Role of the IKKβ/NF-κB pathway in alcoholism

Pro-inflammatory neuroimmune signaling pathways are implicated in the acute and chronic effects of alcohol exposure. Genetic association studies in humans, gene expression microarray studies in postmortem brains of alcoholics, transcriptome meta-analysis in rodents, and drinking models in mice support the role of neuroimmune signaling in alcohol abuse disorder. Nuclear factor kappa-B (NF-κB) is a ubiquitously expressed transcription factor that controls the expression of genes important for innate- and adaptive-immune responses, cell proliferation/death, and inflammation. More specifically, the NF-κB canonical pathway is responsible for the expression of pro-inflammatory genes. The inhibitory kappa-B kinase (IKK) complex, composed of IKKα, IKKβ, and IKKγ represents a point of convergence for many extracellular signals and regulates the NF-κB canonical pathway by targeting the inhibitor of NF-κB (IκB) for degradation. NF-κB is disinhibited, translocates to the nucleus, and acts as a transcription factor for numerous pro-inflammatory chemokines and cytokines. However, IKKβ is the only member of the IKK complex that specifically mediates this pathway. As such, I hypothesized that inhibiting IKKβ/NF-κB pathway would limit/decrease voluntary ethanol consumption. This was studied by determining the brain region and cell type-specificity of all the IKK isoforms. It was observed that all IKKs were primarily expressed in neurons and ubiquitously expressed throughout the brain regions studied [prefrontal cortex (PFC), nucleus accumbens (NAc), amygdala (AMY), and ventral tegmental area (VTA)]. Subsequently, the effects of inhibiting/knocking down IKKβ were investigated both systemically and centrally to determine the effects on voluntary ethanol drinking. It was observed that both antagonizing IKKβ peripherally and genetically knocking it down centrally in the NAc and central amygdala (CeA) reduced voluntary ethanol consumption and preference in two bottle choice (2BC) ethanol drinking paradigms. Lastly, ethanol-responsive microRNAs were explored in the PFC, NAc, and AMY. Several differentially expressed MicroRNAs were discovered that were either predicted/validated to target genes of the IKKβ/NF-κB pathway. One candidate, let-7g, was manipulated in vivo to determine its effect on voluntary ethanol drinking behaviors, however, no significant phenotypes were observed. These results demonstrate that blocking IKKβ decreases voluntary ethanol consumption and indicate its role as a potential therapeutic target for alcohol abuse.Cellular and Molecular Biolog

Computational evidence for an early, amplified systemic inflammation program in polytrauma patients with severe extremity injuries

Extremity and soft tissue injuries contribute significantly to inflammation and adverse in-hospital outcomes for trauma survivors; accordingly, we examined the complex association between clinical outcomes inflammatory responses in this setting using in silico tools. Two stringently propensity-matched, moderately/severely injured (Injury Severity Score > 16) patient sub-cohorts of ~30 patients each were derived retrospectively from a cohort of 472 blunt trauma survivors and segregated based on their degree of extremity injury severity (above or below 3 on the Abbreviated Injury Scale). Serial blood samples were analyzed for 31 plasma inflammatory mediators. In addition to standard statistical analyses, Dynamic Network Analysis (DyNA) and Principal Component Analysis (PCA) were used to model systemic inflammation following trauma. Patients in the severe extremity injury sub-cohort experienced longer intensive care unit length of stay (LOS), total LOS, and days on a mechanical ventilator, with higher Marshall Multiple Organ Dysfunction (MOD) Scores over the first 7 days post-injury as compared to the mild/moderate extremity injury sub-cohort. The higher severity cohort had statistically significant elevated lactate, base deficit, and creatine phosphokinase on first blood draw, along with significant changes in multiple circulating inflammatory mediators. DyNA pointed to a sustained role for type 17 immunity in both sub-cohorts, along with IFN-γ in the severe extremity injury group. DyNA network complexity increased over 7 days post-injury in the severe injury group, while generally decreasing over this same time period in the mild/moderate injury group. PCA suggested a more robust activation of multiple pathways in the severe extremity injury group as compared to the mild/moderate injury group. These studies thus point to the possibility of self-sustaining inflammation following severe extremity injury vs. resolving inflammation following less severe extremity injury

Linking goniometer measurements to hyperspectral and multi-sensor imagery for retrieval of beach properties and coastal characterization

In June 2011, a multi-sensor airborne remote sensing campaign was flown at the Virginia Coast Reserve Long Term Ecological Research site with coordinated ground and water calibration and validation (cal/val) measurements. Remote sensing imagery acquired during the ten day exercise included hyperspectral imagery (CASI-1500), topographic LiDAR, and thermal infra-red imagery, all simultaneously from the same aircraft. Airborne synthetic aperture radar (SAR) data acquisition for a smaller subset of sites occurred in September 2011 (VCR\u2711). Focus areas for VCR\u2711 were properties of beaches and tidal flats and barrier island vegetation and, in the water column, shallow water bathymetry. On land, cal/val emphasized tidal flat and beach grain size distributions, density, moisture content, and other geotechnical properties such as shear and bearing strength (dynamic deflection modulus), which were related to hyperspectral BRDF measurements taken with the new NRL Goniometer for Outdoor Portable Hyperspectral Earth Reflectance (GOPHER). This builds on our earlier work at this site in 2007 related to beach properties and shallow water bathymetry. A priority for VCR\u2711 was to collect and model relationships between hyperspectral imagery, acquired from the aircraft at a variety of different phase angles, and geotechnical properties of beaches and tidal flats. One aspect of this effort was a demonstration that sand density differences are observable and consistent in reflectance spectra from GOPHER data, in CASI hyperspectral imagery, as well as in hyperspectral goniometer measurements conducted in our laboratory after VCR\u2711

A Pivotal Role of Lumbar Spinothalamic Cells in the Regulation of Ejaculation via Intraspinal Connections

Introduction.  A population of lumbar spinothalamic cells (LSt cells) has been demonstrated to play a pivotal role in ejaculatory behavior and comprise a critical component of the spinal ejaculation generator. LSt cells are hypothesized to regulate ejaculation via their projections to autonomic and motor neurons in the lumbosacral spinal cord. Aim.  The current study tested the hypothesis that ejaculatory reflexes are dependent on LSt cells via projections within the lumbosacral spinal cord. Methods.  Male rats received intraspinal injections of neurotoxin saporin conjugated to substance P analog, previously shown to selectively lesion LSt cells. Two weeks later, males were anesthetized and spinal cords were transected. Subsequently, males were subjected to ejaculatory reflex paradigms, including stimulation of the dorsal penile nerve (DPN), urethrogenital stimulation or administration of D3 agonist 7‐OH‐DPAT. Electromyographic recordings of the bulbocavernosus muscle (BCM) were analyzed for rhythmic bursting characteristic of the expulsion phase of ejaculation. In addition, a fourth commonly used paradigm for ejaculation and erections in unanesthetized, spinal‐intact male rats was utilized: the ex copula reflex paradigm. Main Outcome Measures.  LSt cell lesions were predicted to prevent rhythmic bursting of BCM following DPN, urethral, or pharmacological stimulation, and emissions in the ex copula paradigm. In contrast, LSt cell lesions were not expected to abolish erectile function as measured in the ex copula paradigm. Results.  LSt cell lesions prevented rhythmic contractions of the BCM induced by any of the ejaculatory reflex paradigms in spinalized rats. However, LSt cell lesions did not affect erectile function nor emissions determined in the ex copula reflex paradigm. Conclusions.  These data demonstrate that LSt cells are essential for ejaculatory, but not erectile reflexes, as previously reported for mating animals. Moreover, LSt cells mediate ejaculation via projections within the spinal cord, presumably to autonomic and motor neurons. Staudt MD, Truitt WA, McKenna KE, de Oliveira CVR, Lehman MN, and Coolen LM. A pivotal role of lumbar spinothalamic cells in the regulation of ejaculation via intraspinal connections. J Sex Med 2012;9:2256–2265.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93690/1/j.1743-6109.2011.02574.x.pd

Human-in-the-Loop Evaluation of An integrated Arrival/Departure Air Traffic Control Service for Major Metropolitan Airspaces

Abstract The increasing number of U.S. air flights has placed a severe strain on the National Airspace System (NAS), especially airspace surrounding major metropolitan areas. In a recent study, Truitt, McAnulty, and Willems (2004) tested and found benefits in procedures designed to address some of the pressures around New York airspace. The procedures included extending terminal lateral separation standards (3 nm) and procedures (diverging courses) into en route airspace as well as collocating terminal and en route facilities to promote more effective communication and coordination. The Integrated Arrival/Departure Air Traffic Control Service, termed the Big Airspace (BA) concept, applies these procedures to other busy areas and includes the use of Area Navigation(RNAV) routes as well as dynamic resectorization to make airspace boundaries more flexible. Twenty-four controllers from en route and terminal facilities participated in a simulation that compared a baseline (BL) condition using current airspace standards and procedures to two BA conditions. In one condition, en route and terminal participants managed traffic in the same control room, and in the other condition they worked as if in separate facilities. Overall, the results provided support for the BA concept. The aircraft moved through the arrival corridor more efficiently in the BA conditions than in the BL condition, and participants made fewer ground-ground transmissions and issued fewer altitude and heading clearances. Subjective ratings of performance, situation awareness, and the ability to move traffic through the sector were also higher in the BA conditions