In Vitro Antibacterial Activity of Silver Nanoparticles Conjugated with Amikacin and Combined with Hyperthermia against Drug-Resistant and Biofilm-Producing Strains

Antibacterial activity; Biofilms; Silver nanoparticlesActividad antibacteriana; Biopelículas; Nanopartículas de plataActivitat antibacteriana; Biopel·lícules; Nanopartícules de plataIn view of the current increase and spread of antimicrobial resistance (AMR), there is an urgent need to find new strategies to combat it. This study had two aims. First, we synthesized highly monodispersed silver nanoparticles (AgNPs) of approximately 17 nm, and we functionalized them with mercaptopoly(ethylene glycol) carboxylic acid (mPEG-COOH) and amikacin (AK). Second, we evaluated the antibacterial activity of this treatment (AgNPs_mPEG_AK) alone and in combination with hyperthermia against planktonic and biofilm-growing strains. AgNPs, AgNPs_mPEG, and AgNPs_mPEG_AK were characterized using a suite of spectroscopy and microscopy methods. Susceptibility to these treatments and AK was determined after 24 h and over time against 12 clinical multidrug-resistant (MDR)/extensively drug-resistant (XDR) isolates of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The efficacy of the treatments alone and in combination with hyperthermia (1, 2, and 3 pulses at 41°C to 42°C for 15 min) was tested against the same planktonic strains using quantitative culture and against one P. aeruginosa strain growing on silicone disks using confocal laser scanning microscopy. The susceptibility studies showed that AgNPs_mPEG_AK was 10-fold more effective than AK alone, and bactericidal efficacy after 4, 8, 24, or 48 h was observed against 100% of the tested strains. The combination of AgNPs_mPEG_AK and hyperthermia eradicated 75% of the planktonic strains and exhibited significant reductions in biofilm formation by P. aeruginosa in comparison with the other treatments tested, except for AgNPs_mPEG_AK without hyperthermia. In conclusion, the combination of AgNPs_mPEG_AK and hyperthermia may be a promising therapy against MDR/XDR and biofilm-producing strains. IMPORTANCE Antimicrobial resistance (AMR) is one of the greatest public health challenges, accounting for 1.27 million deaths worldwide in 2019. Biofilms, a complex microbial community, directly contribute to increased AMR. Therefore, new strategies are urgently required to combat infections caused by AMR and biofilm-producing strains. Silver nanoparticles (AgNPs) exhibit antimicrobial activity and can be functionalized with antibiotics. Although AgNPs are very promising, their effectiveness in complex biological environments still falls below the concentrations at which AgNPs are stable in terms of aggregation. Thus, improving the antibacterial effectiveness of AgNPs by functionalizing them with antibiotics may be a significant change to consolidate AgNPs as an alternative to antibiotics. It has been reported that hyperthermia has a large effect on the growth of planktonic and biofilm-producing strains. Therefore, we propose a new strategy based on AgNPs functionalized with amikacin and combined with hyperthermia (41°C to 42°C) to treat AMR and biofilm-related infections.This study was supported by research grants from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (FIS 01162); la Marató TV3 (472/U/2018); the CaixaImpulse Program (Fundació LaCaixa); and the Spanish Network for Research in Infectious Diseases (REIPI RD19/0016)

Analyse pollinique du site de Hagenthal‑le‑Bas (Haut‑Rhin, France) et occupations archéologiques de l’est du Sundgau

Un paléochenal du ruisseau (le Kirchbach) parcourant la partie basse du village de Hagenthal-le-Bas (68) a été repéré lors d’une prospection destinée à inventorier les zones susceptibles de faire l’objet d’analyses palynologiques dans cette région du Sundgau, située à l’extrême sud de l’Alsace, sur le piémont au nord du massif jurassien. Cette prospection s’inscrivait dans le cadre du programme de recherche développé autour de l’abri Saint Joseph, situé sur la commune de Lutter à 8 km au sud-ouest de Hagenthal, qui a fait l’objet d’une fouille programmée entre 2005 et 2011. Le forage effectué dans ce paléochenal a permis de recueillir 4,50 mètres de sédiments limono-organiques déposés lors des épisodes de divagations du cours d’eau ; la sédimentation discontinue est affectée par de nombreuses lacunes chronologiques. La mesure en continu de la susceptibilité magnétique montre une succession de cycles et de pics de fortes valeurs répartis sur toute la séquence, traduction pour la plupart des déplacements du cours d’eau dans le fond de la vallée. Douze datations par le radiocarbone ont été effectuées sur cette séquence. La construction du modèle âge/profondeur a été difficile en raison de l’irrégularité de la sédimentation. Ce modèle confirme l’existence d’une importante lacune entre environ 9 000 et 4 000 ans cal. BC (environ 11 000-6 000 BP). Le diagramme palynologique débute au cœur de l’Allerød, entre environ 11 500 et 11 150 ans cal. BC (13 450-13 100 ans cal. BP), dans un environnement très forestier dominé par le pin. La fin de l’Allerød, la totalité du Dryas récent et l’extrême début de l’Holocène correspondent à un régime beaucoup plus actif du ruisseau qui a empêché toute sédimentation fine. À partir d’environ 9 400-9 300 ans cal. BC (vers 11 400 BP) débute alors une longue période largement dominée par le pin qui va durer jusque vers 3 600-3 500 ans cal. BC (vers 5 500 BP). Vers 4 400-4 300 ans cal. BC (environ 6 300 BP), apparaissent quelques grains de pollen de céréales accompagnés d’armoise et de Rubiaceae. Si ces très faibles indices de présence humaine se situent bien dans une phase ancienne du Néolithique, ils sont toutefois plus récents que les occupations les plus anciennes du site archéologique de Lutter. Au cours du Néolithique final, pendant environ un millénaire, des signes plus évidents d’impact de l’homme sur l’environnement de cette micro-région sont visibles. Ensuite, il faudra attendre le milieu de l’Âge du Fer pour que de nouveaux indices polliniques d’anthropisation réapparaissent dans ce diagramme. Jusqu’au ve siècle de notre ère, ils restent pourtant très discrets, masqués par les apports polliniques de la forêt humide qui occupe le fond de la vallée. À partir des ve-vie siècles, jusqu’au xiie-xiiie siècles, des cultures variées, des pâtures et des prairies de fauche occupent une grande partie du territoire alors que les collines proches restent le domaine des forêts. Il est très probable que cette phase de forte emprise agricole se prolonge encore sur plusieurs siècles. En effet, à partir de 90 cm de profondeur, soit vers le xive siècle, une phase détritique (trop pauvre en pollen) se développe et occupe toute la partie supérieure de la séquence. Cette phase détritique pourrait être la conséquence des effets locaux du Petit Âge Glaciaire. Toutefois, les indices polliniques d’anthropisation élevés tendent plutôt à attribuer cette augmentation du détritisme à l’anthropisation de plus en plus importante du bassin versant de ce ruisseau.A stream paleochannel (the Kirchbach) situated in the lower part of the Hagenthal-le-Bas village was spotted during an archaeological survey. One of the aims of this survey was to identify sites suitable for pollen analysis in the Sundgau area, the extreme south of Alsace in the foothills of northern Jura Mountain. The study is part of a research program developed around the Saint Joseph rock shelter, located in the Lutter municipality 8 km southwest of Hagenthal, which was excavated between 2005 and 2011. A 4.5 meter silty organic sequence was found in this paleochannel. The sequence suffered several episodes of flooding and is characterized by a discontinuous sedimentation. Measurements of magnetic susceptibility showed a succession of cycles and peaks of strong values distributed over the entire sequence and correlated with the movements of the stream running in the valley. Twelve radiocarbon dates were performed on this sequence but the construction of an age/depth model was hampered by irregular sedimentation. Nevertheless the estimated age depth model confirmed the existence of a significant gap between ca. 9,000 and 4,000 cal. years BC (about 11,000-6,000 BP). The palynological diagram starts in the middle of the Allerød interstadial, between ca. 11,500 and 11,150 cal. years BC (13,450-13,100 cal. years BP), in a forest environment dominated by pine (Pinus). The end of the Allerød period, i.e. Younger Dryas and early Holocene, was characterized by a stronger stream regime which prevented steady sedimentation. Starting around 9,400-9,300 cal. years BC (ca. 11,400 BP) a long period dominated by pine lasted until around 3,600-3,500 cal. years BC (ca. 5,500 BP). From 4,400-4,300 cal. years BC (ca. 6,300 BP), on the sediments disclose some cereal pollen grains together with Artemisia and Rubiaceae pollen. This weak evidence of possible human impact corresponds to the early phase of the Neolithic period, which is however more recent than the oldest occupations detected in the Lutter archaeological site. During the Neolithic period, unambiguous signs of human impact on the environment are regularly found for a whole millennium. After this time, new anthropogenic indicators reappear in the diagram only in the middle of the Iron Age. They remain discreet until the 5th century AD hidden by the pollens from the wet forest which covers the bottom of the valley. Between the 5th-6th and the 12th-13th centuries, various crops, pastures and hay fields occupy the major part of the territory while the nearby hills remain forested. It is likely that this strong farming activity extended over many centuries. Indeed, from 90 cm deep, i.e. in the 14th century, a detrital phase (poor pollen preservation) is found up to the top of the sequence. This detrital phase could result from local effects of the Little Ice Age. However, palynological evidence of a heavy human impact suggests that it rather derives from the huge environmental footprint of medieval and modern agricultural practices in the stream catchment area

Novel phosphate–phosphonate hybrid nanomaterials applied to biology

International audienceA new process for preparing oligonucleotide arrays is described that uses surface grafting chemistry which is fundamentally different from the electrostatic adsorption and organic covalent binding methods normally employed. Solid supports are modified with a mixed organic/inorganic zirconium phosphonate monolayer film providing a stable, well-defined interface. Oligonucleotide probes terminated with phosphate are spotted directly to the zirconated surface forming a covalent linkage. Specific binding of terminal phosphate groups with minimal binding of the internal phosphate diesters has been demonstrated. On the other hand, the reaction of a bisphosphonate bone resorption inhibitor (Zoledronate) with calcium deficient apatites (CDAs) was studied as a potential route to local drug delivery systems active against bone resorption disorders. A simple mathematical model of the Zoledronate/CDA interaction was designed that correctly described the adsorption of Zoledronate onto CDAs. The resulting Zoledronate-loaded materials were found to release the drug in different phosphate-containing media, with a satisfactory agreement between experimental data and the values predicted from the model

The SuperCam Instrument Suite on the Mars 2020 Rover: Science Objectives and Mast-Unit Description

On the NASA 2020 rover mission to Jezero crater, the remote determination of the texture, mineralogy and chemistry of rocks is essential to quickly and thoroughly characterize an area and to optimize the selection of samples for return to Earth. As part of the Perseverance payload, SuperCam is a suite of five techniques that provide critical and complementary observations via Laser-Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman and Luminescence (TRR/L), visible and near-infrared spectroscopy (VISIR), high-resolution color imaging (RMI), and acoustic recording (MIC). SuperCam operates at remote distances, primarily 2-7 m, while providing data at sub-mm to mm scales. We report on SuperCam's science objectives in the context of the Mars 2020 mission goals and ways the different techniques can address these questions. The instrument is made up of three separate subsystems: the Mast Unit is designed and built in France; the Body Unit is provided by the United States; the calibration target holder is contributed by Spain, and the targets themselves by the entire science team. This publication focuses on the design, development, and tests of the Mast Unit; companion papers describe the other units. The goal of this work is to provide an understanding of the technical choices made, the constraints that were imposed, and ultimately the validated performance of the flight model as it leaves Earth, and it will serve as the foundation for Mars operations and future processing of the data.In France was provided by the Centre National d'Etudes Spatiales (CNES). Human resources were provided in part by the Centre National de la Recherche Scientifique (CNRS) and universities. Funding was provided in the US by NASA's Mars Exploration Program. Some funding of data analyses at Los Alamos National Laboratory (LANL) was provided by laboratory-directed research and development funds

Steel foam for structures: A review of applications, manufacturing and material properties

The objective of this paper is to provide a state-of-the-art review for the structural application, manufacturing, material properties, and modeling of a new material: steel foam. Foamed steel includes air voids in the material microstructure and as a result introduces density as a new design variable in steel material selection. By controlling density the engineering properties of steel components may be altered significantly: improvement in the weight-to-stiffness ratio is particularly pronounced, as is the available energy dissipation and thermal resistivity. Full-scale applications of steel foams in civil structures have not yet been demonstrated. Therefore, existing applications demonstrating either proof-of-concept for steel foam, or full-scale use of aluminum foams in situations with clear civil/structural analogs are highlighted. Adoption of steel foam relies on the manufacturing method, particularly its cost, and the resulting properties of the steel foam. Therefore, published methods for producing steel foam are summarized, along with measurements of steel foam structural (modulus, yield stress, etc.) and non-structural (thermal conductivity, acoustic absorption, etc.) properties. Finally, existing models for predicting foamed steel material properties are summarized to highlight the central role of material density. Taken in total the existing research demonstrates the viability of steel foams for use in civil/structural applications, while also pointing to areas where further research work is required. © 2011 Elsevier Ltd. All rights reserved

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe