Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- ...to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
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•MDS stem cells and progenitors are distinct and hierarchically related•Mutations in low-risk MDS originate exclusively in distinct and rare MDS stem cells•Mutations preceding AML transformation might confer self-renewal to MDS progenitors•del(5q) precedes acquisition of recurrent driver mutations in isolated del(5q) MDS
Using functional analyses and backtracking of somatic genetic alterations, Woll et al. show that in low-intermediate risk human myelodysplastic syndromes (MDS) only the rare Lin−CD34+CD38−CD90+CD45RA− cells function as MDS-propagating cells.
Glycogen is a hyperbranched glucose polymer, serving as a major energy reservoir in animals. Characterization of the size distributions of complex branched polysaccharides helps in the understanding ...of their structural and functional properties. This study compared the effectiveness of various techniques in analyzing glycogen size distributions, namely size-separation-based techniques (size exclusion chromatography (SEC) and asymmetric-flow field-flow fractionation (AF4)) and imaging-based methods (transmission electron microscopy (TEM) and atomic force microscopy (AFM)). SEC and AF4 gave similar glycogen size distributions. TEM was suboptimal for obtaining size distributions due to the difficulty of preventing aggregation artifacts during sample preparation. AFM appeared to avoid the problem, but the size distributions so obtained had substantially lower resolution and were much more laborious to acquire. The microscopy-based techniques, especially TEM, do however provide richer morphological information on individual particles than do SEC and AF4. These results suggest that combining size-separation and microscopy (imaging) techniques could provide a holistic view of glycogen size distribution and morphology, which may also be applicable to the characterization of other complex branched polymers.
The effect of heat treatment on the soluble protein content in oat groats (Kerstin commercial variety) was evaluated using asymmetric flow field-flow fractionation (AF4) in combination with online ...multiangle light scattering (MALS) and UV detection. The AF4 method was used to separate the monomeric proteins from globulin hexamer and aggregate proteins and β-glucan polysaccharides in the soluble oat protein fraction. The total amount of soluble protein (with respect to total protein) was reduced to 35.7 ± 4.5 wt. % in heat treated oats from 74.6 ± 5.3 wt. % in non-heat treated oats. The ratio of monomeric to globulin hexamer and aggregate proteins was reduced from 1.82 to 1.48 as a result of heat treatment. Sodium-dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed the selective elimination of protein bands associated with the albumin and prolamin protein fractions as a result of heat treatment. These results were supported through amino acid analysis by cation exchange chromatography coupled with UV detection which revealed a reduction in amino acid residues associated with prolamin. The globulin proteins were found to be less sensitive to heat treatment.
•Heat treatment reduces the total soluble protein.•Solubility of different oat protein fractions is selective to heat treatment.•AF4 effectively separated protein monomers, globulin hexamers and β-glucans.•A multi-analytical approach yielded in-depth information about oat macromolecules.
•Flow resistance is investigated in disordered 3-dimensional fibrous structures.•Reynolds number ranging from creeping flow to high inertia conditions.•The friction factor is less dependent of fiber ...arrangements at high inertia.•The friction factor shows reasonable results compared to other studies.
The flow resistance in 3-dimensional fibrous structures are investigated in particle Reynolds number representing flow characteristics with strong inertia. The resistance coefficients are established based on steady state simulations of single-phase processes of water numerically. An automatized simulation process in COMSOL is developed with a MATLAB algorithm in which production runs could be carried for various 3-dimensional fibrous structures. Simulation of flow processes ranging from Reynolds numbers at creeping flow levels to high Reynolds number at approximately 1000 are calculated and a numerical data set is established in order to estimate Forchheimer coefficients which are used to correlate a dimensionless friction factor to a modified Reynolds expression for porous media.
The friction factor and dimensionless permeability are calculated for fibrous structures with (i) disordered unidirectional fibers (ii) an isotropic fiber orientation in-plane perpendicular to the flow, and (iii) an isotropic fiber structure in a the 3-dimensional space. Empirical correlations of the friction factor and Reynolds number are used to compare our simulation data in order to assess the validity of our models and flow resistance estimations. The dimensionless permeability is moreover compared to other numerical simulations of flow through fibrous structures in order to assess flow resistance at low Reynolds number.
It is concluded that flow resistance in the isotropic fiber arrangement in space is lower than the in-plane isotropic orientation and disordered unidirectional fiber arrangements at creeping flow conditions, however, all friction actors converges towards the same value at higher Reynolds numbers indicating that fiber orientation is independent at high inertia flow regimes. Overall, our numerical simulations agree well to classical empirical formulations for a wide range of Reynolds number. However, the comparison differs considerably depending on the porosity level.
•A novel method for calibration of channel height, using a nanoemulsion, in AF4.•The method performs well in comparison to previous calibration methods.•The nanoemulsion method remains stable over a ...wide carrier liquid pH range.•XCT imaging of the AF4 channel has been used for orthogonal verification.
This study suggests a novel method for determination of the channel height in asymmetrical flow field-flow fractionation (AF4), which can be used for calibration of the channel for hydrodynamic radius determinations. The novel method uses an oil-in-water nanoemulsion together with multi angle light scattering (MALS) and elution theory to determine channel height from an AF4 experiment. The method is validated using two orthogonal methods; first, by using standard particle elution experiments and, secondly, by imaging an assembled and carrier liquid filled channel by x-ray computed tomography (XCT). It is concluded that the channel height can be determined with approximately the same accuracy as with the traditional channel height determination technique. However, the nanoemulsion method can be used under more challenging conditions than standard particles, as the nanoemulsion remains stable in a wider pH range than the previously used standard particles. Moreover, the novel method is also more cost effective.
Li, J., Nilsson, L.‐G. & Wu, Z. (2004). Effects of age and anxiety on episodic memory: Selectivity and variability. Scandinavian Journal of Psychology, 45, 123–129.
Selective age‐related differences ...in source memory relative to item memory, and individual differences in memory performance in relation to anxiety were explored with high‐ and low‐anxious subjects screened from normal young and elderly adults. They were read false facts about the locations of well‐known and unknown sights in a male or female voice. Intentional and incidental learning instructions were administered for source memory. Selective age‐related deficits in source memory were observed under both encoding conditions. Higher level of anxiety was related to lower memory performance only in the old group; this relation was stronger in source recall. The findings suggest that the presence of such selectivity is unrelated to the tradeoff between item encoding and source encoding. Anxiety affects the variability, and mediates the selectivity of age effects on episodic memory.
In this population-based study, we aimed to characterize and compare subgroups of therapy-related Myelodysplastic syndromes (t-MDS) and define the implications of type of previous treatment and ...primary disease. We combined data from MDS patients, diagnosed between 2009 and 2017 (n = 2705), in the nationwide Swedish MDS register, with several health registers. Furthermore, using matched population controls, we investigated the prevalence of antecedent malignancies in MDS patients in comparison with the general population. This first ever nationwide study on t-MDS confirms a shorter median survival for t-MDS compared to de novo MDS (15.8 months vs 31.1 months, p < 0.001). T-MDS patients previously treated with radiation only had disease characteristics with a striking resemblance to de novo-MDS, in sharp contrast to patients treated with chemotherapy who had a significantly higher risk profile. IPSS-R and the WHO classification differentiated t-MDS into different risk groups. As compared with controls, MDS patients had a six-fold increased prevalence of a previous hematological malignancy but only a 34% increased prevalence of a previous solid tumor. T-MDS patients with a previous hematological malignancy had a dismal prognosis, due both to mortality related to their primary disease and to high-risk MDS.
The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (Abeta) sequence and leads to Alzheimer's disease (AD). Arctic Abeta peptides more easily form Abeta ...protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APPArcSwe) and transgenic mice with the Swedish mutation alone (tg-APPSwe). Intense intraneuronal Abeta-immunoreactive staining was present in young tg-APPArcSwe mice, but not in tg-APPSwe mice. Intracellular Abeta aggregates in tg-APPArcSwe were strongly stained by antibodies recognizing the N-terminus of Abeta, while those recognizing the C-terminus of Abeta stained weakly. The Abeta aggregates inside neurons increased with age and predated extracellular Abeta deposition in both tg-APPArcSwe and tg-APPSwe mice. Senile plaque deposition was markedly accelerated in tg-APPArcSwe mice, as compared to tg-APPSwe mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular Abeta aggregates in association with a rapid onset of senile plaque deposition.
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