Entropy-driven phase transition in a system of long rods on a square lattice

The isotropic-nematic (I-N) phase transition in a system of long straight rigid rods of length k on square lattices is studied by combining Monte Carlo simulations and theoretical analysis. The process is analyzed by comparing the configurational entropy of the system with the corresponding to a fully aligned system, whose calculation reduces to the 1D case. The results obtained (1) allow to estimate the minimum value of k which leads to the formation of a nematic phase and provide an interesting interpretation of this critical value; (2) provide numerical evidence on the existence of a second phase transition (from a nematic to a non-nematic state) occurring at density close to 1 and (3) allow to test the predictions of the main theoretical models developed to treat the polymers adsorption problem.Comment: 14 pages, 6 figures. Accepted for publication in JSTA

ATM regulates ATR chromatin loading in response to DNA double-strand breaks

DNA double-strand breaks (DSBs) are among the most deleterious lesions that can challenge genomic integrity. Concomitant to the repair of the breaks, a rapid signaling cascade must be coordinated at the lesion site that leads to the activation of cell cycle checkpoints and/or apoptosis. In this context, ataxia telangiectasia mutated (ATM) and ATM and Rad-3–related (ATR) protein kinases are the earliest signaling molecules that are known to initiate the transduction cascade at damage sites. The current model places ATM and ATR in separate molecular routes that orchestrate distinct pathways of the checkpoint responses. Whereas ATM signals DSBs arising from ionizing radiation (IR) through a Chk2-dependent pathway, ATR is activated in a variety of replication-linked DSBs and leads to activation of the checkpoints in a Chk1 kinase–dependent manner. However, activation of the G2/M checkpoint in response to IR escapes this accepted paradigm because it is dependent on both ATM and ATR but independent of Chk2. Our data provides an explanation for this observation and places ATM activity upstream of ATR recruitment to IR-damaged chromatin. These data provide experimental evidence of an active cross talk between ATM and ATR signaling pathways in response to DNA damage

Superplastic deformation of directionally solidified nanofibrillar Al2O3-Y3Al5O12-ZrO2 eutectics

Nanofibrillar Al2O3–Y3Al5O12–ZrO2 eutectic rods were manufactured by directional solidification from the melt at high growth rates in an inert atmosphere using the laser-heated floating zone method. Under conditions of cooperative growth, the ternary eutectic presented a homogeneous microstructure, formed by bundles of single-crystal c-oriented Al2O3 and Y3Al5O12 (YAG) whiskers of ≈100 nm in width with smaller Y2O3-doped ZrO2 (YSZ) whiskers between them. Owing to the anisotropic fibrillar microstructure, Al2O3–YAG–YSZ ternary eutectics present high strength and toughness at ambient temperature while they exhibit superplastic behavior at 1600 K and above. Careful examination of the deformed samples by transmission electron microscopy did not show any evidence of dislocation activity and superplastic deformation was attributed to mass-transport by diffusion within the nanometric domains. This combination of high strength and toughness at ambient temperature together with the ability to support large deformations without failure above 1600 K is unique and shows a large potential to develop new structural materials for very high temperature structural applications

A genetic case-control study confirms the implication of SMAD7 and TNF locus in the development of proliferative vitreoretinopathy

PURPOSE: Proliferative vitreoretinopathy (PVR) is still the major cause of failure of retinal detachment (RD) surgery and although the risk for developing this complication is associated with some clinical characteristics, the correlation is far from absolute, raising the possibility of genetic susceptibility. The objective of this study was to analyze the genetic contribution to PVR in patients undergoing RD surgery, the Retina 4 Project. METHODS: A candidate gene association study was conducted in 2006 in a Spanish population of 450 patients suffering from primary rhegmatogenous RD. Replication was carried out in a larger population undergoing RD surgery at several European centers among 546 new patients. Single nucleotide polymorphism (SNP) of 30 genes known to be involved with inflammation were analyzed. For replication stage, those genes previously detected as significantly associated with PVR were genotyped. Distribution of allelic and haplotypic frequencies in case and control group were analyzed. Single and haplotypic analysis were assessed. The Rosenberg two-stage method was used to correct for single and multiple analyses. RESULTS: After correction for multiple comparisons, four genes were significantly associated with PVR: SMAD7 (P = 0.004), PIK3CG (P = 0.009), TNF locus (P = 0.0005), and TNFR2 (P = 0.019) In the European sample, replication was observed in SMAD7 (P = 0.047) and the TNF locus (P = 0.044). CONCLUSIONS: These results confirm the genetic contribution to PVR and the implication of SMAD7 and TNF locus in the development of PVR. This finding may have implications for understanding the mechanisms of PVR and could provide a potential new therapeutic target for PVR prophylaxis

In-depth proteomics characterization of ∆Np73 effectors identifies key proteins with diagnostic potential implicated in lymphangiogenesis, vasculogenesis and metastasis in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Alterations in proteins of the p53-family are a common event in CRC. ΔNp73, a p53-family member, shows oncogenic properties and its effectors are largely unknown. We performed an in-depth proteomics characterization of transcriptional control by ∆Np73 of the secretome of human colon cancer cells and validated its clinical potential. The secretome was analyzed using high-density antibody microarrays and stable isotopic metabolic labeling. Validation was performed by semiquantitative PCR, ELISA, dot-blot and western blot analysis. Evaluation of selected effectors was carried out using 60 plasma samples from CRC patients, individuals carrying premalignant colorectal lesions and colonoscopy-negative controls. In total, 51 dysregulated proteins were observed showing at least 1.5-foldchange in expression. We found an important association between the overexpression of ∆Np73 and effectors related to lymphangiogenesis, vasculogenesis and metastasis, such as brain-derived neurotrophic factor (BDNF) and the putative aminoacyl tRNA synthase complex-interacting multifunctional protein 1 (EMAP-II)–vascular endothelial growth factor C–vascular endothelial growth factor receptor 3 axis. We further demonstrated the usefulness of BDNF as a potential CRC biomarker able to discriminate between CRC patients and premalignant individuals from controls with high sensitivity and specificity.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project “PI18/00473” and co-funded by the European Union (FEDER funds) and Catedra UAM-Roche en Medicina de Innovacion to GD, and the Ramon y Cajal Programme of the MINECO, PI17CIII/00045 and PI20CIII/00019 research projects from AES-ISCIII to RB. MG-A and JR-C were supported by contracts of the Programa Operativo de Empleo Juvenil y la Iniciativa de Empleo Juvenil (YEI) with the participation of the Consejerıa de Educacion, Juventud y Deporte de la Comunidad de Madrid y del Fondo Social Europeo. AM-C FPU predoctoral contract is supported by the MECD. GSF is a recipient of a predoctoral contract (grant number 1193818N) supported by The Flanders Research Foundation (FWO).Peer reviewe

Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice

The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic too

Prediction of peptide and protein propensity for amyloid formation

Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self-assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of β-sheet, normalized frequency of β-sheet from LG, weights for β-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and ΔGº values for peptides extrapolated in 0 M urea). Moreover, these features enabled the development of a new predictor (available at http://cran.r-project.org/web/packages/appnn/index.html) capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation

Capturing the essence of folding and functions of biomolecules using Coarse-Grained Models

The distances over which biological molecules and their complexes can function range from a few nanometres, in the case of folded structures, to millimetres, for example during chromosome organization. Describing phenomena that cover such diverse length, and also time scales, requires models that capture the underlying physics for the particular length scale of interest. Theoretical ideas, in particular, concepts from polymer physics, have guided the development of coarse-grained models to study folding of DNA, RNA, and proteins. More recently, such models and their variants have been applied to the functions of biological nanomachines. Simulations using coarse-grained models are now poised to address a wide range of problems in biology.Comment: 37 pages, 8 figure

The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy

Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1-53.0)/(22.6-32.9), Portugal (39.0-74.4)/(21.4-38.9), Netherlands (40.6-66.3)/(25.3-38.8) and UK (37.5-62.4)/(23.3-34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2-12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8-19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR. Copyright

Tecnologías de materiales con aplicaciones en fusión y su desarrollo en la instalación TechnoFusión

El futuro Centro Nacional de Tecnologías para la Fusión, TechnoFusión, tiene como objetivo desarrollar aquellas tecnologías, relacionadas con materiales, metales líquidos, manipulación remota y simulación, que permitan avanzar en los actuales retos que supone el uso de la fusión nuclear. Sus instalaciones, abiertas al servicio de la comunidad científica externa, garantizarán una destacada participación de empresas y grupos de investigación españoles. En esta contribución se describirán y analizarán las instalaciones que TechnoFusión construirá con capacidad para abordar: la fabricación y procesado de nuevas aleaciones a escala semiindustrial; el comportamiento de materiales, simulando las condiciones durante operación mediante una instalación de triple irradiación (iones pesados, hidrógeno y helio), generadores de plasma lineal (continuo y pulsado) y un circuito de litio líquido; y la caracterización del efecto que las severas condiciones de experimentación producen en las propiedades, en la composición y en la microestructura de materiales estructurales y funcionales (técnicas convencionales e in-situ)