Fabrication and characterisation of poly(sulfonated) and poly(sulfonic acid) dissolving microneedles for delivery of antibiotic and antifungal agents

Skin and soft tissue infections (SSTIs) arise from microbial ingress into the skin. In this study, poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (polyAMPS), which has been reported to exhibit antimicrobial properties was synthesised for the manufacture of microarray patches (MAPs). The free acid and sodium salt of polyAMPS with controlled molar masses and narrow dispersity were synthesised via reversible addition − fragmentation chain-transfer (RAFT) polymerisation reaction with a monomer conversion of over 99%, as determined by 1H NMR. The polymers were shown to be biocompatible when evaluated using a fibroblast dermal cell line while agar plating assay using cultures of C. albican demonstrated that the acid form of polyAMPS exhibited antimicrobial inhibition, which is potentiated in the presence of antimicrobial agents. The synthesised polymers were then used to fabricate dissolving MAPs, which were loaded with either ITRA or levofloxacin (LEV). The MAPs displayed acceptable mechanical resistance and punctured ex vivo skin to a depth of 600 µm. Skin deposition studies revealed that the MAPs were able to administer up to ∼ 1.9 mg of LEV (delivery efficiency: 94.7%) and ∼ 0.2 mg of ITRA (delivery efficiency: 45.9%), respectively. Collectively, the synthesis and development of this novel pharmaceutical system may offer a strategy to manage SSTIs.<br/

In vitro gas production of foliage from three browse tree species treated with different dose levels of exogenous fibrolytic enzymes

The aim of this study was to evaluate the effect of different dose levels of exogenous fibrolytic enzymes (EFE) on in vitro ruminal fermentation kinetics and energy utilization of foliages from three browse trees (Pithecellobium dulce, Heliocarpus velutinus and Guazuma ulmifolia). Mixture of EFE product was added to the leaves of the three browse tree species at three dose levels: 0 (control), 3.5 and 7.0 mg/g of DM. Chemical composition of the foliages, including plant secondary metabolites such as total phenolics (TP), saponins (SAP) and aqueous fraction (AF), was determined. In addition, in vitro assaying of ruminal gas production kinetics was determined for the three browse three foliages treated with EFE. P. dulce had the highest crude protein content (p < 0.05), whereas G. ulmifolia had the highest content of neutral detergent fibre and SAP (p < 0.05) and H. velutinus had the lowest content of TP (p < 0.05). The interaction between tree species and dose level of EFE was significant (p < 0.05) for gas production (GP) at 24 h of incubation, parameters b and c of the accumulated GP curve, short-chain fatty acids (SCFA) and metabolizable energy (ME). The lowest (p < 0.01) extent of accumulated GP as well as the b and c values occurred in G. ulmifolia at 0 mg EFE/g DM. P. dulce had the highest (p < 0.05) values for ME and SCFA at the highest dose of EFE. Tree species and dose level had significant (p < 0.05) effects on all parameters describing in vitro ruminal fermentation kinetics and energy utilization. Addition of EFE improved the fermentation kinetics of the browse species considered in this study.UAE

Productividad, calidad y perfil de ácidos grasos en leche de cabras alimentadas con dos forrajes

Cuarenta cabras Alpino Francés (39.3 2.0 kg PVI, primer parto) fueron usadas bajo un diseño completamente al azar para evaluar el efecto de dos fuentes de forraje en la dieta: Alfalfa (Medicago sativa) (T1) y alfalfa + maralfalfa (Pennisetum purpureum Var CT-115) (T2) sobre la respuesta productiva, calidad y per l de ácidos grasos de la leche de cabra en el primer tercio de la lactación (60 d). El consumo de materia seca (CMS) fue similar (p > 0.05) para ambos grupos. Las cabras que recibieron el T1, produjeron 0.52 kg más de leche (p < 0.01), sin efecto signi cativo en el contenido de grasa y lactosa;T2 presentó mayor (p < 0.5) consentración de proteínas, sólidos totales, densidad y sólidos no grasos. La concentración de ácidos grasos de cadena corta (AGCC) tendió a ser mayor (p = 0.07) en T1, de manera particular aumentó el caprírico (p < 0.05). Por otra parte, tanto los ácidos grasos de cadena larga (AGCL), como los ácidos grasos mono insaturados fueron mayores (p < 0.05) en T2. El ácido linoleico fue menor (p < 0.01) en T2, lo cual se re ejó en una mayor (p < 0.05) concentración de ácido linoleico conjugado (ALC). La inclusión de maralfalfa en la dieta de cabras lecheras Alpino Francés, tiene un efecto positivo en la calidad y per l de ácidos grasos, como el ácido linoleico conjugado, el cual ha demostrado tener efecto bené cos en la nutrición y salud humana.UAE

Retarded photooxidation of cyamemazine in biomimetic microenvironments

Cyamemazine (CMZ) is a neuroleptic drug that mediates cutaneous phototoxicity in humans. Here, the photobehavior of CMZ has been examined within (1)-acid glycoproteins, - and -cyclodextrins and SDS micelles. In all these microenvironments, CMZ emission was enhanced and blue-shifted, and its lifetime was longer. Irradiation of the entrapped drug at 355nm, under air; led to the N,S-dioxide. Within glycoproteins or SDS micelles the reaction was clearly slower than in phosphate buffered solution (PBS); protection by cyclodextrins was less marked. Transient absorption spectroscopy in PBS revealed formation of the triplet state ((3)CMZ*) and the radical cation (CMZ(+center dot)). Upon addition of glycoprotein, the contribution of CMZ(+center dot) became negligible, whereas (3)CMZ* dominated the spectra; in addition, the triplet lifetime became considerably longer. In cyclodextrins, this occurred to a lower extent. In all microheterogeneous systems, quenching by oxygen was slower than in solution; this was most remarkable inside glycoproteins. The highest protection from photooxidation was achieved inside SDS micelles. The results are consistent with photooxidation of CMZ through photoionization and subsequent trapping of the resulting radical cation by oxygen. This reaction is extremely sensitive to the medium and constitutes an appropriate probe for localization of the drug within a variety of biological compartments.Financial support from the Spanish Government (CTQ2010-14882, BES-2011-043706, JCI-2010-06204) and from the Generalitat Valenciana (PROMETEOII/2013/005) is gratefully acknowledged.Limones Herrero, D.; Pérez Ruiz, R.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2014). Retarded photooxidation of cyamemazine in biomimetic microenvironments. Photochemistry and Photobiology. 90(5):1012-1016. https://doi.org/10.1111/php.12303S10121016905Feinberg, A. P., & Snyder, S. H. (1975). Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine. Proceedings of the National Academy of Sciences, 72(5), 1899-1903. doi:10.1073/pnas.72.5.1899Jaszczyszyn, A., Gąsiorowski, K., Świątek, P., Malinka, W., Cieślik-Boczula, K., Petrus, J., & Czarnik-Matusewicz, B. (2012). Chemical structure of phenothiazines and their biological activity. Pharmacological Reports, 64(1), 16-23. doi:10.1016/s1734-1140(12)70726-0Domínguez, J. N., López, S., Charris, J., Iarruso, L., Lobo, G., Semenov, A., … Rosenthal, P. J. (1997). Synthesis and Antimalarial Effects of Phenothiazine Inhibitors of aPlasmodium falciparumCysteine Protease. Journal of Medicinal Chemistry, 40(17), 2726-2732. doi:10.1021/jm970266pAaron, J. J., Gaye Seye, M. D., Trajkovska, S., & Motohashi, N. (2008). Bioactive Phenothiazines and Benzo[a]phenothiazines: Spectroscopic Studies, and Biological and Biomedical Properties and Applications. Bioactive Heterocycles VII, 153-231. doi:10.1007/7081_2008_125White, N. D., & Lenz, T. L. (2013). Drug-Induced Photosensitivity and the Major Culprits. American Journal of Lifestyle Medicine, 7(3), 189-191. doi:10.1177/1559827613475575Onoue, S., Kato, M., Inoue, R., Seto, Y., & Yamada, S. (2013). Photosafety Screening of Phenothiazine Derivatives With Combined Use of Photochemical and Cassette-Dosing Pharmacokinetic Data. Toxicological Sciences, 137(2), 469-477. doi:10.1093/toxsci/kft260Albini , A. E. Fasani B. D. Glass M. E. Brown P. M. Drummond 1998 Photoreactivity versus activity of a selected class of phenothiazines: A comparative study Drugs, Photochemistry and Photostability A. Albini and E. Fasani 134 149 Royal Society of Chemistry CambridgeElisei, F., Latterini, L., Gaetano Aloisi, G., Mazzucato, U., Viola, G., Miolo, G., … Dall’Acqua, F. (2002). Excited-state Properties and In Vitro Phototoxicity Studies of Three Phenothiazine Derivatives¶. Photochemistry and Photobiology, 75(1), 11. doi:10.1562/0031-8655(2002)0752.0.co;2García, C., Piñero, L., Oyola, R., & Arce, R. (2009). Photodegradation of 2-chloro Substituted Phenothiazines in Alcohols. Photochemistry and Photobiology, 85(1), 160-170. doi:10.1111/j.1751-1097.2008.00412.xRonzani, F., Trivella, A., Arzoumanian, E., Blanc, S., Sarakha, M., Richard, C., … Lacombe, S. (2013). Comparison of the photophysical properties of three phenothiazine derivatives: transient detection and singlet oxygen production. Photochemical & Photobiological Sciences, 12(12), 2160. doi:10.1039/c3pp50246eFournier, T., Medjoubi-N, N., & Porquet, D. (2000). Alpha-1-acid glycoprotein. Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1482(1-2), 157-171. doi:10.1016/s0167-4838(00)00153-9Safaa, E.-G., Wollert, U., & Müller, W. E. (1983). Binding of Several Phenothiazine Neuroleptics to a Common Binding Site of α1-Acid Glycoprotein, Orosomucoid. Journal of Pharmaceutical Sciences, 72(2), 202-205. doi:10.1002/jps.2600720229MIYOSHI, T., SUKIMOTO, K., & OTAGIRI, M. (1992). Investigation of the Interaction Mode of Phenothiazine Neuroleptics with α1-Acid Glycoprotein. Journal of Pharmacy and Pharmacology, 44(1), 28-33. doi:10.1111/j.2042-7158.1992.tb14358.xTaheri, S., Cogswell, L. P., Gent, A., & Strichartz, G. R. (2003). Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein. Journal of Pharmacology and Experimental Therapeutics, 304(1), 71-80. doi:10.1124/jpet.102.042028Schill, G., Wainer, I. W., & Barkan, S. A. (1986). Chiral separations of cationic and anionic drugs on an α1-acid glycoprotein-bonded stationary phase (enantiopac®). Journal of Chromatography A, 365, 73-88. doi:10.1016/s0021-9673(01)81544-2Michishita, T., Franco, P., & Zhang, T. (2010). New approaches of LC-MS compatible method development on α1-acid glycoprotein-based stationary phase for resolution of enantiomers by HPLC. Journal of Separation Science, 33(23-24), 3627-3637. doi:10.1002/jssc.201000627Hermansson, J., & Grahn, A. (1995). Optimization of the separation of enantiomers of basic drugs retention mechanisms and dynamic modification of the chiral bonding properties on a α1-acid glycoprotein column. Journal of Chromatography A, 694(1), 57-69. doi:10.1016/0021-9673(94)00936-4Caetano, W., & Tabak, M. (2000). Interaction of Chlorpromazine and Trifluoperazine with Anionic Sodium Dodecyl Sulfate (SDS) Micelles: Electronic Absorption and Fluorescence Studies. Journal of Colloid and Interface Science, 225(1), 69-81. doi:10.1006/jcis.2000.6720Ghosh, H. N., Sapre, A. V., Palit, D. K., & Mittal, J. P. (1997). Picosecond Flash Photolysis Studies on Phenothiazine in Organic and Micellar Solution. The Journal of Physical Chemistry B, 101(13), 2315-2320. doi:10.1021/jp963028zIRIE, T., SUNADA, M., OTAGIRI, M., & UEKAMA, K. (1983). Protective mechanism of .BETA.-cyclodextrin for the hemolysis induced with phenothiazine neuroleptics in vitro. Journal of Pharmacobio-Dynamics, 6(6), 408-414. doi:10.1248/bpb1978.6.408Chankvetadze, B., Kartozia, I., Burjanadze, N., Bergenthal, D., Luftmann, H., & Blaschke, G. (2001). Enantioseperation of chiral phenothiazine derivatives in capillary electrophoresis using cyclodextrin type chiral selectors. Chromatographia, 53(S1), S290-S295. doi:10.1007/bf02490344Conilleau, V., Dompmartin, A., Michel, M., Verneuil, L., & Leroy, D. (2000). Photoscratch testing in systemic drug-induced photosensitivity. Photodermatology, Photoimmunology and Photomedicine, 16(2), 62-66. doi:10.1034/j.1600-0781.2000.d01-5.xMorlière, P., Bosca, F., Miranda, M. A., Castell, J. V., & Santus, R. (2004). Primary Photochemical Processes of the Phototoxic Neuroleptic Cyamemazine: A Study by Laser Flash Photolysis and Steady-state Irradiation¶. Photochemistry and Photobiology, 80(3), 535. doi:10.1562/2004-03-15-ra-114.1Morlière, P., Haigle, J., Aissani, K., Filipe, P., Silva, J. N., & Santus, R. (2004). An Insight into the Mechanisms of the Phototoxic Response Induced by Cyamemazine in Cultured Fibroblasts and Keratinocytes¶. Photochemistry and Photobiology, 79(2), 163. doi:10.1562/0031-8655(2004)0792.0.co;2Garcia, C., Smith, G. A., McGimpsey, W. G., Kochevar, I. E., & Redmond, R. W. (1995). Mechanism and Solvent Dependence for Photoionization of Promazine and Chlorpromazine. Journal of the American Chemical Society, 117(44), 10871-10878. doi:10.1021/ja00149a010Gao, Y., Chen, J., Zhuang, X., Wang, J., Pan, Y., Zhang, L., & Yu, S. (2007). Proton transfer in phenothiazine photochemical oxidation: Laser flash photolysis and fluorescence studies. Chemical Physics, 334(1-3), 224-231. doi:10.1016/j.chemphys.2007.03.00

NIHAO XIII: Clumpy discs or clumpy light in high redshift galaxies?

Many massive star forming disc galaxies in the redshift range 3 to 0.5 are observed to have a clumpy morphology showing giant clumps of size $\sim$1 kpc and masses of about $10^7M_{\odot}$ to $10^{10} M_{\odot}$. The nature and fate of these giant clumps is still under debate. In this work we use 19 high-resolution simulations of disc galaxies from the NIHAO sample to study the formation and the evolution of clumps in the discs of high redshift galaxies. We use mock HST - CANDELS observations created with the radiative transfer code GRASIL-3D to carry out, for the first time, a quantitative comparison of the observed fraction of clumpy galaxies and its evolution with redshift with simulations. We find a good agreement between the observed clumpy fraction and the one of the NIHAO galaxies. We find that dust attenuation can suppress intrinsically bright clumps and enhance less luminous ones. In our galaxy sample we only find clumps in light (u-band) from young stars but not in stellar mass surface density maps. This means that the NIHAO sample does not show clumpy stellar discs but rather a clumpy light distribution originating from clumpy star formation events. The clumps found in the NIHAO sample match observed age/color gradients as a function of distance from the galaxy center but they show no sign of inward migration. Clumps in our simulations disperse on timescales of a about a hundred Myr and their contribution to bulge growth is negligible

Efectos de diferentes sistemas de uso de suelo sobre la diversidad de árboles, almacenamiento de carbono y calidad del suelo en el Bosque Atlántico del Alto Paraná, Paraguay

[Introducción]: La evaluación del suministro de servicios ecosistémicos por los diferentes usos del suelo de la agricultura familiar facilita plantear estrategias para el uso sostenible de la tierra. [Objetivo]: Se determinaron los efectos de diferentes usos del suelo practicados en la agricultura familiar, sobre la conservación de la diversidad arbórea y el suministro de servicios ecosistémicos críticos: almacenamiento de carbono aéreo y subterráneo y servicios de soporte que provienen del suelo, en la Reserva de Biosfera del Bosque Mbaracayú (Canindeyú, Para-guay). [Metodología]: Fue determinada la biodiversidad arbórea, el almacenamiento de carbono aéreo y de suelo, las propiedades químicas y físicas del suelo en 7 fincas con diversos tipos de cobertura: bosque nativo alterado, sistemas agroforestales con yerba mate, cultivo anual de subsistencia y pasturas. En cada uno de los puntos de muestreo, fueron registrados datos de los individuos arbóreos y arbustivos, y fueron tomadas muestras del estrato herbáceo, hojarasca y suelo. [Resultados]: Se registró mayor índice de diversidad y almacenamiento de carbono aéreo en bosques nativos alterados y sistemas agroforestales, sin diferencia significativa entre ellos. Los valores de CIC y Ca+2 de suelo fueron más elevados en los bosques nativos alterados comparado con pasturas, y los otros usos presentaron valores intermedios. No hubo diferencias significativas entre los diferentes usos en cuanto al carbono almacenado ni en estabilidad de la estructura del suelo. Sin embargo, las pasturas presentaron índices de calidad de suelo más bajos. [Conclusiones]: Se demostró que bosques nativos alterados y sistemas agroforestales aportan más a la conservación de la diversidad arbórea, retención de carbono y calidad del suelo

On the Origin of Exponential Galaxy Disks

We use a disk galaxy evolution model to investigate whether galaxies with exponential surface brightness profiles can be produced in a cosmologically motivated framework for disk galaxy formation. Our model follows the accretion, cooling, and ejection of baryonic mass, as a function of radius, inside growing dark matter haloes. The surface density profile of the disk is determined by detailed angular momentum conservation, starting from the distribution of specific angular momentum as found in cosmological simulations. Exponential and quasi-exponential disks can be produced by our model through a combination of supernova driven galactic outflows (which preferentially remove low angular momentum material), intrinsic variation in the angular momentum distribution of the halo gas, and the inefficiency of star formation at large radii. We use observations from the SDSS NYU-VAGC to show that the median Sersic index of blue galaxies is a strong function of stellar mass. For blue galaxies, low mass galaxies have a median n=1.3, while high mass galaxies have a median n=4. Our model with energy driven outflows correctly reproduces this trend, whereas our models with momentum driven outflows and no outflows over predict the Sersic indices in low mass galaxies. We show that the observed fraction of "bulge-less" exponential galaxies is a strong function of stellar mass. For Milky-Way mass galaxies less than 0.1% of blue galaxies are bulge-less, whereas for M33 mass galaxies bulge-less and quasi-bulgeless galaxies are typical. These results suggest that the difficulty of hierarchical formation models to produce bulge-less Milky-Way mass galaxies is in fact not a problem. However, the problem of producing M33 like galaxies remains, and will provide a key test for hierarchical galaxy formation models. [Abridged]Comment: 23 pages, 13 figures, accepted to MNRAS, two new figure

On the nature of disks at high redshift seen by JWST/CEERS with contrastive learning and cosmological simulations

Visual inspections of the first optical rest-frame images from JWST have indicated a surprisingly high fraction of disk galaxies at high redshifts. Here we alternatively apply self-supervised machine learning to explore the morphological diversity at $z \geq 3$. Our proposed data-driven representation scheme of galaxy morphologies, calibrated on mock images from the TNG50 simulation, is shown to be robust to noise and to correlate well with physical properties of the simulated galaxies, including their 3D structure. We apply the method simultaneously to F200W and F356W galaxy images of a mass-complete sample ($M_*/M_\odot>10^9$) at $z \geq 3$ from the first JWST/NIRCam CEERS data release. We find that the simulated and observed galaxies do not populate the same manifold in the representation space from contrastive learning, partly because the observed galaxies tend to be more compact and more elongated than the simulated galaxies. We also find that about half the galaxies that were visually classified as disks based on their elongated images actually populate a similar region of the representation space than spheroids, which according to the TNG50 simulation is occupied by objects with low stellar specific angular momentum and non-oblate structure. This suggests that the disk fraction at $z > 3$ as evaluated by visual classification may be severely overestimated by misclassifying compact, elongated galaxies as disks. Deeper imaging and/or spectroscopic follow-ups as well as comparisons with other simulations will help to unambiguously determine the true nature of these galaxies.Comment: 25 pages, 23 figures. Submitted to ApJ. Comments welcom

Cells of the human intestinal tract mapped across space and time

Acknowledgements We acknowledge support from the Wellcome Sanger Cytometry Core Facility, Cellular Genetics Informatics team, Cellular Generation and Phenotyping (CGaP) and Core DNA Pipelines. This work was financially supported by the Wellcome Trust (W1T20694, S.A.T.; 203151/Z/16/Z, R. A. Barker.); the European Research Council (646794, ThDefine, S.A.T.); an MRC New Investigator Research Grant (MR/T001917/1, M.Z.); and a project grant from the Great Ormond Street Hospital Children’s Charity, Sparks (V4519, M.Z.). The human embryonic and fetal material was provided by the Joint MRC/Wellcome (MR/R006237/1) Human Developmental Biology Resource (https://www.hdbr.org/). K.R.J. holds a Non-Stipendiary Junior Research Fellowship from Christ’s College, University of Cambridge. M.R.C. is supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1) and a Wellcome Trust Investigator Award (220268/Z/20/Z). H.W.K. is funded by a Sir Henry Wellcome Fellowship (213555/Z/18/Z). A.F. is funded by a Wellcome PhD Studentship (102163/B/13/Z). K.T.M. is funded by an award from the Chan Zuckerberg Initiative. H.H.U. is supported by the Oxford Biomedical Research Centre (BRC) and the The Leona M. and Harry B. Helmsley Charitable Trust. We thank A. Chakravarti and S. Chatterjee for their contribution to the analysis of the enteric nervous system. We also thank R. Lindeboom and C. Talavera-Lopez for support with epithelium and Visium analysis, respectively; C. Tudor, T. Li and O. Tarkowska for image processing and infrastructure support; A. Wilbrey-Clark and T. Porter for support with Visium library preparation; A. Ross and J. Park for access to and handling of fetal tissue; A. Hunter for assistance in protocol development; D. Fitzpatrick for discussion on developmental intestinal disorders; and J. Eliasova for the graphical images. We thank the tissue donors and their families, and the Cambridge Biorepository for Translational Medicine and Human Developmental Biology Resource, for access to human tissue. This publication is part of the Human Cell Atlas: https://www.humancellatlas.org/publications.Peer reviewedPublisher PD