Glioblastoma multiforme (GBM) is paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. Growing evidence suggests that different types of CSC lead to the formation of GBM. ...This has prompted the present comparison of gene expression profiles between 17 GBM CSC lines and their different putative founder cells. Using a newly derived 24-gene signature, we can now distinguish two subgroups of GBM: Type I CSC lines display "proneural" signature genes and resemble fetal neural stem cell (fNSC) lines, whereas type II CSC lines show "mesenchymal" transcriptional profiles similar to adult NSC (aNSC) lines. Phenotypically, type I CSC lines are CD133 positive and grow as neurospheres. Type II CSC lines, in contrast, display (semi-)adherent growth and lack CD133 expression. Molecular differences between type I and type II CSC lines include the expression of extracellular matrix molecules and the transcriptional activity of the WNT and the transforming growth factor-beta/bone morphogenetic protein signaling pathways. Importantly, these characteristics were not affected by induced adherence on laminin. Comparing CSC lines with their putative cells of origin, we observed greatly increased proliferation and impaired differentiation capacity in both types of CSC lines but no cancer-associated activation of otherwise silent signaling pathways. Thus, our data suggest that the heterogeneous tumor entity GBM may derive from cells that have preserved or acquired properties of either fNSC or aNSC but lost the corresponding differentiation potential. Moreover, we propose a gene signature that enables the subclassification of GBM according to their putative cells of origin.
Abstract
The expanded hexanucleotide GGGGCC repeat mutation in the
C9orf72
gene is the main genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Under one disease mechanism, ...sense and antisense transcripts of the repeat are predicted to bind various RNA-binding proteins, compromise their function and cause cytotoxicity. Here we identify phenylalanine-tRNA synthetase (FARS) subunit alpha (FARSA) as the main interactor of the CCCCGG antisense repeat RNA in cytosol. The aminoacylation of tRNA
Phe
by FARS is inhibited by antisense RNA, leading to decreased levels of charged tRNA
Phe
. Remarkably, this is associated with global reduction of phenylalanine incorporation in the proteome and decrease in expression of phenylalanine-rich proteins in cellular models and patient tissues. In conclusion, this study reveals functional inhibition of FARSA in the presence of antisense RNA repeats. Compromised aminoacylation of tRNA could lead to impairments in protein synthesis and further contribute to
C9orf72
mutation-associated pathology.
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•Talc is one of the most elastically anisotropic minerals in subduction zone settings.•Talc-bearing lithology can readily explain ultra-slow velocity, high VP/VS ratio, and large ...delay time.•Pressure dependence of the components of the elastic constant tensor exhibits anomalous behavior.
Talc is a layered hydrous silicate mineral that plays a vital role in transporting water into Earth’s interior and is crucial for explaining geophysical observations in subduction zone settings. In this study, we explored the structure, equation of state, and elasticity of both triclinic and monoclinic talc under high pressures up to 18 GPa using first principles simulations based on density functional theory corrected for dispersive forces. Our results indicate that principal components of the full elastic constant tensor C11 and C22, shear components C66, and several off-diagonal components show anomalous pressure dependence. This non-monotonic pressure dependence of elastic constant components is likely related to the structural changes and is often manifested in a polytypic transition from a low-pressure polytype talc-I to a high-pressure polytype talc-II. The polytypic transition of talc occurs at pressures within its thermodynamic stability. However, the bulk and shear elastic moduli show no anomalous softening. Our study also shows that talc has low velocity, extremely high anisotropy, and anomalously high VP/VS ratio, thus making it a potential candidate mineral phase that could readily explain unusually high VP/VS ratio and large shear wave splitting delays as observed from seismological studies in many subduction systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We present a combined experimental and theoretical study of ruthenium doped germanium clusters, RuGen(-) (n = 3-12), and their corresponding neutral species. Photoelectron spectra of RuGen(-) ...clusters are measured at 266 nm. The vertical detachment energies (VDEs) and adiabatic detachment energies (ADEs) are obtained. Unbiased CALYPSO structure searches confirm the low-lying structures of anionic and neutral ruthenium doped germanium clusters in the size range of 3 ≤ n ≤ 12. Subsequent geometry optimizations using density functional theory (DFT) at PW91/LANL2DZ level are carried out to determine the relative stability and electronic properties of ruthenium doped germanium clusters. It is found that most of the anionic and neutral clusters have very similar global features. Although the global minimum structures of the anionic and neutral clusters are different, their respective geometries are observed as the low-lying isomers in either case. In addition, for n > 8, the Ru atom in RuGen(-/0) clusters is absorbed endohedrally in the Ge cage. The theoretically predicted vertical and adiabatic detachment energies are in good agreement with the experimental measurements. The excellent agreement between DFT calculations and experiment enables a comprehensive evaluation of the geometrical and electronic structures of ruthenium doped germanium clusters.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite decades of research on amyotrophic lateral sclerosis (ALS), there is only one approved drug, which minimally extends patient survival. Here, we investigated pathophysiological mechanisms ...underlying ALS using motor neurons (MNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying mutations in FUS or SOD1. Patient‐derived MNs were less active and excitable compared to healthy controls, due to reduced Na+/K+ ratios in both ALS groups accompanied by elevated potassium channel (FUS) and attenuated sodium channel expression levels (FUS, SOD1). ALS iPSC‐derived MNs showed elevated endoplasmic reticulum stress (ER) levels and increased caspase activation. Treatment with the FDA approved drug 4‐Aminopyridine (4AP) restored ion‐channel imbalances, increased neuronal activity levels and decreased ER stress and caspase activation. This study provides novel pathophysiological data, including a mechanistic explanation for the observed hypoexcitability in patient‐derived MNs and a new therapeutic strategy to provide neuroprotection in MNs affected by ALS. Stem Cells 2016;34:1563–1575
High pressure can fundamentally alter the bonding patterns of chemical elements. Its effects include stimulating elements thought to be "inactive" to form unexpectedly stable compounds with unusual ...chemical and physical properties. Here, using an unbiased structure search method based on CALYPSO methodology and density functional total energy calculations, the phase stabilities and crystal structures of Li-Ar compounds are systematically investigated at high pressure up to 300 GPa. Two unexpected LimArn compounds (LiAr and Li3Ar) are predicted to be stable above 112 GPa and 119 GPa, respectively. A detailed analysis of the electronic structure of LiAr and Li3Ar shows that Ar in these compounds attracts electrons and thus behaves as an oxidizing agent. This is markedly different from the hitherto established chemical reactivity of Ar. Moreover, we predict that the P4/mmm phase of Li3Ar has a superconducting transition temperature of 17.6 K at 120 GPa.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The
Topical Collection "Amyotrophic Lateral Sclerosis: Latest Advances and Prospects" started in 2020 and currently includes 11 publications reflecting a broad range of clinical research areas in the ...ALS field ....
In many medical disciplines, red blood cells are discovered to be biomarkers since they "experience" various conditions in basically all organs of the body. Classical examples are diabetes and ...hypercholesterolemia. However, recently the red blood cell distribution width (RDW), is often referred to, as an unspecific parameter/marker (e.g., for cardiac events or in oncological studies). The measurement of RDW requires venous blood samples to perform the complete blood cell count (CBC). Here, we introduce Erysense, a lab-on-a-chip-based point-of-care device, to evaluate red blood cell flow properties. The capillary chip technology in combination with algorithms based on artificial neural networks allows the detection of very subtle changes in the red blood cell morphology. This flow-based method closely resembles
conditions and blood sample volumes in the sub-microliter range are sufficient. We provide clinical examples for potential applications of Erysense as a diagnostic tool here: neuroacanthocytosis syndromes (NAS) and as cellular quality control for red blood cells here: hemodiafiltration (HDF) and erythrocyte concentrate (EC) storage. Due to the wide range of the applicable flow velocities (0.1-10 mm/s) different mechanical properties of the red blood cells can be addressed with Erysense providing the opportunity for differential diagnosis/judgments. Due to these versatile properties, we anticipate the value of Erysense for further diagnostic, prognostic, and theragnostic applications including but not limited to diabetes, iron deficiency, COVID-19, rheumatism, various red blood cell disorders and anemia, as well as inflammation-based diseases including sepsis.
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