Linking nitrogen cycling transformations to microbial diversity in freshwater ecosystems

This is an editorial for a special issu

Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics

[EN] The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm(2) were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm(2) were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical enhancer because it allowed faster delivery of the drug. The DPK method was sufficiently sensitive to detect subtle vehicle-induced effects on the skin permeation of propranolol. The shorter duration of these experiments and their ability to provide mechanistic information about partition between vehicle and skin and diffusivity through skin place them as practical and potentially insightful approach to quantify and, ultimately, optimize topical bioavailability.This research was funded by Ministerio de Ciencia e Innovación (AP2007-03456) and the Universidad CEU Cardenal Herrera.Calatayud-Pascual, M.; Sebastian-Morelló, M.; Balaguer-Fernandez, C.; Delgado-Charro, M.; Lopez-Castellano, A.; Merino Sanjuán, V. (2018). Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics. Pharmaceutics. 10(4):1-15. https://doi.org/10.3390/pharmaceutics10040265S11510

Association of increased plasma cardiotrophin-1 with inappropriate left ventricular mass in essential hypertension

Inappropriate left ventricular mass is present when the value of left ventricular mass exceeds individual needs to compensate hemodynamic load imposed by increased blood pressure. The goal of this study was to investigate whether plasma concentration of cardiotrophin-1, a cytokine that induces exaggerated hypertrophy in cardiomyocytes with hypertensive phenotype, is related to inappropriate left ventricular mass in patients with essential hypertension. The study was performed in 118 patients with never-treated hypertension and without prevalent cardiac disease. The left ventricular mass prediction from stroke work (systolic blood pressurexDoppler stroke volume), sex, and height (in meters(2.7)) was derived. An observed left ventricular mass/predicted left ventricular mass value >128% defined inappropriate left ventricular mass. Plasma cardiotrophin-1 was measured by an enzyme-linked immunosorbent assay. The studies were repeated in a group of 45 patients after 1 year of antihypertensive treatment. At baseline 67 and 51 patients presented with appropriate and inappropriate left ventricular mass, respectively. Plasma cardiotrophin-1 was higher (P<0.001) in patients with inappropriate mass than in patients with appropriate mass and normotensive controls. A direct correlation was found between cardiotrophin-1 and observed left ventricular mass/predicted left ventricular mass ratio (r=0.330, P<0.001) in all hypertensive patients. After treatment, plasma cardiotrophin-1 decreased and increased in patients in which inappropriate left ventricular mass regressed and persisted, respectively, despite a similar reduction of blood pressure in the 2 subgroups of patients. Albeit descriptive in nature, these results suggest the hypothesis that an excess of cardiotrophin-1 may contribute to inappropriate left ventricular growth in hypertensive patients

Elucidating three-way interactions between soil, pasture and animals that regulate nitrous oxide emissions from temperate grazing systems

Pasture-based livestock farming contributes considerably to global emissions of nitrous oxide (N2O), a powerful greenhouse gas approximately 265 times more potent than carbon dioxide. Traditionally, the estimation of N2O emissions from grasslands is carried out by means of plot-scale experiments, where externally sourced animal excreta are applied to soils to simulate grazing conditions. This approach, however, fails to account for the impact of different sward types on the composition of excreta and thus the functionality of soil microbiomes, creating unrealistic situations that are seldom observed under commercial agriculture. Using three farming systems employing contrasting pasture management strategies at the North Wyke Farm Platform, an instrumented ruminant grazing trial in Devon, UK, this study measured N2O emissions from soils treated with cattle urine and dung collected within each system as well as standard synthetic urine shared across all systems, and compared them against two forms of controls with and without inorganic nitrogen fertiliser applications. Soil microbial activity was regularly monitored through gene abundance to evaluate interactions between sward types, soil amendments, soil microbiomes and, ultimately, N2O production. Across all systems, N2O emissions attributable to cattle urine and standard synthetic urine were found to be inconsistent with one another due to discrepancy in nitrogen content. Despite previous findings that grasses with elevated levels of water-soluble carbohydrates tend to generate lower levels of N2O, the soil under high sugar grass monoculture in this study recorded higher emissions when receiving excreta from cattle fed the same grass. Combined together, our results demonstrate the importance of evaluating environmental impacts of agriculture at a system scale, so that the feedback mechanisms linking soil, pasture, animals and microbiomes are appropriately considered

A pseudo-spectral method for the Kardar-Parisi-Zhang equation

We discuss a numerical scheme to solve the continuum Kardar-Parisi-Zhang equation in generic spatial dimensions. It is based on a momentum-space discretization of the continuum equation and on a pseudo-spectral approximation of the non-linear term. The method is tested in (1+1)- and (2+1)- dimensions, where it is shown to reproduce the current most reliable estimates of the critical exponents based on Restricted Solid-on-Solid simulations. In particular it allows the computations of various correlation and structure functions with high degree of numerical accuracy. Some deficiencies which are common to all previously used finite-difference schemes are pointed out and the usefulness of the present approach in this respect is discussed.Comment: 12 pages, 13 .eps figures, revetx4. A few equations have been corrected. Erratum sent to Phys. Rev.

Insights into the reionization epoch from cosmic-noon-CIV emitters in the VANDELS survey

Recently, intense emission from nebular C III] and C IV emission lines have been observed in galaxies in the epoch of reionization ($z>6$) and have been proposed as the prime way of measuring their redshift and studying their stellar populations. These galaxies might represent the best examples of cosmic reionizers, as suggested by recent low-z observations of Lyman Continuum emitting galaxies, but it is hard to directly study the production and escape of ionizing photons at such high redshifts. The ESO spectroscopic public survey VANDELS offers the unique opportunity to find rare examples of such galaxies at cosmic noon ($z\sim 3$), thanks to the ultra deep observations available. We have selected a sample of 39 galaxies showing C IV emission, whose origin (after a careful comparison to photoionization models) can be ascribed to star formation and not to AGN. By using a multi-wavelength approach, we determine their physical properties including metallicity and ionization parameter and compare them to the properties of the parent population to understand what are the ingredients that could characterize the analogs of the cosmic reionizers. We find that C IV emitters are galaxies with high photons production efficiency and there are strong indications that they might have also large escape fraction: given the visibility of C IV in the epoch of reionization this could become the best tool to pinpoint the cosmic reioinzers.Comment: 15 pages, 10 figures, resubmitted to A&A after addressing the referee comment

No strong dependence of Lyman continuum leakage on physical properties of star-forming galaxies at 3.1 ≲ z ≲ 3.5

We present Lyman continuum (LyC) radiation escape fraction (fesc) measurements for 183 spectroscopically confirmed star-forming galaxies in the redshift range 3.11 300 Å. For candidate LyC leakers, we find a weak negative correlation between fesc and galaxy stellar masses, no correlation between fesc and specific star-formation rates (sSFRs) and a positive correlation between fesc and EW0([O III] + Hβ). The weak/no correlations between stellar mass and sSFRs may be explained by misaligned viewing angles and/or non-coincident timescales of starburst activity and periods of high fesc. Alternatively, escaping radiation may predominantly occur in highly localised star-forming regions, or fesc measurements may be impacted by stochasticity of the intervening neutral medium, obscuring any global trends with galaxy properties. These hypotheses have important consequences for models of reionisation

The evolution of clustering length, large-scale bias and host halo mass at 2<z<5 in the VIMOS Ultra Deep Survey (VUDS)

We investigate the evolution of galaxy clustering for galaxies in the redshift range 2.0<$z$<5.0 using the VIMOS Ultra Deep Survey (VUDS). We present the projected (real-space) two-point correlation function $w_p(r_p)$ measured by using 3022 galaxies with robust spectroscopic redshifts in two independent fields (COSMOS and VVDS-02h) covering in total 0.8 deg$^2$. We quantify how the scale dependent clustering amplitude $r_0$ changes with redshift making use of mock samples to evaluate and correct the survey selection function. Using a power-law model $\xi(r) = (r/r_0)^{-\gamma}$ we find that the correlation function for the general population is best fit by a model with a clustering length $r_0$=3.95$^{+0.48}_{-0.54}$ h$^{-1}$Mpc and slope $\gamma$=1.8$^{+0.02}_{-0.06}$ at $z$~2.5, $r_0$=4.35$\pm$0.60 h$^{-1}$Mpc and $\gamma$=1.6$^{+0.12}_{-0.13}$ at $z$~3.5. We use these clustering parameters to derive the large-scale linear galaxy bias $b_L^{PL}$, between galaxies and dark matter. We find $b_L^{PL}$ = 2.68$\pm$0.22 at redshift $z$~3 (assuming $\sigma_8$ = 0.8), significantly higher than found at intermediate and low redshifts. We fit an HOD model to the data and we obtain that the average halo mass at redshift $z$~3 is $M_h$=10$^{11.75\pm0.23}$ h$^{-1}$M$_{\odot}$. From this fit we confirm that the large-scale linear galaxy bias is relatively high at $b_L^{HOD}$ = 2.82$\pm$0.27. Comparing these measurements with similar measurements at lower redshifts we infer that the star-forming population of galaxies at $z$~3 should evolve into the massive and bright ($M_r$<-21.5) galaxy population which typically occupy haloes of mass $\langle M_h\rangle$ = 10$^{13.9}$ h$^{-1}$ $M_{\odot}$ at redshift $z$=0.Comment: 19 pages, 10 figures, submitted to A&

Discovery of a rich proto-cluster at z=2.9 and associated diffuse cold gas in the VIMOS Ultra-Deep Survey (VUDS)

[Abridged] We characterise a massive proto-cluster at z=2.895 that we found in the COSMOS field using the spectroscopic sample of the VIMOS Ultra-Deep Survey (VUDS). This is one of the rare structures at z~3 not identified around AGNs or radio galaxies, so it is an ideal laboratory to study galaxy formation in dense environments. The structure comprises 12 galaxies with secure spectroscopic redshift in an area of 7'x8', in a z bin of Dz=0.016. The measured galaxy number overdensity is delta_g=12+/-2. This overdensity has total mass of M~8.1x10^(14)M_sun in a volume of 13x15x17 Mpc^3. Simulations indicate that such an overdensity at z~2.9 is a proto-cluster that will collapse in a cluster of total mass M~2.5x10^(15)M_sun at z=0. We compare the properties of the galaxies within the overdensity with a control sample at the same z but outside the overdensity. We did not find any statistically significant difference between the properties (stellar mass, SFR, sSFR, NUV-r, r-K) of the galaxies inside and outside the overdensity. The stacked spectrum of galaxies in the overdensity background shows a significant absorption feature at the wavelength of Lya redshifted at z=2.895 (lambda=4736 A), with a rest frame EW = 4+/- 1.4 A. Stacking only background galaxies without intervening sources at z~2.9 along their line of sight, we find that this absorption feature has a rest frame EW of 10.8+/-3.7 A, with a detection S/N of ~4. These EW values imply a high column density (N(HI)~3-20x10^(19)cm^(-2)), consistent with a scenario where such absorption is due to intervening cold gas streams, falling into the halo potential wells of the proto-cluster galaxies. However, we cannot exclude the hypothesis that this absorption is due to the diffuse gas within the overdensity.Comment: 15 pages, 9 figures, accepted for publication in A&A (revised version after referee's comments and language editing

Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer

International audienceBackground: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular sub-types, they have no identified specific target and chemotherapy remains the only available systemic treatment. The adhesion molecule nectin-4 represents a new potential therapeutic target in different cancer models. Here, we have tested the prognos-tic value of nectin-4 expression and assessed the therapeutic efficiency of an anti-nectin 4 antibody drug conjugate (ADC) on localised and metastatic TNBC in vitro and in vivo. Materials and methods: We analysed nectin-4/PVRL4 mRNA expression in 5673 invasive breast cancers and searched for correlations with clinicopathological features including metastasis-free survival (MFS). Immunohistochemistry was carried out in 61 TNBCs and in samples of primary TNBC Patient-Derived Xenografts (PDXs). An anti-nectin-4 antibody eligible for ADC was produced and tested in vitro and in vivo in localised and metastatic TNBC PDXs. Results: High nectin-4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal sub-types. High PVRL4 mRNA expression showed independent negative prognostic value for MFS in multivariate analysis in TNBCs. Nectin-4 protein expression was not detected in adult healthy tissues including mammary tissue. Membranous protein expression was found in 62% of TNBCs, with strong correlation with mRNA expression. We developed an ADC (N41mab-vcMMAE) comprising a human anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalisation as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, this ADC induced rapid, complete and durable responses on nectin-4-positive xenograft TNBC samples including primary tumours, metastatic lesions, and local relapses; efficiency was dependent on both the dose and the nectin-4 tumour expression level. Conclusion: Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC