Grain-size dependence of intergranular magnetic correlations in nanostructured metals

Magnetic small-angle neutron scattering experiments were performed on nanostructured Fe, Co and Ni samples of varying grain size, produced by inert-gas condensation. The experiments show that the spontaneous spatial magnetic correlations forming in zero-field extend over many individual grains. These correlations depend strongly on grain size. In Fe, they have a minimum at a grain size of around 35 nm and increase sharply for smaller grain sizes. The crossover occurs at grain sizes comparable with L_(crit) = πδ, where δ is the bulk domain-wall width. For grain sizes below L_(crit), the results are explained on the basis of the random-anisotropy model, which takes into account that the magnetic alignment between the grains competes with the anisotropies of the individual grains. Above L_(crit), where domain walls can form within one grain, the magnetization direction corresponds to the anisotropy direction varying from grain to grain, and the magnetic correlation length increases approximately linearly with grain size. Furthermore, the measurements on Fe, Co and Ni show that the spatial magnetic correlations measured by SANS are always larger than L_(crit). This is in agreement with results of theoretical studies showing that nonuniform magnetization configurations can only exist in grains with sizes D > L_(crit)

Grain-size dependence of intergranular magnetic correlations in nanostructured metals

Magnetic small-angle neutron scattering experiments were performed on nanostructured Fe, Co and Ni samples of varying grain size, produced by inert-gas condensation. The experiments show that the spontaneous spatial magnetic correlations forming in zero-field extend over many individual grains. These correlations depend strongly on grain size. In Fe, they have a minimum at a grain size of around 35 nm and increase sharply for smaller grain sizes. The crossover occurs at grain sizes comparable with L_(crit) = πδ, where δ is the bulk domain-wall width. For grain sizes below L_(crit), the results are explained on the basis of the random-anisotropy model, which takes into account that the magnetic alignment between the grains competes with the anisotropies of the individual grains. Above L_(crit), where domain walls can form within one grain, the magnetization direction corresponds to the anisotropy direction varying from grain to grain, and the magnetic correlation length increases approximately linearly with grain size. Furthermore, the measurements on Fe, Co and Ni show that the spatial magnetic correlations measured by SANS are always larger than L_(crit). This is in agreement with results of theoretical studies showing that nonuniform magnetization configurations can only exist in grains with sizes D > L_(crit)

Microstructural analysis of TRISO particles using multi-scale X-ray computed tomography

TRISO particles, a composite nuclear fuel built up by ceramic and graphitic layers, have outstanding high temperature resistance. TRISO fuel is the key technology for High Temperature Reactors (HTRs) and the Generation IV Very High Temperature Reactor (VHTR) variant. TRISO offers unparalleled containment of fission products and is extremely robust during accident conditions. An understanding of the thermal performance and mechanical properties of TRISO fuel requires a detailed knowledge of pore sizes, their distribution and interconnectivity. Here 50 nm, nano-, and 1 μm resolution, micro-computed tomography (CT), have been used to quantify non-destructively porosity of a surrogate TRISO particle at the 0.3–10 μm and 3–100 μm scales respectively. This indicates that pore distributions can reliably be measured down to a size approximately 3 times the pixel size which is consistent with the segmentation process. Direct comparison with Scanning Electron Microscopy (SEM) sections indicates that destructive sectioning can introduce significant levels of coarse damage, especially in the pyrolytic carbon layers. Further comparative work is required to identify means of minimizing such damage for SEM studies. Finally since it is non-destructive, multi-scale time-lapse X-ray CT opens the possibility of intermittently tracking the degradation of TRISO structure under thermal cycles or radiation conditions in order to validate models of degradation such as kernel movement. X-ray CT in-situ experimentation of TRISO particles under load and temperature could also be used to understand the internal changes that occur in the particles under accident conditions.Scanning and analysis was performed at the Henry Moseley X-ray Imaging Facility which has been funded through support from EPSRC under Grants EP/F007906, EP/F028431 and EP/I02249X. Imaging on the UltraXRM-L200 system was carried out at Zeiss Xradia Inc., Pleasanton, CA, USA

HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy

BACKGROUND The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level. METHODS Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing. RESULTS The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference. CONCLUSION Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing

A time-resolved proteomic and prognostic map of COVID-19

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease