Respiratory rhythm generation: A modeling study of the respiratory central pattern generator and the phrenic motor neuron

The respiratory central pattern generator is a collection of medullary neurons that generates the rhythm of respiration. The respiratory central pattern generator feeds phrenic motor neurons, which, in turn, drive the main muscle of respiration, the diaphragm. The purpose of this thesis is to understand the neural control of respiration through mathematical models of the respiratory central pattern generator and phrenic motor neurons. ^ We first designed and validated a Hodgkin-Huxley type model that mimics the behavior of phrenic motor neurons under a wide range of electrical and pharmacological perturbations. This model was constrained physiological data from the literature. Next, we designed and validated a model of the respiratory central pattern generator by connecting four Hodgkin-Huxley type models of medullary respiratory neurons in a mutually inhibitory network. This network was in turn driven by a simple model of an endogenously bursting neuron, which acted as the pacemaker for the respiratory central pattern generator. Finally, the respiratory central pattern generator and phrenic motor neuron models were connected and their interactions studied. ^ Our study of the models has provided a number of insights into the behavior of the respiratory central pattern generator and phrenic motor neurons. These include the suggestion of a role for the T-type and N-type calcium channels during single spikes and repetitive firing in phrenic motor neurons, as well as a better understanding of network properties underlying respiratory rhythm generation. We also utilized an existing model of lung mechanics to study the interactions between the respiratory central pattern generator and ventilation. ^

Age determination and stable isotope record of foraminifera of sediment core SO82_5-2

Surface and deepwater paleoclimate records in Irminger Sea core SO82-5 (59°N, 31°W) and Icelandic Sea core PS2644 (68°N, 22°W) exhibit large fluctuations in thermohaline circulation (THC) from 60 to 18 calendar kyr B.P., with a dominant periodicity of 1460 years from 46 to 22 calendar kyr B.P., matching the Dansgaard-Oeschger (D-O) cycles in the Greenland Ice Sheet Project 2 (GISP2) temperature record [Grootes and Stuiver, 1997, doi:10.1029/97JC00880]. During interstadials, summer sea surface temperatures (SSTsu) in the Irminger Sea averaged to 8°C, and sea surface salinities (SSS) averaged to ~36.5, recording a strong Irminger Current and Atlantic THC. During stadials, SSTsu dropped to 2°-4°C, in phase with SSS drops by ~1-2. They reveal major meltwater injections along with the East Greenland Current, which turned off the North Atlantic deepwater convection and hence the heat advection to the north, in harmony with various ocean circulation and ice models. On the basis of the IRD composition, icebergs came from Iceland, east Greenland, and perhaps Svalbard and other northern ice sheets. However, the southward drifting icebergs were initially jammed in the Denmark Strait, reaching the Irminger Sea only with a lag of 155-195 years. We also conclude that the abrupt stadial terminations, the D-O warming events, were tied to iceberg melt via abundant seasonal sea ice and brine water formation in the meltwater-covered northwestern North Atlantic. In the 1/1460-year frequency band, benthic ?18O brine water spikes led the temperature maxima above Greenland and in the Irminger Sea by as little as 95 years. Thus abundant brine formation, which was induced by seasonal freezing of large parts of the northwestern Atlantic, may have finally entrained a current of warm surface water from the subtropics and thereby triggered the sudden reactivation of the THC. In summary, the internal dynamics of the east Greenland ice sheet may have formed the ultimate pacemaker of D-O cycles.

Benthic stable-isotope records of ODP Site 208-1262, South Atlantic

The Late Paleocene and Early Eocene were characterised by warm greenhouse climates, punctuated by a series of rapid warming and ocean acidification events known as "hyperthermals", thought to have been paced or triggered by orbital cycles. While these hyperthermals, such as the Paleocene Eocene Thermal Maximum (PETM), have been studied in great detail, the background low-amplitude cycles seen in carbon and oxygen-isotope records throughout the Paleocene-Eocene have hitherto not been resolved. Here we present a 7.7 million year (myr) long, high-resolution, orbitally-tuned, benthic foraminiferal stable-isotope record spanning the late Paleocene and early Eocene interval (~52.5 - 60.5 Ma) from Ocean Drilling Program (ODP) Site 1262, South Atlantic. This high resolution (~2-4 kyr) record allows the changing character and phasing of orbitally-modulated cycles to be studied in unprecedented detail as it reflects the long-term trend in carbon cycle and climate over this interval. The main pacemaker in the benthic oxygen-isotope (d18O) and carbon-isotope (d13C) records from ODP Site 1262, are the long (405 kyr) and short (100 kyr) eccentricity cycles, and precession (21 kyr). Obliquity (41 kyr) is almost absent throughout the section except for a few brief intervals where it has a relatively weak influence. During the course of the Early Paleogene record, and particularly in the latest Paleocene, eccentricity-paced negative carbon-isotope excursions (d13C, CIEs) and coeval negative oxygen-isotope (d18O) excursions correspond to low carbonate (CaCO3) and coarse fraction (%CF) values due to increased carbonate dissolution, suggesting shoaling of the lysocline and accompanied changes in the global exogenic carbon cycle. These negative CIEs and d18O events coincide with maxima in eccentricity, with changes in d18O leading changes in d13C by ~6 (±5) kyr in the 405-kyr band and by ~3 (±1) kyr in the higher frequency 100-kyr band on average. However, these phase lags are not constant, with the lag in the 405-kyr band extending from ~4 (±5) kyr to ~21 (±2) kyr from the late Paleocene to the early Eocene, suggesting a progressively weaker coupling of climate and the carbon-cycle with time. The higher amplitude 405-kyr cycles in the latest Paleocene are associated with changes in bottom water temperature of 2-4ºC, while the most prominent 100 kyr-paced cycles can be accompanied by changes of up to 1.5ºC. Comparison of the 1262 record with a lower resolution, but orbitally-tuned benthic record for Site 1209 in the Pacific allows for verification of key features of the benthic isotope records which are global in scale including a key warming step at 57.7 Ma.

Monitorización de sistemas en alta disponibilidad

El objetivo del proyecto es implantar un sistema de monitorización, con la peculiaridad de encontrarse en alta disponibilidad, esto es, que el servicio (la monitorización de una infraestructura) se preste forma continua y no se vea interrumpido. Dado que el propósito del sistema es monitorizar activamente una infraestructura, ha sido necesario desplegar una infraestructura, además del sistema de monitorización. La infraestructura en cuestión está compuesta por un servidor de documentación, un servidor de base de datos, un servidor de aplicaciones y un servidor web. El sistema de monitorización se ha desplegado en la misma red de área local de esta infraestructura y monitoriza que los servicios prestados por los componentes de esta infraestructura se encuentren operativos y funcionando adecuadamente. Así pues, se tendría un sistema de monitorización local funcional. No obstante, el proyecto plantea un sistema escalable, que esté preparado para el crecimiento de la infraestructura y continúe siendo eficiente. Para ello, sistema de monitorización se encuentre dividido por dos componentes:  Sonda delegada: monitoriza localmente los activos de la infraestructura a monitorizar, es el escenario anteriormente descrito.  Sonda maestra: recibe los resultados de la monitorización realizada, este sistema puede estar desplegado en otra red distinta a la sonda delegada. Este enfoque no solo es escalable, sino también es fiel a la realidad, pues puede darse el caso de que las sondas pertenezcan a distintas infraestructuras e inclusive, distintas organizaciones, y se comuniquen a través de internet, mediante un mecanismo confiable a ser posible. El proyecto plantea que ambas sondas se encuentren en alta disponibilidad (en adelante HA, referente a high availability), y que cada sonda está compuesta por dos equipos (nodos, en adelante). Como se analizará en posteriores capítulos, existen diversas configuraciones que permiten implantar un sistema en HA, la configuración escogida para el proyecto es Activo – Pasivo(los detalles de esta configuración también se explican en posteriores capítulos). Para finalizar, se estudiara la posibilidad de ofrecer respuestas activas en ciertas situaciones y configuraciones adicionales sobre el sistema de monitorización base. Por otro lado, para la implantación del proyecto se ha usado software de código abierto para la virtualización de la infraestructura (Virtual Box y GNS3), los sistemas operativos base (Linux), el sistema de monitorización(Nagios Core) así como el software que implementa la HA (corosync y pacemaker).---ABSTRACT---The aim of the Project is to implement a monitoring system, with the peculiarity of being deployed in high availability, what it is that the service (monitoring infrastructure) is provided continuously and not interrupted. As the purpose of the system is monitoring infrastructure actively, an infrastructure has been deployed, and also the monitoring system. The infrastructure monitored is composed of a documentation server, a server database, an application server and a Web server. The monitoring system has been also deployed on the same LAN of this infrastructure and monitors the services provided by the components of this infrastructure are operational and working as expected. This is a local monitoring system functional. However, the project also proposes a scalable system that is ready for growth of infrastructure and efficient. This is the reason of divide the system in two components:  Slave Component: monitors locally the infrastructure assets to be monitored, this is the scenario described above.  Master Component: get the results from the monitoring, provided by the Slave Component. This system can be deployed in a different network than the slave component. This approach is not only scalable but also a real scenario, as may be the case that the Components belongs to different infrastructures and even, different organizations, also this components can communicate over the Internet, through a reliable mechanism if possible. The project proposes that both Components are deployed in high availability (HA onwards concerning high availability), each Component is composed of two servers (nodes, hereafter). As will be discussed in later chapters, there are several settings available to deploy a system in HA, the configuration chosen for the project is Active - Passive (details of this configuration are also explained in later chapters). Finally the possibility of offering active responses in certain situations and additional settings on the monitoring system will be discussed. On the other hand, for the implementation of the project, open source software has been used, for virtualization infrastructure (Virtual Box and GNS3), code-based operating systems (Linux), the monitoring system (Nagios core), as well as the software that implements the HA (corosync and pacemaker).

Coordinate regulation of gonadotropin-releasing hormone neuronal firing patterns by cytosolic calcium and store depletion

Elevation of cytosolic free Ca2+ concentration ([Ca2+]i) in excitable cells often acts as a negative feedback signal on firing of action potentials and the associated voltage-gated Ca2+ influx. Increased [Ca2+]i stimulates Ca2+-sensitive K+ channels (IK-Ca), and this, in turn, hyperpolarizes the cell and inhibits Ca2+ influx. However, in some cells expressing IK-Ca the elevation in [Ca2+]i by depletion of intracellular stores facilitates voltage-gated Ca2+ influx. This phenomenon was studied in hypothalamic GT1 neuronal cells during store depletion caused by activation of gonadotropin-releasing hormone (GnRH) receptors and inhibition of endoplasmic reticulum (Ca2+)ATPase with thapsigargin. GnRH induced a rapid spike increase in [Ca2+]i accompanied by transient hyperpolarization, followed by a sustained [Ca2+]i plateau during which the depolarized cells fired with higher frequency. The transient hyperpolarization was caused by the initial spike in [Ca2+]i and was mediated by apamin-sensitive IK-Ca channels, which also were operative during the subsequent depolarization phase. Agonist-induced depolarization and increased firing were independent of [Ca2+]i and were not mediated by inhibition of K+ current, but by facilitation of a voltage-insensitive, Ca2+-conducting inward current. Store depletion by thapsigargin also activated this inward depolarizing current and increased the firing frequency. Thus, the pattern of firing in GT1 neurons is regulated coordinately by apamin-sensitive SK current and store depletion-activated Ca2+ current. This dual control of pacemaker activity facilitates voltage-gated Ca2+ influx at elevated [Ca2+]i levels, but also protects cells from Ca2+ overload. This process may also provide a general mechanism for the integration of voltage-gated Ca2+ influx into receptor-controlled Ca2+ mobilization.

Altered emotional and locomotor responses in mice deficient in the transcription factor CREM

Various transcription factors act as nuclear effectors of the cAMP-dependent signaling pathway. These are the products of three genes in the mouse, CREB, CRE modulator (CREM), and ATF-1. CREM proteins are thought to play important roles within the hypothalamic–pituitary axis and in the control of rhythmic functions in the pineal gland. We have generated CREM-mutant mice and investigated their response in a variety of behavioral tests. CREM-null mice show a drastic increase in locomotion. In contrast to normal mice, the CREM-deficient mice show equal locomotor activity during the circadian cycle. The anatomy of the hypothalamic suprachiasmatic nuclei, the center of the endogenous pacemaker, is normal in mutant mice. Remarkably, CREM mutant mice also elicit a different emotional state, revealed by a lower anxiety in two different behavioral models, but they preserve the conditioned reactiveness to stress. These results demonstrate the high degree of functional specificity of each cAMP-responsive transcription factor in behavioral control.

Circadian modulation of dopamine receptor responsiveness in Drosophila melanogaster

We investigated the circadian function of Drosophila dopamine receptors by using a behaviorally active decapitated preparation that allows for direct application of drugs to the nerve cord. Quinpirole, a D2-like dopamine receptor agonist, induces reflexive locomotion in decapitated flies. We show that the amount of locomotion induced changes as a function of the time of day, with the highest responsiveness to quinpirole during the subjective night. Furthermore, dopamine receptor responsiveness is under circadian control and depends on the normal function of the period gene. The head pacemaker is at least partly dispensable for the circadian modulation of quinpirole-induced locomotion, because changes in agonist responsiveness persist in decapitated flies that are aged for 12 h. This finding suggests a role for the period-dependent molecular oscillators in the body in the modulation of amine receptor responsiveness.

Thyroid hormone receptor β-dependent expression of a potassium conductance in inner hair cells at the onset of hearing

To elucidate the role of thyroid hormone receptors (TRs) α1 and β in the development of hearing, cochlear functions have been investigated in mice lacking TRα1 or TRβ. TRs are ligand-dependent transcription factors expressed in the developing organ of Corti, and loss of TRβ is known to impair hearing in mice and in humans. Here, TRα1-deficient (TRα1−/−) mice are shown to display a normal auditory-evoked brainstem response, indicating that only TRβ, and not TRα1, is essential for hearing. Because cochlear morphology was normal in TRβ−/− mice, we postulated that TRβ regulates functional rather than morphological development of the cochlea. At the onset of hearing, inner hair cells (IHCs) in wild-type mice express a fast-activating potassium conductance, IK,f, that transforms the immature IHC from a regenerative, spiking pacemaker to a high-frequency signal transmitter. Expression of IK,f was significantly retarded in TRβ−/− mice, whereas the development of the endocochlear potential and other cochlear functions, including mechanoelectrical transduction in hair cells, progressed normally. TRα1−/− mice expressed IK,f normally, in accord with their normal auditory-evoked brainstem response. These results establish that the physiological differentiation of IHCs depends on a TRβ-mediated pathway. When defective, this may contribute to deafness in congenital thyroid diseases.

Biopacemaker acceleration without increased synchronization by chronic exposure to phorbol myristate acetate

L'activité électrique du coeur est initiée par la génération spontanée de potentiels d'action venant des cellules pacemaker du noeud sinusal (SN). Toute dysfonction au niveau de cette région entraîne une instabilité électrique du coeur. La majorité des patients souffrant d'un noeud sinusal déficient nécessitent l'implantation chirurgicale d'un pacemaker électronique; cependant, les limitations de cette approche incitent à la recherche d'une alternative thérapeutique. La base moléculaire des courants ioniques jouant un rôle crucial dans l'activité du noeud sinusal sont de plus en plus connues. Une composante importante de l'activité des cellules pacemakers semble être le canal HCN, responsable du courant pacemaker If. Le facteur T-box 3 (Tbx3), un facteur de transcription conservé durant le processus de l'évolution, est nécessaire au développement du système de conduction cardiaque. De précédentes études ont démontré que dans différentes lignées cellulaires le Phorbol 12-myristate 13-acetate (PMA) active l'expression du gène codant Tbx3 via des réactions en cascade partant de la protéine kinase C (PKC). L'objectif principal de cette étude est de tester si le PMA peut augmenter la fréquence et la synchronisation de l'activité spontanée du pacemaker biologique en culture. Plus précisément, nous avons étudié les effets de l'exposition chronique au PMA sur l'expression du facteur de transcription Tbx3, sur HCN4 et l'activité spontanée chez des monocouches de culture de myocytes ventriculaires de rats néonataux (MVRN). Nos résultats démontrent que le PMA augmente significativement le facteur transcription de Tbx3 et l'expression ARNm de HCN4, favorisant ainsi l'augmentation du rythme et de la stabilité de l'activité autonome. De plus, une diminution significative de la vitesse de conduction a été relevée et est attribuée à la diminution du couplage intercellulaire. La diminution de la vitesse de conduction pourrait expliquer l'effet négatif du PMA sur la synchronisation de l'activité autonome du pacemaker biologique. Ces résultats ont été confirmés par un modèle mathématique multicellulaire suggérant que des fréquences et résistances intercellulaires plus élevée pourraient induire une activité plus stable et moins synchrone. Cette étude amène de nouvelles connaissances très importantes destinées à la production d'un pacemaker biologique efficient et robuste.

Surgical cryoablation for ventricular tachyarrhythmia arising from the left ventricular outflow tract region.

BACKGROUND Ventricular arrhythmias (VAs) from the left ventricular outflow tract (LVOT) region can be inaccessible for ablation because of epicardial fat or overlying coronary arteries. OBJECTIVE We describe surgical cryoablation of this type of VA. METHODS From March 2009 to 2014, 190 consecutive patients with VAs originating from the LVOT underwent ablation at our institution. Four patients (2%) underwent surgical cryoablation for highly symptomatic VAs after failing catheter ablation. RESULTS In all patients, endocardial or percutaneous epicardial mapping was consistent with origin in the LVOT. In 2 patients, the points of earliest activation during VAs were marked with a bipolar pacing lead in the overlying cardiac vein for guidance during surgery. Surgical cryoablation was successful in 3 of the 4 patients. The fourth patient subsequently had successful endocardial catheter ablation. During a mean follow-up of 22 ± 16 months (range 4-42 months), all patients showed abolition of or marked reduction in symptomatic VA. However, 1 patient subsequently required percutaneous intervention to the left anterior descending coronary artery; another developed progressive left ventricular systolic dysfunction caused by nonischemic cardiomyopathy; and a third patient underwent permanent pacemaker implantation because of complete atrioventricular block after concomitant aortic valve replacement. CONCLUSION Surgical cryoablation is an option for highly symptomatic drug-resistant VAs emanating from the LVOT region. Despite extensive preoperative mapping, the procedure is not effective for all patients, and coronary injury is a risk.

Stable isotopes measured on Miocene benthic foraminifera from ODP sites 202-1237 and 184-1146

One of the most enigmatic features of Cenozoic long-term climate evolution is the long-lasting positive carbon-isotope excursion or "Monterey Excursion", which started during a period of global warmth after 16.9 Ma and ended at not, vert, similar 13.5 Ma, approximately 400 kyr after major expansion of the Antarctic ice-sheet. We present high-resolution (1-9 kyr) astronomically-tuned climate proxy records in two complete sedimentary successions from the northwestern and southeastern Pacific (ODP Sites 1146 and 1237), which shed new light on the middle Miocene carbon-isotope excursion and associated climatic transition over the interval 17.1-12.7 Ma. We recognize three distinct climate phases with different imprints of orbital variations into the climatic signals (1146 and 1237 d18O, d13C; 1237 XRF Fe, fraction > 63 µm): (1) climate optimum prior to 14.7 Ma characterized by minimum ice volume and prominent 100 and 400 kyr variability, (2) long-term cooling from 14.7 to 13.9 Ma, principally driven by obliquity and culminating with rapid cryosphere expansion and global cooling at the onset of the last and most pronounced d13C increase, (3) "Icehouse" mode after 13.9 Ma with distinct 100 kyr variability and improved ventilation of the deep Pacific. The "Monterey" carbon-isotope excursion (16.9-13.5 Ma) consists overall of nine 400 kyr cycles, which show high coherence with the long eccentricity period. Superposed on these low-frequency oscillations are high-frequency variations (100 kyr), which closely track the amplitude modulation of the short eccentricity period. In contrast to d13C, the d18O signal additionally shows significant power in the 41 kyr band, and the 1.2 Myr amplitude modulation of the obliquity cycle is clearly imprinted in the 1146 d18O signal. Our results suggest that eccentricity was a prime pacemaker of middle Miocene climate evolution through the modulation of long-term carbon budgets and that obliquity-paced changes in high-latitude seasonality favored the transition into the "Icehouse" climate.

Potential environmental effects of 765-kV transmission lines : views before the New York State Public Service Commission, cases 26529 and 26559, 1976-1978 /

Contract no. DE-AM-03-76SF0015.

Evaluation of resynchronization of contractile function following biventricular pacing using colour tissue Doppler imaging

Biventdcular (BV) pacing is evaluated as an alternative treatment for patients with dilated cardiomyppathy (both ischemic and non-ischemic) and end-stage heart failure. Colour tissue Doppler imaging using echocardiography allows noninvasive, quantitative assessment of radial motion in the long-axis with measurement of peak systolic velocity timing. The aim of the present study was to evaluate quantitatively, the systolic performance of the left ventricle and the resynchrenization of contraction (before vs after implantation). Patients and methods: 25 patients with dilated cardiomyopathy (11 ischemic), NYHA class III or IV, QRS duration >120 ms received a biventricular pacemaker. Routine 2D echo and colour tissue Doppler imaging were performed before and within 1 week following implantation. LVEF was assessed using the biplane Sampson's method.Peak systolic velocity (PSV) and time to PSV (TPV) were assessed in 4 regions (basal anterior, inferior, lateral and septal). By averaging the TPV from all 4 regions, a synchronization index was dedved from these measurements. Reaults: LVEF improved by 9±9% following pacing; 17 patients improved LVEF 5% or more. The change in PSV in the septal and lateral regions related significantly to the change in LVEF (r=0.74, r=0.62).The change in synchronization index before vs after pacing (as a measurement of REsynchronization) was related to the change in LVEF (y=120x+5.6, r=0.79, P