Spinal Muscular Atrophy Kolb, Stephen J; Kissel, John T
Neurologic clinics,
11/2015, Letnik:
33, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Spinal muscular atrophy is an autosomal-recessive disorder characterized by degeneration of motor neurons in the spinal cord and caused by mutations in the survival motor neuron 1 gene, SMN1. The ...severity of SMA is variable. The SMN2 gene produces a fraction of the SMN messenger RNA (mRNA) transcript produced by the SMN1 gene. There is an inverse correlation between SMN2 gene copy number and clinical severity. Clinical management focuses on multidisciplinary care. Preclinical models of SMA have led to an explosion of SMA clinical trials that hold great promise of effective therapy in the future.
The electrochemical reduction of CO2 is a promising way to store renewable energy in fuels or other chemicals. However, the high overpotential and low efficiency of the reaction hinder the ...development of the area. More work is needed on the investigation of the mechanism in order to obtain new insights into developing efficient catalysts. We report here a density functional theory (DFT) study of the electrochemical reduction of CO2 on cobalt porphyrin. The CO2 – anion adduct is demonstrated to be the key intermediate formed only when the cobalt center of the complex is in the CoI oxidation state. We find that formic acid can be produced as minor product through a Co(P)–(OCHO) intermediate, while CO is the main product through a decoupled proton–electron transfer. CH4 is produced as minor product from subsequent CO reduction by concerted proton-coupled electron transfers assumed for each electrochemical step. Our theoretical interpretations are consistent with the experimental results presented in our recent experiments and give deeper insights into the mechanism of the CO2 electrochemical reduction on cobalt porphyrin complexes.
In this article the sensitivity of manufacturing tolerances on the output of a permanent magnet synchronous machine with stator segmentation is studied. To reduce the simulation effort, a transition ...of the stator segment air gaps to replacement geometry was applied and the relevant parameters are discussed, whereas the uncertainty of geometric and material parameters is modeled with a normal distribution. Furthermore, tolerance chains are expressed through the convolution of independent probability distributions. For the Design of Experiments Sobol sequences are utilized. To further decrease the number of design parameters an approach is presented to reduce redundant parameters to individual design parameters. For the sensitivity analysis the torque and torque ripple serve as quality objectives. In addition, an approach is revealed to use the variance of the radial forces as quality objective without considering mechanical FE simulations. For manufacturing tolerances a linear regression is satisfying to describe the main effects on the quality objectives. Repetitive machine parameters, e.g. the remanences, have less influence on the machine's output than particular parameters such as the housing radius or static eccentricity. The influences of stator segmentation are negligibly small, whereas the housing radius has the highest sensitivity on the machine's output.
Patients with amyotrophic lateral sclerosis (ALS) often have questions about why they developed the disease and the likelihood that family members will also be affected. In recent years, providing ...answers to these questions has become more complex with the identification of multiple novel genes, the newly recognized etiologic link between ALS and frontotemporal dementia (FTD), and the increased availability of commercial genetic testing. A genetic diagnosis is particularly important to establish in the era of emerging gene-based therapies, such as SOD1 antisense oligonucleotide trials. In the span of a few years, ALS genetic testing options have progressed from testing of a single gene to multigene next-generation sequencing panels and whole-exome sequencing. This article provides suggestions for genetic counseling and genetic testing for ALS in this new environment.
Genet Med19 3, 267–274.
Allogeneic stem cell transplantation is a form of immunotherapy that has increased the chances of survival for patients with relapsed leukemia and high risk leukemia in remission. The major obstacles ...are graft‐vs‐host disease (GVHD) involving vital organs and infections. A most efficacious prophylaxis of GVHD is by depleting of T cells from the graft. However, problems of T‐depleted transplants are rejection, slow recovery of the immune system and high incidence of relapse of leukemia and myeloma. The major problem of allogeneic transplantation is the separation of a graft‐vs‐leukemia (GVL) effect from GVHD. This review will summarize the factors influencing GVHD, ways to exploit rapid advances in our knowledge of histocompatibility, chimerism and tolerance for fostering GVL over GVHD, and in particular the use of cellular therapies including donor lymphocyte infusions for disease control.
Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration, paralysis, and death. Accurate disease modeling, identifying disease mechanisms, and developing therapeutics is urgently needed. ...We previously reported motor neuron toxicity through postmortem ALS spinal cord-derived astrocytes. However, these cells can only be harvested after death, and their expansion is limited. We now report a rapid, highly reproducible method to convert adult human fibroblasts from living ALS patients to induced neuronal progenitor cells and subsequent differentiation into astrocytes (i-astrocytes). Non-cell autonomous toxicity to motor neurons is found following coculture of i-astrocytes from familial ALS patients with mutation in superoxide dismutase or hexanucleotide expansion in C9orf72 (ORF 72 on chromosome 9) the two most frequent causes of ALS. Remarkably, i-astrocytes from sporadic ALS patients are as toxic as those with causative mutations, suggesting a common mechanism. Easy production and expansion of i-astrocytes now enables rapid disease modeling and high-throughput drug screening to alleviate astrocyte-derived toxicity.
PDF
