Fluorescent IGF-II analogues for FRET-based investigations into the binding of IGF-II to the IGF-1R

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.The interaction of IGF-II with the insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-1R) has recently been identified as potential therapeutic target for the treatment of cancer. Understanding the interactions of IGF-II with these receptors is required for the development of potential anticancer therapeutics. This work describes an efficient convergent synthesis of native IGF-II and two nonnative IGF-II analogues with coumarin fluorescent probes incorporated at residues 19 and 28. These fluorescent analogues bind with nanomolar affinities to the IGF-1R and are suitable for use in fluorescence resonance energy transfer (FRET) studies. From these studies the F19Cou IGF-II and F28Cou IGF-II proteins were identified as good probes for investigating the binding interactions of IGF-II with the IGF-1R and its other high affinity binding partners

STING expression and response to treatment with STING ligands in premalignant and malignant disease.

Human papilloma virus positive (HPV+) tumors represent a large proportion of anal, vulvar, vaginal, cervical and head and neck squamous carcinomas (HNSCC) and late stage invasive disease is thought to originate from a premalignant state. Cyclic dinucleotides that activate STimulator of INterferon Genes (STING) have been shown to cause rapid regression of a range of advanced tumors. We aimed to investigate STING ligands as a novel treatment for papilloma. We tested therapies in a spontaneous mouse model of papilloma of the face and anogenital region that histologically resembles human HPV-associated papilloma. We demonstrate that STING ligands cause rapid regression of papilloma, associated with T cell infiltration, and are significantly more effective than Imiquimod, a current immunotherapy for papilloma. In humans, we show that STING is expressed in the basal layer of normal skin and lost during keratinocyte differentiation. We found STING was expressed in all HPV-associated cervical and anal dysplasia and was strongly expressed in the cancer cells of HPV+ HNSCC but not in HPV-unrelated HNSCC. We found no strong association between STING expression and progressive disease in non-HPV oral dysplasia and oral pre-malignancies that are not HPV-related. These data demonstrate that STING is expressed in basal cells of the skin and is retained in HPV+ pre-malignancies and advanced cancers, but not in HPV-unrelated HNSCC. However, using a murine HNSCC model that does not express STING, we demonstrate that STING ligands are an effective therapy regardless of expression of STING by the cancer cells

High Resolution XMM-Newton Spectroscopy of the Cooling Flow Cluster A3112

We examine high signal to noise XMM-Newton European Photon Imaging Camera (EPIC) and Reflection Grating Spectrometer (RGS) observations to determine the physical characteristics of the gas in the cool core and outskirts of the nearby rich cluster A3112. The XMM-Newton Extended Source Analysis Software data reduction and background modeling methods were used to analyze the XMM- Newton EPIC data. From the EPIC data we find that the iron and silicon abundance gradients show significant increase towards the center of the cluster while the oxygen abundance profile is centrally peaked but has a shallower distribution than that of iron. The X-ray mass modeling is based on the temperature and deprojected density distributions of the intra-cluster medium determined from EPIC observations. The total mass of A3112 obeys the M-T scaling relations found using XMM-Newton and Chandra observations of massive clusters at R500. The gas mass fraction f_gas= 0.149^{+0.036}_{-0.032} at R500, is consistent with the seven-year WMAP results. The comparisons of line fluxes and flux limits on the Fe XVII and Fe XVIII lines obtained from high resolution RGS spectra indicate that there is no spectral evidence for cooler gas associated with the cluster with temperature below 1.0 keV in the central <38" (\sim 52 kpc) region of A3112. High resolution RGS spectra also yield an upper limit to the turbulent motions in compact core of A3112 (206 km/s). We find that the energy contribution of turbulence to total energy is less than 6 per cent. This upper limit is consistent with the amount of energy contribution measured in recent high resolution simulations of relaxed galaxy clusters.Comment: Accepted for publication. 14 pages, 12 Figures and 9 Table

Developing colloidal nanoparticles for inkjet printing of devices with optical properties tuneable from the UV to the NIR

Colloidal low-dimensional photo-sensitive nanomaterials have attracted significant interest for optoelectronic device applications where inkjet printing offers a high accuracy and low waste route for their deposition on silicon-based, as well as flexible, devices. However, to achieve photodetection and displays with absorption and emission tuneable across the range from the ultraviolet (UV) to the near infrared (NIR), the availability of printable optically active materials needs to be addressed. In this work we develop printable ink formulations of graphene quantum dots (GQDs), NaYF4:(20%Yb and/or 2%Er doped) upconverting nanoparticles (UCNPs), and PbS quantum dots (QDs) and demonstrate their use in devices such as graphene-based photodetectors and fluorescent displays. The ink formulations, printing strategies and post-deposition techniques were developed and optimised to enable the deposition of photo-sensitive nanomaterial layers in a controllable manner onto flexible polymeric, glass and silicon substrates. The nanomaterials retained their properties post deposition, as we exemplify by photosensitisation of single layer graphene (SLG) photodetector devices, with spectral responsivity tuneable from the UV for GQD/SLG to the NIR for UCNP/SLG and PbS/SLG devices, with photoresponsivity up to R ∼ 103 A W−1. Fluorescent displays were also demonstrated consisting of CsPbBr3 perovskite nanocrystals and UCNPs inkjet printed onto flexible transparent substrates, for selective sensing of UV and NIR light. This work successfully expands the material library of printable optically active materials and demonstrates their potential for printed optoelectronics, including flexible devices

Photosensitisation of inkjet printed graphene with stable all-inorganic perovskite nanocrystals

All-inorganic perovskite nanocrystals (NCs) with enhanced environmental stability are of particular interest for optoelectronic applications. Here we report on the formulation of CsPbX3 (X is Br or I) inks for inkjet deposition and utilise these NCs as photosensitive layers in graphene photodetectors, including those based on single layer graphene (SLG) as well as inkjet-printed graphene (iGr) devices. The performance of these photodetectors strongly depends on the device structure, geometry and the fabrication process. We achieve a high photoresponsivity, R > 106 A W−1 in the visible wavelength range and a spectral response controlled by the halide content of the perovskite NC ink. By utilising perovskite NCs, iGr and gold nanoparticle inks, we demonstrate a fully inkjet-printed photodetector with R ≈ 20 A W−1, which is the highest value reported to date for this type of device. The performance of the perovskite/graphene photodetectors is explained by transfer of photo-generated charge carriers from the perovskite NCs into graphene and charge transport through the iGr network. The perovskite ink developed here enabled realisation of stable and sensitive graphene-based photon detectors. Compatibility of inkjet deposition with conventional Si-technologies and with flexible substrates combined with high degree of design freedom provided by inkjet deposition offers opportunities for partially and fully printed optoelectronic devices for applications ranging from electronics to environmental sciences

Inter-Flake Quantum Transport of Electrons and Holes in Inkjet-Printed Graphene Devices

© 2020 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH 2D materials have unique structural and electronic properties with potential for transformative device applications. However, such devices are usually bespoke structures made by sequential deposition of exfoliated 2D layers. There is a need for scalable manufacturing techniques capable of producing high-quality large-area devices comprising multiple 2D materials. Additive manufacturing with inks containing 2D material flakes is a promising solution. Inkjet-printed devices incorporating 2D materials have been demonstrated, however there is a need for greater understanding of quantum transport phenomena as well as their structural properties. Experimental and theoretical studies of inkjet-printed graphene structures are presented. Detailed electrical and structural characterization is reported and explained by comparison with transport modeling that include inter-flake quantum tunneling transport and percolation dynamics. The results reveal that the electrical properties are strongly influenced by the flakes packing fraction and by complex meandering electron trajectories, which traverse several printed layers. Controlling these trajectories is essential for printing high-quality devices that exploit the properties of 2D materials. Inkjet-printed graphene is used to make a field effect transistor and Ohmic contacts on an InSe phototransistor. This is the first time that inkjet-printed graphene has successfully replaced single layer graphene as a contact material for 2D metal chalcogenides

Whole Genome Sequencing Reveals Local Transmission Patterns of Mycobacterium bovis in Sympatric Cattle and Badger Populations

Whole genome sequencing (WGS) technology holds great promise as a tool for the forensic epidemiology of bacterial pathogens. It is likely to be particularly useful for studying the transmission dynamics of an observed epidemic involving a largely unsampled &lsquo;reservoir' host, as for bovine tuberculosis (bTB) in British and Irish cattle and badgers. BTB is caused by Mycobacterium bovis, a member of the M. tuberculosis complex that also includes the aetiological agent for human TB. In this study, we identified a spatio-temporally linked group of 26 cattle and 4 badgers infected with the same Variable Number Tandem Repeat (VNTR) type of M. bovis. Single-nucleotide polymorphisms (SNPs) between sequences identified differences that were consistent with bacterial lineages being persistent on or near farms for several years, despite multiple clear whole herd tests in the interim. Comparing WGS data to mathematical models showed good correlations between genetic divergence and spatial distance, but poor correspondence to the network of cattle movements or within-herd contacts. Badger isolates showed between zero and four SNP differences from the nearest cattle isolate, providing evidence for recent transmissions between the two hosts. This is the first direct genetic evidence of M. bovis persistence on farms over multiple outbreaks with a continued, ongoing interaction with local badgers. However, despite unprecedented resolution, directionality of transmission cannot be inferred at this stage. Despite the often notoriously long timescales between time of infection and time of sampling for TB, our results suggest that WGS data alone can provide insights into TB epidemiology even where detailed contact data are not available, and that more extensive sampling and analysis will allow for quantification of the extent and direction of transmission between cattle and badgers

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2–Induced Changes for a Randomized Double-blind Controlled Trial

Background:Depression is a significant health and economic burden. In approximately one third of patients, depression is resistant to first line treatments and therefore it is essential that alternative treatments are found. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the UK and the US in treatment resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness and mechanism of action between standard treatment repetitive TMS (rTMS) targeted at the F3 EEG site, with a newer treatment – a type of TMS called theta-burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines the brain imaging acquisition and analysis for the BRIGhTMIND trial that is used to create personalised TMS targets and answer the proposed mechanistic hypotheses.Objective:The objectives of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and cgiTBS and to identify imaging-based markers predicting response to treatment.Methods:The study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of a) TBS or b) standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired per participant at baseline (prior to TMS treatment) with T1-weighted and task-free functional MRI during rest (rsfMRI) utilised to estimate TMS targets. For participants enrolled in the mechanistic substudy additional diffusion-weighted, sequences are acquired at baseline and at post-treatment follow-up 16 weeks after treatment randomisation. Core datasets of T1-weighted and task-free functional MRI during rest (rsfMRI) are acquired for all participants and utilised to estimate TMS targets. Additional sequences of arterial spin labelling, magnetic resonance spectroscopy and diffusion-weighted images are acquired dependent on recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex whilst TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from a level of MRI-guidance but only TBS is provided with precision targeting based on functional brain connectivity.Results:Recruitment began January 2019 and is ongoing. Data collection is expected to continue until January 2023.Conclusions:This trial will determine the impact of precision MRI guidance on rTMS treatment, and furthermore, assess the neural mechanisms underlying this treatment in treatment resistant depressed patients. Clinical Trial: International Standard Randomized Controlled Trial Number (ISRCTN) 19674644; https://www.isrctn.com/ISRCTN19674644. Registered 2nd October 2018

The Suzaku High Resolution X-ray Spectrometer

The high resolution X-Ray Spectrometer (XRS) has been designed to provide the Suzaku Observatory with very high spectral resolution, non-dispersive spectroscopy from 0.3 to 12 keV. This energy range encompasses the most diagnostically-rich part of the x-ray band. The sensor consists of a 32 channel array of x-ray of microcalorimeters, each with an energy resolution of about 6 eV. The very low temperature required for operation of the array (60 mK) is provided by a four-stage cooling system containing a single stage ADR, superfluid He Cryostat, solid Ne Dewar, and a single-stage Stirling-cycle cooler. The Suzaku/XRS is the first orbiting x-ray microcalorimeter spectrometer and has been designed to last more than three years in orbit. The early verification phase of the mission demonstrated that the instrument was working properly and that the cryogen consumption rate was low enough to ensure a mission lifetime exceeding 3 years. However, the liquid He cryogen was completely vaporized two weeks after opening the dewar guard vacuum vent. The problem has been traced to inadequate venting of the dewar He and Ne gases out of the spacecraft into space. In this paper we present the design of the XRS instrument and describe the in-flight performance