Synthesis and reactivity of 4-oxo-5-trimethylsilanyl derived α-amino acids

A Lewis-acid promoted one-carbon homologation of an aspartic acid semialdehyde with trimethylsilyldiazomethane has led to the efficient synthesis of two silicon-containing α-amino acids. The use of trimethylaluminium or catalytic tin(II) chloride gave novel 4-oxo-5-trimethylsilanyl derived amino acids in yields of 71–88%. An investigation into the reactivity of these highly functional α-amino acids showed that selective cleavage of the C–Si bond could be achieved under mild basic conditions to give a protected derivative of the naturally occurring amino acid, 4-oxo-l-norvaline. Alternatively, Peterson olefination with aryl or alkyl aldehydes resulted in the formation of E-enone derived α-amino acids

A Televised, Web-Based Randomised Trial of an Herbal Remedy (Valerian) for Insomnia

BACKGROUND: This trial was conducted as part of a project that aims to enhance public understanding and use of research in decisions about healthcare by enabling viewers to participate in research and to follow the process, through television reports and on the web. Valerian is an herbal over-the-counter drug that is widely used for insomnia. Systematic reviews have found inconsistent and inconclusive results about its effects. METHODS: Participants were recruited through a weekly nationally televised health program in Norway. Enrolment and data collection were over the Internet. 405 participants who were 18 to 75 years old and had insomnia completed a two week diary-keeping run-in period without treatment and were randomised and mailed valerian or placebo tablets for two weeks. All participants and investigators were blind to treatment until after the analysis was completed. FINDINGS: For the primary outcome of a minimally important improvement in self-reported sleep quality (> or = 0.5 units on a 7 point scale), the difference between the valerian group (29%) and the placebo group (21%) was not statistically significant (difference 7.5%; 95% CI-0.9 to 15.9; p = 0.08). On the global self-assessment question at the end of the treatment period 5.5% (95% CI 0.2 to 10.8) more participants in the valerian group perceived their sleep as better or much better (p = 0.04). There were similar trends favouring the valerian group for night awakenings (difference = 6.0%, 95% CI-0.5 to 12.5) and sleep duration (difference = 7.5%, 95% CI-1.0 to 16.1). There were no serious adverse events and no important or statistically significant differences in minor adverse events. INTERPRETATION: Based on this and previous studies, valerian appears to be safe, but with modest beneficial effects at most on insomnia compared to placebo. The combined use of television and the Internet in randomised trials offers opportunities to answer questions about the effects of health care interventions and to improve public understanding and use of randomised trials. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN72748991

Cooling athletes with a spinal cord injury

Cooling strategies that help prevent a reduction in exercise capacity whilst exercising in the heat have received considerable research interest over the past 3 decades, especially in the lead up to a relatively hot Olympic and Paralympic Games. Progressing into the next Olympic/Paralympic cycle, the host, Rio de Janeiro, could again present an environmental challenge for competing athletes. Despite the interest and vast array of research into cooling strategies for the able-bodied athlete, less is known regarding the application of these cooling strategies in the thermoregulatory impaired spinal cord injured (SCI) athletic population. Individuals with a spinal cord injury (SCI) have a reduced afferent input to the thermoregulatory centre and a loss of both sweating capacity and vasomotor control below the level of the spinal cord lesion. The magnitude of this thermoregulatory impairment is proportional to the level of the lesion. For instance, individuals with high-level lesions (tetraplegia) are at a greater risk of heat illness than individuals with lower-level lesions (paraplegia) at a given exercise intensity. Therefore, cooling strategies may be highly beneficial in this population group, even in moderate ambient conditions (~21 °C). This review was undertaken to examine the scientific literature that addresses the application of cooling strategies in individuals with an SCI. Each method is discussed in regards to the practical issues associated with the method and the potential underlying mechanism. For instance, site-specific cooling would be more suitable for an athlete with an SCI than whole body water immersion, due to the practical difficulties of administering this method in this population group. From the studies reviewed, wearing an ice vest during intermittent sprint exercise has been shown to decrease thermal strain and improve performance. These garments have also been shown to be effective during exercise in the able-bodied. Drawing on additional findings from the able-bodied literature, the combination of methods used prior to and during exercise and/or during rest periods/half-time may increase the effectiveness of a strategy. However, due to the paucity of research involving athletes with an SCI, it is difficult to establish an optimal cooling strategy. Future studies are needed to ensure that research outcomes can be translated into meaningful performance enhancements by investigating cooling strategies under the constraints of actual competition. Cooling strategies that meet the demands of intermittent wheelchair sports need to be identified, with particular attention to the logistics of the sport

Scenario-based requirements elicitation for user-centric explainable AI

Explainable Artificial Intelligence (XAI) develops technical explanation methods and enable interpretability for human stakeholders on why Artificial Intelligence (AI) and machine learning (ML) models provide certain predictions. However, the trust of those stakeholders into AI models and explanations is still an issue, especially domain experts, who are knowledgeable about their domain but not AI inner workings. Social and user-centric XAI research states it is essential to understand the stakeholder’s requirements to provide explanations tailored to their needs, and enhance their trust in working with AI models. Scenario-based design and requirements elicitation can help bridge the gap between social and operational aspects of a stakeholder early before the adoption of information systems and identify its real problem and practices generating user requirements. Nevertheless, it is still rarely explored the adoption of scenarios in XAI, especially in the domain of fraud detection to supporting experts who are about to work with AI models. We demonstrate the usage of scenario-based requirements elicitation for XAI in a fraud detection context, and develop scenarios derived with experts in banking fraud. We discuss how those scenarios can be adopted to identify user or expert requirements for appropriate explanations in his daily operations and to make decisions on reviewing fraudulent cases in banking. The generalizability of the scenarios for further adoption is validated through a systematic literature review in domains of XAI and visual analytics for fraud detection

RRM adjacent TARDBP mutations disrupt RNA binding and enhance TDP-43 proteinopathy

Amyotrophic lateral sclerosis (ALS) presents with focal muscle weakness due to motor neuron degeneration that becomes generalized,leading to death from respiratory failure within 3–5 years from symptom onset. Despite the heterogeneity of aetiology, TDP- 43 proteinopathy is a common pathological feature that is observed in 495% of ALS and tau-negative frontotemporal dementia(FTD) cases. TDP-43 is a DNA/RNA-binding protein that in ALS and FTD translocates from being predominantly nuclear to formdetergent-resistant, hyperphosphorylated aggregates in the cytoplasm of affected neurons and glia. Mutations in TARDBP accountfor 1–4% of all ALS cases and almost all arise in the low complexity C-terminal domain that does not affect RNA binding andprocessing. Here we report an ALS/FTD kindred with a novel K181E TDP-43 mutation that is located in close proximity to the RRM1 domain. To offer predictive gene testing to at-risk family members, we undertook a series of functional studies to characterizethe properties of the mutation. Spectroscopy studies of the K181E protein revealed no evidence of significant misfolding.Although it is unable to bind to or splice RNA, it forms abundant aggregates in transfected cells. We extended our study to includeother ALS-linked mutations adjacent to the RRM domains that also disrupt RNA binding and greatly enhance TDP-43 aggregation,forming detergent-resistant and hyperphosphorylated inclusions. Lastly, we demonstrate that K181E binds to, and sequesters, wild-type TDP-43 within nuclear and cytoplasmic inclusions. Thus, we demonstrate that TDP-43 mutations that disrupt RNAbinding greatly enhance aggregation and are likely to be pathogenic as they promote wild-type TDP-43 to mislocalize andaggregate acting in a dominant-negative manner. This study highlights the importance of RNA binding to maintain TDP-43solubility and the role of TDP-43 aggregation in disease pathogenesis

Cognitive Dimensions of Design Rationale

A design rationale (DR) is a representation of the reasoning behind the design of a system. One of the primary goals in developing a usable DR environment is minimising the cognitive overhead of representing design deliberation in a structured form. This paper examines some of the cognitive attributes of various DR notations, focussing on how generic cognitive dimensions of notations can be operationalised to clarify the relationship between DR notations and the DR authoring process. It is shown how cognitive dimensions analysis makes explicit some of the requirements for DR authoring environments, highlighting the importance of supporting intermediate DR representations; these ‘rough DRs ’ evolve as design reasoning unfolds, to reflect new perspectives on the design space