Validated assays for the quantification of C9orf72 human pathology.

A repeat expansion mutation in the C9orf72 gene is the leading known genetic cause of FTD and ALS. The C9orf72-ALS/FTD field has been plagued by a lack of reliable tools to monitor this genomic locus and its RNA and protein products. We have validated assays that quantify C9orf72 pathobiology at the DNA, RNA and protein levels using knock-out human iPSC lines as controls. Here we show that single-molecule sequencing can accurately measure the repeat expansion and faithfully report on changes to the C9orf72 locus in what has been a traditionally hard to sequence genomic region. This is of particular value to sizing and phasing the repeat expansion and determining changes to the gene locus after gene editing. We developed ddPCR assays to quantify two major C9orf72 transcript variants, which we validated by selective excision of their distinct transcriptional start sites. Using validated knock-out human iPSC lines, we validated 4 commercially available antibodies (of 9 tested) that were specific for C9orf72 protein quantification by Western blot, but none were specific for immunocytochemistry. We tested 15 combinations of antibodies against dipeptide repeat proteins (DPRs) across 66 concentrations using MSD immunoassay, and found two (against poly-GA and poly-GP) that yielded a 1.5-fold or greater signal increase in patient iPSC-motor neurons compared to knock-out control, and validated them in human postmortem and transgenic mouse brain tissue. Our validated DNA, RNA and protein assays are applicable to discovery research as well as clinical trials.

Observation of the non-linear Meissner effect.

A long-standing theoretical prediction is that in clean, nodal unconventional superconductors the magnetic penetration depth λ, at zero temperature, varies linearly with magnetic field. This non-linear Meissner effect is an equally important manifestation of the nodal state as the well studied linear-in-T dependence of λ, but has never been convincingly experimentally observed. Here we present measurements of the nodal superconductors CeCoIn5 and LaFePO which clearly show this non-linear Meissner effect. We further show how the effect of a small dc magnetic field on λ(T) can be used to distinguish gap nodes from non-nodal deep gap minima. Our measurements of KFe2As2 suggest that this material has such a non-nodal state.

Comparison of temperature and doping dependence of elastoresistivity near a putative nematic quantum critical point.

Strong electronic nematic fluctuations have been discovered near optimal doping for several families of Fe-based superconductors, motivating the search for a possible link between these fluctuations, nematic quantum criticality, and high temperature superconductivity. Here we probe a key prediction of quantum criticality, namely power-law dependence of the associated nematic susceptibility as a function of composition and temperature approaching the compositionally tuned putative quantum critical point. To probe the 'bare' quantum critical point requires suppression of the superconducting state, which we achieve by using large magnetic fields, up to 45 T, while performing elastoresistivity measurements to follow the nematic susceptibility. We performed these measurements for the prototypical electron-doped pnictide, Ba(Fe1-xCox)2As2, over a dense comb of dopings. We find that close to the putative quantum critical point, the elastoresistivity appears to obey power-law behavior as a function of composition over almost a decade of variation in composition. Paradoxically, however, we also find that the temperature dependence for compositions close to the critical value cannot be described by a single power law.

Coherent Modulation of Quasiparticle Scattering Rates in a Photoexcited Charge-Density-Wave System.

We present a complementary experimental and theoretical investigation of relaxation dynamics in the charge-density-wave (CDW) system TbTe_{3} after ultrafast optical excitation. Using time- and angle-resolved photoemission spectroscopy, we observe an unusual transient modulation of the relaxation rates of excited photocarriers. A detailed analysis of the electron self-energy based on a nonequilibrium Green's function formalism reveals that the phase space of electron-electron scattering is critically modulated by the photoinduced collective CDW excitation, providing an intuitive microscopic understanding of the observed dynamics and revealing the impact of the electronic band structure on the self-energy.

Nonequilibrium charge-density-wave order beyond the thermal limit.

The interaction of many-body systems with intense light pulses may lead to novel emergent phenomena far from equilibrium. Recent discoveries, such as the optical enhancement of the critical temperature in certain superconductors and the photo-stabilization of hidden phases, have turned this field into an important research frontier. Here, we demonstrate nonthermal charge-density-wave (CDW) order at electronic temperatures far greater than the thermodynamic transition temperature. Using time- and angle-resolved photoemission spectroscopy and time-resolved X-ray diffraction, we investigate the electronic and structural order parameters of an ultrafast photoinduced CDW-to-metal transition. Tracking the dynamical CDW recovery as a function of electronic temperature reveals a behaviour markedly different from equilibrium, which we attribute to the suppression of lattice fluctuations in the transient nonthermal phonon distribution. A complete description of the system's coherent and incoherent order-parameter dynamics is given by a time-dependent Ginzburg-Landau framework, providing access to the transient potential energy surfaces.

Frequency-dependent sensitivity of AC elastocaloric effect measurements explored through analytical and numerical models.

We present a comprehensive study of the frequency-dependent sensitivity for measurements of the AC elastocaloric effect by applying both exactly soluble models and numerical methods to the oscillating heat flow problem. These models reproduce the finer details of the thermal transfer functions observed in experiments, considering here representative data for single-crystal Ba(Fe1-xCox)2As2. Based on our results, we propose a set of practical guidelines for experimentalists using this technique. This work establishes a baseline against which the frequency response of the AC elastocaloric technique can be compared and provides intuitive explanations of the detailed structure observed in experiments.

Momentum Dependence of the Nematic Order Parameter in Iron-Based Superconductors.

The momentum dependence of the nematic order parameter is an important ingredient in the microscopic description of iron-based high-temperature superconductors. While recent reports on FeSe indicate that the nematic order parameter changes sign between electron and hole bands, detailed knowledge is still missing for other compounds. Combining angle-resolved photoemission spectroscopy with uniaxial strain tuning, we measure the nematic band splitting in both FeSe and BaFe_{2}As_{2} without interference from either twinning or magnetic order. We find that the nematic order parameter exhibits the same momentum dependence in both compounds with a sign change between the Brillouin center and the corner. This suggests that the same microscopic mechanism drives the nematic order in spite of the very different phase diagrams.

AC elastocaloric effect as a probe for thermodynamic signatures of continuous phase transitions.

Studying the response of materials to strain can elucidate subtle properties of the electronic structure in strongly correlated materials. Here, we focus on the elastocaloric coefficients, forming a second rank tensor quantity describing the relation between entropy and strain. In contrast to the better-known elastoresistivity, the elastocaloric effect is a thermodynamic quantity. Experimentally, elastocaloric effect measurements are demanding since the thermodynamic conditions during the measurement have to be well controlled. In this work, we present a technique to measure the elastocaloric effect under quasiadiabatic conditions. The technique is based on oscillating strain, which allows for increasing the frequency of the elastocaloric effect above the thermal relaxation rate of the sample. We apply the technique to Co-doped iron pnictide superconductors and show that the thermodynamic signatures of second order phase transitions in the elastocaloric effect closely follow those observed in calorimetry experiments. In contrast to heat capacity, elastocaloric effect measurements allow for the electronic signatures to be measured against a small phononic background even at high temperatures and in addition give information on the symmetry of the involved order parameters. This establishes the technique as a powerful complimentary tool for extracting the entropy landscape as a function of strain proximate to a continuous phase transition.

Evidence of Incoherent Carriers Associated with Resonant Impurity Levels and Their Influence on Superconductivity in the Anomalous Superconductor Pb_{1-x}Tl_{x}Te.

We present a combined experimental and theoretical study of the evolution of the Fermi surface of the anomalous superconductor Pb_{1-x}Tl_{x}Te as a function of thallium concentration, drawing on a combination of magnetotransport measurements (Shubnikov-de Haas oscillations and the Hall coefficient), angle resolved photoemission spectroscopy, and density functional theory calculations of the electronic structure. Our results indicate that for Tl concentrations beyond a critical value, the Fermi energy coincides with resonant impurity states in Pb_{1-x}Tl_{x}Te, and we rule out the presence of an additional valence band maximum at the Fermi energy. A comparison to nonsuperconducting Pb_{1-x}Na_{x}Te implies that the presence of these impurity states at the Fermi energy provides the enhanced pairing interaction and thus also the anomalously high temperature superconductivity in this material.

Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation.

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3-4 weeks, were administered fentanyl citrate at a single dose of 5.0 µg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half-life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr-1  kg-1 , volume of distribution at steady-state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half-life, volume of distribution at steady-state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg-1  hr-1 . Fentanyl citrate administered i.v. at 5.0 µg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half-life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.

Anomalous relaxation kinetics and charge-density-wave correlations in underdoped BaPb1-x Bi x O3.

Superconductivity often emerges in proximity of other symmetry-breaking ground states, such as antiferromagnetism or charge-density-wave (CDW) order. However, the subtle interrelation of these phases remains poorly understood, and in some cases even the existence of short-range correlations for superconducting compositions is uncertain. In such circumstances, ultrafast experiments can provide new insights by tracking the relaxation kinetics following excitation at frequencies related to the broken-symmetry state. Here, we investigate the transient terahertz conductivity of BaPb1-x Bi x O3--a material for which superconductivity is "adjacent" to a competing CDW phase--after optical excitation tuned to the CDW absorption band. In insulating BaBiO3 we observed an increase in conductivity and a subsequent relaxation, which are consistent with quasiparticles injection across a rigid semiconducting gap. In the doped compound BaPb0.72Bi0.28O3 (superconducting below TC = 7 K), a similar response was also found immediately above TC This observation evidences the presence of a robust gap up to T [Formula: see text] 40 K, which is presumably associated with short-range CDW correlations. A qualitatively different behavior was observed in the same material for [Formula: see text] 40 K. Here, the photoconductivity was dominated by an enhancement in carrier mobility at constant density, suggestive of melting of the CDW correlations rather than excitation across an optical gap. The relaxation displayed a temperature-dependent, Arrhenius-like kinetics, suggestive of the crossing of a free-energy barrier between two phases. These results support the existence of short-range CDW correlations above TC in underdoped BaPb1-x Bi x O3, and provide information on the dynamical interplay between superconductivity and charge order.

Determination of the resistivity anisotropy of orthorhombic materials via transverse resistivity measurements.

Measurements of the resistivity anisotropy can provide crucial information about the electronic structure and scattering processes in anisotropic and low-dimensional materials, but quantitative measurements by conventional means often suffer very significant systematic errors. Here we describe a novel approach to measuring the resistivity anisotropy of orthorhombic materials, using a single crystal and a single measurement that is derived from a π4 rotation of the measurement frame relative to the crystallographic axes. In this new basis, the transverse resistivity gives a direct measurement of the resistivity anisotropy, which combined with the longitudinal resistivity also gives the in-plane elements of the conventional resistivity tensor via a 5-point contact geometry. This is demonstrated through application to the charge-density wave compound ErTe3, and it is concluded that this method presents a significant improvement on existing techniques, particularly when measuring small anisotropies.

Magnetism and local symmetry breaking in a Mott insulator with strong spin orbit interactions.

Study of the combined effects of strong electronic correlations with spin-orbit coupling (SOC) represents a central issue in quantum materials research. Predicting emergent properties represents a huge theoretical problem since the presence of SOC implies that the spin is not a good quantum number. Existing theories propose the emergence of a multitude of exotic quantum phases, distinguishable by either local point symmetry breaking or local spin expectation values, even in materials with simple cubic crystal structure such as Ba2NaOsO6. Experimental tests of these theories by local probes are highly sought for. Our local measurements designed to concurrently probe spin and orbital/lattice degrees of freedom of Ba2NaOsO6 provide such tests. Here we show that a canted ferromagnetic phase which is preceded by local point symmetry breaking is stabilized at low temperatures, as predicted by quantum theories involving multipolar spin interactions.

Measurement of the B1g and B2g components of the elastoresistivity tensor for tetragonal materials via transverse resistivity configurations.

The elastoresistivity tensor mij,kl relates changes in resistivity to strains experienced by a material. As a fourth-rank tensor, it contains considerably more information about the material than the simpler (second-rank) resistivity tensor; in particular, for a tetragonal material, the B1g and B2g components of the elastoresistivity tensor (mxx,xx - mxx,yy and 2mxy,xy, respectively) can be related to its nematic susceptibility. Previous experimental probes of this quantity have focused exclusively on differential longitudinal elastoresistance measurements, which determine the induced resistivity anisotropy arising from anisotropic in-plane strain based on the difference of two longitudinal resistivity measurements. Here we describe a complementary technique based on transverse elastoresistance measurements. This new approach is advantageous because it directly determines the strain-induced resistivity anisotropy from a single transverse measurement. To demonstrate the efficacy of this new experimental protocol, we present transverse elastoresistance measurements of the 2mxy,xy elastoresistivity coefficient of BaFe2As2, a representative iron-pnictide that has previously been characterized via differential longitudinal elastoresistance measurements.

Does response propensity bias stress audits?

BACKGROUND: Non-response bias in surveys occurs when non-respondents differ from respondents. Methods of dealing with this include measuring 'response propensity'. We propose that response propensity has a trait-like component, measurable within the survey. Covariance of this component with survey items could indicate non-response bias. AIMS: To measure and validate trait-like response propensity, to test whether it co-varied with survey items during a routine stress audit and to test whether a prior staff attitude survey may have been biased. METHODS: Stress survey sent to government employees during a routine audit. We designed two new items to measure trait-like response propensity and completion of a prior staff survey. We calculated an odds ratio, correlations and Mann-Whitney U-tests to assess relationships between trait response propensity, completion of the prior staff survey and current stress survey scores. RESULTS: There were 71 respondents; response rate 68%. The trait response propensity item predicted completion of a prior staff survey (odds ratio 8.75, 95% confidence interval 2.32-33.08). Trait response propensity significantly correlated with two of the 40 survey items and did not significantly correlate with any of the eight 'stressor' sub-scales. Non-respondents to the prior staff survey had a significantly lower risk of stress on two of the eight stressor scales. CONCLUSIONS: Trait response propensity seems to be a valid construct. The weight of evidence does not provide an indication of non-response bias (yet neither does it assure freedom from non-response bias). The prior staff survey may have been affected by non-response bias.

NMR Evidence for Inhomogeneous Nematic Fluctuations in BaFe_{2}(As_{1-x}P_{x})_{2}.

We present evidence for nuclear spin-lattice relaxation driven by glassy nematic fluctuations in isovalent P-doped BaFe_{2}As_{2} single crystals. Both the ^{75}As and ^{31}P sites exhibit a stretched-exponential relaxation similar to the electron-doped systems. By comparing the hyperfine fields and the relaxation rates at these sites we find that the As relaxation cannot be explained solely in terms of magnetic spin fluctuations. We demonstrate that nematic fluctuations couple to the As nuclear quadrupolar moment and can explain the excess relaxation. These results suggest that glassy nematic dynamics are a common phenomenon in the iron-based superconductors.

Persistent order due to transiently enhanced nesting in an electronically excited charge density wave.

Non-equilibrium conditions may lead to novel properties of materials with broken symmetry ground states not accessible in equilibrium as vividly demonstrated by non-linearly driven mid-infrared active phonon excitation. Potential energy surfaces of electronically excited states also allow to direct nuclear motion, but relaxation of the excess energy typically excites fluctuations leading to a reduced or even vanishing order parameter as characterized by an electronic energy gap. Here, using femtosecond time- and angle-resolved photoemission spectroscopy, we demonstrate a tendency towards transient stabilization of a charge density wave after near-infrared excitation, counteracting the suppression of order in the non-equilibrium state. Analysis of the dynamic electronic structure reveals a remaining energy gap in a highly excited transient state. Our observation can be explained by a competition between fluctuations in the electronically excited state, which tend to reduce order, and transiently enhanced Fermi surface nesting stabilizing the order.

Association between use of proton pump inhibitors and non-typhoidal salmonellosis identified following investigation into an outbreak of Salmonella Mikawasima in the UK, 2013.

In November 2013, national public health agencies in England and Scotland identified an increase in laboratory-confirmed Salmonella Mikawasima. The role of proton pump inhibitors (PPIs) as a risk factor for salmonellosis is unclear; we therefore captured information on PPI usage as part of our outbreak investigation. We conducted a case-control study, comparing each case with two controls. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Thirty-nine of 61 eligible cases were included in the study. The median age of cases was 45 years; 56% were female. Of these, 33% were admitted to hospital and 31% reported taking PPIs. We identified an association between PPIs and non-typhoidal salmonellosis (aOR 8·8, 95% CI 2·0-38·3). There is increasing evidence supporting the existence of an association between salmonellosis and PPIs; however, biological studies are needed to understand the effect of PPIs in the pathogenesis of Salmonella. We recommend future outbreak studies investigate PPI usage to strengthen evidence on the relevance of PPIs in Salmonella infection. These findings should be used to support the development of guidelines for patients and prescribers on the risk of gastrointestinal infection and PPI usage.

Stripe-like nanoscale structural phase separation in superconducting BaPb(1-x)Bi(x)O3.

The phase diagram of BaPb(1-x)Bi(x)O3 exhibits a superconducting dome in the proximity of a charge density wave phase. For the superconducting compositions, the material coexists as two structural polymorphs. Here we show, via high-resolution transmission electron microscopy, that the structural dimorphism is accommodated in the form of partially disordered nanoscale stripes. Identification of the morphology of the nanoscale structural phase separation enables determination of the associated length scales, which we compare with the Ginzburg-Landau coherence length. We find that the maximum Tc occurs when the superconducting coherence length matches the width of the partially disordered stripes, implying a connection between the structural phase separation and the shape of the superconducting dome.

Origin of the Resistive Anisotropy in the Electronic Nematic Phase of BaFe(2)As(2) Revealed by Optical Spectroscopy.

We perform, as a function of uniaxial stress, an optical-reflectivity investigation of the representative "parent" ferropnictide BaFe(2)As(2) in a broad spectral range, across the tetragonal-to-orthorhombic phase transition and the onset of the long-range antiferromagnetic (AFM) order. The infrared response reveals that the dc transport anisotropy in the orthorhombic AFM state is determined by the interplay between the Drude spectral weight and the scattering rate, but that the dominant effect is clearly associated with the metallic spectral weight. In the paramagnetic tetragonal phase, though, the dc resistivity anisotropy of strained samples is almost exclusively due to stress-induced changes in the Drude weight rather than in the scattering rate, definitively establishing the anisotropy of the Fermi surface parameters as the primary effect driving the dc transport properties in the electronic nematic state.