Long-term behavioural rewriting of maladaptive drinking memories via reconsolidation-update mechanisms

BACKGROUND: Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. METHODS: Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. RESULTS: Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. CONCLUSIONS: The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions

piggyBac Transposon Somatic Mutagenesis with an Activated Reporter and Tracker (PB-SMART) for Genetic Screens in Mice

Somatic forward genetic screens have the power to interrogate thousands of genes in a single animal. Retroviral and transposon mutagenesis systems in mice have been designed and deployed in somatic tissues for surveying hematopoietic and solid tumor formation. In the context of cancer, the ability to visually mark mutant cells would present tremendous advantages for identifying tumor formation, monitoring tumor growth over time, and tracking tumor infiltrations and metastases into wild-type tissues. Furthermore, locating mutant clones is a prerequisite for screening and analyzing most other somatic phenotypes. For this purpose, we developed a system using the piggyBac (PB) transposon for somatic mutagenesis with an activated reporter and tracker, called PB-SMART. The PB-SMART mouse genetic screening system can simultaneously induce somatic mutations and mark mutated cells using bioluminescence or fluorescence. The marking of mutant cells enable analyses that are not possible with current somatic mutagenesis systems, such as tracking cell proliferation and tumor growth, detecting tumor cell infiltrations, and reporting tissue mutagenesis levels by a simple ex vivo visual readout. We demonstrate that PB-SMART is highly mutagenic, capable of tumor induction with low copy transposons, which facilitates the mapping and identification of causative insertions. We further integrated a conditional transposase with the PB-SMART system, permitting tissue-specific mutagenesis with a single cross to any available Cre line. Targeting the germline, the system could also be used to conduct F1 screens. With these features, PB-SMART provides an integrated platform for individual investigators to harness the power of somatic mutagenesis and phenotypic screens to decipher the genetic basis of mammalian biology and disease

Losses in plasmonics: from mitigating energy dissipation to embracing loss-enabled functionalities

Unlike conventional optics, plasmonics enables unrivalled concentration of optical energy well beyond the diffraction limit of light. However, a significant part of this energy is dissipated as heat. Plasmonic losses present a major hurdle in the development of plasmonic devices and circuits that can compete with other mature technologies. Until recently, they have largely kept the use of plasmonics to a few niche areas where loss is not a key factor, such as surface enhanced Raman scattering and biochemical sensing. Here, we discuss the origin of plasmonic losses and various approaches to either minimize or mitigate them based on understanding of fundamental processes underlying surface plasmon modes excitation and decay. Along with the ongoing effort to find and synthesize better plasmonic materials, optical designs that modify the optical powerflow through plasmonic nanostructures can help in reducing both radiative damping and dissipative losses of surface plasmons. Another strategy relies on the development of hybrid photonic-plasmonic devices by coupling plasmonic nanostructures to resonant optical elements. Hybrid integration not only helps to reduce dissipative losses and radiative damping of surface plasmons, but also makes possible passive radiative cooling of nano-devices. Finally, we review emerging applications of thermoplasmonics that leverage Ohmic losses to achieve new enhanced functionalities. The most successful commercialized example of a loss-enabled novel application of plasmonics is heat-assisted magnetic recording. Other promising technological directions include thermal emission manipulation, cancer therapy, nanofabrication, nano-manipulation, plasmon-enabled material spectroscopy and thermo-catalysis, and solar water treatment.Comment: 43 pages, 18 figure

Efficient, Secure and Privacy-Preserving PMIPv6 Protocol for V2G Networks

To ensure seamless communications between mobile Electric Vehicles (EVs) and EV power supply equipment, support for ubiquitous and transparent mobile IP communications is essential in Vehicle-to-Grid (V2G) networks. However, it initiates a range of privacy-related challenges as it is possible to track connected EVs through their mobile IP addresses. Recent works are mostly dedicated to solving authentication and privacy issues in V2G networks in general. Yet, they do not tackle the security and privacy challenges resulting from enabling mobile IP communications. To address these challenges, this paper proposes an Efficient, Secure and Privacy-preserving Proxy Mobile IPv6 (ESP-PMIPv6) protocol for the protection of mobile IP communications in V2G networks. ESP-PMIPv6 enables authorised EVs to acquire a mobile IPv6 address and access the V2G network in a secure and privacy-preserving manner. While ESP-PMIPv6 offers mutual authentication, identity anonymity and location unlinkability for the mobile EVs, it also achieves authorised traceability of misbehaving EVs through a novel collaborative tracking scheme. Formal and informal security analyses are conducted to prove that ESP-PMIPv6 meets these security and privacy goals. In addition, via a simulated assessment, the ESP-PMIPv6 is proven to achieve low authentication latency, low handover delay, and low packet loss rate in comparison with the PMIPv6 protocol

Probing the energy levels of perovskite solar cells via Kelvin probe and UV ambient pressure photoemission spectroscopy

This work was supported by the Engineering and Physical Sciences Research Council (grant codes EP/M506631/1, EP/ K015540/01, EP/K022237/1 and EP/M025330/1). IDWS and JTSI acknowledge Royal Society Wolfson research merit awards.The field of organo-lead halide perovskite solar cells has been rapidly growing since their discovery in 2009. State of the art devices are now achieving efficiencies comparable to much older technologies like silicon, while utilising simple manufacturing processes and starting materials. A key parameter to consider when optimising solar cell devices or when designing new materials is the position and effects of the energy levels in the materials. We present here a comprehensive study of the energy levels present in a common structure of perovskite solar cell using an advanced macroscopic Kelvin probe and UV air photoemission setup. By constructing a detailed map of the energy levels in the system we are able to predict the importance of each layer to the open circuit voltage of the solar cell, which we then back up through measurements of the surface photovoltage of the cell under white illumination. Our results demonstrate the effectiveness of air photoemission and Kelvin probe contact potential difference measurements as a method of identifying the factors contributing to the open circuit voltage in a solar cell, as well as being an excellent way of probing the physics of new materials.Publisher PDFPeer reviewe

Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics

Objective: To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed. Changes in axitinib plasma exposures in subjects with mild or moderate hepatic impairment were predicted using computer simulations and used to guide initial dosing in the clinical study. Results: Axitinib exposure was similar in subjects with normal hepatic function and those with mild hepatic impairment, but approximately twofold higher in subjects with moderate hepatic impairment. Axitinib exposure weakly correlated with measures of hepatic function but was not affected by smoking status. Axitinib protein binding was similar in the three treatment groups. No significant treatment-related adverse events were reported. Conclusions: Compared with subjects with normal hepatic function, moderate hepatic impairment increased axitinib exposure, suggesting that the oral clearance of axitinib is altered in these subjects. In addition, these data indicate a possible need for a dose reduction in subjects who develop moderate or worse hepatic impairment during axitinib treatment. A single 5-mg dose of axitinib was well tolerated in subjects with mild or moderate hepatic impairment

A Luminous Be+White Dwarf Supersoft Source in the Wing of the SMC: MAXI J0158-744

We present a multi-wavelength analysis of the very fast X-ray transient MAXI J0158-744, which was detected by MAXI/GSC on 2011 November 11. The subsequent exponential decline of the X-ray flux was followed with Swift observations, all of which revealed spectra with low temperatures (~100eV) indicating that MAXI J0158-744 is a new Supersoft Source (SSS). The Swift X-ray spectra near maximum show features around 0.8 keV that we interpret as possible absorption from OVIII, and emission from O, Fe, and Ne lines. We obtained SAAO and ESO optical spectra of the counterpart early in the outburst and several weeks later. The early spectrum is dominated by strong Balmer and HeI emission, together with weaker HeII emission. The later spectrum reveals absorption features that indicate a B1/2IIIe spectral type, and all spectral features are at velocities consistent with the Small Magellanic Cloud. At this distance, it is a luminous SSS (>10^37 erg/s) but whose brief peak luminosity of >10^39 erg/s in the 2-4 keV band makes it the brightest SSS yet seen at "hard" X-rays. We propose that MAXI J0158-744 is a Be-WD binary, and the first example to possibly enter ULX territory. The brief hard X-ray flash could possibly be a result of the interaction of the ejected nova shell with the B star wind in which the white dwarf (WD) is embedded. This makes MAXI J0158-744 only the third Be/WD system in the Magellanic Clouds, but it is by far the most luminous. The properties of MAXI J0158-744 give weight to previous suggestions that SSS in nearby galaxies are associated with early-type stellar systems.Comment: 15 pages, 8 figures; ApJ accepte

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development