Artificial Magnetic Tripod Ice.

We study the collective behavior of interacting arrays of nanomagnetic tripods. These objects have six discrete moment states, in contrast to the usual two states of an Ising-like moment. Our experimental data demonstrate that triangular lattice arrays form a "tripod ice" that exhibits charge ordering among the effective vertex magnetic charges, in direct analogy to artificial kagome spin ice. The results indicate that the interacting tripods have effective moments that act as emergent local variables, with strong connections to the well-studied Potts and clock models. In addition, the tripod moments display a tendency toward a nearest neighbor alignment in our thermalized samples that separates this system from kagome spin ice. Our results open a path toward the study of the collective behavior of nonbinary moments that is unavailable in other physical systems.

Human myeloma cell- and plasma-derived extracellular vesicles contribute to functional regulation of stromal cells.

Circulating small extracellular vesicles (sEV) represent promising non-invasive biomarkers that may aid in the diagnosis and risk-stratification of multiple myeloma (MM), an incurable blood cancer. Here, we comprehensively isolated and characterized sEV from human MM cell lines (HMCL) and patient-derived plasma (psEV) by specific EV-marker enrichment and morphology. Importantly, we demonstrate that HMCL-sEV are readily internalised by stromal cells to functionally modulate proliferation. psEV were isolated using various commercial approaches and pre-analytical conditions (collection tube types, storage conditions) assessed for sEV yield and marker enrichment. Functionally, MM-psEV was shown to regulate stromal cell proliferation and migration. In turn, pre-educated stromal cells favour HMCL adhesion. psEV isolated from patients with both pre-malignant plasma cell disorders (monoclonal gammopathy of undetermined significance [MGUS]; smouldering MM [SMM]) and MM have a similar ability to promote cell migration and adhesion, suggesting a role for both malignant and pre-malignant sEV in disease progression. Proteomic profiling of MM-psEV (305 proteins) revealed enrichment of oncogenic factors implicated in cell migration and adhesion, in comparison to non-disease psEV. This study describes a protocol to generate morphologically-intact and biologically functional sEV capable of mediating the regulation of stromal cells, and a model for the characterization of tumour-stromal cross-talk by sEV in MM.

Emergent dynamic chirality in a thermally driven artificial spin ratchet.

Modern nanofabrication techniques have opened the possibility to create novel functional materials, whose properties transcend those of their constituent elements. In particular, tuning the magnetostatic interactions in geometrically frustrated arrangements of nanoelements called artificial spin ice can lead to specific collective behaviour, including emergent magnetic monopoles, charge screening and transport, as well as magnonic response. Here, we demonstrate a spin-ice-based active material in which energy is converted into unidirectional dynamics. Using X-ray photoemission electron microscopy we show that the collective rotation of the average magnetization proceeds in a unique sense during thermal relaxation. Our simulations demonstrate that this emergent chiral behaviour is driven by the topology of the magnetostatic field at the edges of the nanomagnet array, resulting in an asymmetric energy landscape. In addition, a bias field can be used to modify the sense of rotation of the average magnetization. This opens the possibility of implementing a magnetic Brownian ratchet, which may find applications in novel nanoscale devices, such as magnetic nanomotors, actuators, sensors or memory cells.

Computational logic with square rings of nanomagnets.

Nanomagnets are a promising low-power alternative to traditional computing. However, the successful implementation of nanomagnets in logic gates has been hindered so far by a lack of reliability. Here, we present a novel design with dipolar-coupled nanomagnets arranged on a square lattice to (i) support transfer of information and (ii) perform logic operations. We introduce a thermal protocol, using thermally active nanomagnets as a means to perform computation. Within this scheme, the nanomagnets are initialized by a global magnetic field and thermally relax on raising the temperature with a resistive heater. We demonstrate error-free transfer of information in chains of up to 19 square rings and we show a high level of reliability with successful gate operations of ∼94% across more than 2000 logic gates. Finally, we present a functionally complete prototype NAND/NOR logic gate that could be implemented for advanced logic operations. Here we support our experiments with simulations of the thermally averaged output and determine the optimal gate parameters. Our approach provides a new pathway to a long standing problem concerning reliability in the use of nanomagnets for computation.

Cardiac implantable electronic device hematomas: Risk factors and effect of prophylactic pressure bandaging.

BACKGROUND: Cardiac implantable electronic device (CIED) hematomas are associated with many adverse outcomes. We examined the incidence and risk factors associated with hematoma formation post-CIED implantation, and explored the preventative effect of prophylactic pressure bandaging (PPB) in a large tertiary center. METHODS: 1,091 devices were implanted during October 2011-December 2014. Clinically significant hematomas (CSH) were those that necessitated prolonged admission, including those due to reoperation, and clinically suspicious hematomas were swellings noted by medical/nursing staff. We screened for variables affecting hematoma incidence prior to conducting multivariate logistic regression analyses, one for all hematomas and one for CSH. RESULTS: 61 hematomas were identified (5.6% of patients), with 12 of those clinically significant (1.1% of patients). Factors significantly increasing the odds of developing any hematoma were stage 2 (odds ratio [OR] = 2.93, 95% confidence interval [CI] [1.08-7.94], P = 0.034) and 3 chronic kidney disease (CKD) (OR = 3.39 [1.20-9.56], P = 0.021), unfractionated heparin/therapeutic enoxaparin (OR = 3.15 [1.22-8.14], P = 0.018), and dual antiplatelets-aspirin + clopidogrel (OR = 2.95 [1.14-7.65], P = 0.026) + other combinations. Body Mass index (BMI) 25.0-29.9 (OR 0.52 [0.28-0.98], P = 0.044) and >30 were associated with decreased hematoma risk (OR 0.43 [0.20-0.91], P = 0.028). Factors significant for CSH formation were unfractionated heparin/therapeutic enoxaparin (OR = 9.55 [1.83-49.84], P = 0.007) and aspirin + clopidogrel (OR = 7.19 [1.01-50.91], P = 0.048). PPB nonsignificantly increased the odds of total hematoma development (OR = 1.53 [0.87-2.69], P = 0.135), and reduced CSH (OR = 0.67 [0.18-2.47], P = 0.547). CONCLUSIONS: Heparin and dual antiplatelet use remain strong predictors of overall hematoma formation. CKD is a comparatively moderate predictor. BMI > 25 may decrease the risk of hematoma formation. PPB had nonsignificant effects on hematoma development.

Normalisation of haemoglobin and control of breakthrough haemolysis with increased frequency pegcetacoplan dosing in treated paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinura is an acquired life-threatening haemolytic condition, which is generally well controlled with terminal complement blockade with eculizumab. Whilst almost all patients treated with terminal complement inhibitors develop extravascular haemolysis, only a small proportion of these results in symptomatic anaemia limiting their activities and requiring red cell transfusion. This case highlights the potential role for the C3 inhibitor, pegcetacoplan, in controlling both intravascular and extravascular haemolysis, and is the first case to report on the use of additional doses of pegcetacoplan to control breakthrough haemolysis.

Topological kinetic crossover in a nanomagnet array.

Ergodic kinetics, which are critical to equilibrium thermodynamics, can be constrained by a system's topology. We studied a model nanomagnetic array in which such constraints visibly affect the behavior of the magnetic moments. In this system, magnetic excitations connect into thermally active one-dimensional strings whose motion can be imaged in real time. At high temperatures, our data showed the merging, breaking, and reconnecting of strings, resulting in the system transitioning between topologically distinct configurations. Below a crossover temperature, the string motion is dominated by simple changes in length and shape. In this low-temperature regime, the system is energetically stable because of its inability to explore all possible topological configurations. This kinetic crossover suggests a generalizable conception of topologically broken ergodicity and limited equilibration.

Human Plasma Extracellular Vesicle Isolation and Proteomic Characterization for the Optimization of Liquid Biopsy in Multiple Myeloma.

Cancer cells secrete membranous extracellular vesicles (EVs) which contain specific oncogenic molecular cargo (including oncoproteins, oncopeptides, and RNA) into their microenvironment and the circulation. As such, EVs including exosomes (small EVs) and microvesicles (large EVs) represent important circulating biomarkers for various diseases, including cancer and its progression. These circulating biomarkers offer a potentially minimally invasive and repeatable targets for analysis (liquid biopsy) that could aid in the diagnosis, risk stratification, and monitoring of cancer. Although their potential as cancer biomarkers has been promising, the identification and quantification of EVs in clinical samples remain challenging. Like EVs, other types of circulating biomarkers (including cell-free nucleic acids, cf-NAs; or circulating tumor cells, CTCs) may represent a complementary or alternative approach to cancer diagnosis. In the context of multiple myeloma (MM), a systemic cancer type that causes cancer cells to accumulate in the bone marrow, the specific role for EVs as biomarkers for diagnosis and monitoring remains undefined. Tumor heterogeneity along with the various subtypes of MM (such as non-secretory MM) that cannot be monitored using conventional testing (e.g. sequential serological testing and bone marrow biopsies) render liquid biopsy and circulating tumor-derived EVs a promising approach. In this protocol, we describe the isolation and purification of EVs from peripheral blood plasma (PBPL) collected from healthy donors and patients with MM for a biomarker discovery strategy. Our results demonstrate detection of circulating EVs from as little as 1 mL of MM patients' PBPL. High-resolution mass spectrometry (MS)-based proteomics promises to provide new avenues in identifying novel markers for detection, monitoring, and therapeutic intervention of disease. We describe biophysical characterization and quantitative proteomic profiling of disease-specific circulating EVs which may provide important implications for the development of cancer diagnostics in MM.

Probing spin fluctuations in NaOsO3by muon spin rotation and NMR spectroscopy.

We have used muon spin rotation and relaxation (µSR) and23Na nuclear magnetic resonance (NMR) spectroscopic methods in the NaOsO3antiferromagnetic phase to determine the temperature evolution of the magnetic order parameter and the role of the magnetic fluctuations at the Néel temperature. Additionally, we performed muon spin relaxation measurements in the vicinity ofTA= 30 K, where the appearance of an anomaly in the electrical resistivity was suggested to be due to a progressive reduction of the Os magnetic moment associated with spin fluctuation. Our measurements suggest the absence of prominent change in the spin fluctuations frequency atTA, within the muon probing time scale and the absence of a reduction of the localized Os magnetic moment reflected by the stability within few permille of the local magnetic field strength sensed by the muons below 50 K.

String Phase in an Artificial Spin Ice.

One-dimensional strings of local excitations are a fascinating feature of the physical behavior of strongly correlated topological quantum matter. Here we study strings of local excitations in a classical system of interacting nanomagnets, the Santa Fe Ice geometry of artificial spin ice. We measured the moment configuration of the nanomagnets, both after annealing near the ferromagnetic Curie point and in a thermally dynamic state. While the Santa Fe Ice lattice structure is complex, we demonstrate that its disordered magnetic state is naturally described within a framework of emergent strings. We show experimentally that the string length follows a simple Boltzmann distribution with an energy scale that is associated with the system's magnetic interactions and is consistent with theoretical predictions. The results demonstrate that string descriptions and associated topological characteristics are not unique to quantum models but can also provide a simplifying description of complex classical systems with non-trivial frustration.

The role of cell free DNA and liquid biopsies in haematological conditions.

Cell free nucleic acids (CFNAs) are nucleic acids released from cells that circulate within bodily fluids. Recent advances in molecular techniques have led the ability to interrogate CFNAs in a clinically meaningful way, for example the identification and assessment of foetal CFNAs in maternal blood, allowing minimally invasive testing for foetal genetic abnormalities. The majority of CFNAs arise from haemopoietic cells, making it a particularly rich source of genetic information in haematological conditions. Furthermore, the innate genetic heterogeneity of haematological malignancies, as epitomised by multiple myeloma, lend itself well to "liquid biopsies". This approach promises to provide a more wholistic assessment of whole disease genetics, especially when contrasted against the current gold-standard of single site tissue biopsies. This review briefly summarises the definitions and physiology of CFNAs, both cell free DNA (cfDNA) and extracellular RNA (exRNA), before exploring the literature surrounding the current and future roles of cfDNA in the haematological malignancies and patient care.

An Evidence-Based Approach to Myeloma Bone Disease.

Multiple myeloma is an incurable clonal plasma cell malignancy characterised by osteolytic bone lesions and the presence of a monoclonal immunoglobulin. The bone disease caused by myeloma is a major cause of morbidity with the related complications of pathological fractures, hypercalcaemia and bone pain affecting both quality of life and patient survival. The osteolytic lesions arise due to an imbalance of osteoclast and osteoblast function, arising from complex interactions between myeloma cells, bone marrow stromal cells and the bone marrow microenvironment. These advances in understanding of the pathophysiology have directly led to improvements in patient management and outcomes. Recent advances in myeloma bone disease are reviewed, including the role of novel and emerging therapies, and evidence-based management strategies for myeloma bone disease are discussed.

Nanoparticle-Based Magnetoelectric BaTiO3-CoFe2O4 Thin Film Heterostructures for Voltage Control of Magnetism.

Multiferroic composite materials combining ferroelectric and ferromagnetic order at room temperature have great potential for emerging applications such as four-state memories, magnetoelectric sensors, and microwave devices. In this paper, we report an effective and facile liquid phase deposition route to create multiferroic composite thin films involving the spin-coating of nanoparticle dispersions of BaTiO3, a well-known ferroelectric, and CoFe2O4, a highly magnetostrictive material. This approach offers great flexibility in terms of accessible film configurations (co-dispersed as well as layered films), thicknesses (from 100 nm to several µm) and composition (5-50 wt % CoFe2O4 with respect to BaTiO3) to address various potential applications. A detailed structural characterization proves that BaTiO3 and CoFe2O4 remain phase-separated with clear interfaces on the nanoscale after heat treatment, while electrical and magnetic studies indicate the simultaneous presence of both ferroelectric and ferromagnetic order. Furthermore, coupling between these orders within the films is demonstrated with voltage control of the magnetism at ambient temperatures.

Nanocolumnar interfaces and enhanced magnetic coercivity in preferentially oriented cobalt ferrite thin films grown using oblique-angle pulsed laser deposition.

Highly textured cobalt ferrite (CFO) thin films were grown on Si (100) substrates using oblique-angle pulsed laser deposition (α-PLD). X-ray diffraction and in-depth strain analysis showed that the obliquely deposited CFO films had both enhanced orientation in the (111) crystal direction as well as tunable compressive strains as a function of the film thicknesses, in contrast to the almost strain-free polycrystalline CFO films grown using normal-incidence PLD under the same conditions. Using in situ optical plume diagnostics the growth parameters in the α-PLD process were optimized to achieve smoother film surfaces with roughness values as low as 1-2 nm as compared to the typical values of 10-12 nm in the normal-incidence PLD grown films. Cross-sectional high resolution transmission electron microscope images revealed nanocolumnar growth of single-crystals of CFO along the (111) crystallographic plane at the film-substrate interface. Magnetic measurements showed larger coercive fields (∼10 times) with similar saturation magnetization in the α-PLD-grown CFO thin films as compared to those deposited using normal-incidence PLD. Such significantly enhanced magnetic coercivity observed in CFO thin films make them ideally suited for magnetic data storage applications. A growth mechanism based on the atomic shadowing effect and strain compression-relaxation mechanism was proposed for the obliquely grown CFO thin films.