A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection

For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium versus dysregulated immunity remain unresolved. Here, we take a top-down systems approach to this question. Multigene transcriptional signatures from infected lungs suggested that elevated activation of inflammatory signaling networks distinguished lethal from sublethal infections. Flow cytometry and gene expression analysis involving isolated cell subpopulations from infected lungs showed that neutrophil influx largely accounted for the predictive transcriptional signature. Automated imaging analysis, together with these gene expression and flow data, identified a chemokine-driven feedforward circuit involving proinflammatory neutrophils potently driven by poorly contained lethal viruses. Consistent with these data, attenuation, but not ablation, of the neutrophil-driven response increased survival without changing viral spread. These findings establish the primacy of damaging innate inflammation in at least some forms of influenza-induced lethality and provide a roadmap for the systematic dissection of infection-associated pathology.

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.

The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs.

Short-Term Plasticity in a Computational Model of the Tail-Withdrawal Circuit in Aplysia.

The tail-withdrawal circuit of Aplysia provides a useful model system for investigating synaptic dynamics. Sensory neurons within the circuit manifest several forms of synaptic plasticity. Here, we developed a model of the circuit and investigated the ways in which depression (DEP) and potentiation (POT) contributed to information processing. DEP limited the amount of motor neuron activity that could be elicited by the monosynaptic pathway alone. POT within the monosynaptic pathway did not compensate for DEP. There was, however, a synergistic interaction between POT and the polysynaptic pathway. This synergism extended the dynamic range of the network, and the interplay between DEP and POT made the circuit responded preferentially to long-duration, low-frequency inputs.

Anatomical organization of the memory underlying sensitization in the siphon-withdrawal reflex circuit of {\it Aplysia californica}

Previous studies have shown that short-term sensitization of the Aplysia siphon-withdrawal reflex circuit results in multiple sites of change in synaptic efficacy. In this dissertation I have used a realistic modeling approach (using an integrate-and-fire scheme), in conjunction with electrophysiological experiments, to evaluate the contribution of each site of plasticity to the sensitized response.^ This dissertation contains a detailed description of methodology for the construction of the model circuit, consisting of the LFS motor neurons and ten interneurons known to convey excitatory input to them. The model replicates closely the natural motor neuron firing response to a brief tactile stimulus.^ The various circuit elements have different roles for producing circuit output. For example, the sensory connections onto the motor neuron are important for the production of the phasic response, while the polysynaptic interneuronal connections are important for producing the tonic response.^ The multiple sites of plasticity that produce changes in circuit output also have specialized roles. Presynaptic facilitation of the sensory neuron to LFS connection enhances only the phasic component of the motor neuron firing response. The sensory neuron to interneuron connections primarily enhance the tonic component of the motor neuron firing response. Also, the L29 posttetanic potentiation and the L30 presynaptic inhibition primarily enhance the tonic component of the motor neuron firing response. Finally, the information content at the various sites of plasticity can shift with changes in stimulus intensity. This suggests that while the sites of plasticity encoding memory are fixed, the information content at these sites can be dynamic, shifting in anatomical location with changes in the intensity of the test stimulus.^ These sites of plasticity also produce specific changes in the behavioral response. Sensory-LFS plasticity selectively increases the amplitude of the behavioral response, and has no effect on the duration of the behavioral response. Interneuronal plasticity (L29 and L30) affects both the amplitude and duration of the behavioral response. Other sensory plasticity also affect both the amplitude and duration of the behavioral response, presumably by increasing the recruitment of the interneurons, which provide all of the effect on duration of the behavioral response. ^

Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearman's ρ's⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD.

Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.

Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.

Local changes in neocortical circuit dynamics coincide with the spread of seizures to thalamus in a model of epilepsy

During the generalization of epileptic seizures, pathological activity in one brain area recruits distant brain structures into joint synchronous discharges. However, it remains unknown whether specific changes in local circuit activity are related to the aberrant recruitment of anatomically distant structures into epileptiform discharges. Further, it is not known whether aberrant areas recruit or entrain healthy ones into pathological activity. Here we study the dynamics of local circuit activity during the spread of epileptiform discharges in the zero-magnesium in vitro model of epilepsy. We employ high-speed multi-photon imaging in combination with dual whole-cell recordings in acute thalamocortical (TC) slices of the juvenile mouse to characterize the generalization of epileptic activity between neocortex and thalamus. We find that, although both structures are exposed to zero-magnesium, the initial onset of focal epileptiform discharge occurs in cortex. This suggests that local recurrent connectivity that is particularly prevalent in cortex is important for the initiation of seizure activity. Subsequent recruitment of thalamus into joint, generalized discharges is coincident with an increase in the coherence of local cortical circuit activity that itself does not depend on thalamus. Finally, the intensity of population discharges is positively correlated between both brain areas. This suggests that during and after seizure generalization not only the timing but also the amplitude of epileptiform discharges in thalamus is entrained by cortex. Together these results suggest a central role of neocortical activity for the onset and the structure of pathological recruitment of thalamus into joint synchronous epileptiform discharges.

Psychomotor symptoms of schizophrenia map on the cerebral motor circuit

Schizophrenia is a devastating disorder thought to result mainly from cerebral pathology. Neuroimaging studies have provided a wealth of findings of brain dysfunction in schizophrenia. However, we are still far from understanding how particular symptoms can result from aberrant brain function. In this context, the high prevalence of motor symptoms in schizophrenia such as catatonia, neurological soft signs, parkinsonism, and abnormal involuntary movements is of particular interest. Here, the neuroimaging correlates of these motor symptoms are reviewed. For all investigated motor symptoms, neural correlates were found within the cerebral motor system. However, only a limited set of results exists for hypokinesia and neurological soft signs, while catatonia, abnormal involuntary movements and parkinsonian signs still remain understudied with neuroimaging methods. Soft signs have been associated with altered brain structure and function in cortical premotor and motor areas as well as cerebellum and thalamus. Hypokinesia is suggested to result from insufficient interaction of thalamocortical loops within the motor system. Future studies are needed to address the neural correlates of motor abnormalities in prodromal states, changes during the course of the illness, and the specific pathophysiology of catatonia, dyskinesia and parkinsonism in schizophrenia.

Gasto energético aeróbico y anaeróbico en un circuito con cargas a seis intensidades diferentes. (Aerobic and anaerobic energy expenditure during at circuit weight training through six different intensities).

El entrenamiento con cargas es una actividad anaeróbica glucolítica intensa y se ha comprobado que el error en las estimaciones del gasto energético en esta actividad varía entre un 13 y un 30%. El principal objetivo de este trabajo es describir la contribución anaeróbica de energía en un circuito con cargas. Doce hombres (20-26 años) y diecisiete mujeres (18-29 años) estudiantes de Ciencias de la Actividad Física y del Deporte realizaron un entrenamiento en circuito de cargas a 6 intensidades diferentes (entre el 30% y 80% de su 15RM). Durante la totalidad de los circuitos se registró el gasto energético aeróbico por calorimetría indirecta, la frecuencia cardiaca con pulsómetro Polar® y la concentración de lactato en sangre capilar para medir la contribución anaeróbica. El incremento que produjo la energía anaeróbica se situó entre el 5,1% y un máximo del 13,5%, lo que hace evidente que medir o no la contribución anaeróbica en el entrenamiento en circuito puede provocar un error medio del 9,65%. Existen diferencias significativas (Pmenor que 0,05) entre el gasto energético aeróbico y total (aeróbico+anaeróbico) en todas las intensidades, en un circuito de entrenamiento con cargas a intensidades progresivas.

Study of the II Network as the Compound Slot Equivalent Circuit Model

A combination of Method of Moments (MoM) and compound slot Equivalent Circuit Model for linear array design is presented in this document. From the S Matrix of the single element, the more suitable network for its characterization is analyzed and selected. Then according to the radiation requirements of the desired array, the elements are designed and then properly connected by means of Forward Matching Procedure (FMP), which takes into account impedance matters in order to keep the input matched at the designing frequency. Comparison between HFSS simulations and MoM-FMP results are also presented. First part of this work was introduced in (1)(2) but a summary is included here to make the understanding easier.

Changes in the Papez Circuit in early stages of Alzheimer's Disease

Alzheimer's disease (AD) is the most common cause of demenMa. Neuronal and synapMc losses occur iniMally and predominantly in the medial temporal lobe structures including hippocampus, amygdala and thalamus, structures that belong to the Papez circuit. The integrity of the connecMons amongst them is essenMal for episodic memory, which is specifically impaired in AD. For this reason we have invesMgated the degeneraMon paRern of subcorMcal structures and its relaMon to early stages of AD, i.e. Mild CogniMve Impairment (MCI), both in the amnesic and mulMdomain types using structural magneMc resonance imaging (using a 3T GE scanner) and VBM‐DARTEL.

Validation of the SenseWear armband in circuit resistance training with different loads

The use of the SenseWear™ armband (SWA), an objective monitor of physical activity, is a relatively new device used by researchers to measure energy expenditure. These monitors are practical, relatively inexpensive and easy-to-use. The aim of the present study was to assess the validity of SWAs for the measurement of energy expenditure (EE) in circuit resistance training (CRT) at three different intensities in moderately active, healthy subjects. The study subjects (17 females, 12 males) undertook CRT at 30, 50 and 70% of the 15 repetition maximum for each exercise component wearing an SWA as well as an Oxycon Mobile (OM) portable metabolic system (a gold standard method for measuring EE). The EE rose as exercise intensity increased, but was underestimated by the SWAs. For women, Bland-Altman plots showed a bias of 1.13 ± 1.48 METs and 32.1 ± 34.0 kcal in favour of the OM system, while for men values of 2.33 ± 1.82 METs and 75.8 ± 50.8 kcal were recorded.

Contribution to the design of waveguide-fed compound-slot arrays by means of equivalent circuit modelling

Los arrays de ranuras son sistemas de antennas conocidos desde los años 40, principalmente destinados a formar parte de sistemas rádar de navíos de combate y grandes estaciones terrenas donde el tamaño y el peso no eran altamente restrictivos. Con el paso de los años y debido sobre todo a importantes avances en materiales y métodos de fabricación, el rango de aplicaciones de este tipo de sistemas radiantes creció en gran medida. Desde nuevas tecnologías biomédicas, sistemas anticolisión en automóviles y navegación en aviones, enlaces de comunicaciones de alta tasa binaria y corta distancia e incluso sistemas embarcados en satélites para la transmisión de señal de televisión. Dentro de esta familia de antennas, existen dos grupos que destacan por ser los más utilizados: las antennas de placas paralelas con las ranuras distribuidas de forma circular o espiral y las agrupaciones de arrays lineales construidos sobre guia de onda. Continuando con las tareas de investigación desarrolladas durante los últimos años en el Instituto de Tecnología de Tokyo y en el Grupo de Radiación de la Universidad Politécnica de Madrid, la totalidad de esta tesis se centra en este último grupo, aunque como se verá se separa en gran medida de las técnicas de diseño y metodologías convencionales. Los arrays de ranuras rectas y paralelas al eje de la guía rectangular que las alimenta son, sin ninguna duda, los modelos más empleados debido a la fiabilidad que presentan a altas frecuencias, su capacidad para gestionar grandes cantidades de potencia y la sencillez de su diseño y fabricación. Sin embargo, también presentan desventajas como estrecho ancho de banda en pérdidas de retorno y rápida degradación del diagrama de radiación con la frecuencia. Éstas son debidas a la naturaleza resonante de sus elementos radiantes: al perder la resonancia, el sistema global se desajusta y sus prestaciones degeneran. En arrays bidimensionales de slots rectos, el campo eléctrico queda polarizado sobre el plano transversal a las ranuras, correspondiéndose con el plano de altos lóbulos secundarios. Esta tesis tiene como objetivo el desarrollo de un método sistemático de diseño de arrays de ranuras inclinadas y desplazadas del centro (en lo sucesivo “ranuras compuestas”), definido en 1971 como uno de los desafíos a superar dentro del mundo del diseño de antennas. La técnica empleada se basa en el Método de los Momentos, la Teoría de Circuitos y la Teoría de Conexión Aleatoria de Matrices de Dispersión. Al tratarse de un método circuital, la primera parte de la tesis se corresponde con el estudio de la aplicabilidad de las redes equivalentes fundamentales, su capacidad para recrear fenómenos físicos de la ranura, las limitaciones y ventajas que presentan para caracterizar las diferentes configuraciones de slot compuesto. Se profundiza en las diferencias entre las redes en T y en ! y se condiciona la selección de una u otra dependiendo del tipo de elemento radiante. Una vez seleccionado el tipo de red a emplear en el diseño del sistema, se ha desarrollado un algoritmo de cascadeo progresivo desde el puerto alimentador hacia el cortocircuito que termina el modelo. Este algoritmo es independiente del número de elementos, la frecuencia central de funcionamiento, del ángulo de inclinación de las ranuras y de la red equivalente seleccionada (en T o en !). Se basa en definir el diseño del array como un Problema de Satisfacción de Condiciones (en inglés, Constraint Satisfaction Problem) que se resuelve por un método de Búsqueda en Retroceso (Backtracking algorithm). Como resultado devuelve un circuito equivalente del array completo adaptado a su entrada y cuyos elementos consumen una potencia acorde a una distribución de amplitud dada para el array. En toda agrupación de antennas, el acoplo mutuo entre elementos a través del campo radiado representa uno de los principales problemas para el ingeniero y sus efectos perjudican a las prestaciones globales del sistema, tanto en adaptación como en capacidad de radiación. El empleo de circuito equivalente se descartó por la dificultad que suponía la caracterización de estos efectos y su inclusión en la etapa de diseño. En esta tesis doctoral el acoplo también se ha modelado como una red equivalente cuyos elementos son transformadores ideales y admitancias, conectada al conjunto de redes equivalentes que representa el array. Al comparar los resultados estimados en términos de pérdidas de retorno y radiación con aquellos obtenidos a partir de programas comerciales populares como CST Microwave Studio se confirma la validez del método aquí propuesto, el primer método de diseño sistemático de arrays de ranuras compuestos alimentados por guía de onda rectangular. Al tratarse de ranuras no resonantes, el ancho de banda en pérdidas de retorno es mucho mas amplio que el que presentan arrays de slots rectos. Para arrays bidimensionales, el ángulo de inclinación puede ajustarse de manera que el campo quede polarizado en los planos de bajos lóbulos secundarios. Además de simulaciones se han diseñado, construido y medido dos prototipos centrados en la frecuencia de 12GHz, de seis y diez elementos. Las medidas de pérdidas de retorno y diagrama de radiación revelan excelentes resultados, certificando la bondad del método genuino Method of Moments - Forward Matching Procedure desarrollado a lo largo de esta tésis. Abstract The slot antenna arrays are well known systems from the decade of 40s, mainly intended to be part of radar systems of large warships and terrestrial stations where size and weight were not highly restrictive. Over the years, mainly due to significant advances in materials and manufacturing methods, the range of applications of this type of radiating systems grew significantly. From new biomedical technologies, collision avoidance systems in cars and aircraft navigation, short communication links with high bit transfer rate and even embedded systems in satellites for television broadcast. Within this family of antennas, two groups stand out as being the most frequent in the literature: parallel plate antennas with slots placed in a circular or spiral distribution and clusters of waveguide linear arrays. To continue the vast research work carried out during the last decades in the Tokyo Institute of Technology and in the Radiation Group at the Universidad Politécnica de Madrid, this thesis focuses on the latter group, although it represents a technique that drastically breaks with traditional design methodologies. The arrays of slots straight and parallel to the axis of the feeding rectangular waveguide are without a doubt the most used models because of the reliability that they present at high frequencies, its ability to handle large amounts of power and their simplicity of design and manufacturing. However, there also exist disadvantages as narrow bandwidth in return loss and rapid degradation of the radiation pattern with frequency. These are due to the resonant nature of radiating elements: away from the resonance status, the overall system performance and radiation pattern diminish. For two-dimensional arrays of straight slots, the electric field is polarized transverse to the radiators, corresponding to the plane of high side-lobe level. This thesis aims to develop a systematic method of designing arrays of angled and displaced slots (hereinafter "compound slots"), defined in 1971 as one of the challenges to overcome in the world of antenna design. The used technique is based on the Method of Moments, Circuit Theory and the Theory of Scattering Matrices Connection. Being a circuitry-based method, the first part of this dissertation corresponds to the study of the applicability of the basic equivalent networks, their ability to recreate the slot physical phenomena, their limitations and advantages presented to characterize different compound slot configurations. It delves into the differences of T and ! and determines the selection of the most suitable one depending on the type of radiating element. Once the type of network to be used in the system design is selected, a progressive algorithm called Forward Matching Procedure has been developed to connect the proper equivalent networks from the feeder port to shorted ending. This algorithm is independent of the number of elements, the central operating frequency, the angle of inclination of the slots and selected equivalent network (T or ! networks). It is based on the definition of the array design as a Constraint Satisfaction Problem, solved by means of a Backtracking Algorithm. As a result, the method returns an equivalent circuit of the whole array which is matched at its input port and whose elements consume a power according to a given amplitude distribution for the array. In any group of antennas, the mutual coupling between elements through the radiated field represents one of the biggest problems that the engineer faces and its effects are detrimental to the overall performance of the system, both in radiation capabilities and return loss. The employment of an equivalent circuit for the array design was discarded by some authors because of the difficulty involved in the characterization of the coupling effects and their inclusion in the design stage. In this thesis the coupling has also been modeled as an equivalent network whose elements are ideal transformers and admittances connected to the set of equivalent networks that represent the antennas of the array. By comparing the estimated results in terms of return loss and radiation with those obtained from popular commercial software as CST Microwave Studio, the validity of the proposed method is fully confirmed, representing the first method of systematic design of compound-slot arrays fed by rectangular waveguide. Since these slots do not work under the resonant status, the bandwidth in return loss is much wider than the longitudinal-slot arrays. For the case of two-dimensional arrays, the angle of inclination can be adjusted so that the field is polarized at the low side-lobe level plane. Besides the performed full-wave simulations two prototypes of six and ten elements for the X-band have been designed, built and measured, revealing excellent results and agreement with the expected results. These facts certify that the genuine technique Method of Moments - Matching Forward Procedure developed along this thesis is valid and trustable.