Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro

Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by mutations in the SPTLC1 or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase (SPT). SPT catalyzes the first step of de novo sphingolipid synthesis. Mutations in SPT result in a change in enzyme substrate specificity, which causes the production of atypical deoxysphinganine and deoxymethylsphinganine, rather than the normal enzyme product, sphinganine. Levels of these abnormal compounds are elevated in blood of HSN-1 patients and this is thought to cause the peripheral motor and sensory nerve damage that is characteristic of the disease, by a largely unresolved mechanism. In this study, we show that exogenous application of these deoxysphingoid bases causes dose- and time-dependent neurotoxicity in primary mammalian neurons, as determined by analysis of cell survival and neurite length. Acutely, deoxysphingoid base neurotoxicity manifests in abnormal Ca2+ handling by the endoplasmic reticulum (ER) and mitochondria as well as dysregulation of cell membrane store-operated Ca2+ channels. The changes in intracellular Ca2+ handling are accompanied by an early loss of mitochondrial membrane potential in deoxysphingoid base-treated motor and sensory neurons. Thus, these results suggest that exogenous deoxysphingoid base application causes neuronal mitochondrial dysfunction and Ca2+ handling deficits, which may play a critical role in the pathogenesis of HSN-1

Initial conditions, Discreteness and non-linear structure formation in cosmology

In this lecture we address three different but related aspects of the initial continuous fluctuation field in standard cosmological models. Firstly we discuss the properties of the so-called Harrison-Zeldovich like spectra. This power spectrum is a fundamental feature of all current standard cosmological models. In a simple classification of all stationary stochastic processes into three categories, we highlight with the name ``super-homogeneous'' the properties of the class to which models like this, with $P(0)=0$, belong. In statistical physics language they are well described as glass-like. Secondly, the initial continuous density field with such small amplitude correlated Gaussian fluctuations must be discretised in order to set up the initial particle distribution used in gravitational N-body simulations. We discuss the main issues related to the effects of discretisation, particularly concerning the effect of particle induced fluctuations on the statistical properties of the initial conditions and on the dynamical evolution of gravitational clustering.Comment: 28 pages, 1 figure, to appear in Proceedings of 9th Course on Astrofundamental Physics, International School D. Chalonge, Kluwer, eds N.G. Sanchez and Y.M. Pariiski, uses crckapb.st pages, 3 figure, ro appear in Proceedings of 9th Course on Astrofundamental Physics, International School D. Chalonge, Kluwer, Eds. N.G. Sanchez and Y.M. Pariiski, uses crckapb.st

A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24

Meckel-Gruber syndrome (MKS), the most common monogenic cause of neural tube defects, is an autosomal recessive disorder characterised by a combination of renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalcoele), hepatic ductal dysplasia and cysts, and polydactyly. Locus heterogeneity has been demonstrated by the mapping of the MKS1 locus to 17q21-24 in Finnish kindreds, and of MKS2 to 11q13 in North African-Middle Eastern cohorts. In the present study, we have investigated the genetic basis of MKS in eight consanguineous kindreds, originating from the Indian sub-continent, that do not show linkage to either MKS1 or MKS2. We report the localisation of a third MKS locus (MKS3) to chromosome 8q24 in this cohort by a genome-wide linkage search using autozygosity mapping. We identified a 26-cM region of autozygosity between D8S586 and D8S1108 with a maximum cumulative two-point LOD score at D8S1179 (Z(max)=3.04 at theta=0.06). A heterogeneity test provided evidence of one unlinked family. Exclusion of this family from multipoint analysis maximised the cumulative multipoint LOD score at locus D8S1128 (Z(max)=5.65). Furthermore, a heterozygous SNP in DDEF1, a putative candidate gene, suggested that MKS3 mapped within a 15-cM interval. Comparison of the clinical features of MKS3-linked cases with reports of MKS1- and MKS2-linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3-linked families

Microstructured reactor as a pre-turbo catalytic converter

The idea of a structured catalytic converter placed immediately after engine exhaust valves, thus operating on high gas temperature and velocity, is explored. The assumption is that major part of the reactor operates in the entry region where Nusselt and Sherwood numbers are highly enhanced. In this work, flow resistances as well as heat and mass transfer coefficients were studied for gas velocities exceeding 50 m/s. Consequently, the transition range (between laminar and turbulent flows) was reached. The comparison with classic monolith has shown significant improvement in heat or mass transfer paid by slight increase in flow resistance

Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers

Bolus characteristics based on Magnetic Resonance Angiography

BACKGROUND: A detailed contrast bolus propagation model is essential for optimizing bolus-chasing Computed Tomography Angiography (CTA). Bolus characteristics were studied using bolus-timing datasets from Magnetic Resonance Angiography (MRA) for adaptive controller design and validation. METHODS: MRA bolus-timing datasets of the aorta in thirty patients were analyzed by a program developed with MATLAB. Bolus characteristics, such as peak position, dispersion and bolus velocity, were studied. The bolus profile was fit to a convolution function, which would serve as a mathematical model of bolus propagation in future controller design. RESULTS: The maximum speed of the bolus in the aorta ranged from 5–13 cm/s and the dwell time ranged from 7–13 seconds. Bolus characteristics were well described by the proposed propagation model, which included the exact functional relationships between the parameters and aortic location. CONCLUSION: The convolution function describes bolus dynamics reasonably well and could be used to implement the adaptive controller design

Maximal aerobic and anaerobic power generation in large crocodiles versus mammals: implications for dinosaur gigantothermy

Inertial homeothermy, the maintenance of a relatively constant body temperature that occurs simply because of large size, is often applied to large dinosaurs. Moreover, biophysical modelling and actual measurements show that large crocodiles can behaviourally achieve body temperatures above 30°C. Therefore it is possible that some dinosaurs could achieve high and stable body temperatures without the high energy cost of typical endotherms. However it is not known whether an ectothermic dinosaur could produce the equivalent amount of muscular power as an endothermic one. To address this question, this study analyses maximal power output from measured aerobic and anaerobic metabolism in burst exercising estuarine crocodiles, Crocodylus porosus, weighing up to 200 kg. These results are compared with similar data from endothermic mammals. A 1 kg crocodile at 30°C produces about 16 watts from aerobic and anaerobic energy sources during the first 10% of exhaustive activity, which is 57% of that expected for a similarly sized mammal. A 200 kg crocodile produces about 400 watts, or only 14% of that for a mammal. Phosphocreatine is a minor energy source, used only in the first seconds of exercise and of similar concentrations in reptiles and mammals. Ectothermic crocodiles lack not only the absolute power for exercise, but also the endurance, that are evident in endothermic mammals. Despite the ability to achieve high and fairly constant body temperatures, therefore, large, ectothermic, crocodile-like dinosaurs would have been competitively inferior to endothermic, mammal-like dinosaurs with high aerobic power. Endothermy in dinosaurs is likely to explain their dominance over mammals in terrestrial ecosystems throughout the Mesozoic.Roger S. Seymou

Age-related changes in global motion coherence: conflicting haemodynamic and perceptual responses

Our aim was to use both behavioural and neuroimaging data to identify indicators of perceptual decline in motion processing. We employed a global motion coherence task and functional Near Infrared Spectroscopy (fNIRS). Healthy adults (n = 72, 18-85) were recruited into the following groups: young (n = 28, mean age = 28), middle-aged (n = 22, mean age = 50), and older adults (n = 23, mean age = 70). Participants were assessed on their motion coherence thresholds at 3 different speeds using a psychophysical design. As expected, we report age group differences in motion processing as demonstrated by higher motion coherence thresholds in older adults. Crucially, we add correlational data showing that global motion perception declines linearly as a function of age. The associated fNIRS recordings provide a clear physiological correlate of global motion perception. The crux of this study lies in the robust linear correlation between age and haemodynamic response for both measures of oxygenation. We hypothesise that there is an increase in neural recruitment, necessitating an increase in metabolic need and blood flow, which presents as a higher oxygenated haemoglobin response. We report age-related changes in motion perception with poorer behavioural performance (high motion coherence thresholds) associated with an increased haemodynamic response