Determination of thermal response of Carrara and Sneznikovsky marble used as building material

Physical weathering of marble, widely used as a cladding material on buildings, is one of the most common damaging mechanism caused by anisotropic thermal expansion of calcite grains. The extent of marble deterioration depends mainly on stone fabric and texture. Dry cuboids of Carrara marble and marble from Dolni Morava quarry were subjected to microscopic analysis and thermal cycling, to determine the thermal expansion related to stone fabric and predominant lattice orientation of grains (i.e. texture)

Copper content and resistance mechanisms in the terrestrial moss ptychostomum capillare: A case study in an abandoned Copper Mine in Central Spain

We present a case study on the tissue absorption of copper of a widely distributed moss species, Ptychostomum capillare in the polluted soil of an abandoned copper mine in central Spain. We studied the soil properties in a copper soil pollution gradient and sampled the moss tufts growing on them in four plots with contrasted soil copper levels. We determined the copper content in the soil and in the moss tissues. On these moss samples, we also performed histochemical tests and X-ray dispersive spectrometry coupled with scanning electron microscopy (SEM-EDX), both in untreated shoots and in samples where surface waxes were removed. We checked the behavior of this species using a metallophillous moss, Scopelophila cataractae, for comparative purposes. Copper contents in P. capillare seem to depend more on available, rather than total soil copper contents. Our results indicate that this moss is able to concentrate 12-fold the available soil copper in soil with low available copper content, whereas in the most polluted soil the concentration of Cu in the moss was only half those levels. Both histochemical and SEM-EDX tests show no surface copper in the mosses from the least polluted plot, whereas in samples from the soil with highest copper content, the removal of surface waxes also reduces or removes copper from the moss shoots. Our observations point at a mixed strategy in P. capillare in this copper mine, with metal accumulation behavior in the lowest Cu plot, and an exclusion mechanism involving wax-like substances acting as a barrier in the most polluted plots. These distortions impede the estimation of environmental levels and thus compromise the value of this moss in biomonitoring. We highlight the need of extending these studies to other moss species, especially those used in biomonitoring program

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways

Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential

Spark plasma versus conventional sintering in the electrical properties of Nasicon-type materials

Li_(1+x)M_(x)Ti_(2−x)(PO_(4))_(3) powders with x = 0 and 0.3 and M = Al, Cr and Fe have been sintered by conventional sintering (CS) and Spark Plasma Sintering (SPS), and the electrical properties have been compared. The use of SPS allows preparing samples with higher density at lower temperature and shorter time than the CS, avoiding segregation of secondary phases and with reduced crystallite size. The introduction of aluminum, chromium and iron in the LiTi_(2)(PO_(4))_(3) (LTP) clearly enhances ionic conductivity even if the samples have similar densities. Despite the different level of density reached with CS and SPS, the activation energies of dc and grain boundary contributions are very similar and the differences in ionic conductivity are determined by pre-exponential factors. The samples produced by SPS showed a well-defined grain boundary meaning a more homogenous electrical contact

What potential do mosses have as biomonitors of POPs? A comparative study of hexachlorocyclohexane sorption

Persistent organic pollutants (POPs) pose a significant global threat to human health and the environment, and require continuous monitoring due to their ability to migrate long distances. Active biomonitoring using cloned mosses is an inexpensive but underexplored method to assess POPs, mainly due to the poor understanding of the loading mechanisms of these pollutants in mosses. In this work, Fontinalis antipyretica (aquatic moss) and Sphagnum palustre (terrestrial moss) were evaluated as potential biomonitors of hexachlorocyclohexanes (HCHs: α-, β-, γ-, δ-HCH), crucial POPs. Moss clones, grown in photobioreactors and subsequently oven-dried, were used. Their lipid composition and distribution were characterized through molecular and histochemical studies. Adsorption experiments were carried out in the aqueous phase using the repeated additions method and in the gas phase using an active air sampling technique based on solid-phase extraction, a pioneering approach in moss research. F. antipyretica exhibited greater lipid content in the walls of most cells and higher adsorption capacity for all HCH isomers in both gaseous and liquid environments. These findings highlight the need for further investigation of POP loading mechanisms in mosses and open the door to explore other species based on their lipid content

The Multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug design

The mineralocorticoid receptor modulates timing and location of genomic binding by glucocorticoid receptor in response to synthetic glucocorticoids in keratinocytes

17 páginas, 6 figurasGlucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis. These closely related receptors may homo- or heterodimerize to regulate transcription, and theoretically bind identical GC-response elements (GRE). We assessed the contribution of MR to GR genomic binding and the transcriptional response to the synthetic GC dexamethasone (Dex) using control (CO) and MR knockout (MREKO ) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1 h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO , with significantly decreased GRE enrichment, and reduced nuclear GR. Surface plasmon resonance determined steady state affinity constants, suggesting preferred dimer formation as MR-MR > GR-MR ~ GR-GR; however, kinetic studies demonstrated that GR-containing dimers had the longest lifetimes. Despite GR-binding differences, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3 h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC transcriptional responses in keratinocytes.This research is part of the grants PID2020-114652RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 to PP, and PDC2021-121688-I00 to EE-P. The author's work was also supported by Inserm, Université Paris-Saclay. EC-Z was recipient of a postdoctoral fellowship from 15306860, 2023, 1, Downloaded from https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202201199RR by Csic Organización Central Om (Oficialia Mayor) (Urici), Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | CARCELLER-ZAZO et al. 15 of 17 the Alfonso Martín Escudero Foundation (Spain); OP-A was funded by EDGJID/2021/098 (Generalitat Valenciana) and by ‘ESF Investing in your future.”. We thank NuRCaMeIN (SAF2017-90604-REDT) for support for dissemination. PP is a member of the Scientific Network on ´Strategies for therapeutic targeting of the Aldosterone-Mineralocorticoid Receptor signaling pathway (ADMIRE network) funded by the German Research Foundation (DFG-ID 470188766). This work has benefited from the facilities and expertize of the high-throughput sequencing core facility of I2BC (Centre de Recherche de Gif – http://www.i2bc. paris-saclay.fr/). This work was supported by the DIM Thérapie Génique Paris Ile-de-France Région, IBiSA, and the Labex GR-ExPeer reviewe

Tunable thermal expansion in framework materials through redox intercalation

Thermal expansion properties of solids are of fundamental interest and control of thermal expansion is important for practical applications but can be difficult to achieve. Many framework-type materials show negative thermal expansion when internal cages are empty but positive thermal expansion when additional atoms or molecules fill internal voids present. Here we show that redox intercalation offers an effective method to control thermal expansion from positive to zero to negative by insertion of Li ions into the simple negative thermal expansion framework material ScF3, doped with 10% Fe to enable reduction. The small concentration of intercalated Li ions has a strong influence through steric hindrance of transverse fluoride ion vibrations, which directly controls the thermal expansion. Redox intercalation of guest ions is thus likely to be a general and effective method for controlling thermal expansion in the many known framework materials with phonon-driven negative thermal expansion

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

20 páginas, 7 figurasThe glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug designE.E.-P. thanks the generosity of the Gemma E. Carretero Fund; MINECO [BFU2017-86906-R, SAF2017-71878-REDT, SAF2015-71878-REDT to E.E.-P., RTI2018-101500-B-I00 to P.F.-P., RTI2018-096735-B-100 to A.R.M., PID2019-110167RB-I00 to J.F.-R., SAF2017-89510-R to A.V.F. and C.C.]; G.L.H thanks the NIH Intramural Research Program; D.M.P was supported by CONICET. Funding for open access charge: Spanish Ministry of Science (MINECO).Peer reviewe