Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may ...be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A self-consistent Monte Carlo/3-D Poisson simulator has been developed to analyze the current asymmetry in graphene geometric diodes. The model couples ballistic transport in the graphene layer with ...3-D electrostatics in the graphene and oxide substrate. Results are given in terms of transmission coefficients and currents at the two terminals of the diode. We prove that while the current asymmetry is mainly induced by ballistic transport in the asymmetric structure, the electrostatics plays a relevant role that tends to substantially counterbalance the geometrical effect.
Lineage conversion of one somatic cell type to another is an attractive approach for generating specific human cell types. Lineage conversion can be direct, in the absence of proliferation and ...multipotent progenitor generation, or indirect, by the generation of expandable multipotent progenitor states. We report the development of a reprogramming methodology in which cells transition through a plastic intermediate state, induced by brief exposure to reprogramming factors, followed by differentiation. We use this approach to convert human fibroblasts to mesodermal progenitor cells, including by non-integrative approaches. These progenitor cells demonstrated bipotent differentiation potential and could generate endothelial and smooth muscle lineages. Differentiated endothelial cells exhibited neo-angiogenesis and anastomosis in vivo. This methodology for indirect lineage conversion to angioblast-like cells adds to the armamentarium of reprogramming approaches aimed at the study and treatment of ischemic pathologies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We propose a new, simple approach to enhance the spectral compression process arising from nonlinear pulse propagation in an optical fiber. We numerically show that an additional sinusoidal temporal ...phase modulation of the pulse enables efficient reduction of the intensity level of the side lobes in the spectrum that are produced by the mismatch between the initial linear negative chirp of the pulse and the self-phase modulation-induced nonlinear positive chirp. Remarkable increase of both the extent of spectrum narrowing and the quality of the compressed spectrum is afforded by the proposed approach across a wide range of experimentally accessible parameters.
We propose a novel approach to characterize the parabolically-shaped pulses that can be generated from more conventional pulses via nonlinear propagation in cascaded sections of commercially ...available normally dispersive (ND) fibers. The impact of the initial pulse chirp on the passive pulse reshaping is examined. We furthermore demonstrate that the combination of pulse pre-chirping and propagation in a single ND fiber yields a simple, passive method for generating various temporal waveforms of practical interest.
We discuss the effects of imparting a temporal sinusoidal phase modulation to a continuous wave on the frequency spectrum. While a practical analytical solution to this problem already exists, we ...present here a physical interpretation based on interference processes. This simple model will help students better understand the origin of the oscillatory structure that can be observed in the resulting spectrum and that is characteristic of Bessel functions of the first kind. We illustrate our approach with an example from the field of optics.
Planar quasi-Yagi antennas including a printed balun are designed and experimentally characterised. The parasitic array driver is a folded dipole connected to a parallel stripline. The unbalanced to ...balanced transition between the input microstrip and the folded dipole terminals is obtained by linearly tapering both the microstrip and the ground plane widths. These printed antennas are more compact and directive than their counterparts based on resonant half-wavelength dipole drivers: indeed, in the presence of one director, the size of the board is about 0.4 λ0 × 0.5 λ0 and the measured gain is 7 dB.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Palytoxins are potent marine biotoxins that have recently become endemic to the Mediterranean Sea, and are becoming more frequently associated with seafood. Due to their high toxicity, suitable ...methods to quantify palytoxins are needed. Thus, we developed an indirect sandwich ELISA for palytoxin and 42-hydroxy-palytoxin. An intralaboratory study demonstrated sensitivity (limit of detection, LOD = 1.1 ng/mL; limit of quantitation, LOQ = 2.2 ng/mL), accuracy (bias of 2.1%), repeatability (RSDr = 6% and 9% for intra- and interassay variability, respectively) and specificity: other common marine toxins (okadaic acid, domoic acid, saxitoxin, brevetoxin-3, and yessotoxin) do not cross-react in this assay. It performed well in three different matrices: observed LOQs were 11.0, 9.6, and 2.4 ng/mL for mussel extracts, algal net samples and seawater, respectively, with good accuracy and precision. The LOQ in seafood is 11 μg palytoxin/kg mussel meat, lower than that of the most common detection technique, LC-MS/MS.
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IJS, KILJ, NUK, PNG, UL, UM
Background Field tests measuring the same construct, in this case, aerobic capacity, use different scales, which makes fitness assessment of children and youth potentially confusing. The Primary ...Field Test Centered Equating Method has been developed to set tests on the same scale, as illustrated by the conversion of Progressive Aerobic Capacity Endurance Run (PACER) scores to 1-mile run/walk times to estimate VO2 max. Purpose The purpose of this study was to cross-validate the Primary Field Test Centered Equating Method by using a data set of middle school students to assess its effectiveness. Methods PACER scores of 135 middle school students were converted to 1-mile run/walk times (Mile PEQ) using the proposed method. Several estimates of VO2 max using PACER scores were then compared to estimated VO2 max using Mile PEQ and measured VO2 max. The obtained measures were classified according to the healthy fitness zone (HFZ; FITNESSGRAM® , version 9) and compared to measured VO2 max. BMI estimates based on the sample data and the national average also were considered to assess the method's flexibility. Results Agreement levels with actual values were similar for VO2 max predicted using Mile PEQ and predictions using PACER laps and speed (73%–75%). The t -tests showed no significant difference between actual VO2 max (M=44.43, SD= 8.36) and VO2 max predicted using Mile PEQ (M=44.33, SD=5.88). Using BMI averages from sample data and the national data to estimate VO2 max using Mile PEQ also yields high agreement levels, 70% and 73%, respectively. Conclusions The Primary Field Test Centered Equating Method performs as well or better in estimating VO2 max as several other models using PACER scores, especially for boys, and thus may be successfully used in practice. More research is needed to understand the relatively low prediction and classification accuracy in girls.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Given the association between mutational load and cancer, the observation that genetic aberrations are frequently found in human pluripotent stem cells (hPSCs) is of concern. Prior studies in human ...induced pluripotent stem cells (hiPSCs) have shown that deletions and regions of loss of heterozygosity (LOH) tend to arise during reprogramming and early culture, whereas duplications more frequently occur during long-term culture. For the corresponding experiments in human embryonic stem cells (hESCs), we studied two sets of hESC lines: one including the corresponding parental DNA and the other generated from single blastomeres from four sibling embryos. Here, we show that genetic aberrations observed in hESCs can originate during preimplantation embryo development and/or early derivation. These early aberrations are mainly deletions and LOH, whereas aberrations arising during long-term culture of hESCs are more frequently duplications. Our results highlight the importance of close monitoring of genomic integrity and the development of improved methods for derivation and culture of hPSCs.
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•Subchromosomal deletions and LOH most commonly occur during derivation of hESC lines•Genetic duplications arise most frequently during long-term passage of hESC lines•The timing of duplications and deletions/LOH are similar in hESCs and hiPSCs•There is no detectable parent-of-origin bias for de novo CNVs identified in hESCs
Human embryonic stem cells (hESCs) are potential sources of cells for transplantation therapy. However, given the association between mutations and cancer, the frequency of genetic aberrations observed in hESCs is concerning. Using unique pedigrees of hESC lines, Laurent and colleagues now find that aberrations that occur during cell-line derivation are mainly deletions and loss of heterozygosity, whereas duplications arise more commonly during long-term culture. These results highlight the need for improved methods for derivation and culture that preserve the genetic integrity of hESCs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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