12508 research outputs found
Sort by
(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) - a novel cortical-preferring catecholamine transmission- and cognition-promoting agent
Get PDFYesHere we describe for the first time the distinctive pharmacological profile for IRL752, a new phenyl-pyrrolidine derivative with regio-selective CNS transmission-enhancing properties. IRL752 (3.7-150 μmol/kg, s.c.) was characterised through extensive in vivo studies, using behavioural, tissue neurochemical and gene expression, as well as microdialysis methods. Behaviourally, the compound normalised tetrabenazine-induced hypoactivity, while unable to stimulate basal locomotion in normal animals or to either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across NA- and DA-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related IEGs (immediate early genes) however increased by 1.5- to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600-750% above baseline, while striatal DA remained unaltered and NA rose to ~250%; cortical and hippocampal dialysate ACh increased to ~250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also pro-cognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data, coupled to drug exposure support the hypothesis that 5‑HT7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions where these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson's Disease
Influencing subjective well-being for business and sustainable development using big data and predictive regression analysis
Get PDFYesBusiness leaders and policymakers within service economies are placing greater emphasis on well-being, given the role of workers in such settings. Whilst people’s well-being can lead to economic growth, it can also have the opposite effect if overlooked. Therefore, enhancing subjective well-being (SWB) is pertinent for all organisations for the sustainable development of an economy. While health conditions were previously deemed the most reliable predictors, the availability of data on people’s personal lifestyles now offers a new dimension into well-being for organisations. Using open data available from the national Annual Population Survey in the UK, which measures SWB, this research uncovered that among several independent variables to predict varying levels of people's perceived well-being, long-term health conditions, one's marital status, and age played a key role in SWB. The proposed model provides the key indicators of measuring SWB for organisations using big data
Dielectric-Insensitive Phased Array with Improved Characteristics for 5G Mobile Handsets
Get PDFYesIn this manuscript, a high-performance beam-steerable phased array antenna is introduced for fifth-generation (5G) mobile handsets. The configuration of the design is arranged by employing eight dielectric-insensitive L-ring/slot-loop radiators in a linear form on the top edge of the handset mainboard. The beam-steerable array design exhibits high radiation performances even though it is implemented on a lossy FR-4 material. The proposed design exhibits an impedance bandwidth of 18-20 GHz with the center frequency of 19 GHz. It provides satisfactory characteristics such as wide beam-steering, high gain and efficiency characteristics indicating its promising potential for beam-steerable 5G smartphones. The characteristics of the antenna array are insensitive for different types of dielectrics. Furthermore, the designed antenna array offers quite good radiation behavior in the presence of hand phantom.European Union�s Horizon 2020 research and innovation programme under grant agreement H2020-MSCA-ITN-2016 SECRET-72242
Investigation of the role of VHL-HIF signaling in DNA repair and apoptosis in zebrafish
Get PDFYespVHL is a tumor suppressor. The lack of its function leads to various tumors, among which ccRCC (clear cell renal cell carcinoma) has the most serious outcome due to its resistance to chemotherapies and radiotherapies. Although HIF promotes the progression of ccRCC, the precise mechanism by which the loss of VHL leads to tumor initiation remains unclear. We exploited two zebrafish vhl mutants, vhl and vll, and Tg(phd3The work was supported by two BBSRC Grants: BB/R015457/1 and BB/M02332X/1
Mechanistic understanding of competitive destabilization of carbamazepine cocrystals under solvent free conditions
No full textNoMechanistic understanding of competitive destabilization of carbamazepine:nicotinamide and carbamazepine:saccharin cocrystals under solvent free conditions has been investigated. The crystal phase transformations were monitored using hot stage microscopy, variable-temperature powder X-ray diffraction, and sublimation experiments. The destabilization of the two cocrystals occurs via two distinct mechanisms: vapor and eutectic phase formations. Vapor pressure measurements and thermodynamic calculations using fusion and sublimation enthalpies were in good agreement with experimental findings. The mechanistic understanding is important to maintain the stability of cocrystals during solvent free green manufacturing.EPSRC (EP/J003360/1, EP/ L027011/1). MHD. Bashir would like to thank CARA for providing doctoral degree scholarship
TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts
Get PDFYesEukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate-a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)-is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3' phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the ~90 kDa TOP1 protein is processed upstream of TDP1. Here we find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.Supported by the Medical Research Council programme grant (MC_EX_MR/K022830/1) to K.R. J.F. is supported by a CRUK DPhil studentship. K.W. was supported by an MRC studentship and A.R. is supported by a European Molecular Biology Organization (EMBO) long-term fellowship (ALTF 1109-2017). E.D. is supported by the S:CORT consortium which is funded by a grant from the MRC and CRUK. S.F.E. is funded by a Wellcome Trust Investigator award (103844) and a Lister Institute Fellowship
The RAC1 target NCKAP1 plays a crucial role in progression of BRAF/PTEN -driven melanoma in mice
Get PDFYesBRAF V600E is the most common driver mutation in human cutaneous melanoma and is frequently accompanied by loss of the tumor suppressing phosphatase PTEN. Recent evidence suggests a co-operative role for RAC1 activity in BRAF V600E -driven melanoma progression and drug resistance. However, the underlying molecular mechanisms and the role of RAC1 downstream targets are not well explored. Here, we examine the role of the NCKAP1 subunit of the pentameric cytoskeletal SCAR/WAVE complex, a major downstream target of RAC1, in a mouse model of melanoma driven by BRAF V600E; PTEN loss. The SCAR/WAVE complex is the major driver of lamellipodia formation and cell migration downstream of RAC1 and depends on NCKAP1 for its integrity. Targeted deletion of Nckap1 in the melanocyte lineage delayed tumor onset and progression of a mutant Braf ; Pten loss driven melanoma mouse model. Nckap1 depleted tumors displayed fibrotic stroma with increased collagen deposition concomitant with enhanced immune infiltration. Nckap1 loss slowed proliferation and tumor growth, highlighting a role in cell cycle progression. Altogether, we propose that NCKAP1-orchestrated actin polymerization is essential for tumor progression and maintenance of tumor tissue integrity in a mutant Braf ; Pten loss driven mouse model for melanoma
Big Data Analytics-enabled Sensing Capability and Organizational Outcomes: Assessing the Mediating Effects of Business Analytics Culture
Get PDFYesWith the emergence of information and communication technologies, organizations worldwide have been putting in meaningful efforts towards developing and gaining business insights by combining technology capability, management capability and personnel capability to explore data potential, which is known as big data analytics (BDA) capability. In this context, variables such as sensing capability—which is related to the organization’s ability to explore the market and develop opportunities—and analytics culture—which refers to the organization’s practices and behavior patterns of its analytical principles—play a fundamental role in BDA initiatives. However, there is a considerable literature gap concerning the effects of BDA-enabled sensing capability and analytics culture on organizational outcomes (i.e., customer linking capability, financial performance, market performance, and strategic business value) and on how important the organization’s analytics culture is as a mediator in the relationship between BDA-enabled sensing capability and organizational outcomes. Therefore, this study aims to investigate these relationships. And to attain this goal, we developed a conceptual model supported by dynamics capabilities, BDA, and analytics culture. We then validated our model by applying partial least squares structural equation modeling. The findings showed not only the positive effect of the BDA-enabled sensing capability and analytics culture on organizational outcomes but also the mediation effect of the analytics culture. Such results bring valuable theoretical implications and contributions to managers and practitioners
Highly improved PP/CNTs sheet prepared by tailoring crystallization morphology through solid-phase die drawing and multilayer hot compression
No full textNoSimply melt blended polypropylene/carbon nanotubes composites (PP/CNTs) usually present mechanical deterioration. In this work, multilayered sheet of PP/CNTs with improved tensile property was obtained by solid-phase orientation and hot compression. The initially blended PP/CNTs were highly orientated by employing a constrained slit die and hot compressed under a certain temperature and pressure by stacking eight layers together. The effects of compression temperature and pressure on the tensile property and AC conductivity of the multilayered sheets were examined to explore the evolution of hierarchical crystallization morphology and CNT networks. The multilayered sheet which was hot compressed at 184°C and 5 MPa demonstrated an optimum tensile strength of ∼132.5 MPa and an elongation at break ∼52.7%, respectively, raised by almost 3-fold compared with those initially blended PP/CNTs. By increasing compression temperature and decreasing pressure, the AC conductivity showed an increase of 2 to 4 orders of magnitude.China Scholarship Council. Grant Number: 201806465028
Micro-alloying and surface texturing of Ti-6Al-4V alloy by embedding nanoparticles using gas tungsten arcwelding
Get PDFYesTitanium alloy Ti-6Al-4V is known for both its excellent mechanical properties and its low surface hardness. This study explores a two-step process for depositing a hard nanocrystalline coating onto the surface of the Ti-alloy, followed by surface melting, which embeds hard nanoparticles into a thin surface layer of the alloy. The treated surface layer was studied using X-ray diffraction, scanning electron microscopy, and Vicker's micro-hardness testing. The results of the study show that the surface of the Ti-6Al-4V alloy can be successfully hardened by embedding nanosized Al2O3 particles into the surface using gas tungsten arc welding to melt the surface of the material. Surface melting the Ti-6Al-4V alloy with a 50A welding current produced the maximum microhardness of 701 HV0.2kg. The micro-hardness of the treated surface layer decreased with the increasing size of the nanoparticles, while the roughness of the surface increased with the increasing welding current. The heat input into the surface during the surface melting process resulted in the formation of various intermetallic compounds capable of further increasing the hardness of the Ti-6Al-4V surface