Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide1,2. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations3, with hepatocytes the most likely cell of origin2. However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies4. Despite an increasing range of systemic treatment options for advanced HCC, outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations5,6. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC7. Here we generated a suite of genetically driven immunocompetent in vivo and matched in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance and metastasis. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with the human histopathology. In a proof-of-principle analysis, we verified response to standard-of-care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not previously been linked to HCC treatment. Cladribine acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer related mortality worldwide. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulated progressive driver mutations, with hepatocytes the most likely cell of origin. However, the landscape of driver mutations in HCC is independent of the underlying aetiologies. Despite an increasing range of systemic treatment options for advanced HCC outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC. We generated over twenty-five new genetically-driven in vivo and in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance, and metastasis to distant organs. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with histopathology. In a proof-of-principle analysis, we verified response to standard of care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not been linked to HCC treatment before. Cladribine acts in a highly effective subtype-specific manner in combination with standard of care therapy.

Mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene are the most common genetic cause of Parkinson’s disease (PD), with growing importance also for Crohn’s disease and cancer. LRRK2 is a large and complex protein possessing both GTPase and kinase activity. Moreover, LRRK2 activity and function can be influenced by its phosphorylation status. In this regard, many LRRK2 PD-associated mutants display decreased phosphorylation of the constitutive phosphorylation cluster S910/S935/S955/S973, but the role of these changes in phosphorylation status with respect to LRRK2 physiological functions remains unknown. Here, we propose that the S910/S935/S955/S973 phosphorylation sites act as key regulators of LRRK2-mediated autophagy under both basal and starvation conditions. We show that quadruple LRRK2 phosphomutant cells (4xSA; S910A/S935A/S955A/S973A) have impaired lysosomal functionality and fail to induce and proceed with autophagy during starvation. In contrast, treatment with the specific LRRK2 kinase inhibitors MLi-2 (100 nM) or PF-06447475 (150 nM), which also led to decreased LRRK2 phosphorylation of S910/S935/S955/S973, did not affect autophagy. In explanation, we demonstrate that the autophagy impairment due to the 4xSA LRRK2 phospho-dead mutant is driven by its enhanced LRRK2 kinase activity. We show mechanistically that this involves increased phosphorylation of LRRK2 downstream targets Rab8a and Rab10, as the autophagy impairment in 4xSA LRRK2 cells is counteracted by expression of phosphorylation-deficient mutants T72A Rab8a and T73A Rab10. Similarly, reduced autophagy and decreased LRRK2 phosphorylation at the constitutive sites were observed in cells expressing the pathological R1441C LRRK2 PD mutant, which also displays increased kinase activity. These data underscore the relation between LRRK2 phosphorylation at its constitutive sites and the importance of increased LRRK2 kinase activity in autophagy regulation and PD pathology.

The performance of thermoelectric materials depends on both their atomic-scale chemistry and the nature of microstructural details such as grain boundaries and inclusions. Here, the elemental distribution throughout a TiNiCu0.1Sn thermoelectric material has been examined in a correlative study deploying atom-probe tomography (APT) and electron microscopies and spectroscopies. Elemental mapping and electron diffraction reveal two distinct types of grain boundary that are either topologically rough and meandering in profile or more regular and geometric. Transmission electron microscopy studies indicate that the Cu dopant segregates at both grain boundary types, attributed to extrusion from the bulk during hot-pressing. The geometric boundaries are found to have a degree of crystallographic coherence between neighboring grains; the rough boundaries are decorated with oxide impurity precipitates. APT was used to study the three-dimensional character of rough grain boundaries and reveals that Cu is present as discrete, elongated nanoprecipitates cosegregating alongside larger substoichiometric titanium oxide precipitates. Away from the grain boundary, the alloy microstructure is relatively homogeneous, and the atom-probe results suggest a statistical and uniform distribution of Cu with no evidence for segregation within grains. The extrusion suggests a solubility limit for Cu in the bulk material, with the potential to influence carrier and phonon transport properties across grain boundaries. These results underline the importance of fully understanding localized variations in chemistry that influence the functionality of materials, particularly at grain boundaries.

Cu-doping and crystallographic site occupations within the half-Heusler (HH) TiNiSn, a promising thermoelectric material, have been examined by atom probe tomography. In particular, this investigation aims to better understand the influence of atom probe analysis conditions on the measured chemical composition. Under a voltage-pulsing mode, atomic planes are clearly resolved and suggest an arrangement of elements in-line with the expected HH (F-43m space group) crystal structure. The Cu dopant is also distributed uniformly throughout the bulk material. For operation under laser-pulsed modes, the returned composition is highly dependent on the selected laser energy, with high energies resulting in the measurement of excessively high absolute Ti counts at the expense of Sn and in particular Ni. High laser energies also appear to be correlated with the detection of a high fraction of partial hits, indicating nonideal evaporation behavior. The possible mechanisms for these trends are discussed, along with suggestions for optimal analysis conditions for these and similar thermoelectric materials.

The magnetically frustrated manganese nitride antiperovskite family displays significant changes of entropy under hydrostatic pressure that can be useful for the emerging field of barocaloric cooling. Here we show that barocaloric properties of metallic antiperovskite Mn nitrides can be tailored for room-temperature application through quaternary alloying. We find an enhanced entropy change of $|\mathrm{\ensuremath{\Delta}}{S}_{\mathrm{t}}|=37\phantom{\rule{4pt}{0ex}}\mathrm{J}\phantom{\rule{0.16em}{0ex}}{\mathrm{K}}^{\ensuremath{-}1}\phantom{\rule{0.16em}{0ex}}{\mathrm{kg}}^{\ensuremath{-}1}$ at the ${T}_{t}=300\phantom{\rule{4pt}{0ex}}\mathrm{K}$ antiferromagnetic transition of quaternary ${\mathrm{Mn}}_{3}{\mathrm{Zn}}_{0.5}{\mathrm{In}}_{0.5}\mathrm{N}$ relative to the ternary end members. The pressure-driven barocaloric entropy change of ${\mathrm{Mn}}_{3}{\mathrm{Zn}}_{0.5}{\mathrm{In}}_{0.5}\mathrm{N}$ reaches $|\mathrm{\ensuremath{\Delta}}{S}_{\mathrm{BCE}}|=20\phantom{\rule{4pt}{0ex}}\mathrm{J}\phantom{\rule{0.16em}{0ex}}{\mathrm{K}}^{\ensuremath{-}1}\phantom{\rule{0.16em}{0ex}}{\mathrm{kg}}^{\ensuremath{-}1}$ in 2.9 kbar. Our results open up a large phase space where compounds with improved barocaloric properties may be found.

The upcoming Mars Sample Return (MSR) mission aims to deliver small quantities of Martian rocks to the Earth. Investigating these precious samples requires the development and application of techniques that can extract the greatest amount of high quality data from the minimum sample volume, thereby maximising science return from MSR. Atom probe tomography (APT) and transmission electron microscopy (TEM) are two complementary techniques that can obtain nanoscale structural, geochemical and, in the case of atom probe, isotopic information from small sample volumes. Here we describe how both techniques operate, as well as review recent developments in sample preparation protocols. We also outline how APT has been successfully applied to extraterrestrial materials in the recent past. Finally, we describe how we have studied Martian meteorites using TEM and APT in close coordination in order to characterise the products of water/rock interactions in t h e cru st of Ma r s – a k ey sc ie n ce goal of MSR. Our results provide new insights into the Martian hydrosphere and the mechanisms of anhydrous-hydrous mineral replacement. In light of the unique results provided by these tools, APT and TEM should form a crucial part at the culmination of a correlative analytical pipeline for MSR mission materials.

Using atom beams to image the surface of samples in real space is an emerging technique that delivers unique contrast from delicate samples. Here, we explore the contrast that arises from multiple scattering of helium atoms, a specific process that plays an important role in forming topographic contrast in scanning helium microscopy (SHeM) images. A test sample consisting of a series of trenches of varying depths was prepared by ion beam milling. SHeM images of shallow trenches (depth/width < 1) exhibited the established contrast associated with masking of the illuminating atom beam. The size of the masks was used to estimate the trench depths and showed good agreement with the known values. In contrast, deep trenches (depth/width > 1) exhibited an enhanced intensity. The scattered helium signal was modeled analytically and simulated numerically using Monte Carlo ray tracing. Both approaches gave excellent agreement with the experimental data and confirmed that the enhancement was due to localization of scattered helium atoms due to multiple scattering. The results were used to interpret SHeM images of a bio-technologically relevant sample with a deep porous structure, highlighting the relevance of multiple scattering in SHeM image interpretation.

INTERFACE BETWEEN NAKHLITE OLIVINE AND IDDINGSITE. L. Daly, M. R. Lee, P. A. J. Bagot, L. J. Hallis, J. Halpin, W. Smith, S. McFadzean, School of Geographical and Earth Sciences, University of Glasgow, Glasgow, G12 8QQ, UK. (luke.daly@glasgow.ac.uk). Department of Materials, University of Oxford, Oxford, OX1 3PH, UK. Materials and Condensed Matter Physics, School of Physics and Astronomy, University of Glasgow, Glasgow, G12 8QQ, UK.

Microstructure and point defects are central to thermoelectric performance in vacancy half-Heuslers.

The half-Heusler alloy TiNiSn is a promising material for thermoelectric applications that is inexpensive and non-toxic. We demonstrate the epitaxial growth of smooth TiNiSn thin films on MgO(001) single crystal substrates by pulsed laser deposition, using transmission electron microscopy to investigate nanoscale structural and chemical inhomogeneities. In particular, an interfacial reaction results in the formation of a titanium-rich oxide nanolayer at the substrate interface, and this maintains epitaxy but perturbs film composition. Segregation effects are observed throughout the film, producing a narrow range of off-stoichiometric, half-Heusler compositions. The propensity of titanium to oxidise also leads to the commensurate formation of parasitic titanium oxide nanostructures which may be overlooked in bulk techniques but are a key feature that drives both the formation of Ni-enriched, full-Heusler phases and the local decomposition of the half-Heusler to form additional nickel-stannide phases.

A method for the rapid preparation of atom probe tomography (APT) needles using a xenon plasma-focussed ion beam (FIB) instrument is presented and demonstrated on a test sample of Ti-6Al-4V alloy. The method requires significantly less operator input than the standard lift-out protocol, is site-specific and produces needles with minimal ion-beam damage; electron microscopy indicated the needle's surface amorphised/oxidised region to be less than 2 nm thick. The resulting needles were routinely analysable by APT, confirming the expected microstructure and showing negligible Xe contamination.

Addition of Cu to XNiSn half-Heuslers improves homogeneity and reduces thermal conductivity without affecting electron mobility.

Half-Heusler alloys based on TiNiSn are promising thermoelectric materials characterized by large power factors and good mechanical and thermal stabilities, but they are limited by large thermal conductivities. A variety of strategies have been used to disrupt their thermal transport, including alloying with heavy, generally expensive, elements and nanostructuring, enabling figures of merit, ZT ≥ 1 at elevated temperatures (>773 K). Here, we demonstrate an alternative strategy that is based around the partial segregation of excess Cu leading to grain-by-grain compositional variations, the formation of extruded Cu "wetting layers" between grains, and-most importantly-the presence of statistically distributed interstitials that reduce the thermal conductivity effectively through point-defect scattering. Our best TiNiCuySn (y ≤ 0.1) compositions have a temperature-averaged ZTdevice = 0.3-0.4 and estimated leg power outputs of 6-7 W cm-2 in the 323-773 K temperature range. This is a significant development as these materials were prepared using a straightforward processing method, do not contain any toxic, expensive, or scarce elements, and are therefore promising candidates for large-scale production.

In this work the growth of complex n-type, high Ge content superlattice structures by reduced pressure chemical vapor deposition is presented. The structures feature 50 repeats of a 14 layer period, which includes a main quantum well that is between 13 and 21 nm wide. The total epitaxy thickness is approximately 8 mu m. Diffusion and segregation in the structures was minimized by using a low growth temperature. Materials characterization shows the structures to be of good crystalline quality, with the thickness of all layers close to the design, abrupt interfaces, and uniformity throughout the structures. High angle annular dark field scanning transmission electron microscopy is shown to be an ideal technique for measuring layer thickness and interface quality in these structures.

Germanium membranes and microstructures of 50–1000nm thickness have been fabricated by a combination of epitaxial growth on a Si substrate and simple etching processes. The strain in these structures has been measured by high-resolution micro-X-ray diffraction and micro-Raman spectroscopy. The strain in these membranes is extremely isotropic and the surface is observed to be very smooth, with an RMS roughness below 2nm. The process of membrane fabrication also serves to remove the misfit dislocation network that originally forms at the Si/Ge interface, with benefits for the mechanical, optical and electrical properties of the crystalline membranes.

We present the observation of weak antilocalization due to the Rashba spin-orbit interaction, through magnetoresistance measurements performed at low temperatures and low magnetic fields on a high mobility (777,000 cm(2) V(-1) s(-1)) p-Ge/SiGe quantum well heterostructure. The measured magnetoresistance over a temperature range of 0.44 to 11.2 K shows an apparent transition from weak localization to weak antilocalization. The temperature dependence of the zero field conductance correction is indicative of weak localization using the simplest model, despite the clear existence of weak antilocalization. The Rashba interaction present in this material, and the absence of the un-tuneable Dresselhaus interaction, indicates that Ge quantum well heterostructures are highly suitable for semiconductor spintronic applications, particularly the proposed spin field effect transistor.