Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers : implications for autoimmunity in rheumatoid arthritis

Introduction: Smoking is a well-established risk factor for rheumatoid arthritis (RA), and it has been proposed that smoking-induced citrullination renders autoantigens immunogenic. To investigate this mechanism, we examined human lung tissue from 40 subjects with defined smoking status, with or without chronic obstructive pulmonary disease (COPD), and control tissues from other organs for citrullinated proteins and the deiminating enzymes peptidylarginine deiminase type-2 (PAD2) and -4 (PAD4). Methods: Lung tissue samples, dissected from lobectomy specimens from 10 never smokers, 10 smokers without airflow limitation, 13 COPD smokers and eight COPD ex-smokers, and control tissue samples (spleen, skeletal muscle, liver, ovary, lymph node, kidney and heart), were analysed for citrullinated proteins, PAD2 and PAD4 by immunoblotting. Citrulline and homocitrulline residues in enolase and vimentin were analysed by partial purification by gel electrophoresis followed by mass spectrometry in 12 of the lung samples and one from each control tissues. Band intensities were scored semi-quantitatively and analysed by two-tailed Mann-Whitney T-test. Results: Within the lung tissue samples, citrullinated proteins, PAD2 and PAD4 were found in all samples, with an increase in citrullination in COPD (P = 0.039), but minimal difference between smokers and non-smokers (P = 0.77). Citrullination was also detected at lower levels in the tissues from other organs, principally in lymph node, kidney and skeletal muscle. Mass spectrometry of the lung samples showed that vimentin was citrullinated at positions 71, 304, 346, 410 and 450 in non-smokers and smokers both with and without COPD. A homocitrulline at position 104 was found in four out of six COPD samples and one out of six non-COPD. Citrulline-450 was also found in three of the control tissues. There were no citrulline or homocitrulline residues demonstrated in a-enolase. Conclusions: We have shown evidence of citrullination of vimentin, a major autoantigen in RA, in both non-smokers and smokers. The increase in citrullinated proteins in COPD suggests that citrullination in the lungs of smokers is mainly due to inflammation. The ubiquity of citrullination of vimentin in the lungs and other tissues suggests that the relationship between smoking and autoimmunity in RA may be more complex than previously thought

Analytic approach to the evolutionary effects of genetic exchange

We present an approximate analytic study of our previously introduced model of evolution including the effects of genetic exchange. This model is motivated by the process of bacterial transformation. We solve for the velocity, the rate of increase of fitness, as a function of the fixed population size, $N$. We find the velocity increases with $\ln N$, eventually saturated at an $N$ which depends on the strength of the recombination process. The analytical treatment is seen to agree well with direct numerical simulations of our model equations

Site-specific recognition of SARS-CoV-2 nsp1 protein with a tailored titanium dioxide nanoparticle - elucidation of the complex structure using NMR data and theoretical calculation

The ongoing world-wide Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic shows the need for new potential sensing and therapeutic means against the CoV viruses. The SARS-CoV-2 nsp1 protein is important, both for replication and pathogenesis, making it an attractive target for intervention. In this study we investigated the interaction of this protein with two types of titania nanoparticles by NMR and discovered that while lactate capped particles essentially did not interact with the protein chain, the aminoalcohol-capped ones showed strong complexation with a distinct part of an ordered alpha-helix fragment. The structure of the forming complex was elucidated based on NMR data and theoretical calculation. To the best of our knowledge, this is the first time that a tailored titanium oxide nanoparticle was shown to interact specifically with a unique site of the full-length SARS-CoV-2 nsp1 protein, possibly interfering with its functionality

Modulating Surface Properties of the Linothele fallax Spider Web by Solvent Treatment

[Image: see text] Linothele fallax (Mello-Leitão) (L. fallax) spider web, a potentially attractive tissue engineering material, was investigated using quantitative peak force measurement atomic force microscopy and scanning electron microscopy with energy dispersive spectroscopy both in its natural state and after treatment with solvents of different protein affinities, namely, water, ethanol, and dimethyl sulfoxide (DMSO). Native L. fallax silk threads are densely covered by globular objects, which constitute their inseparable parts. Depending on the solvent, treating L. fallax modifies its appearance. In the case of water and ethanol, the changes are minor. In contrast, DMSO practically removes the globules and fuses the threads into dense bands. Moreover, the solvent treatment influences the chemistry of the threads’ surface, changing their adhesive and, therefore, biocompatibility and cell adhesion properties. On the other hand, the solvent-treated web materials’ contact effect on different types of biological matter differs considerably. Protein-rich matter controls humidity better when wrapped in spider silk treated with more hydrophobic solvents. However, carbohydrate plant materials retain more moisture when wrapped in native spider silk. The extracts produced with the solvents were analyzed using nuclear magnetic resonance (NMR) and liquid chromatography–mass spectrometry techniques, revealing unsaturated fatty acids as representative adsorbed species, which may explain the mild antibacterial effect of the spider silk. The extracted metabolites were similar for the different solvents, meaning that the globules were not “dissolved” but “fused into” the threads themselves, being supposedly rolled-in knots of the protein chain

Hybrid Spider Silk with Inorganic Nanomaterials

High-performance functional biomaterials are becoming increasingly requested. Numerous natural and artificial polymers have already demonstrated their ability to serve as a basis for bio-composites. Spider silk offers a unique combination of desirable aspects such as biocompatibility, extraordinary mechanical properties, and tunable biodegradability, which are superior to those of most natural and engineered materials. Modifying spider silk with various inorganic nanomaterials with specific properties has led to the development of the hybrid materials with improved functionality. The purpose of using these inorganic nanomaterials is primarily due to their chemical nature, enhanced by large surface areas and quantum size phenomena. Functional properties of nanoparticles can be implemented to macro-scale components to produce silk-based hybrid materials, while spider silk fibers can serve as a matrix to combine the benefits of the functional components. Therefore, it is not surprising that hybrid materials based on spider silk and inorganic nanomaterials are considered extremely promising for potentially attractive applications in various fields, from optics and photonics to tissue regeneration. This review summarizes and discusses evidence of the use of various kinds of inorganic compounds in spider silk modification intended for a multitude of applications. It also provides an insight into approaches for obtaining hybrid silk-based materials via 3D printing

Las trayectorias de Organizaciones sociales y sus aportes a las transformaciones territoriales

El presente trabajo refleja los resultados obtenidos en una primera etapa, diagnóstica, del proyecto de investigación CAID orientado a problemas sociales, titulado: “Sistema de indicadores y monitoreo en intervenciones socio-territoriales de organizaciones sociales”. El proyecto de referencia, surge a partir de la demanda de organizaciones sociales con las que la Secretaría de Extensión  de la Universidad Nacional del Litoral viene trabajando desde el año 2000, a través de proyectos de interés social, algunos financiados por dicha universidad, como también por la Secretaría de Políticas Públicas de la Nación (SPU). Las demandas, que surgen de las preocupaciones de las organizaciones por la escasa participación de jóvenes en sus actividades, por la falta de adherencia de nuevos miembros a las instituciones, refieren a la necesidad de contar con instrumentos que permitan a las organizaciones evaluar y medir los impactos de sus prácticas, el alcance de las mismas y las transformaciones socio-territoriales que producen. Los resultados que se presentan  provienen de fuentes primarias: entrevistas focalizadas a referentes claves de las organizaciones con presencia territorial y el primer taller de diagnóstico participativo realizado en el territorio. La presentación se propone rescatar a partir de entrevistas focalizadas a referentes calificados de las organizaciones sociales del barrio Guadalupe (situado en el noreste de la ciudad de Santa Fe), las trayectorias que las organizaciones fueron construyendo en el territorio. Para su análisis se tiene en cuenta las siguientes dimensiones: estructura organizativa (modelo de gestión, misión, visión, objetivos, valores  que orientan las prácticas institucionales); los principales hitos en su evolución histórica,  teniendo en cuenta el contexto en el cual emergen; la vinculación con el Estado, la universidad y  otras organizaciones; su proyección en la ciudad (más allá del territorio). Por otro lado y  a partir del trabajo realizado en taller participativo, se complementa esta información e identifica el grado de conocimiento y reconocimiento que las organizaciones construyen en torno a su territorio, y con los actores sociales con los que se vinculan, las asociaciones que entretejen, la percepción de sus prácticas y los destinatarios de sus intervenciones. Se aplicó la cartografía social, como instrumento que favorece la visualización de estas relaciones, su evolución en el tiempo y su tatuaje espacial. La sistematización de la información relevada, permite comprender y explicar las lógicas que subyacen en las intervenciones; reconocer y socializar el conocimiento que los actores tienen de su territorio, como lo describen y los relatos que construyen en torno al mismo para explicarlo y los obstáculos que descubren en sus prácticas al momento de materializarlas. En tal sentido la articulación investigación-intervención en la práctica extensionista posibilita no solo la construcción de conocimiento convalidado socialmente, sino también sostener una mirada crítica respecto del rol de la universidad en los procesos de intervención comunitaria

Molecular View on the iRGD Peptide Binding Mechanism: Implications for Integrin Activity and Selectivity Profiles

Receptor-selective peptides are widely used as smart carriers for specific tumor-targeted delivery. A remarkable example is the cyclic nonapeptide iRGD (CRGDKPGDC, 1) that couples intrinsic cytotoxic effects with striking tumor-homing properties. These peculiar features are based on a rather complex multistep mechanism of action, where the primary event is the recognition of RGD integrins. Despite the high number of preclinical studies and the recent success of a phase I trial for the treatment of pancreatic ductal adenocarcinoma (PDAC), there is little information available about the iRGD three-dimensional (3D) structure and integrin binding properties. Here, we re-evaluate the peptide's affinity for cancer-related integrins including not only the previously known targets alpha v beta 3 and alpha v beta 5 but also the alpha v beta 6 isoform, which is known to drive cell growth, migration, and invasion in many malignancies including PDAC. Furthermore, we use parallel tempering in the well-tempered ensemble (PT-WTE) metadynamics simulations to characterize the in-solution conformation of iRGD and extensive molecular dynamics calculations to fully investigate its binding mechanism to integrin partners. Finally, we provide clues for fine-tuning the peptide's potency and selectivity profile, which, in turn, may further improve its tumor-homing properties

A intervenção social em chave de inovação social: Uma análise a partir de dois projetos de extensão universitária

El artículo analiza, a partir de dos casos seleccionados que se enmarcan en proyectos de extensión de la Universidad Nacional del Litoral (UNL), las relaciones que se generan entre los equipos extensionistas (conformados por docentes–investigadores, estudiantes y especialistas) y los actores territoriales involucrados en procesos de intervención. Se nutre de los distintos momentos transitados en el marco del proyecto Curso de Acción para la Investigación y el Desarrollo (CAI+D) titulado: “Análisis de las innovaciones sociales, a partir de la transferencia científico–tecnológica, entre la Universidad Nacional del Litoral e instituciones de la esfera pública” (convocatoria 2011). La reflexión se focaliza en el entramado de relaciones que se anudan, los sentidos, las marcas que dichas asociaciones producen en tanto procesos innovadores que intentan ser una respuesta a los problemas que las originan.The article analyzes, from two selected cases that are framed in extension projects of the Universidad Nacional del Litoral, the relationships that are generated between the extension teams (conformed by teachers-researchers, students and specialists) and the territorial actors involved in intervention processes. It is nourished by the different moments in the framework of the project Action Course for Research and Development (CAI + D, in spanish) entitled: “Analysis of social innovation from scientific and technological transfer between Universidad Nacional del Litoral and institutions of the public sphere” (2011). The reflection is focused on the network of relationships that are knotted, the senses, the brands that these associations produce, as innovative processes that try to be an answer to the problems that originate them.O artigo analisa, a partir de dois casos selecionados, no âmbito de projetos de extensão da Universidad Nacional del Litoral, as relações que são geradas entre as equipes de extensão (formadas por professorespesquisadores, estudantes e especialistas) e os atores territoriais envolvidos nos processos de intervenção. Nutre-se dos diferentes momentos do projeto Curso de Ação para a Pesquisa e o Desenvolvimento (CAI+D, em espanhol) intitulado: “Análise das inovações sociais, a partir da transferência científico-tecnológica, entre a Universidad Nacional del Litoral e instituições da esfera pública” (convite 2011). A reflexão se concentra na rede de relacionamentos que se amarram, os sentidos, as marcas que essas associações produzem, como processos inovadores que tentam ser uma resposta aos problemas que os originam.Fil: Angeloni, Marcos Exequiel. Universidad Nacional del Litoral; ArgentinaFil: Lozeco, Julio César. Universidad Nacional del Litoral; ArgentinaFil: Marzioni, Sofía Clarisa. Universidad Nacional del Litoral. Facultad de Ciencias Jurídicas y Sociales. Centro de Investigaciones de la Facultad de Ciencias Jurídicas y Sociales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Kessler, María Elena. Universidad Nacional del Litoral; Argentin

Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis

Abstract Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations

Determinants of self-reported health status in a population-based sample of persons with radiographic knee osteoarthritis

Knee osteoarthritis (OA) is highly prevalent and disabling. Patients with radiographic knee OA may experience pain and functional impairment, which can diminish their health status. Our objective was to determine factors associated with self-reported health status in a national population-based sample with radiographic knee OA