Distribution and targets of the relaxin-3 innervation of the septal area in the rat

Neural tracing studies have revealed that the rat medial and lateral septum are targeted by ascending projections from the nucleus incertus, a population of tegmental GABA neurons. These neurons express the relaxin-family peptide, relaxin-3, and pharmacological modulation of relaxin-3 receptors in medial septum alters hippocampal theta rhythm and spatial memory. In an effort to better understand the basis of these interactions, we have characterized the distribution of relaxin-3 fibers/terminals in relation to different septal neuron populations identified using established protein markers. Dense relaxin-3 fiber plexuses were observed in regions of medial septum containing hippocampal-projecting choline acetyltransferase (ChAT)-, neuronal nitric oxide synthase (nNOS)-, and parvalbumin (PV)-positive neurons. In lateral septum (LS), relaxin-3 fibers were concentrated in the ventrolateral nucleus of rostral LS and the ventral nucleus of caudal LS, with sparse labeling in the dorsolateral and medial nuclei of rostral LS, dorsal nucleus of caudal LS, and ventral portion nuclei. Relaxin-3 fibers were also observed in the septofimbrial and triangular septal nuclei. In the medial septum, we observed relaxin-3-immunoreactive contacts with ChAT-, PV-, and glutamate decarboxylase-67-positive neurons that projected to hippocampus, and contacts between relaxin-3 terminals and calbindin- and calretinin-positive neurons. Relaxin-3 colocalized with synaptophysin in nerve terminals in all septal areas, and ultrastructural analysis revealed these terminals were symmetrical and contacted spines, somata, dendritic shafts, and occasionally other axonal terminals. These data predict that this GABA/peptidergic projection modulates septohippocampal activity and hippocampal theta rhythm related to exploratory navigation, defensive and ingestive behaviors, and responses to neurogenic stressors. J. Comp. Neurol. 520:1903–1939, 2012. © 2011 Wiley Periodicals, Inc. Arousal neural pathways of the brain are associated with modulation of behavior in accordance with environmental requirements and a key node in the regulation of arousal is the forebrain septal area. Ascending connections from the medial septum to the hippocampus are proposed to provide “pacemaker” control of hippocampal theta rhythm (Vertes and Kocsis,1997; Hangya et al.,2009), which may underpin goal-oriented behavior (Vinogradova,1995) and plastic changes occurring during the formation of cognitive maps (O'Keefe,1993), whereas descending projections from the lateral septum target a wide variety of subcortical circuits related to visceral and metabolic functions, ranging from aggression, social and sexual behavior, to circadian rhythms (Albert and Chew,1980; Risold and Swanson,1997a; Veenema and Neumann,2007). The septal area plays a central role in controlling hippocampal function, and the importance of the medial septum for “pacemaking” of hippocampal theta rhythm was noted in early studies (Pestche and Stumpf,1962; Andersen et al.,1979; Vinogradova,1995). This view was strengthened by more recent EEG recordings in freely moving rats that demonstrated that the integrity of the entire medial and lateral septum-hippocampal network is critical for the generation of theta rhythm (Nerad and McNaughton,2006). There has also been a consensus over many years that the different types of neurons in the septal area play specific roles in generating theta synchrony, with slow-firing cholinergic neurons facilitating hippocampal firing, and parvalbumin GABAergic neurons that innervate GABAergic hippocampal interneurons driving disinhibition of pyramidal or granule cell inhibition, allowing hippocampal synchrony (Freund and Antal,1988; Freund and Gulyas,1997; Toth et al., 1997a; Wu et al.,2000), although more recent studies have questioned the relative importance of different neuron populations in awake animals (e.g., Simon et al.,2006). Neural tract-tracing studies in the rat by our laboratory and others have demonstrated that the septal area is targeted by ascending projections arising from the nucleus incertus (Goto et al.,2001; Olucha-Bordonau et al.,2003). Neurons of the nucleus incertus contain GABA and a range of peptides, such as cholecystokinin, neurotensin, neuromedin B, and atrial natriuretic peptide (Kubota et al.,1983; Ryan et al., 1995; Olucha-Bordonau et al.,2003; see Ryan et al.,2011, for review). Recent studies have revealed that a large population of nucleus incertus neurons express high levels of the peptide relaxin-3 (RLN3), which is primarily expressed in this region, in addition to smaller adjacent tegmental and midbrain cell groups (Burazin et al.,2002; Bathgate et al.,2003; Tanaka et al.,2005; Ma et al.,2007). The nucleus incertus provides a distinct pattern of ascending projections to raphé nuclei, periaqueductal gray, supramammillary nucleus, several hypothalamic nuclei, midline intralaminar nuclei, habenula, amygdala, hippocampus, the septal area, and the prefrontal cortex (Goto et al.,2001; Olucha-Bordonau et al.,2003). This pattern of efferents overlaps extensively with the forebrain distribution of RLN3-containing nerve fibers (Tanaka et al.,2005; Ma et al.,2007). The native receptor for RLN3 is G-protein coupled receptor-135 (GPCR135) (Liu et al.,2003) or “RXFP3” (Bathgate et al.,2006) and the regional topography of RXFP3 in rat brain is largely consistent with the distribution of RLN3-positive fibers (Ma et al.,2007). The strong connections of the nucleus incertus with a number of brain areas involved in brainstem-diencephalic modulation of hippocampal theta rhythm, such as the median raphé, supramammillary nucleus and the medial septum (Vertes et al., 1993a; Vertes and Kocsis,1997), led us to hypothesize a role for the nucleus incertus in theta rhythm activation. We subsequently demonstrated that stimulation of nucleus incertus in urethane-anesthetized rats increased theta and decreased delta activity of the hippocampus, whereas electrolytic lesion of the nucleus incertus abolished hippocampal theta induced by stimulation of the nucleus reticularis pontis oralis (RPO) (Nunez et al.,2006), a key brainstem generator of hippocampal theta rhythm (Vertes,1981, 1982; Nunez et al.,1991; Vertes et al., 1993b; Vertes and Kocsis,1997). The hippocampal area in which field potentials were recorded receives only sparse inputs from the nucleus incertus, and it was concluded that the influence of the nucleus incertus on hippocampal theta rhythm was most likely mediated by its effects within the medial septum and/or other lower brain structures. In fact, the nucleus incertus is presumed to be the major relay station of RPO inputs to the medial septum (and hippocampus), as there are no direct projections from the RPO to hippocampus (Teruel-Marti et al.,2008). Additionally, RPO stimulation results in theta synchronization in the hippocampus and nucleus incertus, at the same frequency and with a high degree of coherence (Cervera-Ferri et al.,2011). Furthermore, because the nucleus incertus is an RLN3 locus in the brain, we hypothesized that RLN3 might contribute to these effects. Consistent with the presence of RLN3 and RXFP3 in the medial septum, injections of a selective RXFP3 agonist peptide (R3/I5; Liu et al.,2005) into this area increased theta activity of the hippocampal field potential in urethane-anesthetized rats, which was significantly attenuated by prior injection of a selective RXFP3 antagonist peptide, R3(BΔ23-27)R/I5 (Kuei et al.,2007; Ma et al.,2009b). R3/I5 infusion into the medial septum also increased hippocampal theta in rats in a familiar home cage environment, whereas R3(BΔ23-27)R/I5 decreased hippocampal theta in rats exploring a novel enriched context (Ma et al.,2009b). These data support a significant contribution of nucleus incertus and RLN3 inputs to the septum in regulating a fundamental brain activity and associated complex behaviors, and therefore characterization of the anatomical and cellular interactions between these inputs and their targets is required. The goal of the current study, therefore, was to map the distribution of RLN3 positive-fibers throughout the rat septum in relation to particular “landmark” neuron populations. This was achieved in a series of double-labeling experiments using a characterized RLN3 antiserum and antisera for established protein markers expressed by neurons in the septal area. We examined whether RLN3-positive fibers made close contacts with the major septal neuron types in triple- and quadruple-labeling studies combined with confocal microscopy analysis. We also examined the colocalization of RLN3 staining with that for the presynaptic marker, synaptophysin (Jahn et al.,1985), to assess the presence of RLN3 within synapses in the septum. Finally, we conducted ultrastructural analyses of RLN3-positive synapses in the septal area using electron microscopy. The data obtained provide strong anatomical evidence for a role of RLN3 in modulating the activity of specific neurons in the septum that have direct connections with the hippocampus, which may underlie the effects of RLN3/RXFP3 signaling on hippocampal theta rhythm and associated complex behaviors

Device for negative pressure wound therapy in low-resource regions: open-source description and bench test evaluation

Background: Negative (vacuum) pressure therapy promotes wound healing. However, commercially available devices are unaffordable to most potential users in low- and middle-income countries (LMICs), limiting access to many patients who could benefit from this treatment. This study aimed to design and test a cheap and easy-to-build negative pressure device and provide its detailed open-source description, thereby enabling free replication. Methods: the negative pressure device was built using off-the-shelf materials available via e-commerce and was based on a small pump, a pressure transducer, and the simplest Arduino controller with a digital display (total retail cost ≤ 75 US$). The device allows the user to set any therapeutic range of intermittent negative pressure and has two independent safety mechanisms. The performance of the low-cost device was carefully tested on the bench using a phantom wound, producing a realistic exudate flow rate. Results: the device generates the pressure patterns set by the user (25-175 mmHg of vacuum pressure, 0-60 min periods) and can drain exudate flows within the clinical range (up to 1 L/h). Conclusions: a novel, low-cost, easy-to-build negative pressure device for wound healing displays excellent technical performance. The open-source hardware description provided here, which allows for free replication and use in LMICs, will facilitate the application and wider utilization of this therapy to patients

Finite Element Analysis of Electrically Excited Quartz Tuning Fork Devices

Quartz Tuning Fork (QTF)-based Scanning Probe Microscopy (SPM) is an important field of research. A suitable model for the QTF is important to obtain quantitative measurements with these devices. Analytical models have the limitation of being based on the double cantilever configuration. In this paper, we present an electromechanical finite element model of the QTF electrically excited with two free prongs. The model goes beyond the state-of-the-art of numerical simulations currently found in the literature for this QTF configuration. We present the first numerical analysis of both the electrical and mechanical behavior of QTF devices. Experimental measurements obtained with 10 units of the same model of QTF validate the finite element model with a good agreement

Un mundo escrito: Construcción de un espacio virtual-institucional para archivos de escritores de Misiones. 16H346

Este proyecto es continuación de proyectos de crítica genética que se llevaron a cabo, o están en marcha en la Secretaría de Investigación de la Facultad de Humanidades de la UNaM, que tienen como objeto manuscritos de la literatura provincial. La labor de este proyecto implica una red de acuerdos teóricos, críticos y metodológicos iniciales, un rastreo e identificación de documentos en la región y la tramitación de préstamos ante poseedores actuales de los manuscritos a la que se suma lo interdisciplinario con el diálogo entre la crítica genética y la ciencia de la computación. A la luz de este diálogo el proyecto se propone en esta primera etapa promover tres acciones: a) desarrollar un sitio virtual-institucional que facilite el acceso en línea a archivos de escritores regionales que se vienen estudiando en la UNaM. b) hacer un relevamiento de los archivos de manuscritos que en la actualidad se encuentran diseminados, invisibles a las investigaciones para, en ese gesto, recuperarlos e incentivar su estudio. c) diseñar y construir una base de datos y un repositorio digital de manuscritos, utilizando para esta tarea software Open Source. d) sentar las bases para un estudio sobre la factibilidad de implementar un proceso de Text Mining que automatice la recuperación de información relevante, categorice los documentos y los agrupe de acuerdo a características comunes. e) Afianzar lazos institucionales con otros proyectos existentes en Argentina (UNLP), Francia (CRLA-Archivos), Bélgica (UCLovaina), España ( Universidad de Castilla La Mancha) y con UNNE y la UNLa con quien ya tenemos un convenio de colaboración en Minería de datos

National validation of the Nursing Intensive-Care Satisfaction Scale: research protocol

Aim: Validate the Nursing Intensive-Care Satisfaction Scale in ICUs throughout Spain. Identify the improvement strategies recommended by the patients and professionals. Design: Quantitative psychometric methodology and a cross-sectional descriptive correlational design.Methods: The study population will be all patients discharged from 19 participating ICUs in Spain. Consecutive sampling (n= 564). Once discharged from the ICUs, they will receive the questionnaire and then, after 48 hours it will be given to them again to analyse the temporal stability. To validate the questionnaire, the internal consistency (Cronbach's Alpha) and temporal stability (test-retest) will be analysed. Results: Improve the quality of nursing care by modifying, changing or strengthening behaviours, skills, attitudes or areas for improvement involved in the proces

Early-transition-metal ketenimine complexes:Synthesis, reactivity, and structure of ketenimine-containing titanocene and zirconocene complexes

Reaction of Cp2M(PMe3)(2) complexes (M = Ti, Zr; Cp = eta(5)-C5H5) with the N-(p-tolyl)-diphenylketenimine Ph'N=C=CPh2 (Ph' = p-MeC6H4) in a 1:1 molar ratio affords the ketenimine-containing metallocene derivatives Cp2M(eta(2)-(C,N)-Ph'N=C=CPh2)(PMe3) (M = Ti (1); Zr (2)). The ketenimine ligand reacts in the same way with the ''Cp*M-2'' species (Cp* = eta(5)-C5Me5) generated from the reduction of the corresponding Cp*2MCl2 complexes with (LiBu)-Bu-t (1:2 molar ratio) to give the related complexes Cp*M-2(eta(2)-(C,N)-Ph'N=C=CPh2) (M = Ti (3); Zr (4)). The molecular structure of 3 shows a titanium atom bonded to two eta(5)-cyclopentadienyl rings and a eta(2)-(C,N)-bonded ketenimine ligand. Reaction of ''Cp*Ti-2'' with the ketenimine ligand in a 1:2 molar ratio gives 1,1,5,5-tetraphenyl-3-(p-tolyl)-2-(p-toluidino)-3-aza-1,4-pentadiene, which probably results from the coupling, followed by hydrolysis, of two ketenimine molecules coordinated to one titanocene moiety. Protonation of 3 with Et3NHCl or H2O (1:1 molar ratio) affords the intermediate species Cp*Ti-2(X)(eta(2)-(C,N)-Ph'N=C(H)=CPh2) (X = Cl (5); OH (6)), which on hydrolysis evolves to give the enamine Ph'N(H)-CH=CPh2 as the final product. Finally, 3 reacts reversibly with H-2 to give the hydride enamidate complex Cp*Ti-2(H)(eta(1)-Ph'N-CH=CPh2) (7). The structures of the different compounds have been determined by IR and NMR spectroscopic methods

Timing of Intervention Affects Brain Electrical Activity in Children Exposed to Severe Psychosocial Neglect

Background: Early psychosocial deprivation has profound effects on brain activity in the young child. Previous reports have shown increased power in slow frequencies of the electroencephalogram (EEG), primarily in the theta band, and decreased power in higher alpha and beta band frequencies in infants and children who have experienced institutional care. Methodology/Principal Findings: We assessed the consequences of removing infants from institutions and placing them into a foster care intervention on brain electrical activity when children were 8 years of age. We found the intervention was successful for increasing high frequency EEG alpha power, with effects being most pronounced for children placed into foster care before 24 months of age. Conclusions/Significance: The dependence on age of placement for the effects observed on high frequency EEG alpha power suggests a sensitive period after which brain activity in the face of severe psychosocial deprivation is less amenabl

A novel retinoblastoma therapy from genomic and epigenetic analyses.

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss

La universidad humanista

Esta obra, titulada La universidad humanista, es fruto de la colaboración entre dos instituciones centenarias: la Universidad de Santiago de Compostela, una de las universidades más antiguas de España que ofrece educación superior desde 1495 y la Universidad Autónoma del Estado de México, heredera del Instituto Científico y Literario Autónomo, fundado en 1828, a escasos siete años de que México naciera como entidad política independiente. Ambas instituciones, con un pasado muy diferente, se encuentran hermanadas por la misma vocación de futuro y las preocupaciones propias de las universidades del siglo XXI.Universidad Autónoma del Estado de México y Universidad de Santiago de Compostel