Interface Contracts for Workflow+ Models: an Analysis of Uncertainty across Models

Workflow models are used to rigorously specify and reason about diverse types of processes. The Workflow+ (WF+) framework has been developed to support unified modelling of the control and data in processes that can be used to derive assurance cases that support certification. However, WF+ is limited in its support for precise contracts on workflow models, which can enable powerful forms of static analysis and reasoning. In this paper we propose a mechanism for adding interface contracts to WF+ models, which can thereafter be applied to tracing and reasoning about the uncertainty that arises when combining heterogeneous models. We specifically explore this in terms of design models and assurance case models. We argue that some of the key issues in managing some types of uncertainty can be partly addressed by use of interface contract

Inversion of Plasmaspheric EUV Remote Sensing Data from the STP 72-1 Satellite

Observations of the extreme ultraviolet emission of helium ions at 30.4 nm can be used to study the global shape of the plasmasphere and its dynamical response to geomagnetic forcing. In order to retrieve number densities of plasmaspheric He+ from such observations, we have developed a new inversion technique based on discrete inverse theory, which uses the optical data to optimize a parameterized model of the He+ distribution. We apply this inversion technique to several orbits of data obtained from the Naval Research Laboratory extreme ultraviolet photometric experiment launched on the STP 72-1 satellite in October 1972. The inversion is limited to nighttime conditions where contamination from the topside ionosphere is minimal and where a simple parameterization of the He+ number density is applicable. We obtain excellent fits to the data; however, some of the retrieved model parameters have large uncertainties due to inadequate sampling of the plasmasphere. Our study shows that improved sampling using observations from different locations and view directions would significantly enhance the accuracy of the retrieved model parameters. Using a newly developed three-dimensional imaging tool to visualize the plasmaspheric regions being sampled remotely, we demonstrate that emission features observed from two of the STP 72-1 orbits originate beyond the plasmasphere. Estimated number densities of this feature are roughly consistent with observations of cold plasma seen at geosynchronous orbit by in situ experiments

Temporal overlap and co-occurrence in a guild of sub-tropical tephritid fruit flies

Studies of community assembly have emphasized snapshot comparisons of spatially replicated samples from natural assemblages. Agro-ecosystems are characterized by relatively little habitat heterogeneity and no dispersal barriers for actively flying insects. Therefore, dynamic patterns of species segregation and aggregation are more likely to reflect the direct or indirect effects of species interactions. We studied the temporal organization of a guild of 21 congeneric species of Anastrepha that colonized fruit orchards in Monte Alegre do Sul, São Paulo, Brazil. This assemblage also included the introduced Mediterranean fruit fly Ceratitis capitata. One hundred six consecutive weekly censuses (11 Jan 2002-16 Jan 2004) of flies in guava, loquat, and peach orchards revealed a pattern of minimum abundance during the coldest months of each year (June and July) and a maximum abundance during periods of flowering and fruit ripening. Overall, phenological overlap was greater than expected by chance. However, conditioned on the pattern of seasonal abundances, temporal occurrence and abundance matrices exhibited patterns of significant species segregation and anti-nestedness. In each year, the 3 orchards contained a small number of species pairs that exhibited statistically significant temporal segregation or aggregation. Most aggregated and segregated pairs reflected seasonal shifts in species presences that were not related to variation in air temperature. Most of the significant pairwise associations involved C. capitata: 8 of the 11 segregated pairs and 2 of the 7 aggregated pairs. These results suggest that species interactions between introduced and native species can be an important determinant of species associations in agro-ecosystems

Does Simulated Spaceflight Modify Epigenetic Status During Bone Remodeling?

Little is known about the effects of spaceflight conditions on epigenetics. The term epigenetics describes changes to the genome that can affect expression of a gene without changes to the sequence of DNA. Epigenetic processes are thought to underlie cellular differentiation, where transcription of specific genes occurs in response to key stimuli, and may be heritable - passing from one cell to its daughter cell. We hypothesize that the mechanical environment during spaceflight, namely microgravity-induced weightlessness or exercise regulate gene expression in the osteoblast-lineage cells both to control bone formation by osteoblasts and bone resorption by osteoclasts, which continually shapes bone structure throughout life. Similarly we intend to evaluate how radiation regulates these same bone cell activity and differentiation related genes. We further hypothesize that the regulation in bone cell gene expression is at least partially controlled through epigenetic mechanisms of methylation or small non-coding RNA (microRNAs). We have acquired preliminary data suggesting that global genome methylation is modified in response to axial compression of the tibia - a model of exercise. We intend to pursue these hypotheses wherein we will evaluate changes in gene expression and, congruently, changes in epigenetic state in bones from mice subjected to the aforementioned conditions: hindlimb unloading to simulate weightlessness, axial compression of the tibia, or radiation exposure in order to gain insight into the role of epigenetics in spaceflight-induced bone loss

Complementary Specificity of Unspecific Peroxygenases (UPOs) Enables Access to Diverse Products from Terpene Oxygenation

Unspecific Peroxygenases (UPOs) have emerged as attractive biocatalysts for selective oxygenations as, unlike cytochromes P450, they can be employed as easy-to-use lyophilised powders and depend only upon hydrogen peroxide as the external oxidant. The application of UPOs to a range of synthetic challenges relies on the characterisation of activity and specificity of complementary enzymes. Here we show that two UPOs, artUPO and rAaeUPO-PaDa-I-H, which are representative members of the ‘short’ Family I and ‘long’ Family II UPOs, display complementary activity in a series of scalable, preparative biotransformations of a diverse array of terpenes. The UPOs were also applied to the biotransformation of chrysanthemic acid derived fragments relevant in the agrichemical industry, culminating in the highly diastereoselective and enantioselective oxidation of a racemic synthetic pyrethroid derivative via kinetic resolution

Evolutionary history of human colitis-associated colorectal cancer

Objective: IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. Design: Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. Results: 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated ‘catastrophic’ CNA increase. Conclusions: Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection

Identification of Lineage-Uncommitted, Long-Lived, Label-Retaining Cells in Healthy Human Esophagus and Stomach, and in Metaplastic Esophagus

Background & Aims The existence of slowly cycling, adult stem cells has been challenged by the identification of actively cycling cells. We investigated the existence of uncommitted, slowly cycling cells by tracking 5-iodo-2'-deoxyuridine (IdU) label-retaining cells (LRCs) in normal esophagus, Barrett's esophagus (BE), esophageal dysplasia, adenocarcinoma, and healthy stomach tissues from patients. Methods Four patients (3 undergoing esophagectomy, 1 undergoing esophageal endoscopic mucosal resection for dysplasia and an esophagectomy for esophageal adenocarcinoma) received intravenous infusion of IdU (200 mg/m2 body surface area; maximum dose, 400 mg) over a 30-minute period; the IdU had a circulation half-life of 8 hours. Tissues were collected at 7, 11, 29, and 67 days after infusion, from regions of healthy esophagus, BE, dysplasia, adenocarcinoma, and healthy stomach; they were analyzed by in situ hybridization, flow cytometry, and immunohistochemical analyses. Results No LRCs were found in dysplasias or adenocarcinomas, but there were significant numbers of LRCs in the base of glands from BE tissue, in the papillae of the basal layer of the esophageal squamous epithelium, and in the neck/isthmus region of healthy stomach. These cells cycled slowly because IdU was retained for at least 67 days and co-labeling with Ki-67 was infrequent. In glands from BE tissues, most cells did not express defensin-5, Muc-2, or chromogranin A, indicating that they were not lineage committed. Some cells labeled for endocrine markers and IdU at 67 days; these cells represented a small population (<0.1%) of epithelial cells at this time point. The epithelial turnover time of the healthy esophageal mucosa was approximately 11 days (twice that of the intestine). Conclusions LRCs of human esophagus and stomach have many features of stem cells (long lived, slow cycling, uncommitted, and multipotent), and can be found in a recognized stem cell niche. Further analyses of these cells, in healthy and metaplastic epithelia, is required

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG.We performed a genome-wide association study of IOP in the population-based RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a newlocus associated with IOP. The most significantly associated SNPwas rs58073046 (ß = 0.44, P-value = 1.87 × 10-8, minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (ß = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10-8], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10-9; for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10-2). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinant