julilili42/papers huggingface dataset:
Targeted next generation sequencing as a diagnostic tool in epileptic disorders
2012-05-21

Summary Purpose: Epilepsies have a highly heterogeneous background with a strong genetic contribution. The variety of unspecific and overlapping syndromic and nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents straightforward genetic testing. Knowing the genetic basis of a patient’s epilepsy can be valuable not only for diagnosis but also for guiding treatment and estimating recurrence risks. Methods: To overcome these diagnostic restrictions, we composed a panel of genes for Next Generation Sequencing containing the most relevant epilepsy genes and covering the most relevant epilepsy phenotypes known so far. With this method, 265 genes were analyzed per patient in a single step. We evaluated this panel on a pilot cohort of 33 index patients with concise epilepsy phenotypes or with a severe but unspecific seizure disorder covering both sporadic and familial cases. Key Findings: We identified presumed disease‐causing mutations in 16 of 33 patients comprising sequence alterations in frequently as well as in less commonly affected genes. The detected aberrations encompassed known and unknown point mutations ( SCN1A p.R222X, p. E289V, p.379R, p.R393H; SCN2A p.V208E; STXBP1 p.R122X; KCNJ10 p.L68P, p.I129V; KCTD7 p.L108M; KCNQ3 p.P574S; ARHGEF9 p.R290H; SMS p.F58L; TPP1 p.Q278R, p.Q422H; MFSD8 p.T294K), a putative splice site mutation ( SCN1A c.693A&gt; p.T/P231P) and small deletions ( SCN1A p.F1330L fs 3X [1 bp]; MFSD8 p.A138D fs 10X [7 bp]). All mutations have been confirmed by conventional Sanger sequencing and, where possible, validated by parental testing and segregation analysis. In three patients with either Dravet syndrome or myoclonic epilepsy, we detected SCN1A mutations (p.R222X, p.P231P, p.R393H), even though other laboratories had previously excluded aberrations of this gene by Sanger sequencing or high‐resolution melting analysis. Significance: We have developed a fast and cost‐efficient diagnostic screening method to analyze the genetic basis of epilepsies. We were able to detect mutations in patients with clear and with unspecific epilepsy phenotypes, to uncover the genetic basis of many so far unresolved cases with epilepsy including mutation detection in cases in which previous conventional methods yielded falsely negative results. Our approach thus proved to be a powerful diagnostic tool that may contribute to collecting information on both common and unknown epileptic disorders and in delineating associated phenotypes of less frequently mutated genes.
Harmonization of the intracellular cytokine staining assay
2012-05-21

Active immunotherapy for cancer is an accepted treatment modality aiming to reinforce the T-cell response to cancer. T-cell reactivity is measured by various assays and used to guide the clinical development of immunotherapeutics. However, data obtained across different institutions may vary substantially making comparative conclusions difficult. The Cancer Immunotherapy Immunoguiding Program organizes proficiency panels to identify key parameters influencing the outcome of commonly used T-cell assays followed by harmonization. Our successes with IFNγ-ELISPOT and peptide HLA multimer analysis have led to the current study on intracellular cytokine staining (ICS). We report the results of three successive panels evaluating this assay. At the beginning, 3 out of 9 participants (33 %) were able to detect >6 out of 8 known virus-specific T-cell responses in peripheral blood of healthy individuals. This increased to 50 % of the laboratories in the second phase. The reported percentages of cytokine-producing T cells by the different laboratories were highly variable with coefficients of variation well over 60 %. Variability could partially be explained by protocol-related differences in background cytokine production leading to sub-optimal signal-to-noise ratios. The large number of protocol variables prohibited identification of prime guidelines to harmonize the assays. In addition, the gating strategy used to identify reactive T cells had a major impact on assay outcome. Subsequent harmonization of the gating strategy considerably reduced the variability within the group of participants. In conclusion, we propose that first basic guidelines should be applied for gating in ICS experiments before harmonizing assay protocol variables.
Analysis of ice phenology of lakes on the Tibetan Plateau from MODIS data
2012-05-21

Abstract. Much attention has recently been paid to the impact of climate change at the Tibetan Plateau. This remote and harsh region includes a large system of endorheic (closed basin) lakes. Ice phenology i.e. the timing of freeze-up and break-up and the duration of the ice cover may provide valuable information about climate variations in this region. The ice phenology of 59 large lakes on the Tibetan Plateau was derived from Moderate Resolution Imaging Spectroradiometer (MODIS) 8-day composite data for the period from 2001 to 2010. Duration of the ice cover appears to have a high variability in the studied region due to both climate and local factors. Mean values for the duration of ice cover were calculated for four groups of lakes defined as distinct geographic regions. In each group several lakes showed anomalies in ice cover duration in the studied period. Possible reasons for such anomalous behavior are discussed. Furthermore, many lakes do not freeze up completely during some seasons. This was confirmed by inspection of high resolution optical data. Mild winter seasons, large water volume and/or high salinity are the most likely explanations. Trends in the ice cover duration derived by linear regression for all the studied lakes show a high variation in space. A correlation of ice phenology variables with parameters describing climatic and local conditions showed a high thermal dependency of the ice regime. It appears that the freeze onset and water clean of ice day appear to be more thermally determined than freeze-up and break-up dates in case of the studied lakes.
COMT × DRD4 Epistasis Impacts Prefrontal Cortex Function Underlying Response Control
2012-05-22

The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder). DRD4 and COMT epistatically interacted on the NGA, whereas single genes and diagnosis showed no significant impact. Subjects with presumably relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an inverted U-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose effects and mirrored by reaction time variability (non-significant after multiple testing correction). Combining previous theories of prefrontal DA functioning, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. Our findings might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function.
Determination of content uniformity of busulfan capsules by liquid chromatography–mass spectrometry
2012-05-22

<h3>Study objectives</h3> Oral high dose busulfan (1,4-butanediol dimethanesulfonate) is frequently used in conditioning regimens prior to haematopoietic stem cell transplantation. As tablets with high dose busulfan are not commercially available, it is common practice to extemporaneously prepare capsules in hospital pharmacies. However, proper content uniformity assays are lacking. <h3>Methods</h3> An HPLC–mass spectrometry (MS) method that was previously validated for quantification of plasma levels of busulfan was adapted for determination of the content uniformity of capsules comprising 50 mg of busulfan for high dose regimens. <h3>Results</h3> Intraday and interday variability and imprecision were less than 2.2%. <h3>Conclusions</h3> The data indicate high specificity and sensitivity of this novel assay.
PRRT2 Mutations are the major cause of benign familial infantile seizures
2012-05-23

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone.
Mass spectrometric identification of novel posttranslational modification sites in Huntingtin
2012-05-23

Huntington's disease ( HD ) is caused by a CAG triplet repeat expansion in exon 1 of the H untingtin ( H tt) gene, encoding an abnormal expanded polyglutamine (poly Q ) tract that confers toxicity to the mutant H tt (m H tt) protein. Recent data suggest that posttranslational modifications of m H tt modulate its cytotoxicity. To further understand the cytotoxic mechanisms of m H tt, we have generated HEK 293 cell models stably expressing S trep‐ and FLAG ‐tagged H tt containing either 19 Q (wild‐type H tt), 55 Q (m H tt), or 94 Q (m H tt) repeats. Following tandem affinity purification, the tagged H tt and associated proteins were subjected to tandem mass spectrometry or 2 D nano‐ LC tandem mass spectrometry and several novel modification sites of m H tt containing 55 Q or 94 Q were identified. These were phosphorylation sites located at S er431 and S er432, and ubiquitination site located at L ys444. The two phosphorylation sites were confirmed by W estern blot analysis using phosphorylation site‐specific antibodies. In addition, prevention of phosphorylation at the two serine sites altered m H tt toxicity and accumulation. These modifications of m H tt may provide novel therapeutic targets for effective treatment of the disorder.
Generalized parton distributions in an AdS/QCD hard-wall model
2012-05-23

We use a matching procedure of sum rules relating the electromagnetic form factors to generalized parton distributions (GPDs) and AdS modes. In this way, in the framework of an AdS/QCD hard-wall model, the helicity-independent GPDs of quarks for the nucleon in the zero skewness case are calculated.
Spectral formation in accreting X-ray pulsars: bimodal variation of the cyclotron energy with luminosity
2012-05-24

Accretion-powered X-ray pulsars exhibit significant variability of the\\nCyclotron Resonance Scattering Feature (CRSF) centroid energy on pulse-to-pulse\\ntimescales, and also on much longer timescales. Two types of spectral\\nvariability are observed. For sources in group 1, the CRSF energy is negatively\\ncorrelated with the variable source luminosity, and for sources in group 2, the\\nopposite behavior is observed. The physical basis for this bimodal behavior is\\ncurrently not understood. We explore the hypothesis that the accretion dynamics\\nin the group 1 sources is dominated by radiation pressure near the stellar\\nsurface, and that Coulomb interactions decelerate the gas to rest in the group\\n2 sources. We derive a new expression for the critical luminosity such that\\nradiation pressure decelerates the matter to rest in the supercritical sources.\\nThe formula for the critical luminosity is evaluated for 5 sources, using the\\nmaximum value of the CRSF centroid energy to estimate the surface magnetic\\nfield strength. The results confirm that the group 1 sources are supercritical\\nand the group 2 sources are subcritical, although the situation is less clear\\nfor those highly variable sources that cross over the critical line. We also\\nexplain the variation of the CRSF energy with luminosity as a consequence of\\nthe variation of the characteristic emission height. The sign of the height\\nvariation is opposite in the supercritical and subcritical cases, hence\\ncreating the observed bimodal behavior.\\n
Clinical Significance of Impaired Cerebrovascular Autoregulation After Severe Aneurysmal Subarachnoid Hemorrhage
2012-05-24

Background and Purpose— The purpose of this study was to investigate the relationship between cerebrovascular autoregulation and outcome after aneurysmal subarachnoid hemorrhage. Methods— In a prospective observational study, 80 patients after severe subarachnoid hemorrhage were continuously monitored for cerebral perfusion pressure and partial pressure of brain tissue oxygen for an average of 7.9 days (range, 1.9–14.9 days). Autoregulation was assessed using the index of brain tissue oxygen pressure reactivity (ORx), a moving correlation coefficient between cerebral perfusion pressure and partial pressure of brain tissue oxygen. High ORx indicates impaired autoregulation; low ORx signifies intact autoregulation. Outcome was determined at 6 months and dichotomized into favorable (Glasgow Outcome Scale 4–5) and unfavorable outcome (Glasgow Outcome Scale 1–3). Results— Twenty-four patients had a favorable and 56 an unfavorable outcome. In a univariate analysis, there were significant differences in autoregulation (ORx 0.19±0.10 versus 0.37±0.11, P &lt;0.001, for favorable versus unfavorable outcome, respectively), age (44.1±11.0 years versus 54.2±12.1 years, P =0.001), occurrence of delayed cerebral infarction (8% versus 46%, P &lt;0.001), use of coiling (25% versus 54%, P =0.02), partial pressure of brain tissue oxygen (24.9±6.6 mm Hg versus 21.8±6.3 mm Hg, P =0.048), and Fisher grade ( P =0.03). In a multivariate analysis, ORx ( P &lt;0.001) and age ( P =0.003) retained an independent predictive value for outcome. ORx correlated with Glasgow Outcome Scale ( r =−0.70, P &lt;0.001). Conclusions— The status of cerebrovascular autoregulation might be an important pathophysiological factor in the disease process after subarachnoid hemorrhage, because impaired autoregulation was independently associated with an unfavorable outcome.
The Role of Conserved PEX3 Regions in PEX19‐Binding and Peroxisome Biogenesis
2012-05-24

Abstract The human peroxins PEX3 and PEX19 are essential for peroxisome biogenesis. They mediate the import of membrane proteins as well as the de novo formation of peroxisomes. PEX19 binds newly synthesized peroxisomal membrane proteins post‐translationally and directs them to peroxisomes by engaging PEX3 , a protein anchored in the peroxisomal membrane. After protein insertion into the lipid bilayer, PEX19 is released back to the cytosol. Crystallographic analysis provided detailed insights into the PEX3–PEX19 interaction and identified three highly conserved regions, the PEX19 ‐binding region, a hydrophobic groove and an acidic cluster, on the surface of PEX3 . Here, we used site‐directed mutagenesis and biochemical and functional assays to determine the role of these regions in PEX19 ‐binding and peroxisome biogenesis. Mutations in the PEX19 ‐binding region reduce the affinity for PEX19 and destabilize PEX3 . Furthermore, we provide evidence for a crucial function of the PEX3–PEX19 complex during de novo formation of peroxisomes in peroxisome‐deficient cells, pointing to a dual function of the PEX3–PEX19 interaction in peroxisome biogenesis. The maturation of preperoxisomes appears to require the hydrophobic groove near the base of PEX3 , presumably by its involvement in peroxisomal membrane protein insertion, while the acidic cluster does not appear to be functionally relevant.
The Novel Phenylpropiophenone Derivates Induced Relaxation of Isolated Rat Aorta
2012-05-24

Our aim was to define how different chemical properties of newly developed phenylpropiophenone derivates (PhPds) influenced their potency and efficacy to relax rat aorta. A contribution of ion channels in the PhPds and propafenone mechanism of vasodilatation was tested. PhPds were syntethysed by substitution in the benzyl moiety with -F, -CH3 or -CF3 groups on the ortho or para position. The vasodilatation by PhPds was examined on the rings of rat aorta precontracted with phenylephrine. In order to test involvement of voltage-gated Na+ and K+ channels and L-type Ca2+ channels in a mechanism of action of PhPds, we used their blockers: lidocaine, nifedipine and 4-aminopiridine, respectively. Aorta was more sensitive to 5-ortho-trifluoromethyl derivate than to propafenone and other PhPds. The 5-para-methyl derivate had lower potency and efficacy than propafenone and other PhPds. Lidocaine did not influenced relaxation induced by PhPds, but slightly inhibited the effect of propafenone. The 4-aminopiridine only inhibited relaxation induced by 5-para-methyl derivate. Nifedipine inhibited relaxation of the rat aorta induced by 5-ortho-trifluoromethyl derivate and by propafenone. Introduction of 5-ortho-trifluoromethyl and 5-para-methyl group in the benzyl moiety of propafenone molecule changed its potency, efficacy and mechanism of action in the rat aorta. The 4-aminopiridine- and nifedipine sensitive ion channels are involved in mechanism of action of 5-para-methyl and 5-ortho-trifluoromethyl derivate. The introduction of other tested groups in the benzyl moiety does not affect pharmacological properties of the PhPds in relation to propafenone.
Interstitial 9q34.11–q34.13 deletion in a patient with severe intellectual disability, hydrocephalus, and cleft lip/palate
2012-05-25

Abstract Interstitial deletions of chromosome bands 9q34.11–q34.13 are rare. We report on a 16‐year‐old female patient with severe intellectual disability, congenital hydrocephalus, cleft lip and palate, talipes equinovarus, epilepsy, kyphoscoliosis, convergent strabismus, severe short stature, dystrophy, and facial dysmorphic signs. Array analysis revealed a 3.7 Mb interstitial deletion in 9q34.11–q34.13. The deletion harbors more than 60 genes, including SPTAN1 , DYT1/TOR1A , ABL1 , ASS1 , LAMC3 , POMT1 , DOLK , and GLE1 , mutations in which have previously been associated with monogenic disorders. This is the first patient with a deletion of this size and position in 9q34.11–q34.13. Reports of additional patients with aberrations in this region will be needed to establish karyotype–phenotype correlations and to gain information on the contribution of individual genes for the clinical manifestations. © 2012 Wiley Periodicals, Inc.
Outburst of GX 304–1 monitored with INTEGRAL: positive correlation between the cyclotron line energy and flux
2012-05-25

Context. X-ray spectra of many accreting pulsars exhibit significant variations as a function of flux and thus of mass accretion rate. In some of these pulsars, the centroid energy of the cyclotron line(s), which characterizes the magnetic field strength at the site of the X-ray emission, has been found to vary systematically with flux. Aims. GX 304−1 is a recently established cyclotron line source with a line energy around 50 keV. Since 2009, the pulsar shows regular outbursts with the peak flux exceeding one Crab. We analyze the INTEGRAL observations of the source during its outburst in January − February 2012. Methods. The observations covered almost the entire outburst, allowing us to measure the source’s broad-band X-ray spectrum at different flux levels. We report on the variations in the spectral parameters with luminosity and focus on the variations in the cyclotron line. Results. The centroid energy of the line is found to be positively correlated with the luminosity. We interpret this result as a manifestation of the local sub-Eddington (sub-critical) accretion regime operating in the source.
Chain-length dependent growth dynamics of n-alkanes on silica investigated by energy-dispersive x-ray reflectivity in situ and in real-time
2012-05-28

We compare the growth dynamics of the three n-alkanes C36H74, C40H82, and C44H90 on SiO2 using real-time and in situ energy-dispersive x-ray reflectivity. All molecules investigated align in an upright-standing orientation on the substrate and exhibit a transition from layer-by-layer growth to island growth after about 4 monolayers under the conditions employed. Simultaneous fits of the reflected intensity at five distinct points in reciprocal space show that films formed by longer n-alkanes roughen faster during growth. This behavior can be explained by a chain-length dependent height of the Ehrlich-Schwoebel barrier. Further x-ray diffraction measurements after growth indicate that films consisting of longer n-alkanes also incorporate more lying-down molecules in the top region. While the results reveal behavior typical for chain-like molecules, the findings can also be useful for the optimization of organic field effect transistors where smooth interlayers of n-alkanes without coexistence of two or more molecular orientations are required.
Enhancing learners’ visual search in video cases
2012-05-28

Balslev, T., Jarodzka, H., Holmqvist, K., Nyström, M., Scheiter, K., Gerjets, P., &amp; Eika, B. (2012, May). Enhancing learners’ visual search in video cases. Poster presented at the International Child Neurology Association (ICNA) congress, Brisbane, Australia.
Resting State Changes in Functional Connectivity Correlate With Movement Recovery for BCI and Robot-Assisted Upper-Extremity Training After Stroke
2012-05-29

Background. Robot-assisted training may improve motor function in some hemiparetic patients after stroke, but no physiological predictor of rehabilitation progress is reliable. Resting state functional magnetic resonance imaging (RS-fMRI) may serve as a method to assess and predict changes in the motor network. Objective. The authors examined the effects of upper-extremity robot-assisted rehabilitation (MANUS) versus an electroencephalography-based brain computer interface setup with motor imagery (MI EEG-BCI) and compared pretreatment and posttreatment RS-fMRI. Methods. In all, 9 adults with upper-extremity paresis were trained for 4 weeks with a MANUS shoulder-elbow robotic rehabilitation paradigm. In 3 participants, robot-assisted movement began if no voluntary movement was initiated within 2 s. In 6 participants, MI-BCI–based movement was initiated if motor imagery was detected. RS-fMRI and Fugl-Meyer (FM) upper-extremity motor score were assessed before and after training. Results. The individual gain in FM scores over 12 weeks could be predicted from functional connectivity changes (FCCs) based on the pre-post differences in RS-fMRI measurements. Both the FM gain and FCC were numerically higher in the MI-BCI group. Increases in FC of the supplementary motor area, the contralesional and ipsilesional motor cortex, and parts of the visuospatial system with mostly association cortex regions and the cerebellum correlated with individual upper-extremity function improvement. Conclusion. FCC may predict the steepness of individual motor gains. Future training could therefore focus on directly inducing these beneficial increases in FC. Evaluation of the treatment groups suggests that MI is a potential facilitator of such neuroplasticity.