Neuropathological investigations of three murine models of Huntington’s disease

Huntington’s disease (HD) is a purely genetic neurodegenerative disorder affecting approximately 1 in 10,000 people. It is most commonly associated with excessive involuntary movement, or chorea, combined with varying degrees of other motor, psychiatric and cognitive disturbances. Identification of the mutation in the HD gene prompted the generation of several transgenic mouse models. HD is but one of a family of at least 9 triplet repeat disorders, all of which exhibit protein aggregation by a similar mechanism. The understanding of one disease is therefore of importance to the understanding of them all. This thesis aims to be a comprehensive comparative study of three very different mouse models of HD elucidating the pathological changes that precede and accompany the disease process. The work described in this thesis presents a detailed account of a longitudinal study of the pathological changes that occur within the brains of founder generations of mice transgenic for exon 1 of the HD gene, containing a highly expanded CAG repeat, the R6 lines. I have determined the intracellular sites for deposition and accumulation of the mutant protein huntingtin (htt), within both the neurons and glia of the central nervous system. The progressive accumulation of additional proteins within these aggregates has been described. The temporal evolution and spatial distribution of the neuronal intranuclear inclusion (NII) was determined using both immunohistochemical and morphometric analyses. The cellular consequences resulting from the aggregation of mutant htt were also investigated. I have conducted a detailed morphometric analysis of neurones within the cerebral cortex, striatum and cerebellum throughout the period of protein deposition, until the eventual degeneration of these cells. The dendritic and somal changes resulting from the cellular disruption associated with these NII are also described. In a further series of experiments I have investigated the changes that occur in a novel model of HD, namely the conditional, doxycycline inducible double transgenic mouse, HD94 model. It was interesting to find that the same construct when differently manipulated in two mouse lines can produce such contrasting symptoms and pathology. This was highlighted by the comparison of immunohistochemical and morphometric analyses between the HD94 and the R6 lines, where the pattern of mutant protein deposition was found to vary significantly. Lastly I have studied a more genetically accurate murine model of HD, the HD80 ‘knock-in model’. These mice develop a pathology broadly similar to that of the R6 lines but markedly different to that of the HD94, and over a much longer time frame This detailed comparative analysis of the molecular and cellular pathology of three transgenic mouse models of HD provides new insights identifying novel and unique neuropathology and suggests new approaches for therapeutic treatments for this disease

Optimization of Conditions for Studies of Protein Unfolding by Hydrogen Exchange/Mass Spectrometry

Understanding the forces driving protein folding and aggregation is an essential step in developing means for controlling these important processes. Amide hydrogen exchange, coupled with mass spectrometry, has become an important method for studying protein unfolding and refolding. To extend procedures developed to study unfolding of relatively soluble proteins to less soluble, aggregation-prone proteins requires special considerations. This publication describes a general strategy developed using yeast transaldolase, which aggregates easily under conditions required to study its unfolding. Results presented here show that reducing the protein concentration to the nanomolar range is essential for managing aggregation of transaldolase. In addition, the present results point to use of relatively high concentrations of denaturants and short incubation times to, minimize aggregation. These results also show how amide hydrogen exchange, coupled with mass spectrometry, ran be used to study soluble aggregates

Renewing membership in three community-based health insurance schemes in rural India

Low renewal rate is a key challenge facing the sustainability of Community-based Health Insurance (CBHI) schemes. While there is a large literature on initial enrolment into such schemes, there is limited evidence on the factors that impede renewal. This paper uses longitudinal data to analyse what determines renewal, both one and two years after the introduction of three CBHI schemes, which have been operating in rural Bihar and Uttar Pradesh since 2011. We find that initial scheme uptake is about 23-24 % and that two years after scheme operation, only about 20 % of the initial enrolees maintain their membership. A household’s socio-economic status does not seem to play a large role in impeding renewal. In some instances, a greater understanding of the scheme boosts renewal. The link between health status and use of health care in maintaining renewal is mixed. The clearest effect is that individuals living in households that have received benefits from the scheme are substantially more likely to renew their contracts. We find that having access to a national health insurance scheme is not a substitute for the CBHI. We conclude that the low retention rates may be attributed to limited benefit packages, slow claims processing times and the gaps between the amounts claimed and amounts paid out by insurance

Healthcare seeking behavior among self-help group households in rural Bihar and Uttar Pradesh

Abstract Background: In recent years, supported by non-governmental organizations (NGOs), a number of communitybased health insurance (CBHI) schemes have been operating in rural India. Such schemes design their benefit packages according to local priorities. This paper examines healthcare seeking behaviour among self-help group households with a view to understanding the implications for the benefit packages offered by such schemes. Methods: We use cross-sectional data collected from two of India’s poorest states and estimate an alternativespecific conditional logit model to examine healthcare seeking behaviour. Results: We find that the majority of respondents do access some form of care and that there is overwhelming use of private providers. Non-degree allopathic providers (NDAP) also called rural medical practitioners are the most popular providers. In the case of acute illnesses, proximity plays an important role in determining provider choice. For chronic illnesses, cost of care influences provider choice. Conclusion: Given the importance of proximity in determining provider choice, benefit packages offered by CBHI schemes should consider coverage of transportation costs and reimbursement of foregone earnings

Healthcare Seeking Behavior among Self-help Group Households in Rural Bihar and Uttar Pradesh, India

In recent years, supported by non-governmental organizations (NGOs), a number of demand-driven community-based health insurance (CBHI) schemes have been functioning in rural India. These CBHI schemes may design their benefit packages according to local priorities. In this paper we examine healthcare seeking behavior among self-help group households, with a view to understanding the implications for benefit packages offered by such schemes. This study is based on data from rural locations in two of India’s poorest states.1 We find that the majority of respondents do access some form of care and that there is overwhelming use of private services. Within private services, non-degree allopathic providers (NDAP) also called rural medical practitioners account for a substantial share and the main reason to access such unqualified providers is their proximity. The direct cost of care does not appear to have a bearing on choice of provider. Given the importance of proximity in determining provider choices, several solutions could be foreseen, such as mobile medical tours to villages, and/or that insurance schemes consider coverage of transportation costs and reimbursement of foregone earnings

Identification of parvalbumin interneurons as cellular substrate of fear memory persistence

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR {beta}3L(185L) to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders

From Conventional to State-of-the-Art IoT Access Control Models

open access articleThe advent in Online Social Networks (OSN) and Internet of Things (IoT) has created a new world of collaboration and communication between people and devices. The domain of internet of things uses billions of devices (ranging from tiny sensors to macro scale devices) that continuously produce and exchange huge amounts of data with people and applications. Similarly, more than a billion people are connected through social networking sites to collaborate and share their knowledge. The applications of IoT such as smart health, smart city, social networking, video surveillance and vehicular communication are quickly evolving people’s daily lives. These applications provide accurate, information-rich and personalized services to the users. However, providing personalized information comes at the cost of accessing private information of users such as their location, social relationship details, health information and daily activities. When the information is accessible online, there is always a chance that it can be used maliciously by unauthorized entities. Therefore, an effective access control mechanism must be employed to ensure the security and privacy of entities using OSN and IoT services. Access control refers to a process which can restrict user’s access to data and resources. It enforces access rules to grant authorized users an access to resources and prevent others. This survey examines the increasing literature on access control for traditional models in general, and for OSN and IoT in specific. Challenges and problems related to access control mechanisms are explored to facilitate the adoption of access control solutions in OSN and IoT scenarios. The survey provides a review of the requirements for access control enforcement, discusses several security issues in access control, and elaborates underlying principles and limitations of famous access control models. We evaluate the feasibility of current access control models for OSN and IoT and provide the future development direction of access control for the sam

Green function techniques in the treatment of quantum transport at the molecular scale

The theoretical investigation of charge (and spin) transport at nanometer length scales requires the use of advanced and powerful techniques able to deal with the dynamical properties of the relevant physical systems, to explicitly include out-of-equilibrium situations typical for electrical/heat transport as well as to take into account interaction effects in a systematic way. Equilibrium Green function techniques and their extension to non-equilibrium situations via the Keldysh formalism build one of the pillars of current state-of-the-art approaches to quantum transport which have been implemented in both model Hamiltonian formulations and first-principle methodologies. We offer a tutorial overview of the applications of Green functions to deal with some fundamental aspects of charge transport at the nanoscale, mainly focusing on applications to model Hamiltonian formulations.Comment: Tutorial review, LaTeX, 129 pages, 41 figures, 300 references, submitted to Springer series "Lecture Notes in Physics

National identity predicts public health support during a global pandemic

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = −0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.publishedVersio

Search for Gravitational Waves Associated with Gamma-Ray Bursts Detected by Fermi and Swift during the LIGO-Virgo Run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC-2020 March 27 17:00 UTC). We conduct two independent searches: A generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate. © 2022. The Author(s). Published by the American Astronomical Society