If it’s not one thing, HIF’s another : immunoregulation by hypoxia inducible factors in disease

Hypoxia‐inducible factors (HIFs) have emerged in recent years as critical regulators of immunity. Localised, low oxygen tension is a hallmark of inflamed and infected tissues. Subsequent myeloid cell HIF stabilisation plays key roles in the innate immune response, alongside emerging oxygen‐independent roles. Manipulation of regulatory proteins of the HIF transcription factor family can profoundly influence inflammatory profiles, innate immune cell function and pathogen clearance and, as such, has been proposed as a therapeutic strategy against inflammatory diseases. The direction and mode of HIF manipulation as a therapy are dictated by the inflammatory properties of the disease in question, with innate immune cell HIF reduction being, in general, advantageous during chronic inflammatory conditions, while upregulation of HIF is beneficial during infections. The therapeutic potential of targeting myeloid HIFs, both genetically and pharmacologically, has been recently illuminated in vitro and in vivo , with an emerging range of inhibitory and activating strategies becoming available. This review focuses on cutting edge findings that uncover the roles of myeloid cell HIF signalling on immunoregulation in the contexts of inflammation and infection and explores future directions of potential therapeutic strategies

Improvement in rice seed storage longevity from high-temperature drying is a consistent positive function of harvest moisture content above a critical value

Drying reduces seed moisture content which improves subsequent seed survival periods. Diverse maximum temperatures have been recommended to limit or avoid damage to seeds, but some high-temperature drying regimes may improve subsequent seed quality. Seeds from 20 different accessions of five rice (Oryza sativa L.) variety groups (aromatic, Aus, Indica, temperate Japonica, tropical Japonica) were harvested over several seasons at different stages of maturation and either dried throughout at 15°C/15% RH or for different initial periods (continuous or intermittent) in different drying regimes at 45°C before final equilibrium drying at 15°C/15% RH. Subsequent seed longevity in hermetic storage at 45°C with 10.9% moisture content was determined. In no case did initial drying at 45°C provide poorer longevity than drying at 15°C/15% RH throughout. There was a split-line relation, which did not differ amongst investigations, between longevity after initial drying at 45°C relative to that at 15°C/15% RH throughout and harvest moisture content, with a break point at 16.5% (a seed moisture status of about -14 MPa). Below 16.5%, relative longevity did not differ with harvest moisture content with little or no advantage to longevity from drying at 45°C. Above 16.5%, relative longevity showed a positive relation with harvest moisture content, with substantial benefit from drying at 45°C to subsequent longevity of seeds harvested whilst still moist. Hence there are temporal (immediately ex planta cf. subsequent air-dry storage) and water status discontinuities (above cf. below 16.5%) in the effect of temperature on subsequent air-dry longevity

The effect of neutrinos on the matter distribution as probed by the Intergalactic Medium

We present a suite of full hydrodynamical cosmological simulations that quantitatively address the impact of neutrinos on the (mildly non-linear) spatial distribution of matter and in particular on the neutral hydrogen distribution in the Intergalactic Medium (IGM), which is responsible for the intervening Lyman-alpha absorption in quasar spectra. The free-streaming of neutrinos results in a (non-linear) scale-dependent suppression of power spectrum of the total matter distribution at scales probed by Lyman-alpha forest data which is larger than the linear theory prediction by about 25% and strongly redshift dependent. By extracting a set of realistic mock quasar spectra, we quantify the effect of neutrinos on the flux probability distribution function and flux power spectrum. The differences in the matter power spectra translate into a ~2.5% (5%) difference in the flux power spectrum for neutrino masses with Sigma m_{\nu} = 0.3 eV (0.6 eV). This rather small effect is difficult to detect from present Lyman-alpha forest data and nearly perfectly degenerate with the overall amplitude of the matter power spectrum as characterised by sigma_8. If the results of the numerical simulations are normalized to have the same sigma_8 in the initial conditions, then neutrinos produce a smaller suppression in the flux power of about 3% (5%) for Sigma m_{\nu} = 0.6$eV (1.2 eV) when compared to a simulation without neutrinos. We present constraints on neutrino masses using the Sloan Digital Sky Survey flux power spectrum alone and find an upper limit of Sigma m_{\nu} < 0.9$ eV (2 sigma C.L.), comparable to constraints obtained from the cosmic microwave background data or other large scale structure probes.Comment: 38 pages, 21 figures. One section and references added. JCAP in pres

WMAP constraints on inflationary models with global defects

We use the cosmic microwave background angular power spectra to place upper limits on the degree to which global defects may have aided cosmic structure formation. We explore this under the inflationary paradigm, but with the addition of textures resulting from the breaking of a global O(4) symmetry during the early stages of the Universe. As a measure of their contribution, we use the fraction of the temperature power spectrum that is attributed to the defects at a multipole of 10. However, we find a parameter degeneracy enabling a fit to the first-year WMAP data to be made even with a significant defect fraction. This degeneracy involves the baryon fraction and the Hubble constant, plus the normalization and tilt of the primordial power spectrum. Hence, constraints on these cosmological parameters are weakened. Combining the WMAP data with a constraint on the physical baryon fraction from big bang nucleosynthesis calculations and high-redshift deuterium abundance, limits the extent of the degeneracy and gives an upper bound on the defect fraction of 0.13 (95% confidence).Comment: 10pp LaTeX/RevTeX, 6 eps figs; matches accepted versio

Variation Among Patients With Crohn's Disease in Benefit vs Risk Preferences and Remission Time Equivalents

Background & Aims: Patients with Crohn's disease (CD) must make decisions about their treatment. We aimed to quantify patients’ preferences for different treatment outcomes and adverse events. We also evaluated the effects of latent class heterogeneity on these preferences. Methods: An online stated-preference survey was completed by 812 individuals with CD in the Crohn's and Colitis Foundation Partners cohort (IBD Partners). Patients were given information on symptoms and severity of active disease; duration of therapy with corticosteroids; and risks of serious infection, cancer and surgery. Patients were asked to assume that their treatment was not working and to choose an alternative therapy. The primary outcome was remission-time equivalents (RTE) of a given duration of symptom severity or treatment-related risk. Latent class choice models identified groups of patients with dominant treatment-outcome preferences and associated patient characteristics with these groups. Results: Latent class analysis demonstrated 3 distinct groups of survey responders whose choices were strongly influenced by avoidance of active symptoms (61%), avoidance of corticosteroid use (25%), or avoidance of risks of cancer, infection or surgery (14%) when choosing a therapy. Class membership was correlated with age, sex, mean short CD activity index score and corticosteroid avoidance. RTEs in each latent class differed significantly from the mean RTEs for the overall sample, although the symptom-avoidant class most closely approximated the overall sample. Conclusions: In an online survey of patients with CD, we found substantial heterogeneity in preference for medication efficacy and risk of harm. Physicians and regulators should therefore not assume that all patients have mean-value preferences—this could result in significant differences in health-technology assessment models

Coupled dark matter-dark energy in light of near Universe observations

Cosmological analysis based on currently available observations are unable to rule out a sizeable coupling among the dark energy and dark matter fluids. We explore a variety of coupled dark matter-dark energy models, which satisfy cosmic microwave background constraints, in light of low redshift and near universe observations. We illustrate the phenomenology of different classes of dark coupling models, paying particular attention in distinguishing between effects that appear only on the expansion history and those that appear in the growth of structure. We find that while a broad class of dark coupling models are effectively models where general relativity (GR) is modified --and thus can be probed by a combination of tests for the expansion history and the growth of structure--, there is a class of dark coupling models where gravity is still GR, but the growth of perturbations is, in principle modified. While this effect is small in the specific models we have considered, one should bear in mind that an inconsistency between reconstructed expansion history and growth may not uniquely indicate deviations from GR. Our low redshift constraints arise from cosmic velocities, redshift space distortions and dark matter abundance in galaxy voids. We find that current data constrain the dimensionless coupling to be |xi|<0.2, but prospects from forthcoming data are for a significant improvement. Future, precise measurements of the Hubble constant, combined with high-precision constraints on the growth of structure, could provide the key to rule out dark coupling models which survive other tests. We shall exploit as well weak equivalence principle violation arguments, which have the potential to highly disfavour a broad family of coupled models.Comment: 34 pages, 6 figures; changes to match published versio

Peculiar velocity effects in high-resolution microwave background experiments

We investigate the impact of peculiar velocity effects due to the motion of the solar system relative to the microwave background (CMB) on high resolution CMB experiments. It is well known that on the largest angular scales the combined effects of Doppler shifts and aberration are important; the lowest Legendre multipoles of total intensity receive power from the large CMB monopole in transforming from the CMB frame. On small angular scales aberration dominates and is shown here to lead to significant distortions of the total intensity and polarization multipoles in transforming from the rest frame of the CMB to the frame of the solar system. We provide convenient analytic results for the distortions as series expansions in the relative velocity of the two frames, but at the highest resolutions a numerical quadrature is required. Although many of the high resolution multipoles themselves are severely distorted by the frame transformations, we show that their statistical properties distort by only an insignificant amount. Therefore, cosmological parameter estimation is insensitive to the transformation from the CMB frame (where theoretical predictions are calculated) to the rest frame of the experiment.Comment: 15 pages, 3 figures. Submitted to Phys. Rev.

Functional diversity of chemokines and chemokine receptors in response to viral infection of the central nervous system.

Encounters with neurotropic viruses result in varied outcomes ranging from encephalitis, paralytic poliomyelitis or other serious consequences to relatively benign infection. One of the principal factors that control the outcome of infection is the localized tissue response and subsequent immune response directed against the invading toxic agent. It is the role of the immune system to contain and control the spread of virus infection in the central nervous system (CNS), and paradoxically, this response may also be pathologic. Chemokines are potent proinflammatory molecules whose expression within virally infected tissues is often associated with protection and/or pathology which correlates with migration and accumulation of immune cells. Indeed, studies with a neurotropic murine coronavirus, mouse hepatitis virus (MHV), have provided important insight into the functional roles of chemokines and chemokine receptors in participating in various aspects of host defense as well as disease development within the CNS. This chapter will highlight recent discoveries that have provided insight into the diverse biologic roles of chemokines and their receptors in coordinating immune responses following viral infection of the CNS

Potentiation of 5-fluorouracil encapsulated in zeolites as drug delivery systems for in vitro models of colorectal carcinoma

The studies of potentiation of 5-fluorouracil (5-FU), a traditional drug used in the treatment of several cancers, including colorectal (CRC), were carried out with zeolites Faujasite in the sodium form, with different particle sizes (NaY, 700nm and nanoNaY, 150nm) and Linde type L in the potassium form (LTL) with a particle size of 80nm. 5-FU was loaded into zeolites by liquid-phase adsorption. Characterization by spectroscopic techniques (FTIR, 1H NMR and 13C and 27Al solid-state MAS NMR), chemical analysis, thermal analysis (TGA), nitrogen adsorption isotherms and scanning electron microscopy (SEM), demonstrated the successful loading of 5-FU into the zeolite hosts. In vitro drug release studies (PBS buffer pH 7.4, 37°C) revealed the release of 80-90% of 5-FU in the first 10min. To ascertain the drug release kinetics, the release profiles were fitted to zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Weibull kinetic models. The in vitro dissolution from the drug delivery systems (DDS) was explained by the Weibull model. The DDS efficacy was evaluated using two human colorectal carcinoma cell lines, HCT-15 and RKO. Unloaded zeolites presented no toxicity to both cancer cells, while all DDS allowed an important potentiation of the 5-FU effect on the cell viability. Immunofluorescence studies provided evidence for zeolite-cell internalization.RA is recipient of fellowship SFRH/BI/51118/2010 from Fundacao para a Ciencia e a Tecnologia (FCT, Portugal). This work was supported by the FCT projects refs. PEst-C/QUI/UI0686/2011 and PEst-C/CTM/LA0011/2011 and the Centre of Chemistry and Life and Health Sciences Research Institute (University of Minho, Portugal). The NMR spectrometer is part of the National NMR Network (RNRMN), supported with funds from FCT/QREN (Quadro de Referencia Estrategico Nacional)