Translating the potential of the urine steroid metabolome to stage NAFLD (TrUSt-NAFLD): study protocol for a multicentre, prospective validation study.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) affects approximately one in four individuals and its prevalence continues to rise. The advanced stages of NAFLD with significant liver fibrosis are associated with adverse morbidity and mortality outcomes. Currently, liver biopsy remains the 'gold-standard' approach to stage NAFLD severity. Although generally well tolerated, liver biopsies are associated with significant complications, are resource intensive, costly, and sample only a very small area of the liver as well as requiring day case admission to a secondary care setting. As a result, there is a significant unmet need to develop non-invasive biomarkers that can accurately stage NAFLD and limit the need for liver biopsy. The aim of this study is to validate the use of the urine steroid metabolome as a strategy to stage NAFLD severity and to compare its performance against other non-invasive NAFLD biomarkers. METHODS AND ANALYSIS: The TrUSt-NAFLD study is a multicentre prospective test validation study aiming to recruit 310 patients with biopsy-proven and staged NAFLD across eight centres within the UK. 150 appropriately matched control patients without liver disease will be recruited through the Oxford Biobank. Blood and urine samples, alongside clinical data, will be collected from all participants. Urine samples will be analysed by liquid chromatography-tandem mass spectroscopy to quantify a panel of predefined steroid metabolites. A machine learning-based classifier, for example, Generalized Matrix Relevance Learning Vector Quantization that was trained on retrospective samples, will be applied to the prospective steroid metabolite data to determine its ability to identify those patients with advanced, as opposed to mild-moderate, liver fibrosis as a consequence of NAFLD. ETHICS AND DISSEMINATION: Research ethical approval was granted by West Midlands, Black Country Research Ethics Committee (REC reference: 21/WM/0177). A substantial amendment (TrUSt-NAFLD-SA1) was approved on 26 November 2021. TRIAL REGISTRATION NUMBER: ISRCTN19370855

South Korea's automotive labour regime, Hyundai Motors’ global production network and trade‐based integration with the European Union

This article explores the interrelationship between global production networks(GPNs) and free trade agreements (FTAs) in the South Korean auto industry and its employment relations. It focuses on the production network of the Hyundai Motor Group (HMG) — the third biggest automobile manufacturer in the world — and the FTA between the EU and South Korea. This was the first of the EU’s ‘new generation’ FTAs, which among other things contained provisions designed to protect and promote labour standards. The article’s argument is twofold. First, that HMG’s production network and Korea’s political economy (of which HMG is a crucial part) limited the possibilities for the FTA’s labour provisions to take effect. Second, that the commercial provisions in this same FTA simultaneously eroded HMG’s domestic market and corporate profitability, leading to adverse consequences for auto workers in the more insecure and low-paid jobs. In making this argument, the article advances a multiscalar conceptualization of the labour regime as an analytical intermediary between GPNs and FTAs. It also provides one of the first empirical studies of the EU–South Korea FTA in terms of employment relations, drawing on 105 interviews with trade unions, employer associations, automobile companies and state officials across both parties

Father-daughter Incest: Comparison of Treated Cases to Untreated Control Subjects

Treatment of father daughter incest (FDI) survivors using the victim advocacy/child welfare approach to FDI that predominates today in the US has never been compared to results in untreated control subjects in any published report. In the present study, thirty-two survivors of FDI who received treatment based on the victim advocacy/child welfare approach to FDI were compared to 32 control subjects who did not receive treatment. No significant differences were found using analysis of variance on 21 scales and subscales. Statistical analysis of the data from all 64 of the FDI survivors showed that items reflecting a poor self-image and a history of maternal depression predicted more problematic scores on the depression scale. Those who scored higher on religiosity were less likely to be depressed. Redesigned therapy for FDI aimed, first and foremost, at healing the survivors and validated by prospective randomized trials is needed

Gapless spinons and a field-induced soliton gap in the hyper-honeycomb Cu oxalate framework compound [(C2_{2}H5_{5})3_{3}NH]2_{2}Cu2_{2}(C2_{2}O4_{4})3_{3}

We report a detailed study of the specific heat and magnetic susceptibility of single crystals of a spin liquid candidate: the hyper-honeycomb Cu oxalate framework compound [(C$_2$H$_5$)$_3$NH]$_2$Cu$_2$(C$_2$O$_4$)$_3$. The specific heat shows no anomaly associated with a magnetic transition at low temperatures down to $T\sim$ 180 mK in zero magnetic field. We observe a large linear-in-$T$ contribution to the specific heat $\gamma T$, $\gamma = 98(1)$ mK/mol K$^{2}$, at low temperatures, indicative of the presence of fermionic excitations despite the Mott insulating state. The low-$T$ specific heat is strongly suppressed by applied magnetic fields $H$, which induce an energy gap, $\Delta (H)$, in the spin-excitation spectrum. We use the four-component relativistic density-functional theory (DFT) to calculate the magnetic interactions, including the Dzyaloshinskii-Moriya antisymmetric exchange, which causes an effective staggered field acting on one copper sublattice. The magnitude and field dependence of the field-induced gap, $\Delta (H) \propto H^{2/3}$, are accurately predicted by the soliton mass calculated from the sine-Gordon model of weakly coupled antiferromagnetic Heisenberg chains with all parameters determined by our DFT calculations. Thus our experiment and calculations are entirely consistent with a model of [(C$_2$H$_5$)$_3$NH]$_2$Cu$_2$(C$_2$O$_4$)$_3$ in which anisotropic magnetic exchange interactions due to Jahn-Teller distortion cause one copper sublattice to dimerize, leaving a second sublattice of weakly coupled antiferromagnetic chains. We also show that this model quantitatively accounts for the measured temperature-dependent magnetic susceptibility. Thus [(C$_2$H$_5$)$_3$NH]$_2$Cu$_2$(C$_2$O$_4$)$_3$ is a canonical example of a one-dimensional spin-1/2 Heisenberg antiferromagnet and not a resonating-valence-bond quantum spin liquid, as previously proposed.Comment: 8 pages, 6 figure

Neuronal activity in medial superior temporal area (MST) during memory-based smooth pursuit eye movements in monkeys

We examined recently neuronal substrates for predictive pursuit using a memory-based smooth pursuit task that distinguishes the discharge related to memory of visual motion-direction from that related to movement preparation. We found that the supplementary eye fields (SEF) contain separate signals coding memory and assessment of visual motion-direction, decision not-to-pursue, and preparation for pursuit. Since medial superior temporal area (MST) is essential for visual motion processing and projects to SEF, we examined whether MST carried similar signals. We analyzed the discharge of 108 MSTd neurons responding to visual motion stimuli. The majority (69/108 = 64%) were also modulated during smooth pursuit. However, in nearly all (104/108 = 96%) of the MSTd neurons tested, there was no significant discharge modulation during the delay periods that required memory of visual motion-direction or preparation for smooth pursuit or not-to-pursue. Only 4 neurons of the 108 (4%) exhibited significantly higher discharge rates during the delay periods; however, their responses were non-directional and not instruction specific. Representative signals in the MSTd clearly differed from those in the SEF during memory-based smooth pursuit. MSTd neurons are unlikely to provide signals for memory of visual motion-direction or preparation for smooth pursuit eye movements

Substrate specificity of a long-chain alkylamine-degrading Pseudomonas sp isolated from activated sludge

A bacterium strain BERT, which utilizes primary long-chain alkylamines as nitrogen, carbon and energy source, was isolated from activated sludge. This rod-shaped motile, Gram-negative strain was identified as a Pseudomonas sp. The substrate spectrum of this Pseudomonas strain BERT includes primary alkylamines with alkyl chains ranging from C3 to C18, and dodecyl-1,3-diaminopropane. Amines with alkyl chains ranging from 8 to 14 carbons were the preferred substrates. Growth on dodecanal, dodecanoic acid and acetic acid and simultaneous adaptation studies indicated that this bacterium initiates degradation through a Calkyl–N cleavage. The cleavage of alkylamines to the respective alkanals in Pseudomonas strain BERT is mediated by a PMS-dependent alkylamine dehydrogenase. This alkylamine dehydrogenase produces stoichiometric amounts of ammonium from octylamine. The PMS-dependent alkylamine was found to oxidize a broad range of long-chain alkylamines. PMS-dependent long-chain aldehyde dehydrogenase activity was also detected in cell-free extract of Pseudomonas strain BERT grown on octylamine. The proposed pathway for the oxidation of alkylamine in strain BERT proceeds from alkylamine to alkanal, and then to the fatty acid

FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study

BACKGROUND The burden of non-alcoholic fatty liver disease (NAFLD) is increasing globally, and a major priority is to identify patients with non-alcoholic steatohepatitis (NASH) who are at greater risk of progression to cirrhosis, and who will be candidates for clinical trials and emerging new pharmacotherapies. We aimed to develop a score to identify patients with NASH, elevated NAFLD activity score (NAS≥4), and advanced fibrosis (stage 2 or higher [F≥2]). METHODS This prospective study included a derivation cohort before validation in multiple international cohorts. The derivation cohort was a cross-sectional, multicentre study of patients aged 18 years or older, scheduled to have a liver biopsy for suspicion of NAFLD at seven tertiary care liver centres in England. This was a prespecified secondary outcome of a study for which the primary endpoints have already been reported. Liver stiffness measurement (LSM) by vibration-controlled transient elastography and controlled attenuation parameter (CAP) measured by FibroScan device were combined with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or AST:ALT ratio. To identify those patients with NASH, an elevated NAS, and significant fibrosis, the best fitting multivariable logistic regression model was identified and internally validated using boot-strapping. Score calibration and discrimination performance were determined in both the derivation dataset in England, and seven independent international (France, USA, China, Malaysia, Turkey) histologically confirmed cohorts of patients with NAFLD (external validation cohorts). This study is registered with ClinicalTrials.gov, number NCT01985009. FINDINGS Between March 20, 2014, and Jan 17, 2017, 350 patients with suspected NAFLD attending liver clinics in England were prospectively enrolled in the derivation cohort. The most predictive model combined LSM, CAP, and AST, and was designated FAST (FibroScan-AST). Performance was satisfactory in the derivation dataset (C-statistic 0·80, 95% CI 0·76–0·85) and was well calibrated. In external validation cohorts, calibration of the score was satisfactory and discrimination was good across the full range of validation cohorts (C-statistic range 0·74–0·95, 0·85; 95% CI 0·83–0·87 in the pooled external validation patients' cohort; n=1026). Cutoff was 0·35 for sensitivity of 0·90 or greater and 0·67 for specificity of 0·90 or greater in the derivation cohort, leading to a positive predictive value (PPV) of 0·83 (84/101) and a negative predictive value (NPV) of 0·85 (93/110). In the external validation cohorts, PPV ranged from 0·33 to 0·81 and NPV from 0·73 to 1·0. INTERPRETATION The FAST score provides an efficient way to non-invasively identify patients at risk of progressive NASH for clinical trials or treatments when they become available, and thereby reduce unnecessary liver biopsy in patients unlikely to have significant disease

Optically guided mode study of nematic liquid crystal alignment on a zero-order grating

B. T. Hallam and J. Roy Sambles, Physical Review E, Vol. 61, pp. 6699-6704 (2000). "Copyright © 2000 by the American Physical Society."The characterization of a liquid crystal cell, which comprises one zero-order (that is, at the wavelength of study it is nondiffractive) diffraction grating and one rubbed polyimide-coated substrate, has been performed using an optically guided mode technique. The cell is filled with nematic liquid crystal E7 (manufactured and sold by Merck, Poole, U.K.). The excitation of fully leaky guided modes within the liquid crystal layer has allowed the optical director profile to be quantified under the application of weak in-plane electric fields. The fitting of angle-dependent optical data to multilayer optical theory yields the accurate twist profile of the liquid crystal for different field strengths. Comparisons with profiles predicted from elastic continuum theory, assuming a Rapini-Papoular-type anchoring at the surfaces, allow both the azimuthal anchoring strength at each surface and the twist elastic constant of the bulk to be accurately determined. Repeating these measurements as a function of temperature allows the surface and bulk order parameters of the grating-aligned liquid crystal to be deduced

Photometric study of the late-time near-infrared plateau in Type Ia supernovae

We present an in-depth study of the late-time near-infrared plateau in Type Ia supernovae (SNe Ia), which occurs between 70-500 d. We double the existing sample of SNe Ia observed during the late-time near-infrared plateau with new observations taken with the Hubble Space Telescope, Gemini, New Technology Telescope, the 3.5m Calar Alto Telescope, and the Nordic Optical Telescope. Our sample consists of 24 nearby SNe Ia at redshift < 0.025. We are able to confirm that no plateau exists in the Ks band for most normal SNe Ia. SNe Ia with broader optical light curves at peak tend to have a higher average brightness on the plateau in J and H, most likely due to a shallower decline in the preceding 100 d. SNe Ia that are more luminous at peak also show a steeper decline during the plateau phase in H. We compare our data to state-of-the-art radiative transfer models of nebular SNe Ia in the near-infrared. We find good agreement with the sub-Mch model that has reduced non-thermal ionisation rates, but no physical justification for reducing these rates has yet been proposed. An analysis of the spectral evolution during the plateau demonstrates that the ratio of [Fe II] to [Fe III] contribution in a near-infrared filter determines the light curve evolution in said filter. We find that overluminous SNe decline slower during the plateau than expected from the trend seen for normal SNe IaComment: 17 pages, 8 figures, Accepted for publication in MNRA

Mobilization of HIV Spread by Diaphanous 2 Dependent Filopodia in Infected Dendritic Cells

Paramount to the success of persistent viral infection is the ability of viruses to navigate hostile environments en route to future targets. In response to such obstacles, many viruses have developed the ability of establishing actin rich-membrane bridges to aid in future infections. Herein through dynamic imaging of HIV infected dendritic cells, we have observed how viral high-jacking of the actin/membrane network facilitates one of the most efficient forms of HIV spread. Within infected DC, viral egress is coupled to viral filopodia formation, with more than 90% of filopodia bearing immature HIV on their tips at extensions of 10 to 20 µm. Live imaging showed HIV filopodia routinely pivoting at their base, and projecting HIV virions at µm.sec−1 along repetitive arc trajectories. HIV filopodial dynamics lead to up to 800 DC to CD4 T cell contacts per hour, with selection of T cells culminating in multiple filopodia tethering and converging to envelope the CD4 T-cell membrane with budding HIV particles. Long viral filopodial formation was dependent on the formin diaphanous 2 (Diaph2), and not a dominant Arp2/3 filopodial pathway often associated with pathogenic actin polymerization. Manipulation of HIV Nef reduced HIV transfer 25-fold by reducing viral filopodia frequency, supporting the potency of DC HIV transfer was dependent on viral filopodia abundance. Thus our observations show HIV corrupts DC to CD4 T cell interactions by physically embedding at the leading edge contacts of long DC filopodial networks