CD40 activation induces NREM sleep and modulates genes associated with sleep homeostasis.

The T-cell derived cytokine CD40 ligand is overexpressed in patients with autoimmune diseases. Through activation of its receptor, CD40 ligand leads to a tumor necrosis factor (TNF) receptor 1 (TNFR1) dependent impairment of locomotor activity in mice. Here we report that this effect is explained through a promotion of sleep, which was specific to non-rapid eye movement (NREM) sleep while REM sleep was suppressed. The increase in NREM sleep was accompanied by a decrease in EEG delta power during NREM sleep and by a decrease in the expression of transcripts in the cerebral cortex known to be associated with homeostatic sleep drive, such as Homer1a, Early growth response 2, Neuronal pentraxin 2, and Fos-like antigen 2. The effect of CD40 activation was mimicked by peripheral TNF injection and prevented by the TNF blocker etanercept. Our study indicates that sleep-wake dysregulation in autoimmune diseases may result from CD40 induced TNF:TNFR1 mediated alterations of molecular pathways, which regulate sleep-wake behavior.

Homeodomain binding motifs modulate the probability of odorant receptor gene choice in transgenic mice.

Odorant receptor (OR) genes constitute with 1200 members the largest gene family in the mouse genome. A mature olfactory sensory neuron (OSN) is thought to express just one OR gene, and from one allele. The cell bodies of OSNs that express a given OR gene display a mosaic pattern within a particular region of the main olfactory epithelium. The mechanisms and cis-acting DNA elements that regulate the expression of one OR gene per OSN - OR gene choice - remain poorly understood. Here, we describe a reporter assay to identify minimal promoters for OR genes in transgenic mice, which are produced by the conventional method of pronuclear injection of DNA. The promoter transgenes are devoid of an OR coding sequence, and instead drive expression of the axonal marker tau-β-galactosidase. For four mouse OR genes (M71, M72, MOR23, and P3) and one human OR gene (hM72), a mosaic, OSN-specific pattern of reporter expression can be obtained in transgenic mice with contiguous DNA segments of only ~300 bp that are centered around the transcription start site (TSS). The ~150bp region upstream of the TSS contains three conserved sequence motifs, including homeodomain (HD) binding sites. Such HD binding sites are also present in the H and P elements, DNA sequences that are known to strongly influence OR gene expression. When a 19mer encompassing a HD binding site from the P element is multimerized nine times and added upstream of a MOR23 minigene that contains the MOR23 coding region, we observe a dramatic increase in the number of transgene-expressing founders and lines and in the number of labeled OSNs. By contrast, a nine times multimerized 19mer with a mutant HD binding site does not have these effects. We hypothesize that HD binding sites in the H and P elements and in OR promoters modulate the probability of OR gene choice.

Department of Human Services Proposal for State Mental Health Institute Closure and Consolidation, December 15, 2009

The Department’s recommendation for closure and consolidation is based on an analysis of the existing programs, persons served, physical plant costs, expenses and renovation/infrastructure costs for relocation, and review of the draft report from the MHI Task Force. Further detail surrounding the analysis used to drive the recommendation is found under the Recommendations section, beginning on page 12 of this report. In response to the legislative requirement to recommend closure and consolidation of an MHI, the Department recommends the closure of the Mount Pleasant Mental Health Institute with consolidation of its programs and operational beds at the Independence Mental Health Institute. With this recommendation, Independence MHI will add beds to accommodate the 15 adult psychiatric beds, 14 dual diagnosis beds, and 50 substance abuse treatment beds now located at the Mount Pleasant MHI. This relocation will take an estimated six months from the time statutory authority and corresponding appropriations are received.

Resuming motor vehicle driving following orthopaedic surgery or limb trauma.

Following elective orthopaedic surgery or the treatment of a fracture, patients are temporarily unable to drive. This loss of independence may have serious social and economic consequences for the patient. It is therefore essential to know when it is safe to permit such patients to return to driving. This article, based upon a review of the current literature, proposes recommendations of the time period after which patients may safely return to driving. Practical decisions are made based upon the type of surgical intervention or fracture. Swiss legislation is equally approached so as to better define the decision.

Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC.

Delta(9)-Tetrahydrocannabinol (THC) is frequently found in the blood of drivers suspected of driving under the influence of cannabis or involved in traffic crashes. The present study used a double-blind crossover design to compare the effects of medium (16.5 mg THC) and high doses (45.7 mg THC) of hemp milk decoctions or of a medium dose of dronabinol (20 mg synthetic THC, Marinol on several skills required for safe driving. Forensic interpretation of cannabinoids blood concentrations were attempted using the models proposed by Daldrup (cannabis influencing factor or CIF) and Huestis and coworkers. First, the time concentration-profiles of THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) (active metabolite of THC), and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) in whole blood were determined by gas chromatography-mass spectrometry-negative ion chemical ionization. Compared to smoking studies, relatively low concentrations were measured in blood. The highest mean THC concentration (8.4 ng/mL) was achieved 1 h after ingestion of the strongest decoction. Mean maximum 11-OH-THC level (12.3 ng/mL) slightly exceeded that of THC. THCCOOH reached its highest mean concentration (66.2 ng/mL) 2.5-5.5 h after intake. Individual blood levels showed considerable intersubject variability. The willingness to drive was influenced by the importance of the requested task. Under significant cannabinoids influence, the participants refused to drive when they were asked whether they would agree to accomplish several unimportant tasks, (e.g., driving a friend to a party). Most of the participants reported a significant feeling of intoxication and did not appreciate the effects, notably those felt after drinking the strongest decoction. Road sign and tracking testing revealed obvious and statistically significant differences between placebo and treatments. A marked impairment was detected after ingestion of the strongest decoction. A CIF value, which relies on the molar ratio of main active to inactive cannabinoids, greater than 10 was found to correlate with a strong feeling of intoxication. It also matched with a significant decrease in the willingness to drive, and it matched also with a significant impairment in tracking performances. The mathematic model II proposed by Huestis et al. (1992) provided at best a rough estimate of the time of oral administration with 27% of actual values being out of range of the 95% confidence interval. The sum of THC and 11-OH-THC blood concentrations provided a better estimate of impairment than THC alone. This controlled clinical study points out the negative influence on fitness to drive after medium or high dose oral THC or dronabinol.

Tuning synchronization of integrate-and-fire oscillators through mobility

We analyze the emergence of synchronization in a population of moving integrate-and-fire oscillators. Oscillators, while moving on a plane, interact with their nearest neighbor upon firing time. We discover a nonmonotonic dependence of the synchronization time on the velocity of the agents. Moreover, we find that mechanisms that drive synchronization are different for different dynamical regimes. We report the extreme situation where an interplay between the time scales involved in the dynamical processes completely inhibits the achievement of a coherent state. We also provide estimators for the transitions between the different regimes.

Were Spanish migrants attracted by industrial agglomerations?: an analysis for the interwar years in the light of the new economic geography

In this paper we examine whether access to markets had a significant influence onmigration choices of Spanish internal migrants in the inter-war years. We perform astructural contrast of a New Economic Geography model that focus on the forwardlinkage that links workers location choice with the geography of industrial production,one of the centripetal forces that drive agglomeration in the NEG models. The resultshighlight the presence of this forward linkage in the Spanish economy of the inter-warperiod. That is, we prove the existence of a direct relation between workers¿ localizationdecisions and the market potential of the host regions. In addition, the direct estimationof the values associated with key parameters in the NEG model allows us to simulatethe migratory flows derived from different scenarios of the relative size of regions andthe distances between them. We show that in Spain the power of attraction of theagglomerations grew as they increased in size, but the high elasticity estimated for themigration costs reduced the intensity of the migratory flows. This could help to explainthe apparently low intensity of internal migrations in Spain until its upsurge during the1920s. This also explains the geography of migrations in Spain during this period,which hardly affected the regions furthest from the large industrial agglomerations (i.e.,regions such as Andalusia, Estremadura and Castile-La Mancha) but had an intenseeffect on the provinces nearest to the principal centres of industrial development.

Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function

Cholesterol regulates plasma membrane (PM) association and functioning of syntaxin-4 and soluble N-ethylmaleimide-sensitive fusion protein 23 (SNAP23) in the secretory pathway. However, the molecular mechanism and cellular cholesterol pools that determine the localization and assembly of these target membrane SNAP receptors (t-SNAREs) are largely unknown. We recently demonstrated that high levels of annexin A6 (AnxA6) induce accumulation of cholesterol in late endosomes, thereby reducing cholesterol in the Golgi and PM. This leads to an impaired supply of cholesterol needed for cytosolic phospholipase A2 (cPLA2) to drive Golgi vesiculation and caveolin transport to the cell surface. Using AnxA6-overexpressing cells as a model for cellular cholesterol imbalance, we identify impaired cholesterol egress from late endosomes and diminution of Golgi cholesterol as correlating with the sequestration of SNAP23/syntaxin-4 in Golgi membranes. Pharmacological accumulation of late endosomal cholesterol and cPLA2 inhibition induces a similar phenotype in control cells with low AnxA6 levels. Ectopic expression of Niemann-Pick C1 (NPC1) or exogenous cholesterol restores the location of SNAP23 and syntaxin-4 within the PM. Importantly, AnxA6-mediated mislocalization of these t-SNAREs correlates with reduced secretion of cargo via the SNAP23/syntaxin-4¿dependent constitutive exocytic pathway. We thus conclude that inhibition of late endosomal export and Golgi cholesterol depletion modulate t-SNARE localization and functioning along the exocytic pathway.

Dynamics of a paramagnetic colloidal particle driven on a magnetic-bubble lattice

We present a theoretical study of the recently observed dynamical regimes of paramagnetic colloidal particles externally driven above a regular lattice of magnetic bubbles [P. Tierno, T. H. Johansen, and T. M. Fischer, Phys. Rev. Lett. 99, 038303 (2007)]. An external precessing magnetic field alters the potential generated by the surface of the film in such a way to either drive the particle circularly around one bubble, ballistically through the array, or in triangular orbits on the interstitial regions between the bubbles. In the ballistic regime, we observe different trajectories performed by the particles phase locked with the external driving. Superdiffusive motion, which was experimentally found bridging the localized and delocalized dynamics, emerge only by introducing a certain degree of randomness into the bubbles size distribution.

Tous égaux devant Dieu ? Réflexions sur les logiques d'éligibilité des miraculés

Le pentecôtisme a fait du miracle le coeur de sa théologie et l'élément central de ses activités d'évangélisation. Le catholicisme, par contre, a toujours voulu contrôler l'ensemble des déclarations de manifestations divines. Apparitions et guérisons miraculeuses ont donc systématiquement, et de plus en plus, été soumises à de lentes et rigoureuses procédures d'authentification. Les pentecôtistes voient Dieu comme un être extérieur qui surgit sur la terre pour chasser le mal qui l'envahit. Tous les convertis ont donc droit à la libération et personne ne doit accepter sagement la souffrance. Or, les pèlerins catholiques que nous avons étudiés ne partagent pas ces convictions pentecôtistes. Dieu agit de l'intérieur, non pas en les délivrant, mais en les soutenant dans leurs épreuves quotidiennes. Rare et peu recherchée, la guérison physique cède la place à la guérison spirituelle, accessible à tous. Il nous semble que ces deux types de représentations placent les fidèles dans des dispositions d'esprit très divergentes suscitant, dans un cas ou dans l'autre, des espoirs adaptés à la capacité du groupe à produire des miracles. Pentecostalism placed miracles at the centre of its theology as a key element of its evangelization activities. Catholicism, on the other hand, has always tried to control all declarations of divine demonstrations. Miraculous appearances and recoveries have been more and more systematically subjected to slow and rigorous procedures of verification. The Pentecostals see God as an external force which manifests itself on earth to drive out the evil which invades it. All believers have the right to be free from evil, and nobody should have to accept pain meekly. But the Catholic pilgrims we studied do not share these Pentecostal convictions. God acts from inside, not by delivering them but by supporting them in their daily tests. Physical recovery is rare and not very sought after so it takes second place to spiritual recovery which is accessible to everyone. It seems to us that these two types of representation place believers in very divergent frames of mind giving rise, in one group or the other, to hopes that correspond to the group's capacity to produce miracles.

Resting-State Functional Connectivity Emerges from Structurally and Dynamically Shaped Slow Linear Fluctuations.

Brain fluctuations at rest are not random but are structured in spatial patterns of correlated activity across different brain areas. The question of how resting-state functional connectivity (FC) emerges from the brain's anatomical connections has motivated several experimental and computational studies to understand structure-function relationships. However, the mechanistic origin of resting state is obscured by large-scale models' complexity, and a close structure-function relation is still an open problem. Thus, a realistic but simple enough description of relevant brain dynamics is needed. Here, we derived a dynamic mean field model that consistently summarizes the realistic dynamics of a detailed spiking and conductance-based synaptic large-scale network, in which connectivity is constrained by diffusion imaging data from human subjects. The dynamic mean field approximates the ensemble dynamics, whose temporal evolution is dominated by the longest time scale of the system. With this reduction, we demonstrated that FC emerges as structured linear fluctuations around a stable low firing activity state close to destabilization. Moreover, the model can be further and crucially simplified into a set of motion equations for statistical moments, providing a direct analytical link between anatomical structure, neural network dynamics, and FC. Our study suggests that FC arises from noise propagation and dynamical slowing down of fluctuations in an anatomically constrained dynamical system. Altogether, the reduction from spiking models to statistical moments presented here provides a new framework to explicitly understand the building up of FC through neuronal dynamics underpinned by anatomical connections and to drive hypotheses in task-evoked studies and for clinical applications.

An adeno-associated virus-based intracellular sensor of pathological nuclear factor-κB activation for disease-inducible gene transfer.

Stimulation of resident cells by NF-κB activating cytokines is a central element of inflammatory and degenerative disorders of the central nervous system (CNS). This disease-mediated NF-κB activation could be used to drive transgene expression selectively in affected cells, using adeno-associated virus (AAV)-mediated gene transfer. We have constructed a series of AAV vectors expressing GFP under the control of different promoters including NF-κB -responsive elements. As an initial screen, the vectors were tested in vitro in HEK-293T cells treated with TNF-α. The best profile of GFP induction was obtained with a promoter containing two blocks of four NF-κB -responsive sequences from the human JCV neurotropic polyoma virus promoter, fused to a new tight minimal CMV promoter, optimally distant from each other. A therapeutical gene, glial cell line-derived neurotrophic factor (GDNF) cDNA under the control of serotype 1-encapsidated NF-κB -responsive AAV vector (AAV-NF) was protective in senescent cultures of mouse cortical neurons. AAV-NF was then evaluated in vivo in the kainic acid (KA)-induced status epilepticus rat model for temporal lobe epilepsy, a major neurological disorder with a central pathophysiological role for NF-κB activation. We demonstrate that AAV-NF, injected in the hippocampus, responded to disease induction by mediating GFP expression, preferentially in CA1 and CA3 neurons and astrocytes, specifically in regions where inflammatory markers were also induced. Altogether, these data demonstrate the feasibility to use disease-activated transcription factor-responsive elements in order to drive transgene expression specifically in affected cells in inflammatory CNS disorders using AAV-mediated gene transfer.

Schizotypy as an organizing framework for social and affective sciences

Schizotypy, defined in terms of commonly occurring personality traits related to the schizophrenia spectrum, has been an important construct for understanding the neurodevelopment and stress-diathesis of schizophrenia. However, as schizotypy nears its sixth decade of application, it is important to acknowledge its impressively rich literature accumulating outside of schizophrenia research. In this article, we make the case that schizotypy has considerable potential as a conceptual framework for understanding individual differences in affective and social functions beyond those directly involved in schizophrenia spectrum pathology. This case is predicated on (a) a burgeoning literature noting anomalies in a wide range of social functioning, affiliative, positive and negative emotional, expressive, and social cognitive systems, (b) practical and methodological features associated with schizotypy research that help facilitate empirical investigation, and (c) close ties to theoretical constructs of central importance to affective and social science (eg, stress diathesis, neural compensation). We highlight recent schizotypy research, ie providing insight into the nature of affective and social systems more generally. This includes current efforts to clarify the neurodevelopmental, neurobiological, and psychological underpinnings of affiliative drives, hedonic capacity, social cognition, and stress responsivity systems. Additionally, we discuss neural compensatory and resilience factors that may mitigate the expression of stress-diathesis and functional outcome, and highlight schizotypy's potential role for understanding cultural determinants of social and affective functions.

Were Spanish migrants attracted by industrial agglomerations?: an analysis for the interwar years in the light of the new economic geography

In this paper we examine whether access to markets had a significant influence onmigration choices of Spanish internal migrants in the inter-war years. We perform astructural contrast of a New Economic Geography model that focus on the forwardlinkage that links workers location choice with the geography of industrial production,one of the centripetal forces that drive agglomeration in the NEG models. The resultshighlight the presence of this forward linkage in the Spanish economy of the inter-warperiod. That is, we prove the existence of a direct relation between workers¿ localizationdecisions and the market potential of the host regions. In addition, the direct estimationof the values associated with key parameters in the NEG model allows us to simulatethe migratory flows derived from different scenarios of the relative size of regions andthe distances between them. We show that in Spain the power of attraction of theagglomerations grew as they increased in size, but the high elasticity estimated for themigration costs reduced the intensity of the migratory flows. This could help to explainthe apparently low intensity of internal migrations in Spain until its upsurge during the1920s. This also explains the geography of migrations in Spain during this period,which hardly affected the regions furthest from the large industrial agglomerations (i.e.,regions such as Andalusia, Estremadura and Castile-La Mancha) but had an intenseeffect on the provinces nearest to the principal centres of industrial development.

Iowa Wetland Management District: Environmental Assessment and Draft Comprehensive Conservation Plan

This Environmental Assessment documents the National Environmental Policy Act (NEPA) process for developing a Comprehensive Conservation Plan (CCP) for the Iowa Wetland Management District (WMD, district). In general, scoping reveals issues that drive alternative ways of managing the district. Implementation of each of those alternative management styles (including the No Action Alternative) may have different effects on the physical, biological, and socio-economic environment. Analysis of these effects reveals the “preferred” alternative, which constitutes the CCP. The CCP includes goals, objectives, and strategies for the district to guide overall management for the next 15 years. The Iowa WMD consists of scattered tracts of habitat (both wetland and upland grassland) known as Waterfowl Production Areas (WPAs). As of 2011, there are 75 WPAs in 18 counties in north-central Iowa totaling 24,712 acres in fee title primarily managed by the Iowa Department of Natural Resources (DNR). Even though district acquisition has only occurred in 18 counties to date, a larger 35-county boundary is approved. This boundary follows the historic range of the poorly drained Prairie Pothole Region (PPR) in Iowa, an area known for its waterfowl production. The district also includes 575 WPA acres and approximately 434 Farm Service Agency acres in conservation easements on private land. This plan was prepared with the intent that the strong partnership with the Iowa DNR will continue over the next 15 years.