Melanocortin peptides inhibit urate crystal-induced activation of phagocytic cells

Introduction The melanocortin peptides have marked antiinflammatory potential, primarily through inhibition of proinflammatory cytokine production and action on phagocytic cell functions. Gout is an acute form of arthritis caused by the deposition of urate crystals, in which phagocytic cells and cytokines play a major pathogenic role. We examined whether alpha-melanocyte-stimulating hormone (\u3b1-MSH) and its synthetic derivative (CKPV)2 influence urate crystal-induced monocyte (Mo) activation and neutrophil responses in vitro. Methods Purified Mos were stimulated with monosodium urate (MSU) crystals in the presence or absence of melanocortin peptides. The supernatants were tested for their ability to induce neutrophil activation in terms of chemotaxis, production of reactive oxygen intermediates (ROIs), and membrane expression of CD11b, Toll-like receptor-2 (TLR2) and TLR4. The proinflammatory cytokines interleukin (IL)-1\u3b2, IL-8, and tumor necrosis factor-alpha (TNF-\u3b1) and caspase-1 were determined in the cell-free supernatants. In parallel experiments, purified neutrophils were preincubated overnight with or without melanocortin peptides before the functional assays. Results The supernatants from MSU crystal-stimulated Mos exerted chemoattractant and priming activity on neutrophils, estimated as ROI production and CD11b membrane expression. The supernatants of Mos stimulated with MSU in the presence of melanocortin peptides had less chemoattractant activity for neutrophils and less ability to prime neutrophils for CD11b membrane expression and oxidative burst. MSU crystalstimulated Mos produced significant levels of IL-1\u3b2, IL-8, TNF-\u3b1, and caspase-1. The concentrations of proinflammatory cytokines, but not of caspase-1, were reduced in the supernatants from Mos stimulated by MSU crystals in the presence of melanocortin peptides. Overnight incubation of neutrophils with the peptides significantly inhibited their ability to migrate toward chemotactic supernatants and their capacity to be primed in terms of ROI production. Conclusions \u3b1-MSH and (CKPV)2 have a dual effect on MSU crystal-induced inflammation, inhibiting the Mos' ability to produce neutrophil chemoattractants and activating compounds and preventing the neutrophil responses to these proinflammatory substances. These findings reinforce previous observations on the potential role of \u3b1-MSH and related peptides as a new class of drugs for treatment of inflammatory arthritis

Towards Better Understanding of Cybercrime: The Role of Fine-Tuned LLMs in Translation

Understanding cybercrime communications is paramount for cybersecurity defence. This often involves translating communications into English for processing, interpreting, and generating timely intelligence. The problem is that translation is hard. Human translation is slow, expensive, and scarce. Machine translation is inaccurate and biased. We propose using fine-tuned Large Language Models (LLM) to generate translations that can accurately capture the nuances of cybercrime language. We apply our technique to public chats from the NoName057(16) Russian-speaking hacktivist group. Our results show that our fine-tuned LLM model is better, faster, more accurate, and able to capture nuances of the language. Our method shows it is possible to achieve high-fidelity translations and significantly reduce costs by a factor ranging from 430 to 23,000 compared to a human translator.Comment: 9 pages, 4 figure

Dynamic Spatial Autoregressive Models with Time-varying Spatial Weighting Matrices

We propose a new spatio-temporal model with time-varying spatial weighting matrices, by allowing for a general parameterization of the spatial matrix. The filtering procedure of the time-varying unknown parameters is performed using the information contained in the score of the conditional distribution of the observables. We provide conditions for the stationarity and ergodicity of the filtered sequence of the spatial matrices as well as for the consistency and asymptotic normality of the maximum likelihood estimator (MLE). An extensive Monte Carlo simulation study to investigate the finite sample properties of the maximum likelihood estimator is also reported. We finally analyze the association between eight European countries' perceived risk, suggesting that the economically strong countries have their perceived risk increased due to their spatial connection with the economically weaker countries, and we investigate the evolution of the spatial connection between the house prices in different areas of the UK, identifying periods when the usually adopted sparse weighting matrix is not sufficient to describe the underlying spatial process

Los desafíos del abordaje de la diversidad. Análisis de la educación inclusiva en escuelas de nivel primario, de gestión pública de CABA

La escuela, históricamente, ha intentado homogeneizar al alumnado, clasificándolo según diferentes estándares; ha pretendido normalizar ignorando contextos, culturas e individualidades. Las transformaciones educativas y los avances en Derechos Humanos han puesto en cuestión el tema de la diversidad como elemento enriquecedor y constitutivo de la condición humana. Pensar la realidad en términos de inclusión devela que cada estudiante es singular en intereses, capacidades, necesidades y estilos de aprendizaje; por lo que la atención a la diversidad se erige en un desafío para promover la supresión de los procesos de exclusión generados por su no aceptación en lo social, étnico, religioso, de género, estilos de aprendizaje, etcétera. Se buscó conocer las líneas de acción hacia la Educación Inclusiva y el abordaje de la diversidad, presentes en los Proyectos Educativos Institucionales (PEI) y en los discursos de los actores de las escuelas seleccionadas dentro del ámbito de la Ciudad Autónoma de Buenos Aires; conocer las estrategias que esas escuelas impulsan para concretar la construcción de inclusividad, desde la exploración de sus lineamientos político-ideológicos y el discurso de los actores. Además, y tal como lo proponen Booth y Aincow en la Guía para la evaluación y mejora para la Educación Inclusiva (UNESCO-OREALC, 2001), se analizaron los indicadores de inclusión a través de tres dimensiones propias de la vida escolar: su cultura, su política y sus prácticas. Respecto de los objetivos generales, estos se dirigieron a profundizar el análisis sobre el desarrollo de inclusividad en las escuelas; identificar dificultades que se presentan en el interior y en el entorno social escolar para estos abordajes, e identificar en el campo líneas de trabajo que permitan desarrollar propuestas de educación inclusiva en el nivel. Asimismo, los objetivos específicos se asociaron a conocer las acciones desplegadas por las escuelas para efectivizar el abordaje de la diversidad planteado en sus PEI; identificar dificultades y logros respecto de lo planteado; conocer las reflexiones de los actores sobre las estrategias pedagógicas inclusivas desarrolladas y a desarrollar. La metodología seleccionada remite a un diseño cualitativo y exploratorio desarrollado a través de observaciones no participantes en las 6 escuelas seleccionadas dentro de distintas zonas distritales de CABA y entrevistas en profundidad a directivos y maestras, empleando registros y guías elaboradas a tal fin. Una vez finalizado el proceso de construcción del marco teórico y de realizada y valorada la intervención en el campo, se pudo arribar a importantes conclusiones que, haciendo una apretada síntesis, remiten a limitada conceptualización de la diversidad; importante distancia entre el discurso de lo políticamente correcto y la práctica; debilidad en la conducción directiva y en la autogestión docente hacia la construcción de cultura inclusiva. Se visualizó también como imperativo para la mejora en las culturas y las prácticas, una reconceptualización de la formación docente, inicial y continua.A partir de lo expuesto, puede decirse que los resultados obtenidos de la investigación confirman la importancia de seguir trabajando sobre la diversidad y la inclusión en el campo educativo e impulsan a profundizar la indagación sobre las percepciones, conceptualizaciones, representaciones sociales ymodelos mentales de los propios formadores sobre esas cuestiones, para producir conocimiento específico y generar nuevas líneas de acción direccionadas a operar cambios en formadores y aspirantes aserlo. Se trabajó desde la USAL con alumnos y docentes en talleres sobre la construcción de PEI y en un conversatorio con alumnos, docentes e investigadores brasileño

Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease

Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt-Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases.This research was funded by the Instituto Carlos III (grants CP/00041 and PI19/00144) and by the Fundació La Marató de TV3 (201821‐30‐31‐32) to FL and by the Robert Koch Institute through funds from the Federal Ministry of Health (grant No, 1369‐341) to IZ. This project was also funded at 65% by the Fondo Europeo de Desarrollo Regional (FEDER) through the Interreg V‐A España‐Francia‐Andorra (POCTEFA 2014‐2020) programme. SJC is funded in part by a NHMRC Practitioner Fellowship (identification #APP1105784).S

Epidemic mitigation by statistical inference from contact tracing data

Contact-tracing is an essential tool in order to mitigate the impact of pandemic such as the COVID-19. In order to achieve efficient and scalable contact-tracing in real time, digital devices can play an important role. While a lot of attention has been paid to analyzing the privacy and ethical risks of the associated mobile applications, so far much less research has been devoted to optimizing their performance and assessing their impact on the mitigation of the epidemic. We develop Bayesian inference methods to estimate the risk that an individual is infected. This inference is based on the list of his recent contacts and their own risk levels, as well as personal information such as results of tests or presence of syndromes. We propose to use probabilistic risk estimation in order to optimize testing and quarantining strategies for the control of an epidemic. Our results show that in some range of epidemic spreading (typically when the manual tracing of all contacts of infected people becomes practically impossible, but before the fraction of infected people reaches the scale where a lock-down becomes unavoidable), this inference of individuals at risk could be an efficient way to mitigate the epidemic. Our approaches translate into fully distributed algorithms that only require communication between individuals who have recently been in contact. Such communication may be encrypted and anonymized and thus compatible with privacy preserving standards. We conclude that probabilistic risk estimation is capable to enhance performance of digital contact tracing and should be considered in the currently developed mobile applications.Comment: 21 pages, 7 figure

Antibacterial Properties of Bacterial Endophytes Isolated from the Medicinal Plant Origanum heracleoticum L

Background: Bacterial endophytic communities associated with medicinal plants synthesize a plethora of bioactive compounds with biological activities. Their easy isolation and growth procedures make bacterial endophytes an untapped source of novel drugs, which might help to face the problem of antimicrobial resistance. This study investigates the antagonistic potential of endophytic bacteria isolated from different compartments of the medicinal plant O. heracleoticum against human opportunistic pathogens. Methods: A panel of endophytes was employed in cross-streaking tests against multidrug-resistant human pathogens, followed by high-resolution chemical profiling using headspace-gas chromatography/mass spectrometry. Results: Endophytic bacteria exhibited the ability to antagonize the growth of opportunistic pathogens belonging to the Burkholderia cepacia complex (Bcc). The different inhibition patterns observed were related to their taxonomic attribution at the genus level; most active strains belong to the Gram-positive genera Bacillus, Arthrobacter, and Pseudarthrobacter. Bcc strains of clinical origin were more sensitive than environmental strains. Cross-streaking tests against other 36 human multidrug-resistant pathogens revealed the highest antimicrobial activity towards the Coagulase-negative staphylococci and Klebsiella pneumoniae strains. Interestingly, strains of human origin were the most inhibited, in both groups. Concerning the production of volatile organic compounds (VOCs), the strain Arthrobacter sp. OHL24 was the best producer of such compounds, while two Priestia strains were good ketones producers and so could be considered for further biotechnological applications. Conclusions: Overall, this study highlights the diverse antagonistic activities of O. heracleoticum-associated endophytes against both Bcc and multidrug-resistant (MDR) human pathogens. These findings hold important implications for investigating bacterial endophytes of medicinal plants as new sources of antimicrobial compounds

Treatment of infantile spasms: emerging insights from clinical and basic science perspectives.

Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments of infantile spasms, novel conceptual and experimental approaches to infantile spasms treatment, and a perspective on remaining clinical challenges and current research questions are presented here. This summary derives from a meeting of specialists in infantile spasms clinical care and research held in New York City on June 14, 2010