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BACKGROUND Acute kidney injury (AKI) during hospitalization is frequent and associated with adverse outcomes. We have now evaluated the association between renal function recovery after AKI and short-term post-discharge mortality. METHODS This is a retrospective study of all AKI episodes codified in the electronic records of a single center in 2013 and 2014. Epidemiological data and comorbidities at baseline and laboratory values at admission and discharge were collected. Persistent kidney dysfunction after AKI was defined as a last serum creatinine equal or above 1.2-fold over baseline level. Patients were followed for 30 days after discharge. RESULTS Out of 1720 evaluated patients, 1541 (89%) were analyzed. Of them, 869 (56%) recovered renal function. Independent predictors of renal function recovery after AKI were lower baseline estimated glomerular filtration rate (eGFR) (p

Introduction Tobacco consumption and radon exposure are considered the first and second most common causes of lung cancer, respectively. The aim of this study was to analyze both whether selected genetic polymorphisms in loci that are in DNA repair pathways, are related to non-small-cell lung cancer (NSCLC) and whether they may modulate the association between residential radon exposure and lung cancer in both smokers and never smokers. Methods A multicentre, hospital-based, case–control study with 826 cases and 1201 controls was designed in a radon-prone area. Genotyping was determined in whole blood and residential radon exposure was measured in participants’ dwellings. Results Attending to tobacco exposure, the variant in the gene NBN (rs1805794) was associated with lung cancer in never smokers (OR 2.72; 95%1.44–5.2) and heavy smokers (OR 3.04; 95%CI 1.21–7.69). The polymorphism with the highest lung cancer association was OGG1 (rs125701), showing an OR of 8.04 (95%CI 1.64–58.29) for its homozygous variant genotype in heavy smokers. Attending to indoor radon exposure (>200 Bq/m3), rs1452584, for its homozygous variant genotype, showed the highest association (OR 3.04 (95%CI 1.15–8.48). Conclusion The genes analyzed seem to have no association with the fully adjusted model, but they might modulate lung cancer association when different categories of tobacco consumption are considered (i.e. heavy smokers). This association may similarly be elevated for those individuals having high indoor radon exposures, though at a minor extent.

In this paper, defect detection and identification in aluminium joints is investigated based on guided wave monitoring. Guided wave testing is first performed on the selected damage feature from experiments, namely, the scattering coefficient, to prove the feasibility of damage identification. A Bayesian framework based on the selected damage feature for damage identification of three- dimensional joints of arbitrary shape and finite size is then presented. This framework accounts for both modelling and experimental uncertainties. A hybrid wave and finite element approach (WFE) is adopted to predict the scattering coefficients numerically corresponding to different size defects in joints. Moreover, the proposed approach leverages a kriging surrogate model in combination with WFE to formulate a prediction equation that links scattering coefficients to defect size. This equation replaces WFE as the forward model in probabilistic inference, resulting in a significant enhancement in computational efficiency. Finally, numerical and experimental case studies are used to validate the damage identification scheme. An investigation into how the location of sensors can impact the identified results is provided as well., European Union’s Horizon 2020 Marie Skłodowska-Curie 859957, Science and Technology Development Fund, Macau SAR (File No.: FDCT/0101/2021/A2, FDCT/001/2021/AGJ and SKL-IOTSC(UM)-2021-2023)

Rechargeable batteries based on graphite are considered as promising alternatives for energy storage applications. The charge/discharge mechanisms of these batteries results from the intercalation and de-intercalation driven electrochemically by the atoms or molecules of the electrodes in contact with a liquid electrolyte. These solutions are often complex systems engineered to stabilize and allow the transport of the evolving moieties. In this article, we isolate the effect on the graphite structure of a chemical component of novel electrolytes, the aluminum fluoride (AlF3), by dosing this pure compound in the gas phase over high oriented pyrolitic graphite (HOPG) substrates at 10−9 mbar and 300 K. We performed an extensive experimental study involving surface characterization and beam analysis techniques, and developed a model of the sorption substantiated in ab-initio calculations. We found a preferential interlaminar absorption when dosing in the direction transversal to the carbon planes. The intercalation in the HOPG is spontaneous and non-reactive, and increases the interplanar spacing by 20%. A charge transfer of 0.65 e− per formula from graphite to AlF3 is calculated for the intercalate. Since the absorption depends on the roughness of the substrate we may infer that the intercalation proceeds through the step-edges. These features may contribute to the development of novel quasi-2D devices for special applications.

Made available in DSpace on 2022-04-28T19:44:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 In addition to the normal set of standard (A) chromosomes, some eukaryote species harbor supernumerary (B) chromosomes. In most cases, B chromosomes show differential condensation with respect to A chromosomes and display dark C-bands of heterochromatin, and some of them are highly enriched in repetitive DNA. Here we perform a comprehensive NGS (next-generation sequencing) analysis of the repeatome in the grasshopper Abracris flavolineata aimed at uncovering the molecular composition and origin of its B chromosome. Our results have revealed that this B chromosome shows a DNA repeat content highly similar to the DNA repeat content observed for euchromatic (non-C-banded) regions of A chromosomes. Moreover, this B chromosome shows little enrichment for high-copy repeats, with only a few elements showing overabundance in B-carrying individuals compared to the 0B individuals. Consequently, the few satellite DNAs (satDNAs) mapping on the B chromosome were mostly restricted to its centromeric and telomeric regions, and they displayed much smaller bands than those observed on the A chromosomes. Our data support the intraspecific origin of the B chromosome from the longest autosome by misdivision, isochromosome formation, and additional restructuring, with accumulation of specific repeats in one or both B chromosome arms, yielding a submetacentric B. Finally, the absence of B-specific satDNAs, which are frequent in other species, along with its euchromatic nature, suggest that this B chromosome arose recently and might still be starting a heterochromatinization process. On this basis, it could be a good model to investigate the initial steps of B chromosome evolution. Departamento de Biologia Geral e Aplicada UNESP - Univ Estadual Paulista Instituto de Biociências/IB Evolutionary Biology Centre Department of Organismal Biology – Systematic Biology Uppsala University Norwich Research Park School of Biological Sciences University of East Anglia Departamento de Genética Facultad de Ciencias UGR - Univ de Granada Departamento de Biologia Geral e Aplicada UNESP - Univ Estadual Paulista Instituto de Biociências/IB

A The aluminum smelting industry has some challenges, due to the characteristics of the alloy that cause reactions that should be controlled. During the foundry process, the alloy is oxidized by contact of the molten aluminum with the ambient air. Oxide films forming on the surface of the molten metal must be removed during the cleaning of the furnaces in order to avoid contamination of the alloy to be used in the production of parts. Analyzing the melting process of a metallurgy at the industrial complex in Manaus, we saw that during the cleaning of the furnaces a metal tool is used to remove the slag, which brings with it a high level of aluminum brought about by the mechanical drag of the tool. As the company in question does not have resources to recover the metal aluminum contained in the slag, it is destined for the other institution which carried out the processing through the process of refusion of the slag and extraction of aluminum. The high level of losses in the process due to the discarding of slag generates considerable financial damage to the institution, reflected directly in the cost of manufacturing the products. In this way, the aim of the present work was to develop equipment for the extraction of the metal aluminum contained in the slag and consequently to reduce the losses in the process. The design of the equipment was chosen through a product development methodology, which made it possible to define the design specification, which can count on a container for the receipt and separation of the slag by means of the vibration brought on by motorvibrators installed at its ends, followed by a slingshot drawer responsible for the storage of the metal after the solidification and support/translate cars of the containers.

This study sought to ascertain whether there might be an association between radon concentrations and age, gender, histologic type, and tumor stage at diagnosis.Lung cancer cases from different multicenter case-control studies were analyzed, and clinical data were retrieved from electronic health records and personal interviews. A radon device was placed in all dwellings of participants, and we then tested the existence of an association between residential radon and lung cancer characteristics at diagnosis.Of the total of 829 lung cancer cases included, 56.7% were smokers or ex-smokers. There was no association between indoor radon concentrations and age, gender, histologic type or tumor stage at diagnosis. Median indoor radon concentrations increased with age at diagnosis for men, but not for women. When analyzing participants exposed to more than 1000 Bq/mThere seems to be no association between radon and age, gender, histologic type or tumor stage at diagnosis. Higher radon exposure is more frequent in the case of small-cell lung cancer.

Resumen: Objetivo: Evaluar la asociación entre la exposición al radón y el cáncer genitourinario en población minera a través de una revisión sistemática de la literatura científica. Método: Se realizó una revisión sistemática de la literatura científica en MEDLINE (PubMed) combinando términos MeSH (Medical Subject Heading) y términos libres. Se realizó una escala específica de valoración de la calidad de los estudios incluidos. Resultados: Se incluyeron 17 estudios. Todos fueron estudios de cohortes, excepto uno que fue un pool de datos. Todos los estudios incluían análisis de la relación entre la exposición al radón y el cáncer genitourinario. Los resultados son ambiguos: unos estudios apuntan hacia una asociación entre la exposición y el cáncer genitourinario, especialmente de riñón, y otros no encuentran asociación. Conclusión: Los estudios incluidos presentan una gran heterogeneidad metodológica. No puede concluirse que exista una asociación entre la exposición al radón y el cáncer genitourinario. Es necesaria más investigación sobre el tema, con estudios que tengan más potencia estadística y mejor control de las variables confusoras, y preferentemente que sean prospectivos. Abstract: Objective: To assess the association between exposure to radon and genitourinary cancer in a mining population through a systematic review of the scientific literature. Method: A systematic review of the scientific literature was carried out in MEDLINE (PubMed), combining MeSH (Medical Subject Heading) terms and free terms. We applied a specific scale to assess the quality of the included studies. Results: We included 17 studies; all were cohort studies with the exception of one which was a pooling of data. All studies included analysed the relationship between exposure to radon and genitourinary cancer. While some studies point towards an association between radon exposure and genitourinary cancer, especially kidney cancer, others do not find such association. Conclusions: The included studies showed great heterogeneity. It cannot be concluded that there is an association between exposure to radon and genitourinary cancer. More research is needed on this topic, designing studies with higher statistical power, better control of confounders, and preferably prospective.

Purpose: To determine the nutraceutical effect of mixtures containing Lactobacillus nagelii/betanin on the carbohydrate and lipid metabolism of mice.Methods: Lactobacillus nagelii and betanin were isolated from the raw materials. These components were subsequently assessed for their anti-hyperglycemic and hypolipidemic activities, and administered individually or combined in normoglycemic and diabetic mice. These animals were subjected to a standard OGTT and given an atherogenic diet.Results: The combination of L. nagelii (2.0 × 109 CFU/mL) and betanin (30 mg/kg body weight) exerted a significant (p < 0.01) and prolonged reduction of postprandial blood glucose (30 - 120 min). Interestingly, a mixture of L. nagelii (1 ×107 CFU/mouse/day) with betanin (10 mg/kg body weight) administered for 30 days, produced favourable effects (p < 0.01) in the lipid profile of mice previously treated with an atherogenic diet. These mixtures significantly ameliorated (p < 0.01) hypoinsulinemia, hyperleptinemia and increased the levels of adiponectin.Conclusion: The simultaneous administration of L. nagelii and betanin in mice produced a beneficial change in blood glucose and lipids in mice, indicating a synergistic nutraceutical effect. However, there is a need to develop this therapy further for potential application in humans Keywords: Lactobacillus nagelii, Betanin, Anti-hyperglycemic, Hypolipidemic

Stimuli-responsive biomaterials have attracted significant attention for the construction of on-demand drug release systems. The possibility of using external stimulation to trigger drug release is particularly enticing for hydrophobic compounds, which are not easily released by simple diffusion. In this work, an electrochemically active hydrogel, which has been prepared by gelling a mixture of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) and alginate (Alg), has been loaded with curcumin (CUR), a hydrophobic drug with a wide spectrum of clinical applications. The PEDOT/Alg hydrogel is electrochemically active and organizes as segregated PEDOT- and Alg-rich domains, explaining its behavior as an electroresponsive drug delivery system. When loaded with CUR, the hydrogel demonstrates a controlled drug release upon application of a negative electrical voltage. Comparison with the release profiles obtained applying a positive voltage and in the absence of electrical stimuli indicates that the release mechanism dominating this system is complex because of not only the intermolecular interactions between the drug and the polymeric network but also the loading of a hydrophobic drug in a water-containing delivery system.

We present a highly selective and active Pd carbon catalyst prepared by an easy hydrothermal synthesis method. This synthetic procedure allows the stabilization under mild conditions of interstitial carbon atoms on the surface of a Pd carbon catalyst. The so formed Pd carbide phase appears on the upper surface layers of the Pd carbon catalyst, as demonstrated by X-ray photoelectron depth profile analysis using variable synchrotron X-ray energies. The presence of carbon in the palladium carbide species modifies the electronic state of surface Pd atoms, resulting in more electron positive Pd species (Pd). This influences the adsorption of reactants and reaction intermediates during the hydrogenation of alkynes, dienes and imines, resulting in high selectivities at practically 100% conversion., Funding: The research leading to these results has received funding from the Spanish Ministry of Science, Innovation and Universities through “Severo Ochoa” Excellence Programme (SEV-2016-0683) and the PGC2018-097277-B-100 project. The authors also thank the Microscopy Service of UPV for kind help on measurements. A. García-Ortiz thanks “Severo Ochoa” Programme (SEV-2016-0683) for a predoctoral fellowship. J. Cored thanks the Spanish Government (MINECO) for a “Severo Ochoa” grant (BES-2015-075748). D. R. thanks European Research Council project SYNCATMATCH (671093). The NAP-XPS experiments were performed at the NAPP branch of the CIRCE beamline at the ALBA Synchrotron with the collaboration of ALBA staff.

The factors and mechanisms involved in vacuolar transport in plants, and in particular those directing vesicles to their target endomembrane compartment, remain largely unknown. To identify components of the vacuolar trafficking machinery, we searched for Arabidopsis modified transport to the vacuole (mtv) mutants that abnormally secrete the synthetic vacuolar cargo VAC2. We report here on the identification of 17 mtv mutations, corresponding to mutant alleles of MTV2/VSR4, MTV3/PTEN2A MTV7/EREL1, MTV8/ARFC1, MTV9/PUF2, MTV10/VPS3, MTV11/VPS15, MTV12/GRV2, MTV14/GFS10, MTV15/BET11, MTV16/VPS51, MTV17/VPS54, and MTV18/VSR1. Eight of the MTV proteins localize at the interface between the trans-Golgi network (TGN) and the multivesicular bodies (MVBs), supporting that the trafficking step between these compartments is essential for segregating vacuolar proteins from those destined for secretion. Importantly, the GARP tethering complex subunits MTV16/VPS51 and MTV17/VPS54 were found at endoplasmic reticulum (ER)- and microtubule-associated compartments (EMACs). Moreover, MTV16/VPS51 interacts with the motor domain of kinesins, suggesting that, in addition to tethering vesicles, the GARP complex may regulate the motors that transport them. Our findings unveil a previously uncharacterized compartment of the plant vacuolar trafficking pathway and support a role for microtubules and kinesins in GARP-dependent transport of soluble vacuolar cargo in plants., This work was supported by the Spanish Ministry of Economy and Competitivity and European Regional Development Fund (FEDER) funds (BIO2018-094257-B Ministerio de Ciencia e Innovación/FEDER to E.R., M. Sanmartín, and J.J.S.-S.) and by the Ministry of Education, Youth and Sports of the Czech Republic (LQ1601/CEITEC 2020 grant to J.Z.). G.R. and A.L. were recipients of Formación de Personal Investigador scholarships from the Spanish Ministry of Economy and Competitivity. We thank Dr. Niko Gelner, Dr. Takashi Ueda, Dr. Daniel Van Damme, Dr. Lorenzo Frigerio, Dr. Karin Schumacher, and Dr. Vicente Pallas for kindly providing compartment markers.

Introduction The aim of this study was to analyse the relationship between exposure to residential radon and chronic obstructive pulmonary disease (COPD) by means of a systematic review. Material and methods A search was conducted in PubMed and OVID for papers making reference to the radon-COPD relationship. No search filters were applied, whether by date of publication, study type or sample size. All studies not written in English or Spanish were discarded. Results A total of 174 and 57 papers were found in PubMed and OVID, respectively: of these, 13 (11 on miners and 2 on the general population) fulfilled the inclusion criteria. Only four of the studies on cohorts of miners analysed COPD as a specific disease, and only one reported statistically significant results. In addition, many of these studies lacked information on tobacco use among miners. In contrast, studies conducted on the general public showed an association between mortality and hospital admissions, on the one hand, and residential radon on the other. Conclusion There are not enough studies to provide a basis for confirming or ruling out an association between radon exposure and COPD. Nonetheless, the most recent general population studies point to evidence of a possible association. In view of the heterogeneity of available studies, it is impossible to say whether this gas may or may not affect COPD morbidity and mortality, until such a time as further studies are carried out.

Human metapneumovirus (HMPV) causes severe respiratory diseases in young children. The HMPV RNA genome is encapsidated by the viral nucleoprotein (N), forming an RNA-N complex (N(Nuc)), which serves as the template for genome replication and mRNA transcription by the RNA-dependent RNA polymerase (RdRp). The RdRp is formed by the association of the large polymerase subunit (L), which has RNA polymerase, capping, and methyltransferase activities, and the tetrameric phosphoprotein (P). P plays a central role in the RdRp complex by binding to N(Nuc) and L, allowing the attachment of the L polymerase to the N(Nuc) template. During infection these proteins concentrate in cytoplasmic inclusion bodies (IBs) where viral RNA synthesis occurs. By analogy to the closely related pneumovirus respiratory syncytial virus (RSV), it is likely that the formation of IBs depends on the interaction between HMPV P and N(Nuc), which has not been demonstrated yet. Here, we finely characterized the binding P-N(Nuc) interaction domains by using recombinant proteins, combined with a functional assay for the polymerase complex activity, and the study of the recruitment of these proteins to IBs by immunofluorescence. We show that the last 6 C-terminal residues of HMPV P are necessary and sufficient for binding to N(Nuc) and that P binds to the N-terminal domain of N (N(NTD)), and we identified conserved N residues critical for the interaction. Our results allowed us to propose a structural model for the HMPV P-N(Nuc) interaction. IMPORTANCE Human metapneumovirus (HMPV) is a leading cause of severe respiratory infections in children but also affects human populations of all ages worldwide. Currently, no vaccine or efficient antiviral treatments are available for this pneumovirus. A better understanding of the molecular mechanisms involved in viral replication could help the design or discovery of specific antiviral compounds. In this work, we have investigated the interaction between two major viral proteins involved in HMPV RNA synthesis, the N and P proteins. We finely characterized their domains of interaction and identified a pocket on the surface of the N protein, a potential target of choice for the design of compounds interfering with N-P complexes and inhibiting viral replication.

Cera pepper ( Capsicum pubescens ) is an exotic fruit considered as a rich source of nutraceuticals with known benefits for human health and also an economic resource for local producers in Mexico. The present investigation reports on the in vitro and in situ antifungal activity of the essential oil from Mentha piperita and its two major volatiles (menthol and menthone) against Fusarium sambucinum , which is a causal agent of soft rot in cera pepper. The application of these components in pepper fruits previously infected with F. sambucinum caused a significant delay (p < 0.05) in the emergence of soft rot symptoms. This effect was reflected in the maintenance of pH and fruit firmness during a period of 10 days. The nutrimental content of the fruits (protein, fiber, fat and other proximate parameters) was conserved in the same period of time. The nutraceutical content of these fruits was estimated by the quantification of seven carotenoids (violaxanthin, cis-violaxanthin, luteoxanthin, antheraxanthin, lutein, zeaxanthin and beta-carotene), ascorbic acid and capsaicinoids (capsaicin and dihydrocapsaicin). According to our results, the essential oil from M. piperita and its major volatiles exerted a preservative effect on these metabolites. Our findings demonstrated that the essential oil of M. Piperita and its major volatiles represent an ecological alternative for the control of fusariosis caused by F. sambucinum in cera peppers under postharvest conditions.

In the present study, a composite made of conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), and a biodegradable hydrogel of poly(aspartic acid) (PASP) were electrochemically interpenetrated with poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT) to prepare a new interpenetrated polymer network (IPN). Different cross-linker and PEDOT MPs contents, as well as different electropolymerization times, were studied to optimize the structural and electrochemical properties. The properties of the new material, being electrically conductive, biocompatible, bioactive, and biodegradable, make it suitable for possible uses in biomedical applications.

INTRODUCTION Inflammatory Bowel Disease (IBD) is a multifactorial pathology with an increasing incidence. There is no study having assessed a possible relationship with residential radon exposure, very high in the study area. The aim of the study was to analyze if residential radon concentration is associated with a higher incidence of IBD. MATERIAL AND METHODS An ecological study has been performed. All incident cases of Inflammatory Bowel Disease in the area of Santiago de Compostela were included between January and December 2017. Radon levels at a municipal level were correlated with demographic factors and type of IBD. RESULTS 96 patients were included, 63 (65.6%) with ulcerative colitis, 29 (30.25) with Crohn's disease and 4 (4.2%) with indeterminate colitis. The incidence rate per 100,000 inhabitants-year was 21.6 cases. There were no statistically significant differences on the type of disease developed regarding radon levels (p>0.05). No correlation between radon levels and cumulative incidence of Inflammatory Bowel Disease at municipal level was observed (Spearman's rho = 0.13, p-value 0.5). CONCLUSION In the area of Santiago de Compostela there is a higher incidence of IBD in comparison with previous studies taking western countries as reference, but in this study we have not found any correlation with municipal average radon concentration and incidence of IBD or any of its types.

Sirikwan Sangboonruang,1 Natthawat Semakul,2 Mohammad A Obeid,3 Marta Ruano,4 Kuntida Kitidee,5 Usanee Anukool,6,7 Kidsadagon Pringproa,8 Panuwan Chantawannakul,9 Valerie A Ferro,4 Yingmanee Tragoolpua,9 Khajornsak Tragoolpua6,7 1Biotechnology Section, Graduate School, Chiang Mai University, Chiang Mai, Thailand; 2Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand; 3Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan; 4Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK; 5Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Salaya, Nakhon Pathom, Thailand; 6Division of Clinical Microbiology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; 7Infectious Diseases Research Unit (IDRU), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; 8Department of Veterinary Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai, Thailand; 9Division of Microbiology, Department of Biology, Faculty of Sciences, Chiang Mai University, Chiang Mai, ThailandCorrespondence: Khajornsak TragoolpuaDivision of Clinical Microbiology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, ThailandTel +66 5393 6039Fax +66 5393 6042Email khajornsak.tr@cmu.ac.thBackground: Staphylococcus aureus is an important human pathogen, especially causing skin and soft tissue infections (SSTIs). Over the decades, the infections caused by antibiotic-resistant strains have often become life-threatening. Consequently, exploration and development of competent approaches to combat these serious circumstances are urgently required.Methods: The antibacterial activity of melittin (Mel) on S. aureus, methicillin-resistant S. aureus (MRSA) and clinical isolates of vancomycin-intermediate S. aureus (VISA) was investigated by minimum inhibitory concentration (MIC) and time-killing assays. The localization of Mel on the bacterial cell was visualized by confocal laser scanning microscopy and its effect on the membrane was indicated based on propidium iodide uptake. The non-ionic surfactant vesicle (NISV) or niosome nanocarrier was established for Mel loading (Mel-loaded NISV) by the thin-film hydration method. Physicochemical and in vitro biological properties of Mel-loaded NISVs were characterized. The cellular uptake of Mel-loaded NISVs was evaluated by holotomography analysis. In addition, an ex vivo study was conducted on a porcine ear skin model to assess the permeation ability of Mel-loaded NISVs and their potential to inhibit bacterial skin infection.Results: The effective inhibitory activity of Mel on skin pathogens was demonstrated. Among the tested strains, VISA was most susceptible to Mel. Regarding to its function, Mel targeted the bacterial cell envelope and disrupted cell membrane integrity. Mel-loaded NISVs were successfully fabricated with a nano-size of 120– 200 nm and entrapment efficiency of greater than 90%. Moreover, Mel-loaded NISVs were taken up and accumulated in the intracellular space. Meanwhile, Mel was released and distributed throughout the cytosol and nucleus. Mel-loaded NISVs efficiently inhibited the growth of bacteria, particularly MRSA and VISA. Importantly, they not only penetrated epidermal and dermal skin layers, but also reduced the bacterial growth in infected skin.Conclusion: Mel-loaded NISVs have a great potential to exhibit antibacterial activity. Therapeutic application of Mel-loaded NISVs could be further developed as an alternative platform for the treatment of skin infection via dermal and transdermal delivery.Keywords: melittin, niosome, drug resistance, skin infection, Staphylococcus aureus, dermal and transdermal delivery

Background/Aims: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease’s (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. Methods: We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. Results: Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. Conclusion: Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.

Human metapneumovirus (HMPV) causes severe respiratory diseases in young children. The HMPV RNA genome is encapsidated by the viral nucleoprotein, forming an RNA-N complex (NNuc), which serves as template for genome replication and mRNA transcription by the RNA-dependent RNA polymerase (RdRp). The RdRp is formed by the association of the large polymerase subunit (L), which has RNA polymerase, capping and methyltransferase activities, and the tetrameric phosphoprotein (P). P plays a central role in the RdRp complex by binding to NNuc and L, allowing the attachment of the L polymerase to the nucleocapsid template. During infection these proteins concentrate in cytoplasmic inclusion bodies (IBs) where viral RNA synthesis occurs. By analogy to the closely related pneumovirus respiratory syncytial virus (RSV), it is likely that the formation of IBs depends on the interaction between P and NNuc. However, the HMPV P-NNuc interaction still remains to characterize. Here, we finely characterized the binding domains involved in HMPV P and NNuc interaction by studying binding between recombinant proteins, combined with the use of a functional assay of the polymerase complex activity and the study of the recruitment of these proteins to IBs by immunofluorescence. We show that the last 6 C-terminal residues of HMPV P are necessary and sufficient for binding to NNuc, that P binds the N-terminal domain of N (NNTD), and identified conserved N residues critical for the interaction. Our results allowed to propose a structural model of the HMPV P-NNuc interaction.IMPORTANCELike respiratory syncytial virus (RSV), human metapneumovirus (HMPV) is a leading cause of severe respiratory infections in children but also affects human populations of all ages worldwide. Nowadays, no vaccine or efficient antiviral treatments are available for these two pneumoviruses. A better understanding of the molecular mechanisms involved in viral replication could help the design or discovery of specific antiviral compounds. In this work we have investigated the interaction between two major viral proteins involved in HMPV RNA synthesis, the N and P proteins. We finely characterized their domains of interaction, in particular a pocket on the surface of the N protein that could be used as a template for the design of compounds interfering with N-P complexes and viral replication.

Cells exist in an astonishing range of volumes across and within species. However, our understanding of cell size control remains limited, due in large part to the challenges associated with accurate determination of cell volume. Much of our comprehension of size regulation derives from models such as budding and fission yeast, but even for these morphologically stereotypical cells, assessment of cell volume has relied on proxies and extrapolations from two-dimensional measurements. Recently, the fluorescence exclusion method (FXm) was developed to evaluate the size of mammalian cells, but whether it could be applied to smaller cells remained unknown. Using specifically designed microfluidic chips and an improved data analysis pipeline, we show here that FXm reliably detects subtle difference in the volume of fission yeast cells, even for those with altered shapes. Moreover, it allows for the monitoring of dynamic volume changes at the single-cell level with high time resolution. Collectively, our work reveals how coupling FXm with yeast genetics will bring new insights into the complex biology of cell growth.SUMMARY STATEMENTFluorescence exclusion provides a unique method to accurately measure the volume of yeast cells at both the population and single-cell levels.

Rh2P nanoparticles (NPs) have been identified as suitable mimics of [RhI(Ph3P)3]+, the benchmark of homogeneous catalysts in liquid-phase hydroformylation. For this reason, a fitted synthetic strategy is required to develop catalysts based exclusively on Rh2P NPs. To attain this, two synthetic pathways have been devised. In the first one, two separate sources of Rh and P were used. In the second one, the Wilkinson complex was employed as a unique source of Rh and P to probe the positive influence of the well-defined molecular organization on the preparation of dispersed and controlled Rh2P nanoparticles, stabilized by carbon patches formed during the pyrolysis treatment from PPh3. In addition, metallic Rh nanoparticles were also synthesized to be used as reference. All catalysts have been compared by means of: transmission electron microscopy, X-ray diffraction, and X-ray adsorption spectroscopy. The application of XAS to the study of Rh2P NPs is unusual and has been essential in the discussion of the results. Starting with a well-defined metal precursor leads to the exclusive formation of Rh2P NPs with excellent catalytic activity for the liquid-phase hydroformylation. The role of P is to modulate the particle size and the electronic configuration of Rh species, resulting in the improvement of the catalytic performance and the obtention of turnover frequencies of 5236 h-1 at 60 °C and 17,788 h-1 at 100 °C., Program Severo Ochoa SEV-2016-0683 is gratefully acknowledged. C.G.-R. thanks MINECO for her FPU Ph.D. contract FPU17/04172. The authors thank the financial support by the Spanish Government (RTI2018-096399-A-I00). The authors thank J.G.M. for his technical support. We also thank the Electron Microscopy Service of the UPV for TEM facilities. C.W.L. thanks PRH 50.1 – ANP/FINEP Human Resources Program for the Visiting Researcher Fellowship. This research used resources of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by the Argonne National Laboratory and was supported by the U.S. DOE under contract no. DE-AC02-06CH11357 and the Canadian Light Source and its funding partners.

A modified iron-based superalloy is studied regarding its hot formability. The microstructure contained particles of titanium carbides, carbonitrides and nitrates. Torsion tests at high strain rate at temperatures ranging from 800 to 1200°C were conducted. Results of these tests were correlated by means of the Garofalo hyperbolic sine creep relation. An optimum forming temperature of 1260°C at 10 s−1 is obtained. This temperature is strongly dependent on the strain rate. An activation energy for plastic deformation close to that for the activation energy for lattice diffusion in austenitic stainless steels and a stress exponent near 5 were obtained. These values suggest that plastic deformation is controlled by a dislocation climb mechanism., This research is financially supported by CYCYT, Spain, program MAT2015-68919.

Made available in DSpace on 2021-06-25T10:10:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-09-05 Knowledge of ichthyoplankton dynamics is extremely important for conservation management as it can provide information about preferential spawning sites, reproductive period, migratory routes and recruitment success, which can be used to guide management and conservation efforts. However, identification of the eggs and larvae of Neotropical freshwater fish is a difficult task. DNA barcodes have emerged as an alternative and highly accurate approach for species identification, but DNA barcoding can be time-consuming and costly. To solve this problem, we aimed to develop a simple protocol based on DNA metabarcoding, to investigate whether it is possible to detect and quantify all species present in a pool of organisms. To do this, 230 larvae were cut in half, one half was sequenced by the Sanger technique and the other half was used to compose six arrays with a pool of larvae that were sequenced using a next-generation technique (NGS). The results of the Sanger sequencing allowed the identification of almost all larvae at species level, and the results from NGS showed high accuracy in species detection, ranging from 83% to 100%, with an average of 95% in all samples. No false positives were detected. The frequency of organisms in the two methods was positively correlated (Pearson), with low variation among species. In conclusion, this protocol represents a considerable advance in ichthyoplankton studies, allowing a rapid, cost-effective, quali-quantitative approach that improves the accuracy of identification. Laboratório de Biologia e Genética de Peixes Departamento de Morfologia Evolutionary Genetics group Department of Genetics University of Granada Department of Ecology and Genetics Evolutionary Biology Centre Uppsala University

[EN] The operation of an outdoor membrane photobioreactor plant which treated the effluent of an anaerobic membrane bioreactor was optimised. Biomass retention times of 4.5, 6, and 9 days were tested. At a biomass retention time of 4.5 days, maximum nitrogen recovery rate:light irradiance ratios, photosynthetic efficiencies and carbon biofixations of 51.7¿±¿14.3¿mg¿N·mol¿1, 4.4¿±¿1.6% and 0.50¿±¿0.05¿kg CO2·m3influent, respectively, were attained. Minimum membrane fouling rates were achieved when operating at the shortest biomass retention time because of the lower solid concentration and the negligible amount of cyanobacteria and protozoa. Hydraulic retention times of 3.5, 2, and 1.5 days were tested at the optimum biomass retention times of 4.5 days under non-nutrient limited conditions, showing no significant differences in the nutrient recovery rates, photosynthetic efficiencies and membrane fouling rates. However, nitrogen recovery rate:light irradiance ratios and photosynthetic efficiency significantly decreased when hydraulic retention time was further shortened to 1 day, probably due to a rise in the substrate turbidity which reduced the light availability in the culture. Optimal carbon biofixations and theoretical energy recoveries from the biomass were obtained at hydraulic retention time of 3.5 days, which accounted for 0.55¿±¿0.05¿kg CO2·m¿3influent and 0.443¿±¿0.103¿kWh·m¿3influent, respectively., This research work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, Projects CTM2014-54980-C2-1-R and CTM2014-54980-C2-2-R) jointly with the European Regional Development Fund (ERDF), which are gratefully acknowledged. It also received support from the Spanish Ministry of Education, Culture and Sport via a pre-doctoral FPU fellowship to the first author (FPU14/05082).

Cellulose-based supercapacitors display important advantages in comparison with devices fabricated with other materials, regarding environmental friendliness, flexibility, cost and versatility. Recent progress in the field has been mainly focused on the utilization of cellulose fibres as: structural mechanical reinforcement of electrodes; precursors of electrically active carbon-based materials; or primary electrolytes that act as reservoirs of secondary electrolytes. In this work, a flexible, lightweight, robust, portable and manageable all-carboxymethyl cellulose symmetric supercapacitor has been obtained by assembling two electrodes based on carboxymethyl cellulose hydrogels to a solid electrolytic medium formulated with the same material. Hydrogels, which were made by cross-linking carboxymethyl cellulose paste with citric acid in water, rendered not only effective solid electrolytic media by simply loading NaCl but also electroactive electrodes. For the latter, conducting polymer microparticles, which were loaded into the hydrogel network during the physical cross-linking step, were appropriately connected through the in situ anodic polymerization of a similar conducting polymer in aqueous medium, thus creating conduction paths. The performance of the assembled supercapacitors has been proved by cyclic voltammetry, galvanostatic charge-discharge and electrochemical impedance spectroscopy. This design opens a new window for the green and mass production of flexible cellulose-based supercapacitors

Seven 1.1–1.4-μm-thick hydrogen-free amorphous‑silicon (a-Si) thin films were deposited at high rates (larger than 10 A/s), by rf magnetron sputtering (RFMS) onto room-temperature glass substrates. The influence of argon-gas pressure on the structural and optical properties of these amorphous films has been systematically studied. We have used the Wemple-DiDomenico (WD) single-effective-oscillator model, n2(ℏω) − 1 = EdE0/(E02 − (ℏω)2), in order to determine the WD parameters oscillator strength or dispersion energy, Ed, and oscillator energy, E0. The amorphous-to-crystalline mass-density ratio, ρa/ρx, in the empirical expression for Ed, proposed by Wemple, is the key factor in understanding the refractive-index behaviour of the RFMS-a-Si thin films. The value of the static refractive index, n(0), which is related to both the atomic structure and mass density, remains approximately constant up to a threshold Ar-gas pressure of nearly 1 Pa, and then it starts dropping rather abruptly. The decrease found in the Urbach energy, EU, as well as the increase observed in the Tauc gap and slope, Eg and B respectively, for Ar-gas pressures higher than the voided-structure threshold sputtering pressure, clearly suggests that the amount of intermediate-range order present within the RFMS-a-Si layers under study, is increasing in direct response to the increase in the Ar-gas pressure, during the deposition process. This is independently corroborated by the decreasing values of the Raman-intensity ratio, ITA/ITO, as the sputtering pressure increases, in the case of high Ar pressure a-Si films.

Herein we report on the 1H NMR-based metabolomics profiling of ten new races of Capsicum annuum cv. serrano, cultivated in Mexico. Forty eight metabolites (including sugars, amino acids, organic acids, polyphenolic acids and alcohols) were identified and quantified by 2D NMR and qNMR, respectively. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) separated the ten races into two clusters, from which citric acid, formic acid, fumaric acid, malic acid, glucose, fructose, sucrose and galactose were found as differential metabolites. This is the first study describing the chemical profiling of ten new races of Capsicum annuum cv. serrano and the spectrometric method used presently is characterized by great simplicity, robustness and reproducibility. Thus, this technique can be used for establishing reliable metabolomic fingerprints of different races of Capsicum annuum cv. serrano.

Series of novel chromonyl enaminones 1a–e and 2a–e and 3-alkylated chromones 3a–e were synthesized and evaluated in vitro as α-glucosidase inhibitors as well as antioxidant and antifungal agents. Antifungal activity was tested on strains of Candida albicans. Compounds 2a and 2d–e showed good inhibition of the α-glucosidase enzyme (IC50 = 5.5, 0.9, and 1.5 mM, respectively), their effect being better than that of 1a–e, 3a–e, and acarbose (the standard, IC50 = 7.73 ± 0.9 mM). The structure–activity relationship suggests that the phenyl group at the C-3 position of the chromone ring system and the 4-chlorophenyl group at the enaminone moiety (derivatives 2) increased the inhibition of α-glucosidase. Compounds 2a–e exhibited a slight antioxidant effect, and compounds 3a–e a moderate antifungal activity against C. albicans (IC50 70.5–83.1 µg/mL). Docking studies revealed that compounds 2 interact with the α-glucosidase residues of the binding pocket. Therefore, these chromone derivatives may be considered as potential α-glucosidase inhibitors, as well as antifungal agents against some Candida strains of yeast.

[Background] The hemolysin (Hly) secretion system of E. coli allows the one-step translocation of hemolysin A (HlyA) from the bacterial cytoplasm to the extracellular medium, without a periplasmic intermediate. In this work, we investigate whether the Hly secretion system of E. coli is competent to secrete a repertoire of functional single-domain VHH antibodies (nanobodies, Nbs), facilitating direct screening of VHH libraries and the purification of selected Nb from the extracellular medium., [Results] We employed a phagemid library of VHHs obtained by immunization of a dromedary with three protein antigens from enterohemorrhagic E. coli (EHEC), namely, the extracellular secreted protein A (EspA), the extracellular C-terminal region of Intimin (Int280), and the translocated intimin receptor middle domain (TirM). VHH clones binding each antigen were enriched and amplified by biopanning, and subsequently fused to the C-terminal secretion signal of HlyA to be expressed and secreted in a E. coli strain carrying the Hly export machinery (HlyB, HlyD and TolC). Individual E. coli clones were grown and induced in 96-well microtiter plates, and the supernatants of the producing cultures directly used in ELISA for detection of Nbs binding EspA, Int280 and TirM. A set of Nb sequences specifically binding each of these antigens were identified, indicating that the Hly system is able to secrete a diversity of functional Nbs. We performed thiol alkylation assays demonstrating that Nbs are correctly oxidized upon secretion, forming disulphide bonds between cysteine pairs despite the absence of a periplasmic intermediate. In addition, we show that the secreted Nb-HlyA fusions can be directly purified from the supernatant of E. coli cultures, avoiding cell lysis and in a single affinity chromatography step., [Conclusions] Our data demonstrate the Hly secretion system of E. coli can be used as an expression platform for screening and purification of Nb binders from VHH repertories., We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Work in the lab of LAF is partially supported by the Grants BIO2017-89081-R (Agencia Española de Investigación AEI/MICIU/FEDER, EU), ERC-2012-ADG_20120314 (European Research Council, EU) and LCCM_P59474 (Wellcome Trust, UK).

Hernandulcin (HE) is a non-caloric sweetener biosynthezised by the Mexican medicinal plant Phyla scaberrima . Herein we present the results of HE production through cell suspensions of P. scaberrima as well as the influence of pH, temperature, biosynthetic precursors and potential elicitors to enhance HE accumulation. The incorporation of mevalonolactone (30-400 mg L -1 ) farnesol (30-400 mg L -1 ), AgNO3 (0.025-0.175 M), cellulase (5-60 mg L -1 ; 0.3 units/mg), chitin (20-140 mg L -1 ) and (+)- epi -α-bisabolol (300-210 mg L -1 ) to the cell suspensions, resulted in a differential accumulation of HE and biomass. Among elicitors assayed, chitin, cellulase and farnesol increased HE production from 93.2 to ~160 mg L -1 but, (+)- epi -α-bisabolol (obtained by a synthetic biology approach) increased HE accumulation up to 182.7 mg L -1 . HE produced by the cell suspensions was evaluated against nine strains from six species of gastrointestinal bacteria revealing moderate antibacterial activity (MIC, 214-465 µg mL -1 ) against Staphylococcus aureus, Escherichia coli and Helicobacter pylori . Similarly, HE showed weak toxicity against Lactobacillus sp. and Bifidobacterium bifidum (> 1 mg mL -1 ), suggesting a selective antimicrobial activity on some species of gut microbiota. According to our results, chitin and (+)- epi -α-bisabolol were the most effective molecules to enhance HE accumulation in cell suspensions of P. Scaberrima .

Background: Patients with congenital diaphragmatic hernia (CDH) have a short postnatal period of ventilatory stability called the honeymoon period, after which changes in pulmonary vascular reactivity result in pulmonary hypertension. However, the mechanisms involved are still unknown. The aim of this study was to evaluate mechanical ventilation's effect in the honeymoon period on VEGF, VEGFR-1/2 and eNOS expression on experimental CDH in rats.Materials and Methods: Neonates whose mothers were not exposed to nitrofen formed the control groups (C) and neonates with left-sided defects formed the CDH groups (CDH). Both were subdivided into non-ventilated and ventilated for 30, 60, and 90 min (n = 7 each). The left lungs (n = 4) were evaluated by immunohistochemistry of the pulmonary vasculature (media wall thickness), VEGF, VEGFR-1/2 and eNOS. Western blotting (n = 3) was performed to quantify the expression of VEGF, VEGFR-1/2 and eNOS.Results: CDH had lower biometric parameters than C. Regarding the pulmonary vasculature, C showed a reduction in media wall thickness with ventilation, while CDH presented reduction with 30 min and an increase with the progression of the ventilatory time (honeymoon period). CDH and C groups showed different patterns of VEGF, VEGFR-1/2 and eNOS expressions. The receptors and eNOS findings were significant by immunohistochemistry but not by western blotting, while VEGF was significant by western blotting but not by immunohistochemistry.Conclusion: VEGF, its receptors and eNOS were altered in CDH after mechanical ventilation. These results suggest that the VEGF-NO pathway plays an important role in the honeymoon period of experimental CDH.

This work presents a simple methodology for coating small unilamellar liposomes bearing different degrees of positive charge with polyelectrolyte multilayers using the sequential layer-by-layer deposition method. The liposomes were made of mixtures of 1,2-dioleyl-sn-glycero-3-phosphocoline and dimethyl dioctadecyl ammonium bromide (DODAB) and coated by alternated layers of the sodium salt of poly(4-styrenesulfonate) (PSS) and poly(allylamine) (PAH) as polyanions and polycations, respectively. The results show that the zeta potential of the liposomes was not very sensitive to the mole fraction of DODAB in the membrane, XD, in the range 0.3 ≤ XD ≤ 0.8. We were able to coat the liposomes with up to four polymer bilayers. The growth of the capsule size was followed by dynamic light scattering, and in some cases, by cryo-transmission electron microscopy, with good agreement between both techniques. The thickness of the layers, measured from the hydrodynamic radius of the coated liposome, depends on the polyelectrolyte used, so that the PSS layers adopt a much more packaged conformation than the PAH layers. An interesting finding is that the PSS amount needed to reach the isoelectric point of the capsules increases linearly with the charge density of the bare liposomes, whereas the amount of PAH does not depend on it. As expected, the preparation of the multilayers has to be done in such a way that when the system is close to the isoelectric point, the capsules do not aggregate. For this, we dropped the polyelectrolyte solution quickly, stirred it fast, and used dilute liposome suspensions. The method is very flexible and not limited to liposomes or polyelectrolyte multilayers; also, coatings containing charged nanoparticles can be easily made. Once the liposomes have been coated, lipids can be easily eliminated, giving rise to polyelectrolyte nanocapsules (polyelectrosomes) with potential applications as drug delivery platforms.

Background and Aims Acute kidney injury (AKI) is a major risk factor for development and progression to chronic kidney disease (CKD). The aim of the present study is to assess the incidence of infections after an admission for AKI. Method In this retrospective study all patients who developed AKI during hospitalization and were discharged from 2013 to 2014 were included. Factors associated to infections were evaluated. The mean follow-up after discharge was 39±30 months. Results We included 1255 patients with a mean age of 75±13 years, of which 692 (55%) were men. At baseline, 944 (75%) patients presented with hypertension, 379 (30%) with diabetes, 560 (44%) with hypercholesterolemia and 543 (43%) with CKD. Mean baseline creatinine was 1,3±1,8 mg/dl (glomerular filtration rate [eGFR] estimated by CKD-EPI was 55±25 ml/min/1,73m2). The peak level of creatinine reached during AKI was 2,47±1,97 mg/dl (eGFR 30±18 ml/min/1,73m2). At discharge, creatinine was 1,62 mg/dL and eGFR 53±27 ml/min/1,73m2. Seven hundred and seventy-three (62%) patients presented an eGFR inferior to 60 ml/min/1,73m2. During follow-up, 681(54%) patients presented an infectious event. Urinary tract infection was the most frequent infection (286 patients, 23%) followed by respiratory infection (214 patients, 17%). Factors associated with infection were age (p0,001) and eGFR at discharge (p=0,002). Survival analysis using Kaplan-Meier demonstrated an existing association between eGFR inferior to 60 ml/min/1,73m2 and infections (LogRank 12,2, p Adjusted multivariable analysis demonstrated that age (HR 1,01 [CI95% 1,00-1,02], p=0,009) and the presence of eGFR inferior to 60 ml/min/1,73 m2 (HR 1,45 [CI95% 1,04-2,02], p=0,02) were independent predictors of infection after AKI episode. Conclusion The existence of eGFR inferior to 60 ml/min/1,73 m2 after an hospitalization with AKI shows an independent association with presenting an infection afterwards.

Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further in vivo efficacy studies in thrombosis models.

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival., LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8+ T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.