Three-dimensional mid-infrared tomographic imaging of endogenous and exogenous molecules in a single intact cell with subcellular resolution

Microscopy in the mid-infrared spectral range provides detailed chemical information on a sample at moderate spatial resolution and is being used increasingly in the characterization of biological entities as challenging as single cells. However, a conventional cellular 2D imaging measurement is limited in its ability to associate specific compositional information to subcellular structures because of the interference from the complex topography of the sample. Herein we provide a method and protocols that overcome this challenge in which tilt-series infrared tomography is used with a standard benchtop infrared microscope. This approach gives access to the quantitative 3D distribution of molecular components based on the intrinsic contrast provided by the sample. We demonstrate the method by quantifying the distribution of an exogenous metal carbonyl complex throughout the cell and by reporting changes in its coordination sphere in different locations in the cell

Quantized conductance doubling and hard gap in a two-dimensional semiconductor-superconductor heterostructure

The prospect of coupling a two-dimensional (2D) semiconductor heterostructure to a superconductor opens new research and technology opportunities, including fundamental problems in mesoscopic superconductivity, scalable superconducting electronics, and new topological states of matter. For instance, one route toward realizing topological matter is by coupling a 2D electron gas (2DEG) with strong spin-orbit interaction to an s-wave superconductor. Previous efforts along these lines have been hindered by interface disorder and unstable gating. Here, we report measurements on a gateable InGaAs/InAs 2DEG with patterned epitaxial Al, yielding multilayer devices with atomically pristine interfaces between semiconductor and superconductor. Using surface gates to form a quantum point contact (QPC), we find a hard superconducting gap in the tunneling regime, overcoming the soft-gap problem in 2D superconductor-semiconductor hybrid systems. With the QPC in the open regime, we observe a first conductance plateau at 4e^2/h, as expected theoretically for a normal-QPC-superconductor structure. The realization of a hard-gap semiconductor-superconductor system that is amenable to top-down processing provides a means of fabricating scalable multicomponent hybrid systems for applications in low-dissipation electronics and topological quantum information.Comment: includes main text, supplementary information and code for simulations. Published versio

The frequent and underrecognised co-occurrence of acute exacerbated COPD and depression warrants screening: a systematic review

Patients with acute exacerbated chronic obstructive pulmonary disease (AECOPD) and concurrent depression suffer significant psychological stress and decreased quality of life. The aim of this study was to collate data, guidelines and recommendations from publications on the screening and management of depressive mood disorders in patients hospitalised with AECOPD. We systematically searched four databases for publications reporting screening or management of depression in patients hospitalised for AECOPD. The identification of articles was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Out of 1494 original articles screened, 35 met all inclusion criteria. These report a prevalence of depression in AECOPD ranging between 9.5% and 85.6%. Some studies report high postadmission mortality rates for depressive AECOPD patients, and higher readmission rates in depressive versus nondepressive AECOPD patients. Importantly, none of the 35 publications included suggestions on the screening and management of depression in AECOPD. Depression and AECOPD frequently co-occur, and this worsens outcomes. Yet we did not find recommendations on management, and few interventional studies. Patients hospitalised with AECOPD should be systematically screened for depression and treatment recommendations should be developed for these patients. Randomised studies on how to screen and treat depression in hospitalised AECOPD are necessary

Factor VII activating protease (FSAP) influences vascular remodeling in the mouse hind limb ischemia model

Background: Investigations in factor VII activating protease (FSAP)-/- mice suggest a role for FSAP in stroke, thrombosis and neointima formation. Here, we analyzed the role of FSAP in vascular remodeling processes related to arteriogenesis and angiogenesis in the mouse hind limb ischemia model. Methods and results: Femoral artery ligation was performed in mice and exogenous FSAP was injected locally to examine its effect on arteriogenesis in the adductor and angiogenesis in the gastrocnemius muscle over 21 days. Perfusion was decreased by FSAP, which was reflected in a lower arterial diameter and was associated with reduced monocyte infiltration in the adductor muscle. There was increased angiogenesis in the gastrocnemius muscle triggered indirectly by less blood supply to the lower limb. Comparison of wild-type (WT) and FSAP-/- mice showed that perfusion was not different between the genotypes but there were 2.5-fold more collateral arteries in the adductor muscle of FSAP-/- mice at day 21. This was associated with a higher infiltration of monocytes at day 3. Capillary density in the gastrocnemius muscle was not altered. Activity of the two major proteolytic pathways associated with vascular remodeling; matrix metalloprotease (MMP)-9 and urokinase-type plasminogen activator (uPA) was elevated in the gastrocnemius but not in the adductor muscle in FSAP-/- mice. Conclusions: Arteriogenesis is enhanced, and this is associated with a higher infiltration of monocytes, in the absence of endogenous FSAP but angiogenesis is unchanged. Exogenous FSAP had the opposite effect on arteriogenesis indicating a possible therapeutic potential of modulating endogenous FSAP

An experimentally-validated numerical model of diffusion and speciation of water in rhyolitic silicate melt

The diffusion of water through silicate melts is a key process in volcanic systems. Diffusion controls the growth of the bubbles that drive volcanic eruptions and determines the evolution of the spatial distribution of dissolved water during and after magma mingling, crystal growth, fracturing and fragmentation, and welding of pyroclasts. Accurate models for water diffusion are therefore essential for forward modelling of eruptive behaviour, and for inverse modelling to reconstruct eruptive and post-eruptive history from the spatial distribution of water in eruptive products. Existing models do not include the kinetics of the homogeneous species reaction that interconverts molecular () and hydroxyl () water; reaction kinetics are important because final species distribution depends on cooling history. Here we develop a flexible 1D numerical model for diffusion and speciation of water in silicate melts. We validate the model against FTIR transects of the spatial distribution of molecular, hydroxyl, and total water across diffusion-couple experiments of haplogranite composition, run at 800–1200°C and 5 kbar. We adopt a stepwise approach to analysing and modelling the data. First, we use the analytical Sauer-Freise method to determine the effective diffusivity of total water as a function of dissolved water concentration and temperature for each experiment and find that the dependence of on is linear for wt.% and exponential for wt.%. Second, we develop a 1D numerical forward model, using the method of lines, to determine a piece-wise function for that is globally-minimized against the entire experimental dataset. Third, we extend this numerical model to account for speciation of water and determine globally-minimized functions for diffusivity of molecular water and the equilibrium constant for the speciation reaction. Our approach includes three key novelties: 1) functions for diffusivities of and , and the speciation reaction, are minimized simultaneously against a large experimental dataset, covering a wide range of water concentration ( wt.%) and temperature (), such that the resulting functions are both mutually-consistent and broadly applicable; 2) the minimization allows rigorous and robust analysis of uncertainties such that the accuracy of the functions is quantified; 3) the model can be straightforwardly used to determine functions for diffusivity and speciation for other melt compositions pending suitable diffusion-couple experiments. The modelling approach is suitable for both forward and inverse modelling of diffusion processes in silicate melts; the model is available as a Matlab script from the electronic supplementary material

Quark Spin and the Theta-Term for the QCD String

We describe a way in which spin of quarks can enter a consistent QCD string theory. We show that the spin factor of the 4d massless, spin 1/2 fermions is related to the self-intersection number of a 2d surfaces immersed in the 4d space. We argue that the latter quantity should appear in a consistent description of the QCD string. We also calculate the chiral anomaly and show that the self-intersection number corresponds to the topological charge $F{\tilde F}$ of QCD.Comment: 9 page

Conservative management versus open reduction and internal fixation for mid-shaft clavicle fractures in adults - The Clavicle Trial: Study protocol for a multicentre randomized controlled trial

Background: Clavicle fractures account for around 4% of all fractures and up to 44% of fractures of the shoulder girdle. Fractures of the middle third (or mid-shaft) account for approximately 80% of all clavicle fractures. Management of this group of fractures is often challenging and the outcome can be unsatisfactory. In particular it is not clear whether surgery produces better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform our decision.Methods/Design: We aim to undertake a multicentre randomised controlled trial evaluating the effectiveness and safety of conservative management versus open reduction and internal fixation for displaced mid-shaft clavicle fractures in adults. Surgical treatment will be performed using the Acumed clavicle fixation system. Conservative management will consist of immobilisation in a sling at the side in internal rotation for 6 weeks or until clinical or radiological union. We aim to recruit 300 patients. These patients will be followed-up for at least 9 months. The primary endpoint will be the rate of non-union at 3 months following treatment. Secondary endpoints will be limb function measured using the Constant-Murley Score and the Disabilities of the Arm, Shoulder and Hand (DASH) Score at 3 and 9 months post-operatively.Discussion: This article presents the protocol for a multicentre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity.Trial Registration: United Kingdom Clinical Research Network ID: 8665. The date of registration of the trial is 07/09/2006. The date the first patient was recruited is 18/12/2007. © 2011 Longo et al; licensee BioMed Central Ltd

Management of hyperglycaemia in persons with non-insulin-dependent type 2 diabetes mellitus who are started on systemic glucocorticoid therapy: a systematic review

OBJECTIVES What is the most effective pharmacological intervention for glycaemic control in known type 2 diabetes mellitus (DM) without prior insulin treatment and newly started on systemic glucocorticoid therapy? DESIGN We conducted a systematic literature review. DATA SOURCES We searched MEDLINE, Embase and Cochrane Library databases and Google for articles from 2002 to July 2018. ELIGIBILITY CRITERIA We combined search terms relating to DM (patients, >16 years of age), systemic glucocorticoids, glycaemic control, randomised controlled trials (RCTs) and observational studies. DATA EXTRACTION AND SYNTHESIS We screened and evaluated articles, extracted data and assessed risk of bias and quality of evidence according to Grading of Recommendations Assessment, Development and Evaluation guidelines. RESULTS Eight of 2365 articles met full eligibility criteria. Basal-bolus insulin (BBI) strategy for patients under systemic glucocorticoid therapy was comparatively effective but provided insufficient glucose control, depending on time of day. BBI strategy with long-acting insulin and neutral protamin Hagedorn as basal insulin provided similar overall glycaemic control. Addition of various insulin strategies to standard BBI delivered mixed results. Intermediate-acting insulin (IMI) as additional insulin conferred no clear benefits, and glycaemic control with sliding scale insulin was inferior to BBI or IMI. No studies addressed whether anticipatory or compensatory insulin adjustments are better for glycaemic control. CONCLUSION The lack of suitably designed RCTs and observational studies, heterogeneity of interventions, target glucose levels and glucose monitoring, poor control of DM subgroups and low to moderate quality of evidence render identification of optimal pharmacological interventions for glycaemic control and insulin management difficult. Even findings on the widely recommended BBI regimen as intensive insulin therapy for patients with DM on glucocorticoids are inconclusive. High-quality evidence from studies with well-defined DM phenotypes, settings and treatment approaches is needed to determine optimal pharmacological intervention for glycaemic control. PROSPERO REGISTRATION NUMBER CRD42015024739