Bacillus anthracis: una mirada molecular a un patógeno célebre / Bacillus anthracis: a molecular look at a famous pathogen

Bacillus anthracis es un bacilo gram positivo del grupo Bacillus cereus, que posee un genoma extremadamente monomórfco y comparte gran similitud fsiológica y de estructura genética con B. cereus y Bacillus thuringiensis. En este artículo se describen nuevos métodos moleculares para la identifcación y tipifcación de B. anthracis, basados en repeticiones en tándem de número variable o en diferencias genéticas detectadas por secuenciación, desarrollados en los últimos años. Los aspectos moleculares de los factores de virulencia tradicionales, cápsula, antígeno protector, factor letal y factor edema se describen en profundidad, junto con factores de virulencia recientemente propuestos, como los sideróforos, petrobactina y bacilibactina, la adhesina de la capa S y la lipoproteína MntA. También se detalla la organización molecular de los megaplásmidos pXO1 y pXO2, incluyendo la isla de patogenicidad de pXO1. El esqueleto genético de estos plásmidos se ha encontrado en otras especies relacionadas, probablemente debido a eventos de transferencia lateral. Finalmente, se presentan los dos receptores celulares del antígeno protector, ANTXR1/TEM8 y ANTXR2/CMG2, esenciales en la interacción del patógeno con el hospedador. Los estudios moleculares realizados en los últimos años han permitido aumentar enormemente el conocimiento de los diferentes aspectos de este microorganismo y su relación con el hospedador, pero a la vez han abierto nuevos interrogantes sobre este notorio patógeno.

Bacillus anthracis, a gram-positive rod belonging to the Bacillus cereus group, has an extremely monomorphic genome, and presents high structural and physiological similarity with B. cereus and Bacillus thuringiensis. In this work, the new molecular methods for the identifcation and typing of B. anthracis developed in the last years, based on variable number tandem repeats or on genetic differences detected through sequencing, are described. The molecular aspects of traditional virulence factors: capsule, protective antigen, lethal factor and edema factor are described in depth, together with virulence factors recently proposed, such as the siderophores petrobactin and bacillibactin, the S-layer adhesin and the MntA lipoprotein. It is detailed the molecular organization of megaplasmids pXO1 and pXO2, including the pathogenicity island of pXO1. The genetic skeleton of these plasmids has been observed in related species, and this could be attributed to lateral gene transfer. Finally, the two anthrax toxin protective antigen receptors, ANTXR1/TEM8 and ANTXR2/CMG2, essential for the interaction of the pathogen with the host, are presented. The molecular studies performed in recent years have greatly increased knowledge in different aspects of this microorganism and its relationship with the host, but at the same time they have raised new questions about this noted pathogen.

The role of the SLAM-SAP signaling pathway in the modulation of CD4+ T cell responses

The signaling lymphocytic activation molecule (SLAM), present on the surface of hematopoietic cells, can regulate some events of the immune responses. This modulatory action is associated with the capacity of SLAM to interact with an intracytoplasmic adapter, such as SLAM-associated protein (SAP). SLAM is constitutively expressed in most of these cells, is rapidly induced after antigenic or inflammatory stimuli, and participates in the immunological synapse. Defects in the function of the SLAM-SAP pathway contribute to immunological abnormalities, resulting in autoimmune diseases, tumors of the lymphoid tissues and inadequate responses to infectious agents. Initially, the role of SLAM was investigated using an anti-SLAM monoclonal antibody (α-SLAM mAb) identified as an agonist of the SLAM-SAP pathway, which could induce the production of interferon-γ and could redirect the immune response to a T helper 1 (Th1) cell profile. However, in this review we postulate that the SLAM-SAP pathway primarily induces a Th2 response and secondarily suppresses the Th1 response.

Localización extra nuclear de receptores esteroides y activación de mecanismos no genómicos / Extra nuclear localization of steroid receptors and non genomic activation mechanisms

Los receptores de hormonas esteroides han sido considerados históricamente como factores de transcripción nucleares. Sin embargo, en los últimos años surgieron evidencias que indican que su activación desencadena eventos rápidos, independientes de la transcripción y que involucran a diferentes segundos mensajeros; muchos de estos receptores han sido localizados en la membrana celular. Por otra parte, se han caracterizado varios receptores de hormonas esteroides noveles, de estructura molecular diferente al receptor clásico, localizados principalmente en la membrana celular. Esta revisión enfoca los diferentes efectos iniciados por los glucocorticoides, mineralocorticoides, andrógenos, estrógenos y progesterona, y los posibles receptores involucrados en los mismos.

Steroid hormone receptors have been historically considered as nuclear transcription factors. Nevertheless, in the last years, many of them have been detected in the cellular membrane. It has been postulated that their activation can induce transcription independent rapid events involving different second messengers. In addition, several novel steroid hormone receptors, showing a different molecular structure than the classical ones, have also been characterized and most of them are also located in the plasmatic membrane. This review focuses on the variety of effects initiated by glucocorticoids, mineralocorticoids, androgens, estrogens and progesterone, and the possible receptors involved mediating these effects.

Influencia del género y la percepción de la imagen corporal en las conductas alimentarias de riesgo en adolescentes de Mérida / Influences of gender and body image perception in risk eating disorders in adolescents in Mérida

Este estudio tuvo como objetivo analizar la influencia del género y la percepción de la imagen corporal en las conductas alimentarias de riesgo asociadas con los trastornos de la conducta alimentaria en adolescentes del primero y segundo año de educación media y diversificada en ocho instituciones educativas públicas del Municipio Libertador estado Mérida Venezuela, seleccionadas de forma intencional. Se realizó un estudio de campo, descriptivo, en el cual participaron 421 adolescentes, 56.5 por ciento varones y 43.5 por ciento hembras, el promedio de edad para los varones fue 15.75 ± 1.05 años y para las hembras 15.80 ±1.07 años. Para la recolección de los datos de imagen corporal se diseñó y se validó un instrumento donde el participante seleccionó entre cuatro alternativas la opción que más representaba su condición para el momento. El 57,5 por ciento, se percibió normal, 30.6 por ciento como delgados; y el 11,9 por ciento con sobrepeso. No se reportó percepción de imagen corporal obesa. La imagen corporal normal y delgada fueron percibidas entre los adolescentes con una frecuencia más alta en los varones (32,5 por ciento), mientras que la percepción de la imagen con sobrepeso fue más frecuente en las hembras (7,4 por ciento). El registro de la conducta alimentaria se realizó a través de un cuestionario diseñado y validado por expertos constituidos por nutricionistas, sociólogos y psicólogos clínicos en el que solicitó al entrevistado reportar la conducta alimentaria practicada para el control del peso en los últimos seis meses. Los hallazgos permiten confirmar que las mujeres cuya percepción de su imagen se caracteriza por el exceso, presentan mayor riesgo asociado con los trastornos de la conducta alimentaria (9,586 F=2 p=0,008) (12,622 F=5 p=0,027).

The object of this study was to analyze the influence of gender and body image perception in risk eating conducts associated with the upheavals of eating disorders in adolescents of first and second year of highschool in eight public institutions of the Municipio Libertador in Merida Venezuela, They were selected in an intentional form. A descriptive field, was performed, in which 421 adolescents participated, 56,5% men and 43,5% females, the average of age for the 15,75 men was ± 1,05 years and for 15,80 females ± 1.07 years. For the gathering of the corporal Image data, an instrument was designed and validated, In this the participant chose between four alternatives the option that represented more his/her condition at the moment, 57.5%, perceived themselves as normal, 30.6%, as thin; and 11.9% with overweight. The perception of obese corporal image was not reported. The normal and thin body image were perceived among the adolescents with a higher frequency in men 32.5%, whereas the perception of the image with overweight was more frequent in the females (7.4%). The registry of eating disorders was done through a questionnaire designed and validated by a group of experts constituted by dietitians, sociologists and clinical psychologists in which the interviewed was asked in person to report the eating conduct practiced for the control of weight during the previous six months. The findings allow us to confirm that women whose perception of their image is characterized by the excess present major risks associated with the upheavals of the eating disorders (9,586 F=2 p=0,008 (12,622 F=5 p=0,027).

Filamina plaquetaria: una proteína del citoesqueleto integradora de la función celular / Platelet filamin: a cytoskeletal protein involved in cell signal integration and function

Activation of cellular receptors by diverse stimuli induces dramatic changes in shape and function to respond to the new circumstances of the cell. This modified behavior depends on the reorganization of the peripheral actin meshwork. An outstanding example of these processes can be found in platelets, from which much of the information available on cytoskeletal function has been obtained. Among the many actin-crosslinking proteins like spectrin, fimbrin or alpha actinin, filamin a (FLNa) emerges as the one with the highest potential in initiating the polimerization of actin filaments (F-actin) during the formation of tridimensional actin gels. FLNa also links actin filaments to the cytosolic domain of many membrane glycoproteins in platelets through its C-terminal region. In addition to participating in cell shape changes, FLNa is a scaffoldding protein that recruits numerous proteins involved in a completely different set of functions, including signal transduction, gene transcription regulation, and receptor translocation; however, the physiological role of FLNa in these processes has remained elusive. The purpose of the present communication is to briefly describe the characteristics of the macromolecules able to interact with FLNa and to discuss a possible role of FLNa during the transduction of signals from those molecular elements in platelets.

Specific structural features of syndecans and heparan sulfate chains are needed for cell signaling

The syndecans, heparan sulfate proteoglycans, are abundant molecules associated with the cell surface and extracellular matrix and consist of a protein core to which heparan sulfate chains are covalently attached. Each of the syndecan core proteins has a short cytoplasmic domain that binds cytosolic regulatory factors. The syndecans also contain highly conserved transmembrane domains and extracellular domains for which important activities are becoming known. These protein domains locate the syndecan on cell surface sites during development and tumor formation where they interact with other receptors to regulate signaling and cytoskeletal organization. The functions of cell surface heparan sulfate proteoglycan have been centered on the role of heparan sulfate chains, located on the outer side of the cell surface, in the binding of a wide array of ligands, including extracellular matrix proteins and soluble growth factors. More recently, the core proteins of the syndecan family transmembrane proteoglycans have also been shown to be involved in cell signaling through interaction with integrins and tyrosine kinase receptors.

Extracellular calcium-sensing receptor: structural and functional features and association with diseases

The recently cloned extracellular calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. This receptor is expressed in all tissues related to this control (parathyroid glands, thyroid C-cells, kidneys, intestine and bones) and also in tissues with apparently no role in the maintenance of extracellular calcium levels, such as brain, skin and pancreas. The CaR amino acid sequence is compatible with three major domains: a long and hydrophilic aminoterminal extracellular domain, where most of the activating and inactivating mutations described to date are located and where the dimerization process occurs, and the agonist-binding site is located, a hydrophobic transmembrane domain involved in the signal transduction mechanism from the extracellular domain to its respective G protein, and a carboxyterminal intracellular tail, with a well-established role for cell surface CaR expression and for signal transduction. CaR cloning was immediately followed by the association of genetic human diseases with inactivating and activating CaR mutations: familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism are caused by CaR-inactivating mutations, whereas autosomal dominant hypoparathyroidism is secondary to CaR-activating mutations. Finally, we will comment on the development of drugs that modulate CaR function by either activating (calcimimetic drugs) or antagonizing it (calcilytic drugs), and on their potential therapeutic implications, such as medical control of specific cases of primary and uremic hyperparathyroidism with calcimimetic drugs and a potential treatment for osteoporosis with a calcilytic drug

The role of plasminogen activator receptor in cancer invasion and dormancy

Urokinase plasminogen activator receptor (uPAR) has been identified some 15 years ago and the anticipation was that is presence on the cell surface will provide a focus for anchoring uPA and possibly protect the enzyme from native inhibitors. The studies of the last decade have shown that uPA localized to the surface of cells by uPAR is indeed an important factor in the process of cancer cell invasion and metastasis. We developed a chick embryo model in which we showed that uPAR is crucial in invasion of stroma and in intravasation (breaching of the blood vessels walls). More recently and unexpectedly, uPAR-a protein anchored in the outer leaflet of the plasma membrane, has been shown to initiate signal transduction events and affect cell migration. We have shown that uPAR co-associates with fibronectin binding integrin, alpha5beta1, activates them and that this interaction leads to a greatly increased level of active ERK. When the association between uPAR and integrin or integrin and fibronectin are interrupted either by reduction of surface uPAR expression, or by other means, human carcinoma cells enter a state of protracted dormancy. We show that very high levels of active ERK are required to keep cancer cells proliferating in vivo.

Receptores de membrana y sus mecanismos enzimáticos de acción: patologías endocrinas asociadas / Membrane receptors, their enzymatic mechanisms of action and associated endocrine diseases

The cell, as a functional unit of a living individual, has the capacity to recognize signals from the extracellular compartment and to respond to these signals in a specific, precise and characteristic way. This review analyzes some membrane receptor mediated processes, characterized by a complex chain of events from the external signal to the induction of specific genes. Additionally, some endocrine diseases associated with molecular defects in some of these stages are analyzed

Melatonin, biological rhythm disorders and phototherapy.

Biological rhythms are endogenous in nature and are generated by self sustained oscillators present in the living organisms themselves. Of these, circadian rhythms are the most thoroughly studied and are driven by the suprachiasmatic (SCN) of hypothalamus. The recent discovery of high affinity melatonin receptors ML1, ML2 in SCN suggests that melatonin is involved in the control of circadian rhythm generation. The fact that biological rhythm disorders like delayed sleep phase syndrome (DSPS), Jet lag, shift-work disorders, seasonal effective disorder (SAD) respond well either to phototherapy or melatonin adds further support to the concept that melatonin is involved in the pathogenesis of these conditions. Indeed altered melatonin rhythms have bee documented in MDP, shift work disorder, endogenous depression etc. In addition to functioning as a rhythm regulator, melatonin is also involved in the control of sleep, regulation of body temperature, reproduction, and as a free radical scavanger and antioxidant protecting the cells and tissues of our body against oxidative damage. Low levels of melatonin in cancer patients and patients with coronary heart disease indicate that melatonin may be involved in these disorders also.

Melatonin: a master hormone and a candidate for universal panacea.

The molecule of melatonin seems to have been evolutionarily conserved. Its presence has been demonstrated in almost all groups of organisms, from plants, protozoa to people. During evolution, melatonin is claimed to have mediated dark adaptation. The universal presence of melatonin may be because it is lipophilic in nature which enables it to cross all biological (lipid membrane) barriers and to diffuse into every compartment of the cell, and because it serves as an antioxidant and is used as a free radical scavenger. In vertebrates, the pineal gland is the single largest source of melatonin production although, especially in non-mammalian vertebrates, other organs (e.g. retina, harderian gland etc.) may contribute significantly to the blood melatonin levels. In invertebrates, on the other hand, the pineal gland is absent and, therefore, melatonin secretion is clearly derived from another source(s). Regardless of the site of synthesis and the nature of organisms (diurnal, nocturnal or crepuscular), melatonin is secreted in the night and melatonin biosynthetic pathway remains essentially the same. Tryptophan, an amino acid derived from dietary sources, undergoes a series of enzymatic reactions to produce melatonin. The rhythm in melatonin secretion is generated endogenously by the circadian pacemaker(s) in the suprachiasmatic nuclei (SCN), and regulated by environmental light:dark cycle. Melatonin through its action on the SCN synchronizes disrupted or free-running circadian rhythms, and regulates a variety of daily and seasonal changes in the physiology and behaviour of animals. Emerging scientific evidence for the role of melatonin as therapeutic agent in the treatment of circadian rhythm-associated sleep disorders in persons having normal social working hours and shift workers, in jet lag, in immunological functions etc. have considerably increased interest in this hormone molecule. The role of melatonin in organisms physiology has now been widely recognized, and the wealth of information accumulated in the past two decades indicate it to be the best hormone candidate to be investigated for a universal panacea.

Neuroimunoendocrinologia: uma inter-relaçäo molecular para comunicaçäo entre os sistemas imunológicos e neuroendócrino / Neuroimmunendocrinology: a molecular interelation for comunication between the immunologic and neurosecretory system

De acordo com vários estudos clínicos realizados, observamos que as açöes dos componentes celulares do sistema imunológico e neuroendócrino devem ser estudadas em conjunto, visto que existem várias evidências sugerindo uma intercomunicaçäo entre estes sistemas através de receptores e mensageiros neuroquímicos específicos de ambos. Abordamos a inter-relaçäo molecular entre os sistemas neuroendócrino e imunológico

Macrophages in host defence--an overview.

The importance of macrophages in host defence is well documented. They are distributed in various tissues where they perform functions in normal steady state as well as in diseased condition. Macrophages secrete a number of enzymes, plasma proteins, complement and coagulation factors which regulate the effector functions of the macrophages. Exposure of macrophages to pathogens results in further metabolic changes which activate the former to secrete oxygen metabolites leading to their augmented microbicidal activity. Macrophages respond to the external stimuli by expressing a large repertoire of surface receptors which play an important role in the activation, recognition and endocytosis of foreign microorganisms. A large number of intracellular pathogens are harboured in the macrophages which can reside and replicate in them. A variety of strategem has been employed to target drugs to vacuolar apparatus of the macrophages in order to combat intracellular pathogens. This review covers some of these aspects particularly in relation to hose defence and methods by which therapeutic agents could be specifically delivered to macrophages.

Basic fibroblast growth factor does not initiate mitogenic signalling via phosphoinositide hydrolysis in PC12 cells.

Basic fibroblast growth factor (b FGF) was found to be equally potent mitogen as compared to alpha-thrombin to reinitiate DNA synthesis in quiescent PC12 cells. Whereas thrombin was found to be an activator of phospholipase C as judged by a rapid increase in the formation of inositol triphosphate, inositol biphosphate and a massive accumulation of inositol phosphate when 20 mM LiCl was present as an inhibitor of inositol mono phosphatases, basic FGF failed to induce the breakdown of the polyphosphoinositides in quiescent PC12 cells to any appreciable levels, however, a simultaneous increase in the level of diacylglycerol was observed. b FGF also failed to stimulate protein kinase C which is believed to be activated by diacylglycerol. It is therefore concluded that bFGF receptor mediated 'signalling is not via phospholipase C activation and bFGF's early mitogenic responses and DNA synthesis are initiated independent of the inositol lipids and protein kinase C activation. Thus bFGF must have its own unique signal transducing mechanism independent of inositol pathways.

Receptores celulares / Cellular receptors

Los receptores celulares son moléculas constituidas fundamentalmente por proteínas, de localización a nivel de la membrana celular, citoplasma o núcleo. Se encargan de recibir-las señales del primer mensajero, las cuales culminan con el efecto biológico característico del órgano blanco. En la presente revisión se estudian las características, los mecanismos de acción, regulación, metodología de estudio y finalmente las aplicaciones de los receptores celulares

Plasma membrane mechanisms for intracellular calcium regulation in squid axons

La regulación del Ca iónico en estado estacionario en la mayoria de las células eucariotas es consecuencia de la operación de dos mecanismos diferentes de transporte de Ca presentes en la membrana celular, la bomba de calcio, con alta afinidad por Ca y baja capacidad de transporte. El intercambio Na/Ca no sólo puede producir transporte neto de Ca hacia el exterior celular sino también hacerlo en sentido inverso cuando se modifican el gradiente electroquímico de Na y/o el potencial eléctrico transmembrana. Las evidencias experimentales en axones de calamar dializados y con potencial eléctrico transmembrana controlado indican que el intercambio Na/Ca es un sistema complejo que tiene interacciones con múltiples ligando intracelulares (Na, Mg, ATP, ADP, Ca, K). POor otra parte, el intercambio Na/Ca está sujeto a fosforilación y desfosforilación, procesos que son regulados por los niveles de Ca iónico intracelular. Las características cinéticas de las reacciones parciales del intercambio, así como su estequiometria, propiedades eléctricas y por último la estructura química del transportador, aún no han sido elucidadas