Dissecting the Extracellular Complexity of Neuromuscular Junction Organizers

Synapse formation is a very elaborate process dependent upon accurate coordination of pre and post-synaptic specialization, requiring multiple steps and a variety of receptors and signaling molecules. Due to its relative structural simplicity and the ease in manipulation and observation, the neuromuscular synapse or neuromuscular junction (NMJ)—the connection between motor neurons and skeletal muscle—represents the archetype junction system for studying synapse formation and conservation. This junction is essential for survival, as it controls our ability to move and breath. NMJ formation requires coordinated interactions between motor neurons and muscle fibers, which ultimately result in the formation of a highly specialized post-synaptic architecture and a highly differentiated nerve terminal. Furthermore, to ensure a fast and reliable synaptic transmission following neurotransmitter release, ligand-gated channels (acetylcholine receptors, AChRs) are clustered on the post-synaptic muscle cell at high concentrations in sites opposite the presynaptic active zone, supporting a direct role for nerves in the organization of the post-synaptic membrane architecture. This organized clustering process, essential for NMJ formation and for life, relies on key signaling molecules and receptors and is regulated by soluble extracellular molecules localized within the synaptic cleft. Notably, several mutations as well as auto-antibodies against components of these signaling complexes have been related to neuromuscular disorders. The recent years have witnessed strong progress in the understanding of molecular identities, architectures, and functions of NMJ macromolecules. Among these, prominent roles have been proposed for neural variants of the proteoglycan agrin, its receptor at NMJs composed of the lipoprotein receptor-related protein 4 (LRP4) and the muscle-specific kinase (MuSK), as well as the regulatory soluble synapse-specific protease Neurotrypsin. In this review we summarize the current state of the art regarding molecular structures and (agrin-dependent) canonical, as well as (agrin-independent) non-canonical, MuSK signaling mechanisms that underscore the formation of neuromuscular junctions, with the aim of providing a broad perspective to further stimulate molecular, cellular and tissue biology investigations on this fundamental intercellular contact

Croup: diagnosis and treatment

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Modelling Pancreatic Neuroendocrine Cancer: From Bench Side to Clinic

Pancreatic neuroendocrine tumours (pNETs) are a heterogeneous group of epithelial tumours with neuroendocrine differentiation. Although rare (incidence of <1 in 100,000), they are the second most common group of pancreatic neoplasms after pancreatic ductal adenocarcinoma (PDAC). pNET incidence is however on the rise and patient outcomes, although variable, have been linked with 5-year survival rates as low as 40%. Improvement of diagnostic and treatment modalities strongly relies on disease models that reconstruct the disease ex vivo. A key constraint in pNET research, however, is the absence of human pNET models that accurately capture the original tumour phenotype. In attempts to more closely mimic the disease in its native environment, three-dimensional culture models as well as in vivo models, such as genetically engineered mouse models (GEMMs), have been developed. Despite adding significant contributions to our understanding of more complex biological processes associated with the development and progression of pNETs, factors such as ethical considerations and low rates of clinical translatability limit their use. Furthermore, a role for the site-specific extracellular matrix (ECM) in disease development and progression has become clear. Advances in tissue engineering have enabled the use of tissue constructs that are designed to establish disease ex vivo within a close to native ECM that can recapitulate tumour-associated tissue remodelling. Yet, such advanced models for studying pNETs remain underdeveloped. This review summarises the most clinically relevant disease models of pNETs currently used, as well as future directions for improved modelling of the disease

An amino acid mixture, enriched with Krebs cycle intermediates, enhances extracellular matrix gene expression in cultured human fibroblasts

: In the human body, the skin is one of the organs most affected by the aging process. Nutritional approaches aimed to counteract the age-induced decline of extracellular matrix (ECM) deposition could be a valuable tool to decrease the degenerative processes underlying skin aging. Here, we investigated the ability of a six-amino acid plus hyaluronic acid (6AAH) formulation enriched with tricarboxylic acid (TCA) intermediates to stimulate ECM gene expression. To this aim, human BJ fibroblasts were treated with 6AAH alone or plus succinate or malate alone or succinate plus malate (6AAHSM), and mRNA levels of several ECM markers were evaluated. 6AAHSM increased the expression of all the ECM markers significantly above 6AAH alone or plus only succinate or malate. Furthermore, in an in vitro oxidative damage model, 6AAHSM blunted the hydrogen peroxide-induced decline in ECM gene expression. Our data suggest that feeding cells with 6AAH enriched with TCAs could efficiently be employed as a non-pharmacological approach for counteracting skin aging

Heart rate variability in patients with cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Cirrhosis is associated with abnormal autonomic function and regulation of cardiac rhythm. Measurement of heart rate variability (HRV) provides an accurate and non-invasive measurement of autonomic function as well as liver disease severity currently calculated using the MELD, UKELD, or Child-Pugh scores. This review assesses the methods employed for the measurement of HRV, and evaluates the alteration of HRV indices in cirrhosis, as well as their value in prognosis. METHOD: We undertook a systematic review using Medline, Embase and Pubmed databases in July 2020. Data were extracted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias of included studies was assessed by a modified version of the Newcastle-Ottawa Scale. The studies descriptive were analysed and the standardized mean differences of HRV indices were pooled. RESULTS: Of the 247 studies generated from our search, 14 studies were included. One of the 14 studies was excluded from meta-analysis because it reported only median of HRV indices. The studies included have a low risk of bias, and include 583 patients with cirrhosis and 349 healthy controls. The HRV time and frequency domains were significantly lower in cirrhotic patients. Between-studies heterogeneity was high in most of the pooled studies (P<0.05). Further, HRV indices predict survival independent of the severity of liver disease as assessed by MELD. CONCLUSION: HRV is decreased in patients with cirrhosis compared with healthy matched controls. HRV correlated with severity of liver disease and independently predicted survival. There was considerable variation in the methods used for HRV analysis, and this impedes interpretation and clinical applicability. Based on the data analysed, SDNN (standard deviation of inter-beat intervals) and cSDNN (i.e. SDNN corrected for basal heart rate) are the most suitable indices for prognosis in patients with cirrhosis

Characterization of a 2-D laser scanner for outdoor wide range measurement

This paper presents a metrological characterization study of SICK LMS 511 laser scanner, with an extended analysis of its main acquisition issues. Various parameters that could affect the sensor performances, such as warm-up time, target properties (color and material), and target position (distance and orientation) are investigated. Moreover, the mixed pixel problem is introduced and, finally, since the sensor is designed to work in a wide outdoor environment, the effect of direct sun light is taken into account. Some cases of faulty data are identified and explanations discussed

O Sistema Nacional de Pesquisa Agropecuária: proposta de implentação para um novo modelo de gestão e governança.

A agropecuária há muitos anos vem desempenhando um papel de grande relevância para o crescimento econômico brasileiro, possibilitando ao país ser um dos maiores exportadores mundiais de produtos agrícolas. Uma importante estrutura que contribui para este resultado positivo é o Sistema Nacional de Pesquisa Agropecuária (SNPA), que atualmente se encontra fragilizado devido à falta de coordenação e cooperação entre os atores, além da redução de recursos. Neste contexto, o Centro de Gestão e Estudos Estratégicos (CGEE), propôs uma alternativa de arranjo para a pesquisa agropecuária, que compreende a estruturação, no médio e longo prazo, de uma plataforma, que possibilitará a articulação, alinhamento e sinergia entre os atores envolvidos no processo de pesquisa e inovação para a agricultura do País. Este trabalho objetiva apresentar uma proposta de implementação, no curto prazo, para se alcançar o modelo formulado pelo CGEE. Realizamos um estudo de caso sobre o SNPA, por meio de uma breve revisão bibliográfica de conceitos pertinentes às necessidades de análise do Sistema. Descrevemos os principais eventos da trajetória do SNPA ocorridos entre 1972 e 2015 para entender seu funcionamento e sua dinâmica. A análise do Sistema foi realizada por meio do estudo de artigos, livros e teses sobre o caso e, em especial, por meio das entrevistas efetuadas com diferentes atores que representam o Sistema: acadêmicos, dirigentes e colaboradores das Organizações Estaduais de Pesquisa Agropecuária (OEPAs), dirigentes dos conselhos de representação, gestores públicos e representantes do setor privado. Constatamos que a implementação do modelo, para ser factível no curto prazo, deveria ser realizada por uma instituição que ocupasse papel preponderante no SNPA e que já dispusesse de mecanismos legais e de capacidade técnico-operacional necessários à validação e à execução do novo modelo. Foi possível identificar também a necessidade de inovações institucionais e organizacionais do Sistema, principalmente para atender às demandas dos produtores e da sociedade. Por fim, uma das mais relevantes constatações é a de que: a efetividade do novo arranjo só ocorrerá se as instituições e atores envolvidos se reconhecerem como coautores, tiverem proatividade e perceberem seu papel e suas responsabilidades.Orientada por Ana Cristina Braga Martes, FGV

"Lucha de calles, lucha de clases" : Un análisis historiográfico

En el presente trabajo tenemos por objetivo acercar algunas reflexiones sobre la metodología y el rol de los historiadores que optamos por trabajar la perspectiva analítica de la historia política reciente o historia reciente o historia también denominada historia del presente. Tomamos el texto “Lucha de calles, lucha de Clases” porque consideramos que del análisis de los dos aspectos señalados en el texto elegido pueden surgir reflexiones que sin duda aportarán a la tarea en que estamos abocados.Facultad de Humanidades y Ciencias de la Educació

Dental treatment of a rare case of pyoderma gangrenosum with aggressive periodontal disease

Background and Overview: Pyoderma gangrenosum (PG) is a rare neutrophil-mediated autoinflammatory dermatosis that can involve the oral mucosa. Dental surgery is a potential triggering factor for the onset of PG lesions. The authors describe and discuss the dental management of a rare case of aggressive periodontitis in a patient with PG, from multiple tooth extractions to prosthetic rehabilitation, including administration of systemic steroid prophylaxis before surgery to prevent the potential onset of PG-related lesions. Case Description: A 22-year-old man who had a diagnosis of PG and who had aggressive periodontal disease underwent dental extractions, gingivoplastic surgery, and prosthetic rehabilitation. The patient received 8 milligrams of betamethasone intramuscularly 20 minutes before the oral surgery. The tissues healed perfectly, and no adverse effects were reported. Conclusions and Practical Implications: For minor oral surgery, prophylactic corticosteroids might help reduce the risk of developing PG-related lesions. The clinician should plan the prosthetic devices to be as atraumatic as possible

Il Percorso Diagnostico Terapeutico Assistenziale del paziente con melanoma metastatico presso l\u2019Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone di Palermo come strumento applicativo della clinical governance

L\u2019evoluzione dello scenario internazionale relativo alla sanit\ue0 identifica cinque specifiche dimensioni come driver del cambiamento: il sistema, la finanza, le persone, i processi e la tecnologia. In linea con tali elementi, il patto per la salute 2014-2016 esplicita la necessit\ue0 di una rivisitazione a tutti i livelli del sistema salute, sia organizzativo che gestionale, con l\u2019intento di aumentare l\u2019efficienza e l\u2019efficacia, sviluppando nuovi modelli assistenziali, anche nella logica delle reti cliniche, dove tra gli \u201cstrumenti\u201d viene identificata l\u2019attivazione di Percorsi Diagnostico Terapeutico Assistenziali (PDTA). I percorsi condivisi e codificati per i vari stadi di patologia, con un sistema di raccolta dei dati clinici che possa generare gli indicatori di processo e di esito, sono ritenuti indispensabili per innescare il miglioramento della qualit\ue0 e valutare l\u2019efficacia e l\u2019efficienza. Tenendo conto di queste premesse, nell\u2019ambito dell\u2019Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone di Palermo \ue8 stata sviluppata una progettualit\ue0 al fine di formalizzare e studiare il PDTA del paziente con melanoma metastatico, identificando il percorso ideale e descrivendo il percorso applicabile con le relative leve del cambiamento. Il progetto ha reso evidente come la gestione consapevole del \u201cprofondo cambiamento\u201d in essere nelle organizzazioni clinico assistenziali pu\uf2 essere \u201cgovernata\u201d grazie anche alla \u201cdocumentazione\u201d del proprio modo di operare in riferimento alle Linee Guida di riferimento e alle relative raccomandazioni. Il progetto ha reso evidente inoltre come la sostenibilit\ue0 dei percorsi passa anche attraverso la definizione di opportuni indicatori, correlati alle diverse fasi ed attivit\ue0 chiave, da poter monitorare nella \u201cvita corrente dell\u2019organizzazione\u201d