Dissection of the amyloid formation pathway in AL amyloidosis

In antibody light chain (AL) amyloidosis, overproduced light chain (LC) fragments accumulate as fibrils in organs and tissues of patients. In vitro, AL fibril formation is a slow process, characterized by a pronounced lag phase. The events occurring during this lag phase are largely unknown. We have dissected the lag phase of a patient-derived LC truncation and identified structural transitions that precede fibril formation. The process starts with partial unfolding of the V-L domain and the formation of small amounts of dimers. This is a prerequisite for the formation of an ensemble of oligomers, which are the precursors of fibrils. During oligomerization, the hydrophobic core of the LC domain rearranges which leads to changes in solvent accessibility and rigidity. Structural transitions from an anti-parallel to a parallel beta-sheet secondary structure occur in the oligomers prior to amyloid formation. Together, our results reveal a rate-limiting multi-step mechanism of structural transitions prior to fibril formation in AL amyloidosis, which offers, in the long run, opportunities for therapeutic intervention. AL amyloidosis is caused by the accumulation of overproduced light chain (LC) fragments as fibrils in patient organs and it is the most prevalent systemic amyloidosis. Here, the authors combine biochemical and biophysical experiments to characterise the lag phase of a patient-derived truncated LC and they identify structural transitions that precede fibril formation

Exploring initial challenges for green software engineering: summary of the first GREENS workshop, at ICSE 2012

The GREENS workshop provides a forum for practitioners and academics to share knowledge, ideas, practices and current results related to green and sustainable software engineering. This first workshop was held at ICSE 2012 in Zurich, Switzerland. It featured a keynote talk, twelve research position statements and two breakout sessions that discussed topics that ranged from bringing sustainability and energy efficiency into all software lifecycle stages, to green measures and estimations, practices, notations, and tools to both greening the software engineering process, and greening the resulting Information and Communication Technology systems. This report presents the themes of the workshop, summarizes the results of the discussions held in the breakout sessions, as well as the identified research challenge

The combined effects of coping and pain interference on army readiness

IntroductionChronic pain and associated interference with daily activities are common in the military and impact Force readiness. Chronic pain affects one-third of service members and is a leading cause of medical non-readiness (MNR) in the military. Research suggests that underlying psychological mechanisms related to trait coping styles and pain interference (PI) affect functional outcomes, but little research exists examining this relationship within an Army population. The purpose of this study was to examine the combined effects of PI and coping on U.S. Army soldier readiness by using annual well-being data from the Global Assessment Tool (GAT) and medical non-readiness (MNR) based on duty restriction records.MethodsThe sample comprised 866,379 soldiers who completed the GAT between 2014 and 2017 with no duty restrictions at the time of baseline GAT completion; subjects were observed through 2018 for duty restrictions. Parametric survival regression models with a Weibull distribution predicted demographic-adjusted hazards of MNR by dichotomized PI (no PI/PI) and beneficial/non-beneficial use of GAT coping components (good coping, bad coping, catastrophizing-flexibility, and catastrophizing-hopelessness). Incident MNR was evaluated for all duty restrictions, and stratified by selected body systems (upper extremity, lower extremity, psychiatric).ResultsAmong soldiers with PI, hazards were higher in those reporting non-beneficial coping styles (bad coping, hopelessness) and lower in those reporting beneficial coping styles (good coping, flexibility). Across all coping styles, PI/coping interactions were particularly strong for catastrophizing-hopelessness and when examining MNR from psychiatric conditions.DiscussionThese findings suggest some synergistic associations between pain and coping that may impact pain-related occupational disability. Coping skills may be an effective interventional target for chronic pain reduction/prevention within military programs, such as the Master Resilience Training Course offered to soldiers in the Army. Further research should assess whether early coping style interventions can reduce pain-related outcomes

Microservice Transition and its Granularity Problem: A Systematic Mapping Study

Microservices have gained wide recognition and acceptance in software industries as an emerging architectural style for autonomic, scalable, and more reliable computing. The transition to microservices has been highly motivated by the need for better alignment of technical design decisions with improving value potentials of architectures. Despite microservices' popularity, research still lacks disciplined understanding of transition and consensus on the principles and activities underlying "micro-ing" architectures. In this paper, we report on a systematic mapping study that consolidates various views, approaches and activities that commonly assist in the transition to microservices. The study aims to provide a better understanding of the transition; it also contributes a working definition of the transition and technical activities underlying it. We term the transition and technical activities leading to microservice architectures as microservitization. We then shed light on a fundamental problem of microservitization: microservice granularity and reasoning about its adaptation as first-class entities. This study reviews state-of-the-art and -practice related to reasoning about microservice granularity; it reviews modelling approaches, aspects considered, guidelines and processes used to reason about microservice granularity. This study identifies opportunities for future research and development related to reasoning about microservice granularity.Comment: 36 pages including references, 6 figures, and 3 table

Software Architecture and Dependability

International audienceDependable systems are characterized by a number of attributes including: reliability, availability, safety and security. For some attributes (namely for reliability, availability, safety), there exist probability- based theoretic foundations, enabling the application of dependability analysis techniques. The goal of dependability analysis is to forecast the values of dependability attributes, based on certain properties (e.g. failure rate, MTBF, etc.) that characterize the system's constituent elements. Nowadays, architects, designers and developers build systems based on an architecture-driven approach. They specify the system's software architecture using Architecture Description Languages or other standard modeling notations like UML. Given the previous, we examine what we need to specify at the architectural level to enable the automated generation of models for dependability analysis. In this paper, we further present a prototype implementation of the proposed approach, which relies on UML specifications of dependable systems' software architectures. Moreover, we exemplify our approach using a case study system