Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development

<p>Abstract</p> <p>Background</p> <p>SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1^-/-mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1^-/-embryo development.</p> <p>Methods</p> <p>Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1^+/+and Aldh5a1^-/-) for each gestational age group. Data was evaluated using the <it>t </it>test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95^thcentile.</p> <p>Results</p> <p>GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1^-/-mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA.</p> <p>Conclusion</p> <p>Our findings indicate early GABAergic alterations in Aldh5a1^-/-mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.</p

Porosities of building limestones: using the solid density to assess data quality

A good knowledge of the volume-fraction porosity is essential in any technical work on porous materials. In construction materials the porosity is commonly measured by the Archimedes buoyancy method, from which the bulk density of the test specimen is also obtained. The porosity and the bulk density together fix the solid density of the specimen, as only two of the three quantities are independent. The solid density, although rarely discussed, is determined by the mineralogy of the specimen, and therefore can provide a valuable check on the accuracy of porosity and bulk density measurements. Our analysis of published data on calcitic limestones shows that the solid density is generally close to the ideal crystallographic density of calcite. Small deviations can often be traced to variations in mineral composition. However some published porosity–density data are inconsistent with the known mineralogy. Deviations which cannot be ascribed to composition may be assumed to arise from measurement errors. We show the value of using the solid density as a quality check on the measured porosity. We recommend that the solid density should always be calculated for this purpose when the Archimedes method is used. This check can be useful also when porosities are measured by helium pycnometry or by mercury intrusion porosimetry

An exact expression to calculate the derivatives of position-dependent observables in molecular simulations with flexible constraints

In this work, we introduce an algorithm to compute the derivatives of physical observables along the constrained subspace when flexible constraints are imposed on the system (i.e., constraints in which the hard coordinates are fixed to configuration-dependent values). The presented scheme is exact, it does not contain any tunable parameter, and it only requires the calculation and inversion of a sub-block of the Hessian matrix of second derivatives of the function through which the constraints are defined. We also present a practical application to the case in which the sought observables are the Euclidean coordinates of complex molecular systems, and the function whose minimization defines the constraints is the potential energy. Finally, and in order to validate the method, which, as far as we are aware, is the first of its kind in the literature, we compare it to the natural and straightforward finite-differences approach in three molecules of biological relevance: methanol, N-methyl-acetamide and a tri-glycine peptideComment: 13 pages, 8 figures, published versio

THE HST/ACS COMA CLUSTER SURVEY. VIII. BARRED DISK GALAXIES IN THE CORE OF THE COMA CLUSTER

We use high-resolution (~0. ��1) F814W Advanced Camera for Surveys (ACS) images from the Hubble Space Telescope ACS Treasury survey of the Coma cluster at z ~ 0.02 to study bars in massive disk galaxies (S0s), as well as low-mass dwarf galaxies in the core of the Coma cluster, the densest environment in the nearby universe. Our study helps to constrain the evolution of bars and disks in dense environments and provides a comparison point for studies in lower density environments and at higher redshifts. Our results are: (1) we characterize the fraction and properties of bars in a sample of 32 bright (MV � -18, M* > 109.5M�) S0 galaxies, which dominate the population of massive disk galaxies in the Coma core. We find that the measurement of a bar fraction among S0 galaxies must be handled with special care due to the difficulty in separating unbarred S0s from ellipticals, and the potential dilution of the bar signature by light from a relatively large, bright bulge. The results depend sensitively on the method used: the bar fraction for bright S0s in the Coma core is 50% ± 11%, 65% ± 11%, and 60% ± 11% based on three methods of bar detection, namely, strict ellipse fit criteria, relaxed ellipse fit criteria, and visual classification. (2)We compare the S0 bar fraction across different environments (the Coma core, A901/902, and Virgo) adopting the critical step of using matched samples and matched methods in order to ensure robust comparisons. We find that the bar fraction among bright S0 galaxies does not show a statistically significant variation (within the error bars of ±11%) across environments which span two orders of magnitude in galaxy number density (n ~ 300–10,000 galaxies Mpc-3) and include rich and poor clusters, such as the core of Coma, the A901/902 cluster, and Virgo. We speculate that the bar fraction among S0s is not significantly enhanced in rich clusters compared to low-density environments for two reasons. First, S0s in rich clusters are less prone to bar instabilities as they are dynamically heated by harassment and are gas poor as a result of ram pressure stripping and accelerated star formation. Second, high-speed encounters in rich clusters may be less effective than slow, strong encounters in inducing bars. (3) We also take advantage of the high resolution of the ACS (~50 pc) to analyze a sample of 333 faint (MV > -18) dwarf galaxies in the Coma core. Using visual inspection of unsharp-masked images, we find only 13 galaxies with bar and/or spiral structure. An additional eight galaxies show evidence for an inclined disk. The paucity of disk structures in Coma dwarfs suggests that either disks are not common in these galaxies or that any disks present are too hot to develop instabilities

RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

Comparing the effectiveness of monetary versus moral motives in environmental campaigning

Environmental campaigns often promote energy conservation by appealing to economic (for example, lower electricity bills) rather than biospheric concerns (for example, reduced carbon emissions), assuming that people are primarily motivated by economic self-interest. However, people also care about maintaining a favourable view of themselves (they want to maintain a 'positive self-concept'), and may prefer to see themselves as 'green' rather than 'greedy'. Consequently, people may find economic appeals less attractive than biospheric appeals. Across two studies, participants indicated feeling better about biospheric ('Want to protect the environment? Check your car's tire pressure') than economic ('Want to save money? Check your car's tire pressure') tyre-check appeals. In a field experiment, we found that an economic tyre-check appeal ('Do you care about your finances? Get a free tire check') elicited significantly less compliance than parallel biospheric and neutral appeals. Together, these studies discredit the conventional wisdom that appealing to economic self-interest is the best way to secure behaviour change. At least in some cases, our studies suggest, this strategy is not effective.</p

Large scale analytic calculations in quantum field theories

We present a survey on the mathematical structure of zero- and single scale quantities and the associated calculation methods and function spaces in higher order perturbative calculations in relativistic renormalizable quantum field theories.Comment: 25 pages Latex, 1 style fil

The burden of neglected tropical diseases in Ethiopia, and opportunities for integrated control and elimination

Background: Neglected tropical diseases (NTDs) are a group of chronic parasitic diseases and related conditions that are the most common diseases among the 2·7 billion people globally living on less than US$2 per day. In response to the growing challenge of NTDs, Ethiopia is preparing to launch a NTD Master Plan. The purpose of this review is to underscore the burden of NTDs in Ethiopia, highlight the state of current interventions, and suggest ways forward. Results: This review indicates that NTDs are significant public health problems in Ethiopia. From the analysis reported here, Ethiopia stands out for having the largest number of NTD cases following Nigeria and the Democratic Republic of Congo. Ethiopia is estimated to have the highest burden of trachoma, podoconiosis and cutaneous leishmaniasis in sub-Saharan Africa (SSA), the second highest burden in terms of ascariasis, leprosy and visceral leishmaniasis, and the third highest burden of hookworm. Infections such as schistosomiasis, trichuriasis, lymphatic filariasis and rabies are also common. A third of Ethiopians are infected with ascariasis, one quarter is infected with trichuriasis and one in eight Ethiopians lives with hookworm or is infected with trachoma. However, despite these high burdens of infection, the control of most NTDs in Ethiopia is in its infancy. In terms of NTD control achievements, Ethiopia reached the leprosy elimination target of 1 case/10,000 population in 1999. No cases of human African trypanosomiasis have been reported since 1984. Guinea worm eradication is in its final phase. The Onchocerciasis Control Program has been making steady progress since 2001. A national blindness survey was conducted in 2006 and the trachoma program has kicked off in some regions. Lymphatic Filariasis, podoconiosis and rabies mapping are underway. Conclusion: Ethiopia bears a significant burden of NTDs compared to other SSA countries. To achieve success in integrated control of NTDs, integrated mapping, rapid scale up of interventions and operational research into co implementation of intervention packages will be crucial

Comparative Analysis of Cervical Spine Management in a Subset of Severe Traumatic Brain Injury Cases Using Computer Simulation

BACKGROUND: No randomized control trial to date has studied the use of cervical spine management strategies in cases of severe traumatic brain injury (TBI) at risk for cervical spine instability solely due to damaged ligaments. A computer algorithm is used to decide between four cervical spine management strategies. A model assumption is that the emergency room evaluation shows no spinal deficit and a computerized tomogram of the cervical spine excludes the possibility of fracture of cervical vertebrae. The study's goal is to determine cervical spine management strategies that maximize brain injury functional survival while minimizing quadriplegia. METHODS/FINDINGS: The severity of TBI is categorized as unstable, high risk and stable based on intracranial hypertension, hypoxemia, hypotension, early ventilator associated pneumonia, admission Glasgow Coma Scale (GCS) and age. Complications resulting from cervical spine management are simulated using three decision trees. Each case starts with an amount of primary and secondary brain injury and ends as a functional survivor, severely brain injured, quadriplegic or dead. Cervical spine instability is studied with one-way and two-way sensitivity analyses providing rankings of cervical spine management strategies for probabilities of management complications based on QALYs. Early collar removal received more QALYs than the alternative strategies in most arrangements of these comparisons. A limitation of the model is the absence of testing against an independent data set. CONCLUSIONS: When clinical logic and components of cervical spine management are systematically altered, changes that improve health outcomes are identified. In the absence of controlled clinical studies, the results of this comparative computer assessment show that early collar removal is preferred over a wide range of realistic inputs for this subset of traumatic brain injury. Future research is needed on identifying factors in projecting awakening from coma and the role of delirium in these cases

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration