Momentum-dependent scaling exponents of nodal self-energies measured in strange metal cuprates and modelled using semi-holography.

The anomalous strange metal phase found in high-Tc cuprates does not follow the conventional condensed-matter principles enshrined in the Fermi liquid and presents a great challenge for theory. Highly precise experimental determination of the electronic self-energy can provide a test bed for theoretical models of strange metals, and angle-resolved photoemission can provide this as a function of frequency, momentum, temperature and doping. Here we show that constant energy cuts through the nodal spectral function in (Pb,Bi)2Sr2-xLaxCuO6+δ have a non-Lorentzian lineshape, consistent with a self-energy that is k dependent. This provides a new test for aspiring theories. Here we show that the experimental data are captured remarkably well by a power law with a k-dependent scaling exponent smoothly evolving with doping, a description that emerges naturally from anti-de Sitter/conformal-field-theory based semi-holography. This puts a spotlight on holographic methods for the quantitative modelling of strongly interacting quantum materials like the cuprate strange metals.

Crossover from lattice to plasmonic polarons of a spin-polarised electron gas in ferromagnetic EuO.

Strong many-body interactions in solids yield a host of fascinating and potentially useful physical properties. Here, from angle-resolved photoemission experiments and ab initio many-body calculations, we demonstrate how a strong coupling of conduction electrons with collective plasmon excitations of their own Fermi sea leads to the formation of plasmonic polarons in the doped ferromagnetic semiconductor EuO. We observe how these exhibit a significant tunability with charge carrier doping, leading to a polaronic liquid that is qualitatively distinct from its more conventional lattice-dominated analogue. Our study thus suggests powerful opportunities for tailoring quantum many-body interactions in solids via dilute charge carrier doping.

Fermiology and Superconductivity of Topological Surface States in PdTe_{2}.

We study the low-energy surface electronic structure of the transition-metal dichalcogenide superconductor PdTe_{2} by spin- and angle-resolved photoemission, scanning tunneling microscopy, and density-functional theory-based supercell calculations. Comparing PdTe_{2} with its sister compound PtSe_{2}, we demonstrate how enhanced interlayer hopping in the Te-based material drives a band inversion within the antibonding p-orbital manifold well above the Fermi level. We show how this mediates spin-polarized topological surface states which form rich multivalley Fermi surfaces with complex spin textures. Scanning tunneling spectroscopy reveals type-II superconductivity at the surface, and moreover shows no evidence for an unconventional component of its superconducting order parameter, despite the presence of topological surface states.

Ubiquitous formation of bulk Dirac cones and topological surface states from a single orbital manifold in transition-metal dichalcogenides.

Transition-metal dichalcogenides (TMDs) are renowned for their rich and varied bulk properties, while their single-layer variants have become one of the most prominent examples of two-dimensional materials beyond graphene. Their disparate ground states largely depend on transition metal d-electron-derived electronic states, on which the vast majority of attention has been concentrated to date. Here, we focus on the chalcogen-derived states. From density-functional theory calculations together with spin- and angle-resolved photoemission, we find that these generically host a co-existence of type-I and type-II three-dimensional bulk Dirac fermions as well as ladders of topological surface states and surface resonances. We demonstrate how these naturally arise within a single p-orbital manifold as a general consequence of a trigonal crystal field, and as such can be expected across a large number of compounds. Already, we demonstrate their existence in six separate TMDs, opening routes to tune, and ultimately exploit, their topological physics.

Maximal Rashba-like spin splitting via kinetic-energy-coupled inversion-symmetry breaking.

Engineering and enhancing the breaking of inversion symmetry in solids-that is, allowing electrons to differentiate between 'up' and 'down'-is a key goal in condensed-matter physics and materials science because it can be used to stabilize states that are of fundamental interest and also have potential practical applications. Examples include improved ferroelectrics for memory devices and materials that host Majorana zero modes for quantum computing. Although inversion symmetry is naturally broken in several crystalline environments, such as at surfaces and interfaces, maximizing the influence of this effect on the electronic states of interest remains a challenge. Here we present a mechanism for realizing a much larger coupling of inversion-symmetry breaking to itinerant surface electrons than is typically achieved. The key element is a pronounced asymmetry of surface hopping energies-that is, a kinetic-energy-coupled inversion-symmetry breaking, the energy scale of which is a substantial fraction of the bandwidth. Using spin- and angle-resolved photoemission spectroscopy, we demonstrate that such a strong inversion-symmetry breaking, when combined with spin-orbit interactions, can mediate Rashba-like spin splittings that are much larger than would typically be expected. The energy scale of the inversion-symmetry breaking that we achieve is so large that the spin splitting in the CoO2- and RhO2-derived surface states of delafossite oxides becomes controlled by the full atomic spin-orbit coupling of the 3d and 4d transition metals, resulting in some of the largest known Rashba-like spin splittings. The core structural building blocks that facilitate the bandwidth-scaled inversion-symmetry breaking are common to numerous materials. Our findings therefore provide opportunities for creating spin-textured states and suggest routes to interfacial control of inversion-symmetry breaking in designer heterostructures of oxides and other material classes.

Spin-valley locking in the normal state of a transition-metal dichalcogenide superconductor.

Metallic transition-metal dichalcogenides (TMDCs) are benchmark systems for studying and controlling intertwined electronic orders in solids, with superconductivity developing from a charge-density wave state. The interplay between such phases is thought to play a critical role in the unconventional superconductivity of cuprates, Fe-based and heavy-fermion systems, yet even for the more moderately-correlated TMDCs, their nature and origins have proved controversial. Here, we study a prototypical example, 2H-NbSe2, by spin- and angle-resolved photoemission and first-principles theory. We find that the normal state, from which its hallmark collective phases emerge, is characterized by quasiparticles whose spin is locked to their valley pseudospin. This results from a combination of strong spin-orbit interactions and local inversion symmetry breaking, while interlayer coupling further drives a rich three-dimensional momentum dependence of the underlying Fermi-surface spin texture. These findings necessitate a re-investigation of the nature of charge order and superconducting pairing in NbSe2 and related TMDCs.

Negative electronic compressibility and tunable spin splitting in WSe2.

Tunable bandgaps, extraordinarily large exciton-binding energies, strong light-matter coupling and a locking of the electron spin with layer and valley pseudospins have established transition-metal dichalcogenides (TMDs) as a unique class of two-dimensional (2D) semiconductors with wide-ranging practical applications. Using angle-resolved photoemission (ARPES), we show here that doping electrons at the surface of the prototypical strong spin-orbit TMD WSe2, akin to applying a gate voltage in a transistor-type device, induces a counterintuitive lowering of the surface chemical potential concomitant with the formation of a multivalley 2D electron gas (2DEG). These measurements provide a direct spectroscopic signature of negative electronic compressibility (NEC), a result of electron-electron interactions, which we find persists to carrier densities approximately three orders of magnitude higher than in typical semiconductor 2DEGs that exhibit this effect. An accompanying tunable spin splitting of the valence bands further reveals a complex interplay between single-particle band-structure evolution and many-body interactions in electrostatically doped TMDs. Understanding and exploiting this will open up new opportunities for advanced electronic and quantum-logic devices.

Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA.

Inhibition of matrix metalloproteinases (MMPs) is an attractive approach to adjuvant therapy in the treatment of cancer. Marimastat is the first orally administered, synthetic MMP inhibitor to be evaluated, in this capacity, in the clinic. Measurement of the rate of change of circulating tumour antigens was used for evaluating biological activity and defining optimum dosage in the early clinical trials of marimastat. Although tumour antigen levels have been used in the clinical management of cancer for many years, they have not been validated as markers of disease progression. In order to investigate the relationship between the effects of marimastat on tumour growth and circulating tumour antigen levels, mice bearing the human gastric tumour, MGLVA1, were treated with marimastat. The MMP inhibitor exerted a significant therapeutic effect, reducing tumour growth rate by 48% (P = 0.0005), and increasing median survival from 19 to 30 days (P = 0.0001). In addition, carcinoembryonic antigen (CEA) levels were measured in serum samples from animals sacrificed at regular intervals, and correlated with excised tumour weight. It was shown that the natural log of the CEA concentration was linearly related to the natural log of the tumour weight and that treatment was not a significant factor in this relationship (P = 0.7). In conclusion, circulating CEA levels were not directly affected by marimastat, but did reflect tumour size. These results support the use of cancer antigens as markers of biological activity in early phase trials of non-cytotoxic anticancer agents.

Atrial fibrillation amongst the Indo-Asian general practice population. The West Birmingham Atrial Fibrillation Project.

Whilst there are recognised ethnic differences in cardiovascular disease, with a higher prevalence of hypertension and complications such as stroke amongst black/Afro-Caribbean populations, and ischaemic heart disease being more prevalent amongst Indo-Asians, the literature describing the clinical epidemiology of atrial fibrillation (AF) in non-caucasian groups is scarce. To survey the clinical features and management amongst Indo-Asian patients with known AF, we studied patients from six general practices in the west of Birmingham. The six general practices had a combined practice population of 25051, from which, the Indo-Asian population was 14670. A total of 12 Indo-Asian patients (six male, six female; mean age, 67 years; range, 42 to 95 years) with known AF were identified, suggesting a prevalence of AF in Indo-Asians aged >50 years of 0.6%. Six patients had chronic AF, two had recent onset (defined as onset

BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties.

The stem cell inhibitor, macrophage inflammatory protein-1 alpha (MIP-1 alpha) or LD78, protects multipotent hematopoietic progenitors in murine models from the cytotoxic effects of chemotherapy. Clinical use of human MIP-1 alpha during chemotherapy could therefore lead to faster hematologic recovery and may allow dose intensification. We have also shown that human MIP-1 alpha causes the rapid mobilization of hematopoietic cells, suggesting an additional clinical use in peripheral blood stem cell transplantation. However, the clinical evaluation of human MIP-1 alpha is complicated by its tendency to associate and form high molecular weight polymers. We have produced a variant of rhMIP-1 alpha, BB-10010, carrying a single amino acid substitution of Asp26 > Ala, with a reduced tendency to form large polymers at physiologic pH and ionic strength. This greatly increases its solubility, facilitating its production and clinical formulation. We confirmed the potency of BB-10010 as a human MIP-1 alpha-like agonist in receptor binding, calcium mobilization, inhibition of colony formation, and thymidine suicide assays. The myeloprotective activity of BB-10010 was shown in a murine model of repeated chemotherapy using hydroxyurea. BB-10010 is therefore an ideal variant with which to evaluate the therapeutic potential of recombinant human MIP-1 alpha.

Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor.

The synthetic matrix metalloproteinase inhibitor batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of batimastat was examined on s.c. growth of B16-BL6 melanoma. Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.

Purification and analysis of proteinase-resistant mutants of recombinant platelet-derived growth factor-BB exhibiting improved biological activity.

Recombinant platelet-derived growth factor (PDGF)-BB was expressed and secreted from yeast in order to study the structure-function relationships of this mitogen. A simple purification scheme has been developed which yields greater than 95% pure PDGF-BB. Analysis of this recombinant PDGF-BB shows partial proteolysis after arginine-32. Substitution of this arginine residue, or arginine-28 [a potential KEX2 (lysine-arginine endopeptidase) cleavage site], prevents or reduces cleavage of PDGF-BB respectively. These mutations result in a 5-fold increase in expression levels of PDGF-BB, and the resulting mutant proteins show higher activity in a number of biological assays than the cleaved wildtype PDGF-BB. These data are in accord with previous work by Giese, LaRochelle, May-Siroff, Robbins & Aaronson [(1990) Mol. Cell Biol. 10, 5496-5501] suggesting that the region isoleucine-25-phenylalanine-37 is involved in PDGF-receptor binding.

Two PDGF-B chain residues, arginine 27 and isoleucine 30, mediate receptor binding and activation.

PDGF may be involved in the pathogenesis of a variety of disorders including atherosclerosis and certain types of cancer. There is currently little understanding of the molecular structure of PDGF and of the critical amino acid residues involved in receptor binding and cell activation. Two such PDGF-B chain residues, arginine 27 and isoleucine 30, have been identified by a site-directed mutagenesis programme. Substitutions in these positions can lead to PDGF mutants defective in both receptor affinity and cell activation as judged by displacement of [125I]PDGF-BB, mitogenic assay and inositol lipid turnover. Circular dichroism and fluorescence spectroscopy show that such mutations do not disrupt the structure of PDGF.

Purification and sequencing of glycosylation variants of BSF-1, as a MAF, from the EL-4 leukaemia cell line.

Macrophage activation activity was characterized from a PMA-induced subclone of the murine EL-4 leukaemic cell line. The MAF was purified from the cell line culture supernatant by concentration, CM-Sepharose and lentil lectin Sepharose chromatography, AcA 54 gel filtration, Mono Q FPLC and reverse phase HPLC. Four protein bands of different abundance were observed on SDS-PAGE with molecular weights of 17,500 to 21,000 Da. Three of the four proteins were sequenced from the N-terminal and shared homology with the published sequence of BSF-1. Variation of the molecular weight due to glycosylation was demonstrated by N-glycanase treatment, all four proteins gave a band of 14,200 Da after deglycosylation. Both glycosylated and deglycosylated forms of BSF-1 were equally active in the MAF assay. A monoclonal antibody to BSF-1 neutralized 80% of the activity from crude culture supernatants in the MAF assay. These studies have indicated that BSF-1 is the major, if not the only, MAF activity from this particular subline of the murine EL-4 leukaemic cell line.

The antiproliferative activity of interferons assayed by measuring growth medium color changes related to cell number.

A simple colorimetric assay for estimating cell numbers has been developed based on the observation that the indicator color in cell culture medium is proportional to viable cell number. The assay is performed in multiwell plates to take advantage of the rapid color measurement and computerized data handling capabilities of multiwell scanning spectrophotometers. Since no centrifugation or washing steps are involved, the technique is particularly useful for cells that grow in suspension, although it is equally applicable to monolayer cultures. The assay was developed to measure the antiproliferative activity of interferons on Daudi lymphoblastoid cells but could equally well be applied to other cell growth inhibition or stimulation assays.

Single-step monoclonal antibody affinity purification of human urogastrone from urine.

The use of a monoclonal antibody (MAb) affinity column to purify epidermal growth factor/urogastrone from human urine in a single-step process is described. The MAb was raised against purified recombinant human urogastrone derived from the expression of a cloned synthetic urogastrone gene. The MAb was characterised and shown to cross-react fully with recombinant and native human urogastrones. The material eluted from the column was shown to have retained biological activity. When the eluted material was run on SDS/PAGE under reducing conditions an apparently homogeneous species of 5400 Da apparent molecular weight was seen. When examined on acid PAGE, 2 molecular species corresponding to beta and gamma urogastrone were observed.