for understanding complex biological phenomena such as development, disease, and evolution. In this study, we have designed and implemented a procedure that combines in silico target screens with zebrafish and mouse validation, in order to identify cis-elements and genes directly regulated by Pax6. We chose Pax6 as the paradigm because of its crucial roles in organogenesis and human disease. We identified over 600 putative Pax6 binding sites and more than 200 predicted direct target genes, conserved in evolution from zebrafish to human and to mouse. This was accomplished using hidden Markov models (HMMs) generated from experimentally validated Pax6 binding sites. A small sample of genes, expressed in the neural lineage, was chosen from the predictions for RNA in situ validation using zebrafish and mouse models. Validation of DNA binding to some predicted cis-elements was also carried out using chromatin immunoprecipitation (ChIP) and zebrafish reporter transgenic studies. The results show that this combined procedure is a highly efficient tool to investigate the architecture of TNs and constitutes a useful complementary resource to ChIP and expression data sets because of its inherent spatiotemporal independence. We have identified several novel direct targets, including some putative disease genes, among them Foxp2; these will allow further dissection of Pax6 function in development and disease.

alpha-Hemoglobin stabilizing protein is not a suitable marker for a screening test for variant Creutzfeldt-Jakob disease.

BACKGROUND: A test is needed to identify blood donors who are in the preclinical phase of variant Creutzfeldt-Jakob disease (CJD). alpha-Hemoglobin stabilizing protein (AHSP; syn. ERAF, EDRF) transcript levels are reduced in the blood of mice incubating transmissible spongiform encephalopathy. STUDY DESIGN AND METHODS: Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay were used to measure AHSP transcript and protein levels in normal blood donors, patients with CJD, and patients with other neuronal and hematologic diseases. Temporal AHSP expression was measured in sheep incubating bovine spongiform encephalopathy (BSE). RESULTS: Quantitation of AHSP in peripheral blood from normal blood donors revealed that protein levels, but not transcript levels, are influenced by sex with higher levels found in males, suggesting posttranslational regulation involving the product of an X-linked gene. When AHSP mRNA and protein levels were quantitated in peripheral blood from patients with variant and sporadic CJD, no consistent differences from normal were found. Serial quantitation of AHSP in individual BSE-infected sheep did not reveal any disease-related changes. CONCLUSION: We conclude that quantitation of AHSP is not likely to be useful for detection of preclinical prion disease in man.

Splicing regulation at the second catalytic step by Sex-lethal involves 3' splice site recognition by SPF45.

The Drosophila protein Sex-lethal (SXL) promotes skipping of exon 3 from its own pre-mRNA. An unusual sequence arrangement of two AG dinucleotides and an intervening polypyrimidine (Py)-tract at the 3' end of intron 2 is important for Sxl autoregulation. Here we show that U2AF interacts with the Py-tract and downstream AG, whereas the spliceosomal protein SPF45 interacts with the upstream AG and activates it for the second catalytic step of the splicing reaction. SPF45 represents a new class of second step factors, and its interaction with SXL blocks splicing at the second step. These results are in contrast with other known mechanisms of splicing regulation, which target early events of spliceosome assembly. A similar role for SPF45 is demonstrated in the activation of a cryptic 3' ss generated by a mutation that causes human beta-thalassemia.