Managing Process Variants in the Process Life Cycle

When designing process-aware information systems, often variants of the same process have to be specified. Each variant then constitutes an adjustment of a particular process to specific requirements building the process context. Current Business Process Management (BPM) tools do not adequately support the management of process variants. Usually, the variants have to be kept in separate process models. This leads to huge modeling and maintenance efforts. In particular, more fundamental process changes (e.g., changes of legal regulations) often require the adjustment of all process variants derived from the same process; i.e., the variants have to be adapted separately to meet the new requirements. This redundancy in modeling and adapting process variants is both time consuming and error-prone. This paper presents the Provop approach, which provides a more flexible solution for managing process variants in the process life cycle. In particular, process variants can be configured out of a basic process following an operational approach; i.e., a specific variant is derived from the basic process by applying a set of well-defined change operations to it. Provop provides full process life cycle support and allows for flexible process configuration resulting in a maintainable collection of process variants

Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes

Background: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 post-mortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment

Variants of Schroeder Dissections

Some formulae are given for the enumeration of certain types of dissections of the convex (n+2)-gon by non-crossing diagonals. The classical Schroeder and Motzkin numbers are addressed using a cataloguing tool, the "reversive symbol". The elementary details are referred to three Web addresses.Comment: 2 page

Product line architecture recovery with outlier filtering in software families: the Apo-Games case study

Software product line (SPL) approach has been widely adopted to achieve systematic reuse in families of software products. Despite its benefits, developing an SPL from scratch requires high up-front investment. Because of that, organizations commonly create product variants with opportunistic reuse approaches (e.g., copy-and-paste or clone-and-own). However, maintenance and evolution of a large number of product variants is a challenging task. In this context, a family of products developed opportunistically is a good starting point to adopt SPLs, known as extractive approach for SPL adoption. One of the initial phases of the extractive approach is the recovery and definition of a product line architecture (PLA) based on existing software variants, to support variant derivation and also to allow the customization according to customers’ needs. The problem of defining a PLA from existing system variants is that some variants can become highly unrelated to their predecessors, known as outlier variants. The inclusion of outlier variants in the PLA recovery leads to additional effort and noise in the common structure and complicates architectural decisions. In this work, we present an automatic approach to identify and filter outlier variants during the recovery and definition of PLAs. Our approach identifies the minimum subset of cross-product architectural information for an effective PLA recovery. To evaluate our approach, we focus on real-world variants of the Apo-Games family. We recover a PLA taking as input 34 Apo-Game variants developed by using opportunistic reuse. The results provided evidence that our automatic approach is able to identify and filter outlier variants, allowing to eliminate exclusive packages and classes without removing the whole variant. We consider that the recovered PLA can help domain experts to take informed decisions to support SPL adoption.This research was partially funded by INES 2.0; CNPq grants 465614/2014-0 and 408356/2018-9; and FAPESB grants JCB0060/2016 and BOL2443/201

Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1

Background: Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype–phenotype correlations. Methods: We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (ExAC). Results: Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype–phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP1 pathogenic variants did not present with very early-onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. Conclusion: Variants across STXBP1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants

De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder