Gene expression patterns following unilateral traumatic brain injury reveals a local pro-inflammatory and remote anti-inflammatory response.

BackgroundTraumatic brain injury (TBI) results in irreversible damage at the site of impact and initiates cellular and molecular processes that lead to secondary neural injury in the surrounding tissue. We used microarray analysis to determine which genes, pathways and networks were significantly altered using a rat model of TBI. Adult rats received a unilateral controlled cortical impact (CCI) and were sacrificed 24 h post-injury. The ipsilateral hemi-brain tissue at the site of the injury, the corresponding contralateral hemi-brain tissue, and naïve (control) brain tissue were used for microarray analysis. Ingenuity Pathway Analysis (IPA) software was used to identify molecular pathways and networks that were associated with the altered gene expression in brain tissues following TBI.ResultsInspection of the top fifteen biological functions in IPA associated with TBI in the ipsilateral tissues revealed that all had an inflammatory component. IPA analysis also indicated that inflammatory genes were altered on the contralateral side, but many of the genes were inversely expressed compared to the ipsilateral side. The contralateral gene expression pattern suggests a remote anti-inflammatory molecular response. We created a network of the inversely expressed common (i.e., same gene changed on both sides of the brain) inflammatory response (IR) genes and those IR genes included in pathways and networks identified by IPA that changed on only one side. We ranked the genes by the number of direct connections each had in the network, creating a gene interaction hierarchy (GIH). Two well characterized signaling pathways, toll-like receptor/NF-kappaB signaling and JAK/STAT signaling, were prominent in our GIH.ConclusionsBioinformatic analysis of microarray data following TBI identified key molecular pathways and networks associated with neural injury following TBI. The GIH created here provides a starting point for investigating therapeutic targets in a ranked order that is somewhat different than what has been presented previously. In addition to being a vehicle for identifying potential targets for post-TBI therapeutic strategies, our findings can also provide a context for evaluating the potential of therapeutic agents currently in development

Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke.

Identifying novel neuroprotectants that can halt or reverse the neurological effects of stroke is of interest to both clinicians and scientists. We and others previously showed the pre-clinical neuroprotective efficacy of neuregulin-1 (NRG-1) in rats following focal brain ischemia. In this study, we examined neuroprotection by exogenous and endogenous NRG-1 using a mouse model of ischemic stroke. C57BL6 mice were subjected to middle cerebral artery occlusion (MCAO) followed by reperfusion. NRG-1 or vehicle was infused intra-arterially (i.a.) or intravenously (i.v.) after MCAO and before the onset of reperfusion. NRG-1 treatment (16 μg/kg; i.a.) reduced cerebral cortical infarct volume by 72% in mice when delivered post-ischemia. NRG-1 also inhibited neuronal injury as measured by Fluoro Jade B labeling and rescued NeuN immunoreactivity in neurons. Neuroprotection by NRG-1 was also observed in mice when administered i.v. (100 μg/kg) in both male and female mice. We investigated whether endogenous NRG-1 was neuroprotective using male and female heterozygous NRG-1 knockout mice (NRG-1+/-) compared with wild-type mice (WT) littermates. NRG-1+/- and WT mice were subjected to MCAO for 45 min, and infarct size was measured 24 h following MCAO. NRG-1+/- mice displayed a sixfold increase in cortical infarct size compared with WT mice. These results demonstrate that NRG-1 treatment mitigates neuronal damage following cerebral ischemia. We further showed that reduced endogenous NRG-1 results in exacerbated neuronal injury in vivo. These findings suggest that NRG-1 represents a promising therapy to treat stroke in human patients

A Uniformly Derived Catalogue of Exoplanets from Radial Velocities

A new catalogue of extrasolar planets is presented by re-analysing a selection of published radial velocity data sets using EXOFIT (Balan & Lahav 2009). All objects are treated on an equal footing within a Bayesian framework, to give orbital parameters for 94 exoplanetary systems. Model selection (between one- and two-planet solutions) is then performed, using both a visual flagging method and a standard chi-square analysis, with agreement between the two methods for 99% of the systems considered. The catalogue is to be made available online, and this 'proof of concept' study may be maintained and extended in the future to incorporate all systems with publicly available radial velocity data, as well as transit and microlensing data.Comment: 16 pages, 6 figures, 6 table

Inferring the eccentricity distribution

Standard maximum-likelihood estimators for binary-star and exoplanet eccentricities are biased high, in the sense that the estimated eccentricity tends to be larger than the true eccentricity. As with most non-trivial observables, a simple histogram of estimated eccentricities is not a good estimate of the true eccentricity distribution. Here we develop and test a hierarchical probabilistic method for performing the relevant meta-analysis, that is, inferring the true eccentricity distribution, taking as input the likelihood functions for the individual-star eccentricities, or samplings of the posterior probability distributions for the eccentricities (under a given, uninformative prior). The method is a simple implementation of a hierarchical Bayesian model; it can also be seen as a kind of heteroscedastic deconvolution. It can be applied to any quantity measured with finite precision--other orbital parameters, or indeed any astronomical measurements of any kind, including magnitudes, parallaxes, or photometric redshifts--so long as the measurements have been communicated as a likelihood function or a posterior sampling.Comment: Ap

A Bayesian Approach to the Detection Problem in Gravitational Wave Astronomy

The analysis of data from gravitational wave detectors can be divided into three phases: search, characterization, and evaluation. The evaluation of the detection - determining whether a candidate event is astrophysical in origin or some artifact created by instrument noise - is a crucial step in the analysis. The on-going analyses of data from ground based detectors employ a frequentist approach to the detection problem. A detection statistic is chosen, for which background levels and detection efficiencies are estimated from Monte Carlo studies. This approach frames the detection problem in terms of an infinite collection of trials, with the actual measurement corresponding to some realization of this hypothetical set. Here we explore an alternative, Bayesian approach to the detection problem, that considers prior information and the actual data in hand. Our particular focus is on the computational techniques used to implement the Bayesian analysis. We find that the Parallel Tempered Markov Chain Monte Carlo (PTMCMC) algorithm is able to address all three phases of the anaylsis in a coherent framework. The signals are found by locating the posterior modes, the model parameters are characterized by mapping out the joint posterior distribution, and finally, the model evidence is computed by thermodynamic integration. As a demonstration, we consider the detection problem of selecting between models describing the data as instrument noise, or instrument noise plus the signal from a single compact galactic binary. The evidence ratios, or Bayes factors, computed by the PTMCMC algorithm are found to be in close agreement with those computed using a Reversible Jump Markov Chain Monte Carlo algorithm.Comment: 19 pages, 12 figures, revised to address referee's comment

Preferential Quadriceps Activation in Female Athletes with Incremental Increases in Landing Intensity

The purpose of this study was to identify alterations in preparatory muscle activation patterns across different drop heights in female athletes. Sixteen female high school volleyball players performed the drop vertical jump from three different drop heights. Surface electromyography of the quadriceps and hamstrings were collected during the movement trials. As the drop height increased, muscle activation of the quadriceps during preparatory phase also increased (p \u3c .05). However, the hamstrings activation showed no similar increases relative to drop height. Female athletes appear to preferentially rely on increased quadriceps activation, without an increase in hamstrings activation, with increased plyometric intensity. The resultant decreased activation ratio of the hamstrings relative to quadriceps before landing may represent altered dynamic knee stability and may contribute to the increased risk of ACL injury in female athletes

Longitudinal Sex Differences During Landing in Knee Abduction in Young Athletes

Purpose— The objective of this study was to determine if biomechanical and neuromuscular risk factors related to abnormal movement patterns increased in females, but not males, during the adolescent growth spurt. Methods— 315 subjects participated in two testing sessions approximately one year apart. Male and female subjects were classified based on their maturation status as pubertal or post-pubertal.Three trials of a drop vertical jump (DVJ) were collected. Maximum knee abduction angle and external moments were calculated during the DVJ deceleration phase using a 3D motion analysis system. Changes in knee abduction from the first to second year were compared among four subject groups (female pubertal, female post-pubertal, male pubertal and male post-pubertal). Results— There were no sex differences in peak knee abduction angle or moment during DVJ between pubertal males and females (p\u3e0.05). However, pubertal females increased peak abduction angle from the first to second year (pp=0.90) in the matched developmental stages. Following puberty, the peak abduction angle and moment were greater in females relative to males (angle: female -9.3±5.7°, male -3.6±4.6°, pp=0.017). Conclusion— This study identified, through longitudinal analyses, that knee abduction angle was significantly increased in pubertal females during rapid adolescent growth, while males showed no similar change. In addition, knee abduction motion and moments were significantly greater for subsequent year in young female athletes, following rapid adolescent growth, compared to males

Longitudinal Sex Differences During Landing in Knee Abduction in Young Athletes

Purpose— The objective of this study was to determine if biomechanical and neuromuscular risk factors related to abnormal movement patterns increased in females, but not males, during the adolescent growth spurt. Methods— 315 subjects participated in two testing sessions approximately one year apart. Male and female subjects were classified based on their maturation status as pubertal or post-pubertal.Three trials of a drop vertical jump (DVJ) were collected. Maximum knee abduction angle and external moments were calculated during the DVJ deceleration phase using a 3D motion analysis system. Changes in knee abduction from the first to second year were compared among four subject groups (female pubertal, female post-pubertal, male pubertal and male post-pubertal). Results— There were no sex differences in peak knee abduction angle or moment during DVJ between pubertal males and females (p\u3e0.05). However, pubertal females increased peak abduction angle from the first to second year (pp=0.90) in the matched developmental stages. Following puberty, the peak abduction angle and moment were greater in females relative to males (angle: female -9.3±5.7°, male -3.6±4.6°, pp=0.017). Conclusion— This study identified, through longitudinal analyses, that knee abduction angle was significantly increased in pubertal females during rapid adolescent growth, while males showed no similar change. In addition, knee abduction motion and moments were significantly greater for subsequent year in young female athletes, following rapid adolescent growth, compared to males

Skeletal muscle AMPK is essential for the maintenance of FNDC5 expression

Fibronectin type III domain‐containing protein 5 (FNDC5) expression is controlled by the transcriptional co‐activator, peroxisome proliferator‐activated receptor gamma, coactivator 1 alpha (PGC1α). FNDC5 expression has been shown to be increased in muscle in response to endurance exercise in some but not all studies, therefore a greater understanding of the mechanisms controlling this process are needed. The AMP‐activated protein kinase (AMPK) is activated by exercise in an intensity dependent manner and is an important regulator of PGC1α activity; therefore, we explored the role of AMPK in the regulation of FNDC5 using AMPK β1β2 double muscle‐null mice (AMPK DMKO), which lack skeletal muscle AMPK activity. We found that FNDC5 expression is dramatically reduced in resting muscles of AMPK DMKO mice compared to wild‐type littermates. In wild‐type mice, activating phosphorylation of AMPK was elevated immediately post contraction and was abolished in muscle from AMPK DMKO mice. In contrast, PGC1α was increased in both wild‐type and AMPK DMKO mice 3 h post contraction but FNDC5 protein expression was not altered. Lastly, acute or chronic activation of AMPK with the pharmacological AMPK activator AICAR did not increase PGC1α or FNDC5 expression in muscle. These data indicate that skeletal muscle AMPK is required for the maintenance of basal FNDC5 expression

Constituting monetary conservatives via the 'savings habit': New Labour and the British housing market bubble

The ongoing world credit crunch might well kill off the most recent bubble dynamics in the British housing market by driving prices systematically downwards from their 2007 peak. Nonetheless, the experience of that bubble still warrants analytical attention. The Labour Government might not have been responsible for consciously creating it, but it has certainly grasped the opportunities the bubble has provided in an attempt to enforce a process of agential change at the heart of the British economy. The key issue in this respect is the way in which the Government has challenged the legitimacy of passive welfare receipts in favour of establishing a welfare system based on incorporating the individual into an active asset-holding society. The housing market has taken on new political significance as a means for individuals first to acquire assets and then to accumulate wealth on the back of asset ownership. The ensuing integration of the housing market into an increasingly reconfigured welfare system has permeated into the politics of everyday life. It has been consistent with individuals remaking their political subjectivities in line with preferences for the type of conservative monetary policies that typically keep house price bubbles inflated