Jorge Ben Jor Vivo

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The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

The Alvarez lab aims to define how CNS-intrinsic signals modulate immune cell function within different neurovascular niches. Upon infection or injury, the concerted actions of both systems create a balance between immune attack and tissue repair to promote healing. Nonetheless, during disease these protective mechanisms can be inadequate or aberrant, leading to persistent inflammation and long-term sequelae. As the first line of defense against chemicals and blood-borne molecules, the CNS barriers shield the delicate CNS microenvironment from the constant fluctuations of the periphery. They are composed of the blood-brain barrier (BBB) and the blood-meningeal barrier (BMB). However, their roles during neuroinflammation remain poorly characterized. Thus, my research program has been built to identify the mechanisms regulating the immune and neurovascular interactions initiating at the level of the CNS barriers and progressing to the perivascular space into the brain parenchyma. Currently, we use a combination of ex-vivo, in vitro, in vivo, and post-mortem approaches to determine the neurovascular mechanisms supporting the pathogenesis of neuroinflammatory diseases like multiple sclerosis (MS) and neuropsychiatric disorders.

To study these complex diseases, my laboratory primarily uses mouse models that recapitulate key aspects of the cognitive dysfunction and pathology of these conditions to dissect network and circuits mechanisms of brain dysfunction in mouse models of AD. We use electroencephalography (EEG), local field potentials (LFP), and single-unit recordings to assess neuron activity in vivo, optogenetic approaches to modulate interneuron function in vivo, genetic and pharmacological manipulations to manipulate specific pathways in vivo, and behavioral assessment to determine the cognitive consequences of our mechanistic interventions.

Network hypersynchrony in AD and related mouse models: We discovered that mouse models of AD (hAPP mice) develop aberrant patterns of neuronal network activity, including epileptiform activity and non-convulsive seizures, that result in profound anatomical and physiological alterations in learning and memory centers (e.g., calbindin depletions). These unexpected findings may be related to the epileptic phenotype of many pedigrees of patients with early-onset familial AD and to the hyperactivation of neuronal networks in patients with sporadic AD and amyloid-positive nondemented subjects. Thus, network abnormalities leading to, or induced by, A accumulation appear to be a relatively early pathogenic event in AD. These results prompted the field to reexamine the effects of abnormal patterns of network activity on cognitive dysfunction in AD. We are investigating mechanisms of network hypersynchronization in AD and testing novel therapies to prevent such deficits.

Altered interneuron dysfunction and oscillatory rhythms in cognitive disorders: Inhibitory interneurons regulate oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in AD. We are currently focused on understanding the role of inhibitory interneurons and oscillatory brain rhythms in cognitive functions in health and disease. We discovered that impaired inhibitory interneurons lead to altered oscillatory activity, network hypersynchrony, and cognitive deficits in mouse models of AD. Importantly, cognitive performance in AD mouse models was improved when interneuron-dependent oscillatory brain activity was enhanced by restoration of Nav1.1 levels in endogenous inhibitory interneurons. We are currently profiling inhibitory interneuron cell types in mouse models of AD to identify potential molecular mechanisms of interneuron dysfunction and potential targets of intervention. We are also dissecting the circuit and neuron alterations in behaving mouse models of AD using single-unit recordings and optogenetic approaches. Thus, we are identifying molecular and circuit mechanisms of brain dysfunction and exploring the therapeutic implications of enhancing inhibitory functions and/or restoring oscillatory rhythms in brain disorders associated with abnormal synchronization of neuronal networks, such as AD, schizophrenia, autism, or epilepsy.

Interneuron cell-based therapy in AD and related models: During brain development, embryonic interneuron precursors are generated in the medial ganglionic eminence (MGE) and retain a remarkable capacity for migration and integration in adult host brains, where they fully mature into functional inhibitory interneurons. Thus, MGE, or MGE-like, precursors provide a great opportunity for cell-based therapy in animal models of neurological disorders linked to impaired inhibitory function. We discovered that transplanting Nav1.1-overexpressing, but not wildtype, MGE-derived interneurons enhanced behavior-related modulation of gamma oscillatory activity, reduced network hypersynchrony, and improved cognitive function in hAPP mice. Interestingly, Nav1.1-deficient interneuron transplants were sufficient to cause behavioral abnormalities in wild-type mice, indicating the key functional role of interneurons and Nav1.1 for cognitive functions. These findings highlight the potential of Nav1.1 and inhibitory interneurons as a therapeutic target in AD and that disease-specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions.

Translational focus: We hope to translate our basic research to develop novel treatments. We are evaluating the therapeutic potential of interneuron-based interventions by using cell-based therapy and pharmacology. We established formal partnerships with major pharmaceutical and biotechnology companies to develop compounds or identify targets that enhance interneuron function or restore brain rhythms in models of AD and epilepsy. We are currently developing small molecule Nav1.1 activators that increase Nav1.1 currents and interneuron-dependent gamma oscillations in vitro and in vivo to develop novel therapies for conditions with impaired interneuron function, including AD and Dravet syndrome.

Bacterial vectors offer many advantages over other antigen delivery systems for the construction of cancer vaccines because they are usually endowed with the ability to potently stimulate the innate immune system (1). This is particularly the case for Salmonella typhimurium, which has been extensively used as an antigen delivery vector to construct vaccines against various infectious diseases (2). We have recently developed a system that significantly improves the utility of Salmonella as an antigen delivery vehicle (3, 4). This system is based on the use of a specialized protein secretion apparatus (termed type III) that is normally utilized by Salmonella to deliver effector bacterial proteins into the extracellular medium as well as into the cytosol of infected cells (5). We have adapted this system to deliver heterologous proteins into class I- and class-II antigen presenting compartments and found that antigens delivered by this system stimulate strong immune responses both in vivo and in vitro. We have engineered a Salmonella typhimurium vaccine strain that delivers the NY-ESO-1 tumor antigen through its type III protein secretion system. Sal-NY-ESO-1 efficiently elicited NY-ESO-1-specific CD8+ and CD4+ T cell responses in vitro. Oral administration of Sal-NY-ESO-1 to mice resulted in the regression of established NY-ESO-1-expressing tumors. Tumor regression was significantly accelerated in NY-ESO-1 DNA-primed animals. Epitope spreading to at least two tumor antigens not contained in the vaccine was observed in vaccinated animals. We propose that tumor-antigen delivery through the Salmonella typhimurium type III secretion system constitutes a promising novel strategy for cancer vaccine development.

Miles de vidas cambiadas y sueos americanos fueron logrados por aquellos que confiaron su caso al abogado. l ha ofrecido asesora legal a inmigrantes en situacin de desventaja por ms de 25 aos, a travs de eventos en vivo, televisin, radio, peridicos, chats y blogs en Internet, siendo una gran ayuda y apoyo a la comunidad.

Hosted by Univision News and ABC News, the Debate Will Take Place at Texas Southern University; It Will Be Broadcast LIVE on the Univision and ABC Networks and Livestreamed on all Univision News and ABC Digital Platforms

During his distinguished broadcast journalism career spanning over 30 years, Jorge Ramos has interviewed many of the most influential political leaders in the U.S. and Latin America, including Barack Obama, Mitt Romney, George W. Bush, Bill Clinton, Hillary Clinton, Harry Reid, Newt Gingrich, John McCain, John Edwards, Al Gore, George Bush Sr., John Kerry, Fidel Castro, Hugo Chvez, and Felipe Caldern, among others. He has also moderated numerous debates and townhalls since 1996, most recently with figures such as President Obama, Mitt Romney, Hillary Clinton, and Bernie Sanders.

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