Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline

Rationale: Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. Objective: In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Methods: Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/− mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Results: Once stable performance had been achieved, Map2k7+/− mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline—a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia—signs of improvement in attentional performance were detected. Conclusions: Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline

Exploring the challenges in developing a multi-criteria assessment for smart local energy systems

Several countries worldwide, including the United Kingdom, are investing in and introducing policies to foster the development and deployment of Smart Local Energy Systems. Smart Local Energy Systems are complex and socio-technical, with a wide range of stakeholders and multiple social, technical, environmental and economic aims. It is, therefore, essential to develop a standardised assessment tool to monitor the implementation of these systems and their social, technological, environmental and economic benefits and impacts. This paper presents work related to developing such a multi-criteria assessment tool, focusing on exploring and identifying the challenges of applying multi-criteria assessment to the development and deployment of Smart Local Energy Systems. The research involved semi-structured interviews with relevant expert stakeholders concerning six core assessment themes, corresponding sub-themes, and associated criteria/metrics. The results provide insights into the challenges of applying multi-criteria assessment to Smart Local Energy Systems and highlight the complex nature of these systems. Furthermore, stakeholder burnout (due to too many stakeholder engagement activities), data collection issues, and the broad definition and/or limited scope of assessment criteria were identified as the principal challenges faced in developing such an assessment tool, potentially affecting the reliability of its outputs

Developing the framework for multi-criteria assessment of smart local energy systems

In response to the climate emergency, energy landscapes are rapidly shifting to cleaner, decentralised smart local energy systems (SLESs). SLES will facilitate connection of transport, heat and power through flexible energy supply, demand and storage options supported by digital technology. SLESs are expected to contribute to tackling the energy trilemma (cost, security and sustainability), but there is also scope for them to offer many co-benefits aligned with the United Nations (UN) Sustainable Development Goals (SDGs). These benefits may drive for ongoing political and financial investment in SLES; therefore, there’s a need to indicate how a SLES is performing over time relative to each of them. Currently, there is no standardised approach to evaluate SLES and most of the existing techno-socio-economic tools have limited scope to assess the complex multiple performance indices, scenarios and stakeholders. The Innovate UK-funded EnergyREV research consortium is developing a multi-criteria assessment tool (MCA) for SLES. This paper describes the first step in this process – developing a simplified and standardised framework for assessing the performance of the system and the realization of benefits. It explores existing protocols and stakeholder opinion to identify 50 potential factors that are important in monitoring the system performance. These are clustered into 10 key themes to create a taxonomy for SLES performance that are aligned with relevant UN SDGs to track wider co-benefits. The resulting MCA tool will be instrumental to project stakeholders in providing evidence to support performance claims and identifying potential benefits beyond targeted key performance indicators

Weighting Key Performance Indicators of Smart Local Energy Systems: A Discrete Choice Experiment

The development of Smart Local Energy Systems (SLES) in the UK is part of the energy transition tackling the energy trilemma and contributing to achieving the Sustainable Development Goals (SDGs). Project developers and other stakeholders need to independently assess the performance of these systems: how well they meet their aims to successfully deliver multiple benefits and objectives. This article describes a step undertaken by the EnergyREV Research Consortium in developing a standardised Multi-Criteria Assessment (MCA) tool—specifically a discrete choice experiment (DCE) to determine the weighting of key performance indicators (KPIs). The MCA tool will use a technology-agnostic framework to assess SLES projects, track system performance and monitor benefit realisation. In order to understand the perceived relative importance of KPIs across different stakeholders, seven DCEs were conducted via online surveys (using 1000minds software). The main survey (with 234 responses) revealed that Environment was considered the most important criterion, with a mean weight of 21.6%. This was followed by People and Living (18.9%), Technical Performance (17.8%) and Data Management (14.7%), with Business and Economics and Governance ranked the least important (13.9% and 13.1%, respectively). These results are applied as weightings to calculate overall scores in the EnergyREV MCA-SLES tool

Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal–PFC connectivity. Altered hippocampal–PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1–PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity

Generic Finite Size Enhancement of Pairing in Mesoscopic Fermi Systems

The finite size dependent enhancement of pairing in mesoscopic Fermi systems is studied under the assumption that the BCS approach is valid and that the two body force is size independent. Different systems are investigated such as superconducting metallic grains and films as well atomic nuclei. It is shown that the finite size enhancement of pairing in these systems is in part due to the presence of a surface which accounts quite well for the data of nuclei and explains a good fraction of the enhancement in Al grains.Comment: Updated version 17/02/0

Regulation of WNT Signaling by VSX2 During Optic Vesicle Patterning in Human Induced Pluripotent Stem Cells

Few gene targets of Visual System Homeobox 2 (VSX2) have been identified despite its broad and critical role in the maintenance of neural retina (NR) fate during early retinogenesis. We performed VSX2 ChIP-seq and ChIP-PCR assays on early stage optic vesicle-like structures (OVs) derived from human iPS cells (hiPSCs), which highlighted WNT pathway genes as direct regulatory targets of VSX2. Examination of early NR patterning in hiPSC-OVs from a patient with a functional null mutation in VSX2 revealed mis-expression and upregulation of WNT pathway components and retinal pigmented epithelium (RPE) markers in comparison to control hiPSCOVs. Furthermore, pharmacological inhibition of WNT signaling rescued the early mutant phenotype, whereas augmentation of WNT signaling in control hiPSC-OVs phenocopied the mutant. These findings reveal an important role for VSX2 as a regulator of WNT signaling and suggest that VSX2 may act to maintain NR identity at the expense of RPE in part by direct repression of WNT pathway constituents

Formulation and Characterization of Patient-Friendly Dosage Form of Ondansetron Hydrochloride

Ondansetron hydrochloride is an intensely bitter antiemetic drug used to treat nausea and vomiting following chemotherapy. The purpose of the present work was to mask the taste of ondansetron hydrochloride and to formulate its patient-friendly dosage form. Complexation technique using indion 234 (polycyclic potassium with carboxylic functionality) and an ion-exchange resin was used to mask the bitter taste and then the taste-masked drug was formulated into an orodispersible tablet (ODT). The drug loading onto the ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug to resin and temperature. The resinate was evaluated for taste masking and characterized by X-ray diffraction study and infrared spectroscopy. ODTs were formulated using the drug–resin complex. The developed tablets were evaluated for hardness, friability, drug content, weight variation, content uniformity, friability, water absorption ratio, in vitro and in vivo disintegration time and in vitro drug release. The tablets disintegrated in vitro and in vivo within 24 and 27 s, respectively. Drug release from the tablet was completed within 2 min. The obtained results revealed that ondansetron HCl has been successfully taste masked and formulated into an ODT as a suitable alternative to the conventional tablets