Historical roots of Agile methods: where did “Agile thinking” come from?

The appearance of Agile methods has been the most noticeable change to software process thinking in the last fifteen years [16], but in fact many of the “Agile ideas” have been around since 70’s or even before. Many studies and reviews have been conducted about Agile methods which ascribe their emergence as a reaction against traditional methods. In this paper, we argue that although Agile methods are new as a whole, they have strong roots in the history of software engineering. In addition to the iterative and incremental approaches that have been in use since 1957 [21], people who criticised the traditional methods suggested alternative approaches which were actually Agile ideas such as the response to change, customer involvement, and working software over documentation. The authors of this paper believe that education about the history of Agile thinking will help to develop better understanding as well as promoting the use of Agile methods. We therefore present and discuss the reasons behind the development and introduction of Agile methods, as a reaction to traditional methods, as a result of people's experience, and in particular focusing on reusing ideas from histor

Vision Paper: Make a Difference! (Semantically)

International audienceSyntactic difference between models is a wide research area with applications in tools for model evolution, model synchronization and version control. On the other hand, semantic difference between models is rarely discussed. We point out to main use cases of semantic difference between models, and then propose a framework for defining well-formed difference operators on model semantics as adjoints of model combinators such as conjunction, disjunction and structural composition. The framework is defined by properties rather than constructively. We instantiate the framework for two rather different modeling languages: feature models and automata specifications. We believe that the algebraic theory of semantic difference will allow to define practical model differencing tools in the future

Living with sand: A record of landscape change and storminess during the Bronze and Iron Ages Orkney, Scotland

Palaeoenvironmental analyses of an exposed sequence of interbedded sand and peat overlying glacial till on Stronsay, Orkney, has revealed evidence of dynamic landscape change during the Holocene. AMS radiocarbon and OSL dating are used to identify periods of minerogenic and organic sediment accumulation. A lengthy period of stability during the early Holocene is inferred from the development of a deeply weathered till surface with pollen and soil micromorphological evidence suggesting prolonged woodland cover. During the mid to late Holocene phases of wind-blown sand that inundated the landscape are defined from the sedimentary record and are interpreted as periods of increased storminess between c. 3400-3100 cal. BP and c. 2800-2260 cal. BP. The palaeoecological evidence points to continuity of human exploitation, despite the phases of increased storminess during the Bronze Age and into the Iron Age. Rising sea levels and a severe storm event at c. 650 years BP inundated the site with massive sands and truncated the record. These storm events recorded on Stronsay are part of a regionally synchronous record for periods of increased storminess across the North Atlantic region during the Holocene

Clinical features, molecular heterogeneity, and prognostic implications in <em>YARS2</em>-related mitochondrial myopathy.

Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. Main Outcome and Measures: The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Results: Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes. Conclusions and Relevance: The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder

Design of Collaborative Information Agents

. Effective development of nontrivial systems of collaborative information agents requires that an in-depth analysis is made resulting in (1) specification of requirements at different levels of the system, (2) specification of design structures, and (3) a systematic verification. To support a widespread use of intelligent information agents for the Internet, the challenges are (1) to identify and classify a variety of instances of the different types of reusable (requirement, design and proof) patterns, (2) build libraries of them, and (3) provide corresponding easy-to-use plug-in information agent components to the common user. In a simplified example it is shown which types of reusable requirements patterns, design patterns, and proof patterns can be exploited, and how these patterns relate to each other. 1 Introduction The domain of collaborative information agents (cf. [27]) imposes specific requirements on the functionality and behaviour of the agents and their inter..

Retrospective natural history of thymidine kinase 2 deficiency

Background Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. Objective To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. Methods The study was conducted by 42 investigators across 31 academic medical centres. Results We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. Conclusions In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder

Mutations in <em>GTPBP3</em> cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy.

Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (&tau;m(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease