Combinatorial wound dressings loaded with synergistic antibiotics in the treatment of chronic infected wounds

Advanced medicated wound dressings fabricated by electrospinning and electrospraying were prepared for the eradication of topical bacterial infections potentially applied in the management of infected acute and chronic non-healing wounds. Two different antibiotics (ciprofloxacin and rifampicin), with different aqueous solubilities and different mechanisms of antimicrobial action, were loaded within electrosprayed polymer microparticles and within electrospun nanofibers, respectively, to provide the resulting wound dressing with dually controlled antibiotic release kinetics. Due to the large surface area per volume ratio of the electrosprayed microparticles containing ciprofloxacin, an initial burst release was obtained. Simultaneously, the reduced surface area per volume ratio for the electrospun nanofibers together with the reduced aqueous solubility of rifampicin produced an extended rifampicin release over time. More importantly, a synergistic antimicrobial effect against Gram-positive and Gram-negative bacteria was observed when both antibiotics were combined. Biofilm formation prevention and the elimination of already formed mature bacterial biofilms were also successfully achieved using our advanced dressings. The lack of cytotoxicity of the advanced wound dressings here reported against eukaryotic cells at antimicrobial doses was also demonstrated using three different mammalian cell lines. Moreover, the advanced wound dressings successfully eliminated a Staphylococcus aureus mediated experimental infection in a chronic wound murine model showing their efficacy for the treatment of these complicated non-healing wounds. The strategy of advanced medicated wound dressings developed here may be used as a potential methodology for the fabrication of functional combinatorial materials that offer the ability to eradicate bacterial infections

Autophagy-mediated NCOR1 degradation is required for brown fat maturation and thermogenesis

Brown adipose tissue (BAT) thermogenesis affects energy balance, and thereby it has the potential to induce weight loss and to prevent obesity. Here, we document a macroautophagic/autophagic-dependent mechanism of peroxisome proliferator-activated receptor gamma (PPARG) activity regulation that induces brown adipose differentiation and thermogenesis and that is mediated by TP53INP2. Disruption of TP53INP2-dependent autophagy reduced brown adipogenesis in cultured cells. In vivo specific-tp53inp2 ablation in brown precursor cells or in adult mice decreased the expression of thermogenic and mature adipocyte genes in BAT. As a result, TP53INP2-deficient mice had reduced UCP1 content in BAT and impaired maximal thermogenic capacity, leading to lipid accumulation and to positive energy balance. Mechanistically, TP53INP2 stimulates PPARG activity and adipogenesis in brown adipose cells by promoting the autophagic degradation of NCOR1, a PPARG co-repressor. Moreover, the modulation of TP53INP2 expression in BAT and in human brown adipocytes suggests that this protein increases PPARG activity during metabolic activation of brown fat. In all, we have identified a novel molecular explanation for the contribution of autophagy to BAT energy metabolism that could facilitate the design of therapeutic strategies against obesity and its metabolic complications

Source identification of amphetamine-like stimulants in Spanish wastewater through enantiomeric profiling

Amphetamine (AMP), methamphetamine (MAMP) and 3,4-methylenedioxymethamphetamine (MDMA) occur in wastewater not only as a result of illicit consumption, but also, in some cases, from prescription drug use or by direct drug disposal into the sewage system. Enantiomeric profiling of these chiral drugs could give more insight into the origin of their occurrence. In this manuscript, a new analytical methodology for the enantiomeric analysis of amphetamine-like substances in wastewater has been developed. The method consists of a solid-phase extraction (SPE) followed by liquid chromatography-triple quadrupole-tandem mass spectrometry (LC-MS/MS), which showed low quantification limits in the 2.4–5.5 ng L−1 range. The LC-MS/MS method was first applied to characterize a total of 38 solid street drug samples anonymously provided by consumers. The results of these analysis showed that AMP and MDMA trafficked into Spain are synthesized as racemate, while MAMP is exclusively produced as the S(+)-enantiomer. Then, the analytical method was employed to analyse urban wastewater samples collected from the wastewater treatment plants (WWTPs) of five different cities in 2018 and 2019. Consumption estimated through normalized population loads in wastewater showed an increased pattern of AMP use in the Basque Country. Furthermore, the enantiomeric profiling of wastewater samples was contrasted to lisdexamfetamine (LIS) and selegiline (SEL) prescription figures, two pharmaceuticals which metabolize to S(+)-AMP, and to R(-)-AMP and R(-)-MAMP, respectively. From this analysis, and considering uncertainties derived from metabolism and adherence to treatment, it was concluded that LIS is a relevant source of AMP in those cases with low wastewater loads, i.e. up to a maximum of 60% of AMP detected in wastewater in some samples could originate from LIS prescription, while SEL does not represent a significant source of AMP nor MAMP. Finally, removal efficiencies could be evaluated for the WWTP (serving ca. 860,000 inhabitants) with higher AMP influent concentrations. The removal of AMP was satisfactory with rates higher than 99%, whereas MDMA showed an average removal of approximately 60%, accompanied by an enrichment of R(-)-MDMAThis study was supported by MINECO/MICINN/AEI projects (CTM2016-81935-REDT, CTM2017-84763-C3-2-R, CTM2017-84763-C3-1-R, CTM2017-84763-C3-3-R, PID2020-117686RB-C32, PID2020-117686RB-C31, PID2020-117686RB-C33), Galician Council of Culture, Education and Universities (ED481D-2017/003, ED431C-2017/36, ED481A-2020/258 and ED431C 2021/06), cofounded by FEDER/ERDF. UJI authors acknowledge the financial support of Generalitat Valenciana (Excellence Research Group, Prometeo 2019/040). Alberto Celma acknowledges the Spanish Ministry of Economy and Competitiveness for his predoctoral Grant (BES-2016-076914). Vanessa Gutmann acknowledges the support of the ERASMUS+ program.S

Children’s imaginaries in the city: on things and materials

The article is an exploration of urban imaginaries emerging through a play with materials. Starting from a complex activist exercise for reimagining the space of a park in decay, whose protagonists are children, we propose a reflection on the productivity and resilience of matter. We argue that a new materialist sociology is one that takes disappearances seriously. Capitalism renders space abstract not only through flow and circulation, but also through stillness. We follow the curious disappearances and reappearances of the park in question, tracing the mutations of urban planning, of the juridical domain, and of the everyday use of space. Finally, we analyse the making of a maquette of the park by a group of children and their alliances with activists. The maquette is a political “thing”: it leads us away from an urban imaginary populated by discrete objects to an urban imaginary of depth and it reconcretises space

Nanogels with high loading of anesthetic nanocrystals for extended duration of sciatic nerve block

The development of thermoresponsive nanogels loaded with nanocrystals of the local anesthetic bupivacaine nanocrystals (BNCs) for prolonged peripheral nerve pain relief is reported here. BNCs were prepared using the antisolvent precipitation method from the hydrophobic form of bupivacaine (bupivacaine free base). The as-prepared BNCs were used stand-alone or encapsulated in temperature-responsive poly(ethylene glycol) methyl ether methacrylate (OEGMA)-based nanogels, resulting in bupivacaine NC-loaded nanogels (BNC-nanogels) of monodisperse size. The synthesis protocol has rendered high drug loadings (i.e., 93.8 ± 1.5 and 84.8 ± 1.2 wt % for the NC and BNC-nanogels, respectively) and fast drug dissolution kinetics in the resulting composite material. In vivo tests demonstrated the efficacy of the formulation along with an extended duration of sciatic nerve block in murine models of more than 8 h with a formulation containing only 2 mg of the local anesthetic thanks to the thermoresponsive character of the polymer, which, at body temperature, becomes hydrophobic and acts as a diffusion barrier for the encapsulated drug nanocrystals. The hydrophobicity of the encapsulated bupivacaine free base probably facilitates its pass through cell membranes and also binds strongly to their hydrophobic lipid bilayer, thereby protecting molecules from diffusion to extracellular media and to the bloodstream, reducing their clearance. When using BNC-nanogels, the duration of the anesthetic blockage lasted twice as long as compared to the effect of just BNCs or a conventional bupivacaine hydrochloride solution both containing equivalent amounts of the free drug. Results of the in vivo tests showed enough sensory nerve block to potentially relieve pain, but still having mobility in the limb, which enables motor function when required. The BNC-nanogels presented minimal toxicity in the in vivo study due to their sustained drug release and excellent biocompatibility. The encapsulation of nano-sized crystals of bupivacaine provides a prolonged regional anesthesia with reduced toxicity, which could be advantageous in the management of chronic pain.The authors thank financial support from the ERC Consolidator Grant program (ERC-2013-CoG-614715, NANOHEDONISM). V.S. acknowledges the financial support from Ministerio de Ciencia, Innovación y Universidades, Programa Retos Investigación, Proyecto REF: RTI2018-099019-A-I00. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III with the assistance of the European Regional Development Fund. The microscopy works have been conducted in the “Laboratorio de Microscopias Avanzadas” at “Instituto de Nanociencia de Aragon─Universidad de Zaragoza”. The authors acknowledge the LMA-INA, the Histopathology Unit from CNIO (Madrid, Spain), and Cell Separation and Flow Cytometry, Cell Culture, Animal Care and Pathological Anatomy Core Units from IACS/IIS Aragon (Spain) for granting access to their instruments and expertise. The authors also acknowledge Drs. Elena Tapia, Jorge Palacio, Cristina Pastor, and Eduardo Romanos for their helpful advice and comments regarding the in vivo model. S.G.-S. and G.L. gratefully acknowledge the support from the FPI program (BES-2015-073735 and PRE2018-085769). G.M. thanks the support from the Miguel Servet Program (MS19/00092; Instituto de Salud Carlos III).Peer reviewe

Translating environments

Far from being inert materials activated by human ingenuity, natural resources come to be made and unmade through ongoing processes of translation, through which they acquire new potentialities and meanings. In this introduction, we review the key concept of translation for anthropology and explore some of its multiple analytical possibilities in the context of human-environment relations. Based on insights offered by the articles in this collection, we propose a twofold definition of environments as both translating subjects and objects of translation. In grounding our analytical definition, we focus on the enactment of material transformations (as the result of both relations of mutual determination with humans and processes of objectification of the environment), the implications of incommensurability and erasure in processes of (attempted) translation, and the indeterminacy that accompanies (re)configurations of materials, relations and values

Comparative Effect between Antidepressants and D-phenylalanine, a Phenethylamine Precursor, in an Animal Model of Depression

A relevant role has been attributed to phenethylamine in depressive disorders. It has been measured in human urine and rat brain in pathological conditions and after drug administration. Furthermore, a clinical correlation has been proposed between urinary elimination and depressive symptoms. Furthermore, its metabolic predecessor, D-phenylalanine, has been used as an antidepressant drug in the treatment of depressive disorders. The use of this amino acid has been realized alone, or in combination with classical antidepressants. In the present study, we tried to characterize its behavioural profile comparing it with imipramine and fluoxetine. Antidepressant drugs have been studied using diverse animal models. We used here the Porsolt test, or Forced Swimming Test (FST), measuring times of climbing, swimming and resting. When a comparison was performed between groups in climbing behaviour, significant differences were observed between imipramine treated group and saline controls (p < 0.05), and imipramine versus fluoxetine and D-phenylalanine (p < 0.01). When swimming was evaluated, clear differences between D-phenylalanine and the other groups were observed (p < 0.001). Additionally, a significant difference was also observed between imipramine and fluoxetine (p < 0.01). When resting was evaluated, high differences between D-phenylalanine versus all other groups were shown (p < 0.001). Observed behavioural profile was according to serotonergic antidepressant drugs effects. It is supported by the fact that swimming behaviours were increased, and a correlative decrease in resting was also present. We conclude that D-phenylalanine showed higher antidepressant potency than other classical antidepressants, at least at the doses used