Transmission electron microscope characterisation of iron-rhodium epilayers

Iron-rhodium (FeRh) alloys exhibit an unusual magnetostructural transition, making them a fascinating topic of research. When the alloy is approximately equiatomic (Fe48Rh52 to Fe56Rh44) it is in a caesium chloride (CsCl) structure. At room temperature it is antiferromagnetic (AFM), making a first-order phase transition to a ferromagnetic (FM) state when heated above ~350K. There is also a 1% increase in unit lattice volume upon heating to the FM phase, as well as an increase in entropy and decrease in resistivity. The transition can be modified by doping, applied strain and applied magnetic field among other methods. Thin film FeRh has potential uses as part of a spin valve system for magnetic data storage and as a suitable choice for a memristor. The work presented here demonstrates the methods approached to preparing a variety of sputter-deposited thin film FeRh samples for characterisation in a transmission electron microscope (TEM) as well as by techniques such as X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). These include samples capped with epitaxial chromium (Cr) and tungsten (W) to raise and lower the transition temperature respectively. After cross-section or plan-view preparation using either a conventional ion polishing method or a focused ion beam, the samples were characterised using a variety of methods in the TEM. Initial characterisation has examined the crystal structure, layer thickness and interfacial roughness of these films, confirming results from bulk X-ray measurements. It has been found that FIB-prepared samples do not exhibit the phase transition whereas ion polished samples are unaffected. Compositional analysis of the interface FeRh makes with a magnesium oxide (MgO) substrate finds a change in iron-to-rhodium ratio while characterising the FeRh/cap interface finds significant Fe diffusion into Cr-capped samples with no interdiffusion seen in identical W-capped FeRh films. Analysis of the transition dynamics observing changes in strain and ferromagnetic domains via heating experiments have confirmed the nucleation and growth of the phase change at the interfaces. Finally, there is some evidence to suggest that a martensitic change is occurring in FeRh through the transition. The presence of twins in the FeRh as well as extra ordering spots in a FIB-prepared cross-section allude to a more complex transition than previously thought

GaN Nanowire Schottky Barrier Diodes

A new concept of vertical gallium nitride (GaN) Schottky barrier diode based on nanowire (NW) structures and the principle of dielectric REduced SURface Field (RESURF) is proposed in this paper. High-threading dislocation density in GaN epitaxy grown on foreign substrates has hindered the development and commercialization of vertical GaN power devices. The proposed NW structure, previously explored for LEDs offers an opportunity to reduce defect density and fabricate low cost vertical GaN power devices on silicon (Si) substrates. In this paper, we investigate the static characteristics of high-voltage GaN NW Schottky diodes using 3-D TCAD device simulation. The NW architecture theoretically achieves blocking voltages upward of 700 V with very low specific on-resistance. Two different methods of device fabrication are discussed. Preliminary experimental results are reported on device samples fabricated using one of the proposed methods. The fabricated Schottky diodes exhibit a breakdown voltage of around 100 V and no signs of current collapse. Although more work is needed to further explore the nano-GaN concept, the preliminary results indicate that superior tradeoff between the breakdown voltage and specific on-resistance can be achieved, all on a vertical architecture and a foreign substrate. The proposed NW approach has the potential to deliver low cost reliable GaN power devices, circumventing the limitations of today's high electron mobility transistors (HEMTs) technology and vertical GaN on GaN devices

CD8+ T-cell specificity is compromised at a defined MHCI/CD8 affinity threshold

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity

CD8+ T-­cell specificity is compromised at a defined major histocompatibility complex class I/CD8 affinity threshold

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity

Divergent roles for antigenic drive in the aetiology of primary versus dasatinib-associated CD8(+) TCR-Vβ(+) expansions

CD8(+) T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8(+) T-cell receptor (TCR)-V beta(+) populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-V beta(+)) and residual (TCR-V beta(-)) CD8(+) T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8(+) TCR-V beta(+) expansions in T-LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8(+) TCR-V beta(+) expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8(+) TCR-V beta(+) expansions.Peer reviewe

CD8+ T-cell specificity is compromised at a defined MHCI/CD8 affinity threshold

The CD8 coreceptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR) binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~ 1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~ 10-fold). In this study, we used a panel of MHCI mutants with altered CD8 binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity. The pMHCI/CD8 interaction controls specificit

Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies

CD8+ T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8+ T-cell population are not desirable because the associated lack of speci city can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8+ T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-speci c CD8+ T-cells are relatively CD8-independent. These generic di erences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-speci c TCRs according to the monomeric interaction a nity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, “blocking” anti-CD8 antibodies can suppress autoreactive CD8+ T-cell activation in a relatively selective manner. These ndings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8+ T-cell compartment

A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.This research was supported with funding from Cancer Research UK and from the European Union to the EUROCAN Network of Excellence (FP7; grant numnumber 260791). M.C. has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sk1odowska-Curie grant agreement no. 660060 and was supported by the Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. R.N.B. is supported by the Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. S-J.S. is supported by the Wellcome Trust PhD Programme for Clinicians in Cambridge. A.Bruna, O.M.R., E.M., V.S., and C.C. are members of the EurOPDX Consortium. Weare very grateful for the generosity of all the patients that donated samples for implantation. We are also deeply indebted to all the staff (surgeons, pathologists, oncologists, theatre staff, and other ancillary personnel) at the Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, for facilitating the timely collection of samples. We thank the Cancer Research UK Cambridge Institute Genomics, Bioinformatics, Histopathology, Flow Cytometry, Biological Resource, and Bio-repository Core Facilities for support during the execution of this project.This is the final version of the article. It first appeared from Elsevier at http://dx.doi.org/10.1016/j.cell.2016.08.041