Investigating the Role of T-Cell Avidity and Killing Efficacy in Relation to Type 1 Diabetes Prediction

During the progression of the clinical onset of Type 1 Diabetes (T1D), high-risk individuals exhibit multiple islet autoantibodies and high-avidity T cells which progressively destroy beta cells causing overt T1D. In particular, novel autoantibodies, such as those against IA-2 epitopes (aa1-577), had a predictive rate of 100% in a 10-year follow up (rapid progressors), unlike conventional autoantibodies that required 15 years of follow up for a 74% predictive rate (slow progressors). The discrepancy between these two groups is thought to be associated with T-cell avidity, including CD8 and/or CD4 T cells. For this purpose, we build a series of mathematical models incorporating first one clone then multiple clones of islet-specific and pathogenic CD8 and/or CD4 T cells, together with B lymphocytes, to investigate the interaction of T-cell avidity with autoantibodies in predicting disease onset. These models are instrumental in examining several experimental observations associated with T-cell avidity, including the phenomenon of avidity maturation (increased average T-cell avidity over time), based on intra- and cross-clonal competition between T cells in high-risk human subjects. The model shows that the level and persistence of autoantibodies depends not only on the avidity of T cells, but also on the killing efficacy of these cells. Quantification and modeling of autoreactive T-cell avidities can thus determine the level of risk associated with each type of autoantibodies and the timing of T1D disease onset in individuals that have been tested positive for these autoantibodies. Such studies may lead to early diagnosis of the disease in high-risk individuals and thus potentially serve as a means of staging patients for clinical trials of preventive or interventional therapies far before disease onset

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Radicais livres de oxigênio e exercício: mecanismos de formação e adaptação ao treinamento físico Radicales libres de oxigeno y ejercicio: mecanismos de formación y adaptación al entrenamiento Oxygen free radicals and exercise: mechanisms of synthesis and adaptation to the physical training

O interesse acerca dos mecanismos de geração e adaptação de radicais livres de oxigênio (RLO) ao exercício aumentou significativamente a partir da demonstração de sua relação com o consumo de oxigênio. Os RLO são formados pela redução incompleta do oxigênio, gerando espécies que apresentam alta reatividade para outras biomoléculas, principalmente lipídios e proteínas das membranas celulares e, até mesmo, o DNA. As injúrias provocadas por estresse oxidativo apresentam efeitos cumulativos e estão relacionadas a uma série de doenças, como o câncer, a aterosclerose e o diabetes. O exercício físico agudo, em função do incremento do consumo de oxigênio, promove o aumento da formação de RLO. No entanto, o treinamento físico é capaz de gerar adaptações capazes de mitigar os efeitos deletérios provocados pelos RLO. Estas adaptações estão relacionadas a uma série de sistemas, dos quais os mais importantes são os sistemas enzimáticos, compostos pela superóxido dismutase, catalase e glutationa peroxidase, e o não enzimático, composto por ceruloplasmina, hormônios sexuais, coenzima Q, ácido úrico, proteínas de choque térmico e outros. Tais adaptações, apesar das controvérsias sobre os mecanismos envolvidos, promovem maior resistência tecidual a desafios oxidativos, como aqueles proporcionados pelo exercício de alta intensidade e longa duração. As técnicas de avaliação de estresse oxidativo, na maioria das vezes, não são capazes de detectar injúria em exercícios de curta duração. Dessa forma, esforços estão sendo feitos para o estudo de esforços físicos realizados por longos períodos de tempo ou efetuados até a exaustão. Novos marcadores de lesão por ação dos RLO estão sendo descobertos e novas técnicas para sua determinação estão sendo criadas. O objetivo deste trabalho é discutir os mecanismos da formação dos RLO e das adaptações ao estresse oxidativo crônico provocado pelo treinamento físico.<br>El interés a cerca de los mecanismos de generación y adaptación de radicales libres de oxígeno (RLO) al ejercicio aumentó significativamente a partir de la demostración de su relación con el consumo de oxígeno. Los RLO son formados por la reducción incompleta de del oxígeno, generando especies que presentan una alta reactividad para otras biomoléculas, principalmente lípidos y proteínas de las membranas celulares y, así mismo, el DNA. Las injurias provocadas por el estrés oxidativo presentan efectos acumulativos y están relacionados a una serie de enfermedades, como el cáncer, la arteriosclerosis o la diabetes. El ejercicio físico agudo, en función del incremento del consumo de oxígeno promueve un aumento en la formación de los RLO. No en tanto, el entrenamiento físico es capaz de generar adaptaciones capaces de mitigar los efectos deletéreos provocados por los RLO. Estas adaptaciones están relacionadas a una serie de sistemas de los cuales los mas importantes son los sistemas enzimáticos, compuestos por la peróxido dismutasa, catalasa y glutation peroxidasa y los sistemas no enzimáticos compuestos por ceruloplasmina, hormonas sexuales, la coenzima Q, ácido úrico, proteínas de choque térmico, y otros. Tales adaptaciones, a pesar de las controversias sobre los mecanismos comprendidos, promueven una mayor resistencia tisular a los desafíos oxidativos, como son aquellos proporcionados por el ejercicio físico de alta intensidad y de larga duración. Las técnicas de evaluación del estrés oxidativo, la mayoría de las veces, no son capaces de detectar injurias en ejercicios de corta duración. De esta forma, los esfuerzos están siendo realizados por largos periodos de tiempo o realizados hasta la extenuación. Nuevos marcadores de lesión por acción de los RLO están siendo descubiertos y nuevas técnicas para su determinación están siendo creadas. El objetivo de este trabajo es discutir los mecanismos de formación de los RLO y de adaptación al estrés oxidativo crónico provocado por el entrenamiento físico.<br>The interest about the mechanisms of generation and adaptation of oxygen free radicals (OFR) to exercise has increased significantly from the demonstration of its relation with the oxygen intake. The OFR are formed through the incomplete reduction of oxygen, generating species presenting high reactivity to other biomolecules, especially lipids and proteins of the cell membranes and even DNA. The injuries caused by the oxidative stress present accumulative effects, being related to several diseases such as cancer, arteriosclerosis and diabetes. The acute physical exercise furthers the increase on the formation of OFR in function of the increment on the oxygen intake. However, the physical training generates adaptations able to soften the harmful effects caused by OFR. These adaptations are related to several systems, among which the most important are the enzymatic system, composed by the superoxide dysmutase, catalase and glutathione peroxidase; and the non-enzymatic system, composed by the ceruloplasmine, the sexual hormones, co-enzyme Q, uric acid, thermal shock proteins, among others. Such adaptations, despite the controversies about the mechanisms involved, further a higher tissue resistance and oxidative challenges such as those provided by long-duration high intensity exercises. The evaluations techniques of the oxidative stress, most times are not able to detect injuries in short-duration exercises. Thus, studies of physical efforts performed for long periods or until exhaustion have been conducted. New lesion markers by OFR action have been discovered and new techniques for its determination have been created. The objective of this work is discuss the formation mechanisms of OFR and the adaptations to the chronic oxidative stress caused by physical training

Role of the serotoninergic system in the sodium appetite control

The present article reviews the role of the serotoninergic system in the regulation of the sodium appetite. Data from the peripheral and icv administration of serotoninergic (5-HTergic) agents showed the participation of 5-HT2/3 receptors in the modulation of sodium appetite. These observations were extended with the studies carried out after brain serotonin depletion, lesions of DRN and during blockade of 5-HT2A/2C receptors in lateral parabrachial nucleus (LPBN). Brain serotonin depletion and lesions of DRN increased the sodium appetite response, in basal conditions, after sodium depletion and hypovolemia or after beta-adrenergic stimulation as well. These observations raised the hypothesis that the suppression of ascending pathways from the DRN, possibly, 5-HTergic fibers, modifies the angiotensinergic or sodium sensing mechanisms of the subfornical organ involved in the control of the sodium appetite. 5-HTergic blockade in LPBN induced to similar results, particularly those regarded to the natriorexigenic response evoked by volume depletion or increase of the hypertonic saline ingestion induced by brain angiotensinergic stimulation. In conclusion, many evidences lead to acceptation of an integrated participation resulting of an interaction, between DRN and LPBN, for the sodium appetite control.<br>Este artigo revisa o papel do sistema serotoninérgico no controle do apetite ao sódio. Dados derivados da administração periférica e icv de agentes serotoninérgicos demonstraram a participação de receptores 5-HT2/3 na modulação do apetite ao sódio. Estas observações foram estendidas com os estudos realizados após a depleção cerebral de serotonina, lesões do NDR e durante o bloqueio 5-HT2A/2C no núcleo parabraquial lateral (NPBL). A depleção cerebral de serotonina e as lesões do NDR aumentaram o apetite ao sódio, em condições basais, após depleção de sódio, durante a hipovolemia ou após a estimulação beta-adrenérgica. Estas evidências suscitaram a hipótese de que a supressão de vias ascendentes do NDR, possivelmente 5-HT, alteram os mecanismos angiotensinérgicos e a atividade dos sensores de sódio do órgão subfornicial envolvidos no controle do apetite ao sódio. O bloqueio serotoninérgico no NPBL induziu a resultados similares, particularmente aqueles relacionados com a resposta natriorexigênica provocada pela depleção de volume ou o aumento da ingestão de salina hipertônica induzida pela estimulação angiotensinérgica cerebral. Em resumo, as evidências convergem para a admissão de uma participação integrada resultante da interação recíproca entre NDR e NPBL objetivando controlar o apetite ao sódio

The interest of the Spanish network of investigators in back pain for rehabilitation physician

Background: The Spanish Back Pain Research Network (REIDE) brings together teams of researchers and clinicians who are interested in nonspecific neck and back pain (BP). Its objective is to improve the efficacy, safety, effectiveness, and efficiency of the clinical management of BP. Method: The Network welcomes clinicians and researchers interested in BP. The only requirement to become a member of REIDE is to take part in one of its research projects, and any member can propose a new one. The Network supports those projects that are of interest to two or more groups by assuming their administration and management, which allows the researchers to focus on their task. Its working method ensures methodological quality, a multidisciplinary approach, and the clinical relevance of those projects that are carried out. Results: 179 researchers from 11 areas in Spain are involved in REIDE, including experts in all of the relevant fields of BP research. Most Spanish studies on BP that have been published in international scientific journals come from the teams involved in REIDE, and it currently has 13 ongoing research projects. Conclusions: The Network can help to enhance research among rehabilitation specialists who are interested in BP, and can contribute to the development of research projects which are of interest to the specialty. © 2005 Sociedad Española de Rehabilitación y Medicina Física (SERMEF) y Elsevier España, S.L