Early changes in brain structure correlate with language outcomes in children with neonatal encephalopathy.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes

Finding black holes in numerical spacetimes

We have constructed a numerical code that finds black hole event horizons in an axisymmetric rotating spacetime. The spacetime is specified numerically by giving metric coefficients on a spatial grid for a series of time slices. The code solves the geodesic equation for light rays emitted from a suitable sample of points in the evolving spacetime. The algorithm for finding the event horizon employs the apparent horizon, which can form much later than the event horizon, to distinguish between light rays that escape to infinity and light rays that are captured. Simple geometries can be diagnosed on a workstation; more complicated cases are computationally intensive. However, the code is easily parallelized and has been efficiently run on the IBM SP-1 parallel machine. We have illustrated the use of the event horizon code on two cases. One is the head-on collision of two black holes that form from the collapse of collisionless matter, coalescing to a single Schwarzschild black hole. The other is the collapse of a rotating toroid to form a Kerr black hole. In this case the horizon initially appears with a toroidal topology. This is the first known example of this phenomenon

All talk and no action: a transcranial magnetic stimulation study of motor cortex activation during action word production

A number of researchers have proposed that the premotor and motor areas are critical for the representation of words that refer to actions, but not objects. Recent evidence against this hypothesis indicates that the left premotor cortex is more sensitive to grammatical differences than to conceptual differences between words. However, it may still be the case that other anterior motor regions are engaged in processing a word's sensorimotor features. In the present study, we used single- and paired-pulse transcranial magnetic stimulation to test the hypothesis that left primary motor cortex is activated during the retrieval of words (nouns and verbs) associated with specific actions. We found that activation in the motor cortex increased for action words compared with non-action words, but was not sensitive to the grammatical category of the word being produced. These results complement previous findings and support the notion that producing a word activates some brain regions relevant to the sensorimotor properties associated with that word regardless of its grammatical category

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

BackgroundAmyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM.ResultsWe find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1-/- had increased brain Aβ42, whereas Cyp7b1-/- mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency.ConclusionThese data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished

A Genetically Encoded AND Gate for Cell-Targeted Metabolic Labeling of Proteins

We describe a genetic AND gate for cell-targeted metabolic labeling and proteomic analysis in complex cellular systems. The centerpiece of the AND gate is a bisected methionyl-tRNA synthetase (MetRS) that charges the Met surrogate azidonorleucine (Anl) to tRNAMet. Cellular protein labeling occurs only upon activation of two different promoters that drive expression of the N- and C-terminal fragments of the bisected MetRS. Anl-labeled proteins can be tagged with fluorescent dyes or affinity reagents via either copper-catalyzed or strain-promoted azide–alkyne cycloaddition. Protein labeling is apparent within 5 min after addition of Anl to bacterial cells in which the AND gate has been activated. This method allows spatial and temporal control of proteomic labeling and identification of proteins made in specific cellular subpopulations. The approach is demonstrated by selective labeling of proteins in bacterial cells immobilized in the center of a laminar-flow microfluidic channel, where they are exposed to overlapping, opposed gradients of inducers of the N- and C-terminal MetRS fragments. The observed labeling profile is predicted accurately from the strengths of the individual input signals

Increased wind risk from sting-jet windstorms with climate change

Extra-tropical cyclones dominate autumn and winter weather over western Europe. The strongest cyclones, often termed windstorms, have a large socio-economic impact on landfall due to strong surface winds and coastal storm surges. Climate model integrations have predicted a future increase in the frequency of, and potential damage from, European windstorms and yet these integrations cannot properly represent localised jets, such as sting jets, that may significantly enhance damage. Here we present the first prediction of how the climatology of sting-jet-containing cyclones will change in a future warmer climate, considering the North Atlantic and Europe. A proven sting-jet precursor diagnostic is applied to 13-year present-day and future ($\sim$2100) climate integrations from the Met Office Unified Model in its Global Atmosphere 3.0 configuration. The present-day climate results are consistent with previously-published results from a reanalysis dataset (with around 32\% of cyclones exhibiting the sing-jet precursor), lending credibility to the analysis of the future-climate integration. The proportion of cyclones exhibiting the sting-jet precursor in the future-climate integration increases to 45\%. Furthermore, while the proportion of explosively-deepening storms increases only slightly in the future climate, the proportion of those storms with the sting-jet precursor increases by 60\%. The European resolved-wind risk associated with explosively-deepening storms containing a sting-jet precursor increases substantially in the future climate; in reality this wind risk is likely to be further enhanced by the release of localised moist instability, unresolved by typical climate models

Binary-induced collapse of a compact, collisionless cluster

We improve and extend Shapiro's model of a relativistic, compact object which is stable in isolation but is driven dynamically unstable by the tidal field of a binary companion. Our compact object consists of a dense swarm of test particles moving in randomly-oriented, initially circular, relativistic orbits about a nonrotating black hole. The binary companion is a distant, slowly inspiraling point mass. The tidal field of the companion is treated as a small perturbation on the background Schwarzschild geometry near the hole; the resulting metric is determined by solving the perturbation equations of Regge and Wheeler and Zerilli in the quasi-static limit. The perturbed spacetime supports Bekenstein's conjecture that the horizon area of a near-equilibrium black hole is an adiabatic invariant. We follow the evolution of the system and confirm that gravitational collapse can be induced in a compact collisionless cluster by the tidal field of a binary companion.Comment: 9 Latex pages, 14 postscript figure

Testing for Network and Spatial Autocorrelation

Testing for dependence has been a well-established component of spatial statistical analyses for decades. In particular, several popular test statistics have desirable properties for testing for the presence of spatial autocorrelation in continuous variables. In this paper we propose two contributions to the literature on tests for autocorrelation. First, we propose a new test for autocorrelation in categorical variables. While some methods currently exist for assessing spatial autocorrelation in categorical variables, the most popular method is unwieldy, somewhat ad hoc, and fails to provide grounds for a single omnibus test. Second, we discuss the importance of testing for autocorrelation in data sampled from the nodes of a network, motivated by social network applications. We demonstrate that our proposed statistic for categorical variables can both be used in the spatial and network setting

A prospective registry of emergency department patients admitted with infection

<p>Abstract</p> <p>Background</p> <p>Patients with infections account for a significant proportion of Emergency Department (ED) workload, with many hospital patients admitted with severe sepsis initially investigated and resuscitated in the ED. The aim of this registry is to systematically collect quality observational clinical and microbiological data regarding emergency patients admitted with infection, in order to explore in detail the microbiological profile of these patients, and to provide the foundation for a significant programme of prospective observational studies and further clinical research.</p> <p>Methods/design</p> <p>ED patients admitted with infection will be identified through daily review of the computerised database of ED admissions, and clinical information such as site of infection, physiological status in the ED, and components of management abstracted from patients' charts. This information will be supplemented by further data regarding results of investigations, microbiological isolates, and length of stay (LOS) from hospital electronic databases. Outcome measures will be hospital and intensive care unit (ICU) LOS, and mortality endpoints derived from a national death registry.</p> <p>Discussion</p> <p>This database will provide substantial insights into the characteristics, microbiological profile, and outcomes of emergency patients admitted with infections. It will become the nidus for a programme of research into compliance with evidence-based guidelines, optimisation of empiric antimicrobial regimens, validation of clinical decision rules and identification of outcome determinants. The detailed observational data obtained will provide a solid baseline to inform the design of further controlled trials planned to optimise treatment and outcomes for emergency patients admitted with infections.</p