Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats

Background: Vectors based on adeno-associated virus-8 (AAV8) have shown efficiency and efficacy for liver-directed gene therapy protocols following intravascular injection, particularly in relation to haemophilia gene therapy. AAV8 has also been proposed for gene therapy targeted at skeletal and cardiac muscle, again via intravascular injection. It is important to assess vector targeting at the level of virion accumulation and transgene expression in multiple species to ascertain potential issues relating to species variation in infectivity profiles. Methods: We used AAV8 vectors expressing human factor IX (FIX) from the liver-specific LP-1 promoter and administered this virus via the intravascular route of injection into 12 week old Wistar Kyoto rats. We assessed FIX levels in serum by ELISA and transgene expression at sacrifice by immunohistochemistry using anti-FIX antibodies. Vector DNA levels in organs we determined by real time PCR. Results: Administration of 1 × 1011 or 5 × 1011 scAAV8-LP1-hFIX vector particles/rat resulted in efficient production of physiological hFIX levels, respectively in blood assessed 4 weeks post-injection. This was maintained for the 4 month duration of the study. At 4 months we observed liver persistence of vector with minimal non-hepatic distribution. Conclusion: Our results demonstrate that AAV8 is a robust vector for delivering therapeutic genes into rat liver following intravascular injection

Kinetic theory of the nonlocal electrodynamic response in anisotropic metals: Skin effect in 2D systems

The electrodynamic response of ultrapure materials at low temperatures becomes spatially nonlocal. This nonlocality gives rise to phenomena such as hydrodynamic flow in transport and the anomalous skin effect in optics. In systems characterized by an anisotropic electronic dispersion, the nonlocal dynamics becomes dependent on the relative orientation of the sample with respect to the applied field, in ways that go beyond the usual, homogeneous response. Such orientational dependence should manifest itself not only in transport experiments, as recently observed, but also in optical spectroscopy. In this paper, we develop a kinetic theory for the distribution function and the transverse conductivity of two- and three-dimensional Fermi systems with anisotropic electronic dispersion. By expanding the collision integral into the eigenbasis of a collision operator, we include momentum-relaxing scattering as well as momentum-conserving collisions. We examine the isotropic 2D case as a reference, as well as anisotropic hexagonal and square Fermi-surface shapes. We apply our theory to the quantitative calculation of the skin depth and the surface impedance, in all regimes of skin effect. We find qualitative differences between the frequency dependence of the impedance in isotropic and anisotropic systems. Such differences are shown to persist even for more complex 2D Fermi surfaces, including the “supercircle” geometry and an experimental parametrization for PdCoO$_2$, which deviate from an ideal polygonal shape. We study the orientational dependence of skin effect due to Fermi-surface anisotropy, thus providing guidance for the experimental study of nonlocal optical effects

Tracing the metasomatic and magmatic evolution of continental mantle roots with Sr, Nd, Hf and Pb isotopes : a case study of Middle Atlas (Morocco) peridotite xenoliths

We studied clinopyroxenes from spinel-facies peridotite xenoliths sampled by the Quaternary intra-plate volcanism of the Middle Atlas (Morocco) and present new trace element and Sr–Nd–Hf isotope data. However, we focus in particular on Pb isotope data and 238U/204Pb and 232Th/204Pb ratios of these clinopyroxenes. This data allows us to investigate: (a) the timing of metasomatic events, (b) the prevalence and persistence of elevated 238U/204Pb, 232Th/238U and 232Th/204Pb in continental mantle roots and (c) the 238U/204Pb and 232Th/204Pb composition of putative basaltic melts generated from such metasomatised sub-continental lithospheric mantle (SCLM). Incompatible trace element concentrations in these clinopyroxenes are elevated, marked by high-field strength element depletion and fractionated elemental ratios (e.g., U/Nb, Zr/Hf) most consistent with enrichment due to carbonatitic liquids. Sr, Nd and Hf isotopes have an affinity to HIMU. U, Th and Pb abundances in the clinopyroxenes generally exceed estimates of primitive mantle clinopyroxene. Pb isotope compositions of these clinopyroxenes are radiogenic and vary between 206Pb/204Pb = 19.93–20.25, 207Pb/204Pb = 15.63–15.66 and 208Pb/204Pb = 39.72–40.23. These Pb isotope systematics result in generally negative Δ7/4 but positive Δ8/4; setting these samples distinctly apart from typical HIMU. These Pb isotope compositions are also distinct from the associated host volcanic rocks. 238U/204Pb and 232Th/204Pb of these clinopyroxenes, which range from 26 to 81 and 136 to 399, respectively, are elevated and more extreme than estimates of MORB- and HIMU-source mantle. The Pb isotope evolution of the clinopyroxenes suggests that the metasomatic enrichment is younger than 200 Ma, which discounts the volcanic activity due to the opening of the Atlantic and the onset of the collision of the African and Eurasian plates as processes generating the lithophile element and isotope composition of this continental mantle root. Instead, the enrichment is thought to be associated with the Quaternary intra-plate volcanism in the Middle Atlas. However, the erupted mafic melts have unradiogenic Pb isotopes and lower 238U/204Pb, 232Th/204Pb and 232Th/238U relative to the clinopyroxene and do not seem to have equilibrated with the clinopyroxenes. The high Th abundances and the high 232Th/238U also suggest that the metasomatism was due to carbonatitic liquids. When literature data for Pb isotopes in mantle minerals are considered, the Pb isotope range of Archean, Proterozoic and Phanerozoic continental mantle roots is remarkable in that they are similar to the convecting mantle. This observation does not support the existence of sub-continental lithospheric mantle with high 238U/204Pb and 232Th/204Pb for long periods of time. Consequently, the narrow range of Pb isotopes in SCLM worldwide suggests that only the youngest metasomatic events are recorded by incompatible elements such as U, Th and Pb. Numerical modelling of putative magmas generated from Middle Atlas SCLM by fractional, non-modal melting calculations yield extremely high 238U/204Pb and 232Th/204Pb ratios. For example, pure SCLM magmas generated from 0.5% to 10% melting are anticipated to have 232Th/204Pb ratios exceeding those known from terrestrial basalts

A major element, PGE and Re-Os isotope study of Middle Atlas (Morocco) peridotite xenoliths : evidence for coupled introduction of metasomatic sulphides and clinopyroxene

We present major element and PGE (platinum-group-element) abundances in addition to Re–Os isotope data for 11 spinel-facies whole rock peridotites from a single maar from the Middle Atlas Mountains, Morocco. Major element systematics of these xenoliths are generally correlated with indices of depletion. FeO–MgO systematics appear to suggest spinel-facies melting in the range of 5 to 25%. However, Al2O3 abundances in these xenoliths appear elevated relative to primitive mantle (Prima). The Al2O3 abundances in conjunction with other major elements require distinct re-enrichment of the Middle Atlas continental mantle root due to melt/rock reaction and precipitation of amphibole and/or clinopyroxene from passing silicate melts akin to MORB or OIB that evolved in reverse direction along the melting curves in e.g. FeO–MgO space. Sc and V confirm the range of apparent depletion and also indicate that the currently preserved fO2 in these peridotites is distinctly different from fO2 conditions observed in subduction zones. The majority of these xenoliths have low Os and Ir (I-PGEs) concentrations relative to Prima and modelled sulphide- and clinopyroxene-depleted residues of mantle melting under low fO2, mid-ocean ridge-like conditions. Moreover, Pt and Pd (P-PGE) abundances are elevated when compared to their expected abundances after substantial melt extraction. Importantly, the systematically low Ir abundances in the majority of samples show well-correlated trends with Al2O3, MgO and Cu that are inconsistent with established melting trends. Os isotopes in the Middle Atlas xenoliths range from 187Os/188Os = 0.11604 to 0.12664 although most samples are close to chondritic. The Os isotope ratios are decoupled from 187Re/188Os but, together with Re abundances, also exhibit a good correlation with Al2O3, MgO and Cu. The major element, I-PGE and Os isotope correlations suggest that the initial melt depletion led to the exhaustion of sulphide and clinopyroxene (20 to 30%) without significant stabilization of I-PGE-rich alloys. During later modal metasomatism of the refractory Middle Atlas continental mantle root with silicate melts akin to MORB or OIB the introduction of clinopyroxene/amphibole reduced the volume of the melt inducing sulphur saturation in these melts causing precipitation of secondary sulphides. This coupled crystallization of pyroxenes and sulphides (chalcopyrite) resulted in the two-component mixing systematics exhibited by I-PGEs, Os isotopes with major elements and Cu preserved in the Middle Atlas continental mantle root

A mixed method evaluation of a theory based intervention to reduce sedentary behaviour in contact centres- the stand up for health stepped wedge feasibility study

INTRODUCTION: Contact centres have higher levels of sedentary behaviour than other office-based workplaces. Stand Up for Health (SUH) is a theory-based intervention developed using the 6SQuID framework to reduce sedentary behaviour in contact centre workers. The aim of this study was to test acceptability and feasibility of implementing SUH in UK contact centres.METHODS: The study was conducted in 2020-2022 (pre COVID and during lockdown) and used a stepped-wedge cluster randomised trial design including a process evaluation. The intervention included working with contact centre managers to develop and implement a customised action plan aligning with SUH's theory of change. Workplace sedentary time, measured using activPAL™ devices, was the primary outcome. Secondary outcomes included productivity, mental wellbeing, musculoskeletal health and physical activity. Empirical estimates of between-centre standard deviation and within-centre standard deviation of outcomes from pre-lockdown data were calculated to inform sample size calculations for future trials. The process evaluation adopted the RE-AIM framework to understand acceptability and feasibility of implementing the intervention. Interviews and focus groups were conducted with contact centre employees and managers, and activity preferences were collected using a questionnaire.RESULTS: A total of 11 contact centres participated: 155 employees from 6 centres in the pre-lockdown data collection, and 54 employees from 5 centres post-lockdown. Interviews and focus groups were conducted with 33 employees and managers, and 96 participants completed an intervention activity preference questionnaire. Overall, the intervention was perceived as acceptable and feasible to deliver. Most centres implemented several intervention activities aligned with SUH's theory of change and over 50% of staff participated in at least one activity (pre-lockdown period). Perceived benefits including reduced sedentary behaviour, increased physical activity, and improved staff morale and mood were reported by contact centre employees and managers.CONCLUSIONS: SUH demonstrates potential as an appealing and acceptable intervention, impacting several wellbeing outcomes.TRIAL REGISTRATION: The trial has been registered on the ISRCTNdatabase: http://www.isrctn.com/ISRCTN11580369.</p

Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2

Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis

Does physical activity counselling enhance the effects of a pedometer-based intervention over the long-term : 12-month findings from the Walking for Wellbeing in the West study

Peer reviewedPublisher PD

Bose-Einstein-condensed systems in random potentials

The properties of systems with Bose-Einstein condensate in external time-independent random potentials are investigated in the frame of a self-consistent stochastic mean-field approximation. General considerations are presented, which are valid for finite temperatures, arbitrary strengths of the interaction potential, and for arbitrarily strong disorder potentials. The special case of a spatially uncorrelated random field is then treated in more detail. It is shown that the system consists of three components, condensed particles, uncondensed particles and a glassy density fraction, but that the pure Bose glass phase with only a glassy density does not appear. The theory predicts a first-order phase transition for increasing disorder parameter, where the condensate fraction and the superfluid fraction simultaneously jump to zero. The influence of disorder on the ground-state energy, the stability conditions, the compressibility, the structure factor, and the sound velocity are analyzed. The uniform ideal condensed gas is shown to be always stochastically unstable, in the sense that an infinitesimally weak disorder destroys the Bose-Einstein condensate, returning the system to the normal state. But the uniform Bose-condensed system with finite repulsive interactions becomes stochastically stable and exists in a finite interval of the disorder parameter.Comment: Latex file, final published varian