An Approach to Relate Viewpoints and Modeling Languages

The architectural design of distributed enterprise applications from the viewpoints of different stakeholders has been proposed for some time, for example, as part of RM-ODP and IEEE 1471, and seems now-a-days to gain acceptance in practice. However, much work remains to be done on the relationships between different viewpoints. Failing to relate viewpoints may lead to a collection of viewpoint models that is inconsistent, and may therefore lead to an incorrect implementation. This paper defines an approach that helps designers to relate different viewpoints to each other. Thereby, it helps to enforce the consistency of the overall design. The results of this paper are expected to be particularly interesting for Model Driven Architecture (MDA) projects, since the proposed models can be used for the explicit definition of the models and relationships between models in an MDA trajectory

Spatial distribution of micrometre‐scale porosity and permeability across the damage zone of a reverse‐reactivated normal fault in a tight sandstone : Insights from the Otway Basin, SE Australia

This research forms part of a PhD project supported by the Australian Research Council [Discovery Project DP160101158] and through an Australian Government Research Training Program Scholarship. Dave Healy acknowledges the support of the Natural Environment Research Council (NERC, UK) through the award NE/N003063/1 ‘Quantifying the Anisotropy of Permeability in Stressed Rock’. This study was also funded by scholarships from the Petroleum Exploration Society of Australia and the Australian Petroleum Production and Exploration Association. We thank Gordon Holm for preparing thin sections and Colin Taylor for carrying out particle size measurements and mercury injection capillary pressure analyses. Aoife McFadden and David Kelsey from Adelaide Microscopy, Braden Morgan, and Sophie Harland are acknowledged for their assistance with laboratory work. Field assistants James Hall, Rowan Hansberry, and Lachlan Furness are also gratefully acknowledged for their assistance with sample collection. Discussions with Ian Duddy on the mineralogy of the Eumeralla Formation are also greatly appreciated. This forms TRaX record 416.Peer reviewedPublisher PD

Molecular and Cellular Mechanisms Affected in ALS

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways

RIPK3-mediated cell death is involved in DUX4-mediated toxicity in facioscapulohumeral dystrophy

BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is caused by mutations leading to the aberrant expression of the DUX4 transcription factor in muscles. DUX4 was proposed to induce cell death, but the involvement of different death pathways is still discussed. A possible pro-apoptotic role of DUX4 was proposed, but as FSHD muscles are characterized by necrosis and inflammatory infiltrates, non-apoptotic pathways may be also involved. METHODS: We explored DUX4-mediated cell death by focusing on the role of one regulated necrosis pathway called necroptosis, which is regulated by RIPK3. We investigated the effect of necroptosis on cell death in vitro and in vivo experiments using RIPK3 inhibitors and a RIPK3-deficient transgenic mouse model. RESULTS: We showed in vitro that DUX4 expression causes a caspase-independent and RIPK3-mediated cell death in both myoblasts and myotubes. In vivo, RIPK3-deficient animals present improved body and muscle weights, a reduction of the aberrant activation of the DUX4 network genes, and an improvement of muscle histology. CONCLUSIONS: These results provide evidence for a role of RIPK3 in DUX4-mediated cell death and open new avenues of research

The role of trust and hope in antipsychotic medication reviews between GPs and service users a realist review

Abstract Background Increasing number of service users diagnosed with schizophrenia and psychosis are being discharged from specialist secondary care services to primary care, many of whom are prescribed long-term antipsychotics. It is unclear if General Practitioners (GPs) have the confidence and experience to appropriately review and adjust doses of antipsychotic medication without secondary care support. Aim To explore barriers and facilitators of conducting antipsychotic medication reviews in primary care for individuals with no specialist mental health input. Design &amp; setting Realist review in general practice settings. Method A realist review has been conducted to synthesise evidence on antipsychotic medication reviews conducted in primary care with service users diagnosed with schizophrenia or psychosis. Following initial scoping searches and discussions with stakeholders, a systematic search and iterative secondary searches were conducted. Articles were systematically screened and analysed to develop a realist programme theory explaining the contexts (C) and mechanisms (M) which facilitate or prevent antipsychotic medication reviews (O) in primary care settings, and the potential outcomes of medication reviews. Results Meaningful Antipsychotic medication reviews may not occur for individuals with only primary care medical input. Several, often mutually reinforcing, mechanisms have been identified as potential barriers to conducting such reviews, including low expectations of recovery for people with severe mental illness, a perceived lack of capability to understand and participate in medication reviews, linked with a lack of information shared in appointments between GPs and Service Users, perceived risk and uncertainty regarding antipsychotic medication and illness trajectory. Conclusions The review identified reciprocal and reinforcing stereotypes affecting both GPs and service users. Possible mechanisms to counteract these barriers are discussed, including realistic expectations of medication, and the need for increased information sharing and trust between GPs and service users. </jats:sec

Evaluation of expression and function of the H+/myo-inositol transporter HMIT;

BACKGROUND: The phosphoinositide (PIns) signalling pathway regulates a series of neuronal processes, such as neurotransmitter release, that are thought to be altered in mood disorders. Furthermore, mood-stabilising drugs have been shown to inhibit key enzymes that regulate PIns production and alter neuronal growth cone morphology in an inositol-reversible manner. Here, we describe analyses of expression and function of the recently identified H+/myo-inositol transporter (HMIT) investigated as a potential regulator of PIns signalling. RESULTS: We show that HMIT is primarily a neuronal transporter widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex, as shown by immunohistochemistry. The transporter is localised at the Golgi apparatus in primary cultured neurones. No HMIT-mediated electrophysiological responses were detected in rat brain neurones or slices; in addition, inositol transport and homeostasis were unaffected in HMIT targeted null-mutant mice. CONCLUSION: Together, these data do not support a role for HMIT as a neuronal plasma membrane inositol transporter, as previously proposed. However, we observed that HMIT can transport inositol triphosphate, indicating unanticipated intracellular functions for this transporter that may be relevant to mood control

Evaluation of expression and function of the H+/myo-inositol transporter HMIT;

BACKGROUND: The phosphoinositide (PIns) signalling pathway regulates a series of neuronal processes, such as neurotransmitter release, that are thought to be altered in mood disorders. Furthermore, mood-stabilising drugs have been shown to inhibit key enzymes that regulate PIns production and alter neuronal growth cone morphology in an inositol-reversible manner. Here, we describe analyses of expression and function of the recently identified H+/myo-inositol transporter (HMIT) investigated as a potential regulator of PIns signalling. RESULTS: We show that HMIT is primarily a neuronal transporter widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex, as shown by immunohistochemistry. The transporter is localised at the Golgi apparatus in primary cultured neurones. No HMIT-mediated electrophysiological responses were detected in rat brain neurones or slices; in addition, inositol transport and homeostasis were unaffected in HMIT targeted null-mutant mice. CONCLUSION: Together, these data do not support a role for HMIT as a neuronal plasma membrane inositol transporter, as previously proposed. However, we observed that HMIT can transport inositol triphosphate, indicating unanticipated intracellular functions for this transporter that may be relevant to mood control

Children’s, parents’ and educators’ understandings and experiences of digital resilience: A systematic review and meta-ethnography

Supporting children to be digitally resilient when facing online adversity is an increasingly important developmental task. However, conceptual knowledge underpinning digital resilience and how this operates among children and across their home, community and societal contexts is embryonic. A systematic review and meta-ethnography of research focusing on the understandings and experiences of digital resilience of children aged 8–12, their parents and educators identified 11 studies conducted since 2011 across 14 countries. Four main themes, ‘Using connective technologies’, ‘Risky online experiences’, ‘Mediation strategies’ (comprised of sub-themes ‘Proactive coping’ and ‘Reactive coping’), and ‘Risk and protective factors’ were constructed from our translation of first- and second-order constructs, with the overarching theme ‘Constant balancing’ cross-cutting these themes. We argue one cannot have risky online experiences without the potential to develop digital resilience and vice versa. Insofar as current conceptualisations of digital resilience underestimate the role played by wider contexts, important knowledge gaps are highlighted