67 research outputs found
Latent cluster analysis of ALS phenotypes identifies prognostically differing groups
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes.
METHODS
Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method.
RESULTS
The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001).
CONCLUSION
The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research
Литейная форма
Полезная модель относится к литейным формам, имеющим защитное покрытие. Технической задачей полезной модели является создание литейных форм, в том числе и крупных с красочным слоем на рабочей поверхности, обеспечивающей получение тяжелых отливок без ужимин и газовых раковин. Поставленная задача решается за счет того, что красочный защитный слой формы выполнен дискретным, а именно в виде отдельных окрашенных площадок, с зазорами между ними из неокрашенной поверхности формы. Зазоры между отдельными площадками краски позволяют при заполнении формы расплавом свободно удалятся газам, образующимся в стенке формы, а площадкам свободно расширяться, кроме того, абсолютное значение температурного расширения каждой отдельной площадки будет во много раз меньше непрерывного слоя краски, тем самым исключается уровень напряжений способный отслоить краску от стенки формы
Электрод для электроискрового легирования
Полезная модель относится к электрофизическим и электрохимическим методам обработки, в частности к электродным материалам для электроискрового легирования металлических поверхностей. Технической задачей полезной модели является получение электродов для электроискрового легирования, которые увеличили бы массоперенос и соответственно эффективность процесса упрочнения детали. Техническая задача достигается за счет того, что электрод для электроискрового легирования, содержащий хром и другие химические элементы, выполненный полым и обдуваемым охладителем с внутренней и внешней стороны, дополнительно выполнен с покрытием, а в качестве покрытия используют обмазку на основе огнеупорной каолиновой глины толщиной 0,2-0,5 мм
Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS.
Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS
Benchmark thermochemistry of the C_nH_{2n+2} alkane isomers (n=2--8) and performance of DFT and composite ab initio methods for dispersion-driven isomeric equilibria
The thermochemistry of linear and branched alkanes with up to eight carbons
has been reexamined by means of W4, W3.2lite and W1h theories. `Quasi-W4'
atomization energies have been obtained via isodesmic and hypohomodesmotic
reactions. Our best atomization energies at 0 K (in kcal/mol) are: 1220.04
n-butane, 1497.01 n-pentane, 1774.15 n-hexane, 2051.17 n-heptane, 2328.30
n-octane, 1221.73 isobutane, 1498.27 isopentane, 1501.01 neopentane, 1775.22
isohexane, 1774.61 3-methylpentane, 1775.67 diisopropyl, 1777.27 neohexane,
2052.43 isoheptane, 2054.41 neoheptane, 2330.67 isooctane, and 2330.81
hexamethylethane. Our best estimates for are: -30.00
n-butane, -34.84 n-pentane, -39.84 n-hexane, -44.74 n-heptane, -49.71 n-octane,
-32.01 isobutane, -36.49 isopentane, -39.69 neopentane, -41.42 isohexane,
-40.72 3-methylpentane, -42.08 diisopropyl, -43.77 neohexane, -46.43
isoheptane, -48.84 neoheptane, -53.29 isooctane, and -53.68 hexamethylethane.
These are in excellent agreement (typically better than 1 kJ/mol) with the
experimental heats of formation at 298 K obtained from the CCCBDB and/or NIST
Chemistry WebBook databases. However, at 0 K a large discrepancy between theory
and experiment (1.1 kcal/mol) is observed for only neopentane. This deviation
is mainly due to the erroneous heat content function for neopentane used in
calculating the 0 K CCCBDB value. The thermochemistry of these systems,
especially of the larger alkanes, is an extremely difficult test for density
functional methods. A posteriori corrections for dispersion are essential.
Particularly for the atomization energies, the B2GP-PLYP and B2K-PLYP
double-hybrids, and the PW6B95 hybrid-meta GGA clearly outperform other DFT
functionals.Comment: (J. Phys. Chem. A, in press
Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis
Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity
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