Temporal Data Modeling and Reasoning for Information Systems

Temporal knowledge representation and reasoning is a major research field in Artificial Intelligence, in Database Systems, and in Web and Semantic Web research. The ability to model and process time and calendar data is essential for many applications like appointment scheduling, planning, Web services, temporal and active database systems, adaptive Web applications, and mobile computing applications. This article aims at three complementary goals. First, to provide with a general background in temporal data modeling and reasoning approaches. Second, to serve as an orientation guide for further specific reading. Third, to point to new application fields and research perspectives on temporal knowledge representation and reasoning in the Web and Semantic Web

A Type Language for Calendars

Time and calendars play an important role in databases, on the Semantic Web, as well as in mobile computing. Temporal data and calendars require (specific) modeling and processing tools. CaTTS is a type language for calendar definitions using which one can model and process temporal and calendric data. CaTTS is based on a "theory reasoning" approach for efficiency reasons. This article addresses type checking temporal and calendric data and constraints. A thesis underlying CaTTS is that types and type checking are as useful and desirable with calendric data types as with other data types. Types enable (meaningful) annotation of data. Type checking enhances efficiency and consistency of programming and modeling languages like database and Web query languages

A Reasoner for Calendric and Temporal Data

Calendric and temporal data are omnipresent in countless Web and Semantic Web applications and Web services. Calendric and temporal data are probably more than any other data a subject to interpretation, in almost any case depending on some cultural, legal, professional, and/or locational context. On the current Web, calendric and temporal data can hardly be interpreted by computers. This article contributes to the Semantic Web, an endeavor aiming at enhancing the current Web with well-defined meaning and to enable computers to meaningfully process data. The contribution is a reasoner for calendric and temporal data. This reasoner is part of CaTTS, a type language for calendar definitions. The reasoner is based on a "theory reasoning" approach using constraint solving techniques. This reasoner complements general purpose "axiomatic reasoning" approaches for the Semantic Web as widely used with ontology languages like OWL or RDF

A Reasoner for Calendric and Temporal Data

Calendric and temporal data are omnipresent in countless Web and Semantic Web applications and Web services. Calendric and temporal data are probably more than any other data a subject to interpretation, in almost any case depending on some cultural, legal, professional, and/or locational context. On the current Web, calendric and temporal data can hardly be interpreted by computers. This article contributes to the Semantic Web, an endeavor aiming at enhancing the current Web with well-defined meaning and to enable computers to meaningfully process data. The contribution is a reasoner for calendric and temporal data. This reasoner is part of CaTTS, a type language for calendar definitions. The reasoner is based on a \theory reasoning" approach using constraint solving techniques. This reasoner complements general purpose \axiomatic reasoning" approaches for the Semantic Web as widely used with ontology languages like OWL or RDF

Skeletal Muscle 11beta-HSD1 Controls Glucocorticoid-Induced Proteolysis and Expression of E3 Ubiquitin Ligases Atrogin-1 and MuRF-1

Recent studies demonstrated expression and activity of the intracellular cortisone-cortisol shuttle 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in skeletal muscle and inhibition of 11beta-HSD1 in muscle cells improved insulin sensitivity. Glucocorticoids induce muscle atrophy via increased expression of the E3 ubiquitin ligases Atrogin-1 (Muscle Atrophy F-box (MAFbx)) and MuRF-1 (Muscle RING-Finger-1). We hypothesized that 11beta-HSD1 controls glucocorticoid-induced expression of atrophy E3 ubiquitin ligases in skeletal muscle. Primary human myoblasts were generated from healthy volunteers. 11beta-HSD1-dependent protein degradation was analyzed by [3H]-tyrosine release assay. RT-PCR was used to determine mRNA expression of E3 ubiquitin ligases and 11beta-HSD1 activity was measured by conversion of radioactively labeled [3H]-cortisone to [3H]-cortisol separated by thin-layer chromatography. We here demonstrate that 11beta-HSD1 is expressed and biologically active in interconverting cortisone to active cortisol in murine skeletal muscle cells (C2C12) as well as in primary human myotubes. 11beta-HSD1 expression increased during differentiation from myoblasts to mature myotubes (p<0.01), suggesting a role of 11beta-HSD1 in skeletal muscle growth and differentiation. Treatment with cortisone increased protein degradation by about 20% (p<0.001), which was paralleled by an elevation of Atrogin-1 and MuRF-1 mRNA expression (p<0.01, respectively). Notably, pre-treatment with the 11beta-HSD1 inhibitor carbenoxolone (Cbx) completely abolished the effect of cortisone on protein degradation as well as on Atrogin-1 and MuRF-1 expression. In summary, our data suggest that 11beta-HSD1 controls glucocorticoid-induced protein degradation in human and murine skeletal muscle via regulation of the E3 ubiquitin ligases Atrogin-1 and MuRF-1

47 patients with FLNA associated periventricular nodular heterotopia

Background: Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established. Methods: Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients. Results: Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age. Conclusions: We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males

Identification of FOXP1 Deletions in Three Unrelated Patients with Mental Retardation and Significant Speech and Language Deficits

Mental retardation affects 2-3% of the population and shows a high heritability. Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors. We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language. ©2010 Wiley-Liss, Inc

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. Results: Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. Conclusion: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics