Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAGERT2cre∕+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction—mimicking pharmacological inhibition—strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development

Kinetics of exciton photoluminescence in type-II semiconductor superlattices

The exciton decay rate at a rough interface in type-II semiconductor superlattices is investigated. It is shown that the possibility of recombination of indirect excitons at a plane interface essentially affects kinetics of the exciton photoluminescence at a rough interface. This happens because of strong correlation between the exciton recombination at the plane interface and at the roughness. Expressions that relate the parameters of the luminescence kinetics with statistical characteristics of the rough interface are obtained. The mean height and length of roughnesses in GaAs/AlAs superlattices are estimated from the experimental data.Comment: 3 PostScript figure

Agile SoC Development with Open ESP

ESP is an open-source research platform for heterogeneous SoC design. The platform combines a modular tile-based architecture with a variety of application-oriented flows for the design and optimization of accelerators. The ESP architecture is highly scalable and strikes a balance between regularity and specialization. The companion methodology raises the level of abstraction to system-level design and enables an automated flow from software and hardware development to full-system prototyping on FPGA. For application developers, ESP offers domain-specific automated solutions to synthesize new accelerators for their software and to map complex workloads onto the SoC architecture. For hardware engineers, ESP offers automated solutions to integrate their accelerator designs into the complete SoC. Conceived as a heterogeneous integration platform and tested through years of teaching at Columbia University, ESP supports the open-source hardware community by providing a flexible platform for agile SoC development.Comment: Invited Paper at the 2020 International Conference On Computer Aided Design (ICCAD) - Special Session on Opensource Tools and Platforms for Agile Development of Specialized Architecture

Increasing Incidence of Geomyces destructans Fungus in Bats from the Czech Republic and Slovakia

BACKGROUND: White-nose syndrome is a disease of hibernating insectivorous bats associated with the fungus Geomyces destructans. It first appeared in North America in 2006, where over a million bats died since then. In Europe, G. destructans was first identified in France in 2009. Its distribution, infection dynamics, and effects on hibernating bats in Europe are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We screened hibernacula in the Czech Republic and Slovakia for the presence of the fungus during the winter seasons of 2008/2009 and 2009/2010. In winter 2009/2010, we found infected bats in 76 out of 98 surveyed sites, in which the majority had been previously negative. A photographic record of over 6000 hibernating bats, taken since 1994, revealed bats with fungal growths since 1995; however, the incidence of such bats increased in Myotis myotis from 2% in 2007 to 14% by 2010. Microscopic, cultivation and molecular genetic evaluations confirmed the identity of the recently sampled fungus as G. destructans, and demonstrated its continuous distribution in the studied area. At the end of the hibernation season we recorded pathologic changes in the skin of the affected bats, from which the fungus was isolated. We registered no mass mortality caused by the fungus, and the recorded population decline in the last two years of the most affected species, M. myotis, is within the population trend prediction interval. CONCLUSIONS/SIGNIFICANCE: G. destructans was found to be widespread in the Czech Republic and Slovakia, with an epizootic incidence in bats during the most recent years. Further development of the situation urgently requires a detailed pan-European monitoring scheme

Do Bat Gantries and Underpasses Help Bats Cross Roads Safely?

Major roads can reduce bat abundance and diversity over considerable distances. To mitigate against these effects and comply with environmental law, many European countries install bridges, gantries or underpasses to make roads permeable and safer to cross. However, through lack of appropriate monitoring, there is little evidence to support their effectiveness. Three underpasses and four bat gantries were investigated in northern England. Echolocation call recordings and observations were used to determine the number of bats using underpasses in preference to crossing the road above, and the height at which bats crossed. At gantries, proximity to the gantry and height of crossing bats were measured. Data were compared to those from adjacent, severed commuting routes that had no crossing structure. At one underpass 96% of bats flew through it in preference to crossing the road. This underpass was located on a pre-construction commuting route that allowed bats to pass without changing flight height or direction. At two underpasses attempts to divert bats from their original commuting routes were unsuccessful and bats crossed the road at the height of passing vehicles. Underpasses have the potential to allow bats to cross roads safely if built on pre-construction commuting routes. Bat gantries were ineffective and used by a very small proportion of bats, even up to nine years after construction. Most bats near gantries crossed roads along severed, pre-construction commuting routes at heights that put them in the path of vehicles. Crossing height was strongly correlated with verge height, suggesting that elevated verges may have some value in mitigation, but increased flight height may be at the cost of reduced permeability. Green bridges should be explored as an alternative form of mitigation. Robust monitoring is essential to assess objectively the case for mitigation and to ensure effective mitigation

Assessing road effects on bats: the role of landscape, road features, and bat activity on road-kills

Recent studies suggest that roads can significantly impact bat populations. Though bats are one of the most threatened groups of European vertebrates, studies aiming to quantify bat mortality and determine the main factors driving it remain scarce. Between March 16 and October 31 of 2009, we surveyed road-killed bats daily along a 51-km-long transect that incorporates different types of roads in southern Portugal. We found 154 road-killed bats of 11 species. The two most common species in the study area, Pipistrellus kuhlii and P. pygmaeus, were also the most commonly identified road-kill, representing 72 % of the total specimens collected. About two-thirds of the total mortality occurred between mid July and late September, peaking in the second half of August. We also recorded casualties of threatened and rare species, including Miniopterus schreibersii, Rhinolophus ferrumequinum, R. hipposideros, Barbastella barbastellus, and Nyctalus leisleri. These species were found mostly in early autumn, corresponding to the mating and swarming periods. Landscape features were the most important variable subset for explaining bat casualties. Road stretches crossing or in the vicinity of high-quality habitats for bats—including dense Mediterranean woodland (‘‘montado’’) areas, water courses with riparian gallery, and water reservoirs—yielded a significantly higher number of casualties. Additionally, more roadkilled bats were recorded on high-traffic road stretches with viaducts, in areas of higher bat activity and near known roosts

Differential responses to woodland character and landscape context by cryptic bats in urban environments

© 2015 Lintott et al. Urbanisation is one of the most dramatic forms of land use change which relatively few species can adapt to. Determining how and why species respond differently to urban habitats is important in predicting future biodiversity loss as urban areas rapidly expand. Understanding how morphological or behavioural traits can influence species adaptability to the built environment may enable us to improve the effectiveness of conservation efforts. Although many bat species are able to exploit human resources, bat species richness generally declines with increasing urbanisation and there is considerable variation in the responses of different bat species to urbanisation. Here, we use acoustic recordings from two cryptic, and largely sympatric European bat species to assess differential responses in their use of fragmented urban woodland and the surrounding urban matrix. There was a high probability of P. pygmaeus activity relative to P. pipistrellus in woodlands with low clutter and understory cover which were surrounded by low levels of built environment. Additionally, the probability of recording P. pygmaeus relative to P. pipistrellus was considerably higher in urban woodland interior or edge habitat in contrast to urban grey or non-wooded green space. These results show differential habitat use occurring between two morphologically similar species; whilst the underlying mechanism for this partitioning is unknown it may be driven by competition avoidance over foraging resources. Their differing response to urbanisation indicates the difficulties involved when attempting to assess how adaptable a species is to urbanisation for conservation purposes

Habitat Composition and Connectivity Predicts Bat Presence and Activity at Foraging Sites in a Large UK Conurbation

Background: Urbanization is characterized by high levels of sealed land-cover, and small, geometrically complex, fragmented land-use patches. The extent and density of urbanized land-use is increasing, with implications for habitat quality, connectivity and city ecology. Little is known about densification thresholds for urban ecosystem function, and the response of mammals, nocturnal and cryptic taxa are poorly studied in this respect. Bats (Chiroptera) are sensitive to changing urban form at a species, guild and community level, so are ideal model organisms for analyses of this nature. Methodology/Principal Findings: We surveyed bats around urban ponds in the West Midlands conurbation, United Kingdom (UK). Sites were stratified between five urban land classes, representing a gradient of built land-cover at the 1 km 2 scale. Models for bat presence and activity were developed using land-cover and land-use data from multiple radii around each pond. Structural connectivity of tree networks was used as an indicator of the functional connectivity between habitats. All species were sensitive to measures of urban density. Some were also sensitive to landscape composition and structural connectivity at different spatial scales. These results represent new findings for an urban area. The activity of Pipistrellus pipistrellus (Schreber 1774) exhibited a non-linear relationship with the area of built land-cover, being much reduced beyond the threshold of,60 % built surface. The presence of tree networks appears to mitigate the negative effects of urbanization for this species

Diseases and Causes of Death in European Bats: Dynamics in Disease Susceptibility and Infection Rates

Bats receive increasing attention in infectious disease studies, because of their well recognized status as reservoir species for various infectious agents. This is even more important, as bats with their capability of long distance dispersal and complex social structures are unique in the way microbes could be spread by these mammalian species. Nevertheless, infection studies in bats are predominantly limited to the identification of specific pathogens presenting a potential health threat to humans. But the impact of infectious agents on the individual host and their importance on bat mortality is largely unknown and has been neglected in most studies published to date.) were collected in different geographic regions in Germany. Most animals represented individual cases that have been incidentally found close to roosting sites or near human habitation in urban and urban-like environments. The bat carcasses were subjected to a post-mortem examination and investigated histo-pathologically, bacteriologically and virologically. Trauma and disease represented the most important causes of death in these bats. Comparative analysis of pathological findings and microbiological results show that microbial agents indeed have an impact on bats succumbing to infectious diseases, with fatal bacterial, viral and parasitic infections found in at least 12% of the bats investigated.Our data demonstrate the importance of diseases and infectious agents as cause of death in European bat species. The clear seasonal and individual variations in disease prevalence and infection rates indicate that maternity colonies are more susceptible to infectious agents, underlining the possible important role of host physiology, immunity and roosting behavior as risk factors for infection of bats