Modulation of the GABAergic pathway for the treatment of fragile X syndrome.

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS

Island syndrome in rodents; a comparative study on island forms of the bank vole, Myodes glareolus

PhD 2009 QMIslands are extremely variable habitats, differing in shape, size, degree of isolation, geography and climate. They are often described as ‘natural laboratories’ and have proven beneficial for testing theories on evolution and adaptation. Rodents on islands are often characterised by differences in demography, morphology and behaviour compared to adjacent mainland populations. One of the most notable and extensively reported differences is in body size. Several adaptive theories have been suggested to explain these phenomena, which have been termed ‘island syndrome’, yet few have been empirically tested. The bank vole (Myodes glareolus) is a good model for studying the evolution of island syndrome, being present throughout the British mainland as well as on 13 small offshore islands. Voles on four of these islands exhibit the gigantism characteristic of island syndrome. The aim of this study was to compare insular and mainland populations of voles to determine whether island syndrome is truly an adaptive response to life in insular habitats, or whether it is driven by more random processes such as founder effects and genetic drift. In this thesis, I present data on body size, demography and skull morphology along with phylogenetic analyses based on mitochondrial DNA sequences from island and mainland populations of bank voles around the UK. Whilst I was able to demonstrate insular changes in body size, I was unable to demonstrate any demographic differences consistent with the predictions of island syndrome. Phylogenetic analyses revealed that body size differentiation on islands was not related to phylogeographic history. There was little evidence for a single unifying theory explaining the existence of island syndrome, thus I conclude that this biological pattern is probably caused by multiple environmental and genetic factors.Natural Environment Research Council (NERC), Countryside Council for Wales and the States of Jerse

Modulation of the GABAergic pathway for the treatment of fragile X syndrome

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS

Atmospheric CO2 effect on stable carbon isotope composition of terrestrial fossil archives.

The 13C/12C ratio of C3 plant matter is thought to be controlled by the isotopic composition of atmospheric CO2 and stomatal response to environmental conditions, particularly mean annual precipitation (MAP). The effect of CO2 concentration on 13C/12C ratios is currently debated, yet crucial to reconstructing ancient environments and quantifying the carbon cycle. Here we compare high-resolution ice core measurements of atmospheric CO2 with fossil plant and faunal isotope records. We show the effect of pCO2 during the last deglaciation is stronger for gymnosperms (-1.4 ± 1.2‰) than angiosperms/fauna (-0.5 ± 1.5‰), while the contributions from changing MAP are -0.3 ± 0.6‰ and -0.4 ± 0.4‰, respectively. Previous studies have assumed that plant 13C/12C ratios are mostly determined by MAP, an assumption which is sometimes incorrect in geological time. Atmospheric effects must be taken into account when interpreting terrestrial stable carbon isotopes, with important implications for past environments and climates, and understanding plant responses to climate change

A review of metrology in lithium-ion electrode coating processes

Lithium-ion battery electrode design and manufacture is a multi-faceted process where the link between underlying physical processes and manufacturing outputs is not yet fully understood. This is in part due to the many parameters and variables involved and the lack of complete data sets under different processing conditions. The slurry coating step has significant implications for electrode design and advanced metrology offers opportunities to improve understanding and control at this stage. Here, metrology options for slurry coating are reviewed as well as opportunities for in-line integration, discussing the benefits of combining advanced metrology to provide comprehensive characterisation, improve understanding and feed into predictive design models. There is a comprehensive range of metrology which needs little improvement to provide the relevant quantifiable measures during coating, with one exception of particle sizing, where more precise, in-line measurement would be beneficial. However, there is a lack of studies that bring together the latest advancements in electrode coating metrology which is crucial to understanding the interdependency of myriad processing and product parameters. This review highlights the need for a comprehensive metrological picture whose value would be much greater than the sum of its parts for the next generation of multiphysics and data-driven models

Taking the Leap: Implementing a Migration to OJS 3

The Public Knowledge Project announced the release of Open Journal Systems (OJS) 3 in August 2016. In addition to a more streamlined interface OJS 3 offers important functionality, including more flexible roles, new plugins, and even the ability to operationalize XML-first publishing. However, almost two years after the official release, several library publishers have not yet migrated to the newest version of OJS. In addition to the technical support needed to successfully plan and execute the migration, implementation often involves extensive outreach to editors on system changes and new functionality. At the same time, library publishers that do decide to migrate often work in isolation, asking colleagues on listservs, Github, or other online forums for advice or information about their experience migrating. There are no formal community-developed outreach materials for library publishers to share communally and implement locally. This session will present three case studies for the transition to OJS 3. One case study, from the University of Minnesota, will explore the migration from bepress to OJS 3. Two others, from Indiana University and Indiana University-Purdue University Indianapolis, will explore migrating a multi-site instance from OJS 2 to OJS 3. Each case study will be grounded in information about the library publishing program, timeline, size of the department, and level of technical support available. In addition to presenting our process for completing the migration, we will share tangible outreach materials with participants. These include communication templates, training outlines, videos, and wikis created to support journal editors transition to OJS 3. The session will also present obstacles to success, which we hope will prompt a discussion about how to improve others’ planning process and eventually build community around this topic

‘The opportunity to have their say’? Identifying mechanisms of community engagement in local alcohol decision-making

Background Engaging the community in decisions-making is recognised as important for improving public health, and is recommended in global alcohol strategies, and in national policies on controlling alcohol availability. Yet there is little understanding of how to engage communities to influence decision-making to help reduce alcohol-related harms. We sought to identify and understand mechanisms of community engagement in decision-making concerning the local alcohol environment in England. Methods We conducted case studies in three local government areas in England in 2018, purposively selected for examples of community engagement in decisions affecting the local alcohol environment. We conducted 20 semi-structured interviews with residents, workers, local politicians and local government practitioners, and analysed documents linked to engagement and alcohol decision-making. Results Four rationales for engaging the community in decision-making affecting the alcohol environment were identified: i) as part of statutory decision-making processes; ii) to develop new policies; iii) as representation on committees; and iv) occurring through relationship building. Many of the examples related to alcohol licensing processes, but also local economy and community safety decision-making. The impact of community inputs on decisions was often not clear, but there were a few instances of engagement influencing the process and outcome of decision-making relating to the alcohol environment. Conclusions While influencing statutory licensing decision-making is challenging, community experiences of alcohol-related harms can be valuable ‘evidence’ to support new licensing policies. Informal relationship-building between communities and local government is also beneficial for sharing information about alcohol-related harms and to facilitate future engagement. However, care must be taken to balance the different interests among diverse community actors relating to the local alcohol environment, and extra support is needed for those with least capacity to engage but who face more burden of alcohol-related harms, to avoid compounding existing inequalities

On deflationary accounts of human action understanding

A common deflationary tendency has emerged recently in both philosophical accounts and comparative animal studies concerned with how subjects understand the actions of others. The suggestion emerging from both arenas is that the default mechanism for understanding action involves only a sensitivity to the observable, behavioural (non-mental) features of a situation. This kind of ‘smart behaviour reading’ thus suggests that, typically, predicting or explaining the behaviour of conspecifics does not require seeing the other through the lens of mental state attribution. This paper aims to explore and assess this deflationary move. In §1 I clarify what might be involved in a smart behaviour reading account via looking at some concrete examples. Then in §2 I critically assess the deflationary move, arguing that, at least in the human case, it would in fact be a mistake to assume that our default method of action understanding proceeds without appeal to mental state attribution. Finally in §3 I consider briefly how the positive view proposed here relates to discussions about standard two-system models of cognition

Roadmap on Li-ion battery manufacturing research

Growth in the Li-ion battery market continues to accelerate, driven primarily by the increasing need for economic energy storage for electric vehicles. Electrode manufacture by slurry casting is the first main step in cell production but much of the manufacturing optimisation is based on trial and error, know-how and individual expertise. Advancing manufacturing science that underpins Li-ion battery electrode production is critical to adding to the electrode manufacturing value chain. Overcoming the current barriers in electrode manufacturing requires advances in materials, manufacturing technology, in-line process metrology and data analytics, and can enable improvements in cell performance, quality, safety and process sustainability. In this roadmap we explore the research opportunities to improve each stage of the electrode manufacturing process, from materials synthesis through to electrode calendering. We highlight the role of new process technology, such as dry processing, and advanced electrode design supported through electrode level, physics-based modelling. Progress in data driven models of electrode manufacturing processes is also considered. We conclude there is a growing need for innovations in process metrology to aid fundamental understanding and to enable feedback control, an opportunity for electrode design to reduce trial and error, and an urgent imperative to improve the sustainability of manufacture