The vision to manipulate and control magnetism with light is driven on the one hand by fundamental questions of direct and indirect photon-spin interactions, and on the other hand by the necessity to ...cope with ever growing data volumes, requiring radically new approaches on how to write, read and process information. Here, we present two complementary experimental geometries to access the element-specific magnetization dynamics of complex magnetic systems via ultrafast magneto-optical spectroscopy in the extreme ultraviolet spectral range. First, we employ linearly polarized radiation of a free electron laser facility to demonstrate decoupled dynamics of the two sublattices of an FeGd alloy, a prerequisite for all-optical magnetization switching. Second, we use circularly polarized radiation generated in a laboratory-based high harmonic generation setup to show optical inter-site spin transfer in a CoPt alloy, a mechanism which only very recently has been predicted to mediate ultrafast metamagnetic phase transitions.
•Chitosan/siRNA nanoplexes can be modified with defined degrees of PEG.•PEG has little influence on physicochemical characteristics of nanoplexes.•PEG has strong influence on biological function of ...nanoplexes.•Biological functionality cannot be predicted only from physicochemical studies.•Degree of PEG grafting has to be fine-tuned and verified in biological systems.
Polyethylene glycol (PEG) is a widely used modification for drug delivery systems. It reduces undesired interaction with biological components, aggregation of complexes and serves as a hydrophilic linker of ligands for targeted drug delivery. However, PEGylation can also lead to undesired changes in physicochemical characteristics of chitosan/siRNA nanoplexes and hamper gene silencing.
To address this conflicting issue, PEG-chitosan copolymers were synthesized with stepwise increasing degrees of PEG substitution (1.5% to 8.0%). Subsequently formed PEG-chitosan/siRNA nanoplexes were characterized physicochemically and biologically. The results showed that small ratios of chitosan PEGylation did not affect nanoplex stability and density. However, higher PEGylation ratios reduced nanoplex size and charge, as well as cell uptake and final siRNA knockdown efficiency.
Therefore, we recommend fine-tuning of PEGylation ratios to generate PEG-chitosan/siRNA delivery systems with maximum bioactivity. The degree of PEGylation for chitosan/siRNA nanoplexes should be kept low in order to maintain optimal nanoplex efficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The Tso Kar lake basin in Ladakh, northwestern Himalayas (33°18′N, 78°E, 4527
m a.s.l.) is located close to the modern boundary of effective moisture transport from the Indian summer monsoon. In ...order to reconstruct the possible monsoonal impact on the hydrology of the lake basin during the last 15
kyr, we studied the geomorphology of the basin and combined the results with multi-proxy records from Tso Kar lake sediments. Major analyses comprise geochemical data (high-resolution X-ray fluorescence, XRF), mineral composition (XRD), aquatic pollen and non-pollen palynomorphs (NPP). Although the chronological framework based on 41
14C AMS dates remains speculative for the Lateglacial and late Holocene periods, our results indicate major hydrological phases linked to regional climate variations and tectonic activity. The maximum glacier advance falls within the period between the global LGM and ca 15
kyr
BP, while the basin remained open and may have drained along the paleo Tso Kar River. Tectonic pulses may have triggered terrace development and the closure of the lake. The estimated mean vertical displacement rate accounts for 7–9
mm/yr. Considerable summer monsoon moisture supply occurred for the periods around 12.5
kyr
BP and between ca 11.5 and 8.6
kyr
BP, indicated by deposition of more profundal lake facies and the development of aquatic fauna and flora. The lake level rise about 11.8
kyr
BP was due to intensified glacier melt and summer monsoon effective moisture supply. The lake reached its maximum level and extent between 8.5 and 7
kyr
BP under warm-moist climate conditions. Permafrost was absent from the basin. Summer monsoon influence weakened after 8
kyr
BP with a short reverse trend at ca 5–6
kyr
BP. The lake shrank gradually after 7
kyr
BP towards its lowest stand at about 4.2
kyr
BP, with return of permafrost activity. Subsequent terrace formation was probably amplified by tectonic movement. The lake remained at a low level with minor fluctuations. The results indicate that the orbitally driven regional climate variability is well reflected in the Tso Kar basin by hydrological variations. Considerable summer monsoon moisture seems to have influenced the area only during the early Holocene. The late Quaternary evolution of the Tso Kar was controlled by the interplay of climate forces, local morphodynamics and tectonic impact.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background & objective
Contralesional 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis combined with speech-language therapy (SLT) has shown positive results ...on the recovery of naming in subacute (5–45 days) post-stroke aphasia. NORTHSTAR-CA is an extension of the previously reported NORTHSTAR trial to chronic aphasia (>6 months post-stroke) designed to compare the effectiveness of the same rTMS protocol in both phases.
Methods
Sixty-seven patients with left middle cerebral artery infarcts (28 chronic, 39 subacute) were recruited (01-2014 to 07-2019) and randomized to receive rTMS (N = 34) or sham stimulation (N = 33) with SLT for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment. Chronic and subacute results were compared.
Results
Adverse events were rare, mild, and did not differ between groups. Language outcomes improved significantly in all groups irrespective of treatment and recovery phase. At 30-day follow-up, there was a significant interaction of stimulation and recovery phase on naming recovery (P <.001). Naming recovery with rTMS was larger in subacute (Mdn = 1.91/IQR = .77) than chronic patients (Mdn = .15/IQR = 1.68/P = .015). There was no significant rTMS effect in the chronic aphasia group.
Conclusions
The addition of rTMS to SLT led to significant supplemental gains in naming recovery in the subacute phase only. While this needs confirmation in larger studies, our results clarify neuromodulatory vs training-induced effects and indicate a possible window of opportunity for contralesional inhibitory stimulation interventions in post-stroke aphasia.
NORTHSTAR trial registration
https://clinicaltrials.gov/ct2/show/NCT02020421.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is a neurodegenerative disorder leading to dementia. Aggregation of the amyloid-β peptide (Aβ) plays an important role in the disease, with Aβ oligomers representing the most ...toxic species. Previously, we have developed the Aβ oligomer eliminating therapeutic compound RD2 consisting solely of D-enantiomeric amino acid residues. RD2 has been described to have an oral bioavailability of more than 75% and to improve cognition in transgenic Alzheimer's disease mouse models after oral administration. In the present study, we further examined the stability of RD2 in simulated gastrointestinal fluids, blood plasma and liver microsomes. In addition, we have examined whether RD2 is a substrate for the human D-amino acid oxidase (hDAAO). Furthermore, metabolite profiles of RD2 incubated in human, rodent and non-rodent liver microsomes were compared across species to search for human-specific metabolites that might possibly constitute a threat when applying the compound in humans. RD2 was remarkably resistant against metabolization in all investigated media and not converted by hDAAO. Moreover, RD2 did not influence the activity of any of the tested enzymes. In conclusion, the high stability and the absence of relevant human-specific metabolites support RD2 to be safe for oral administration in humans.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic ...dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (
H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/Glu
GSCs were found to be resistant to glutamine deprivation, whereas Gln/Glu
GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This article discusses modeling aspects of fiber circumplacement around a hole using continuous functions. Here, spatially inhomogeneous transversal isotropy is formulated on the basis of patches ...using B-spline approaches generating the fiber orientation. For this purpose, experiments with different fiber orientations and “hole”-concepts are provided for both the identification of material parameters as well as for model validation. The validation examples are a plate with uniform fiber distribution, where the hole is drilled after the production process, and a plate with circumplacement around the hole, where the fibers are bypassed before the matrix material is injected. The entire numerical problems are treated using finite elements. Furthermore, the material parameters are identified using – within a least-square approach – the combination of finite element simulations and optical results of a digital image correlation system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
X‐ray free‐electron lasers (FELs) enable crystallographic data collection using extremely bright femtosecond pulses from microscopic crystals beyond the limitations of conventional radiation damage. ...This diffraction‐before‐destruction approach requires a new crystal for each FEL shot and, since the crystals cannot be rotated during the X‐ray pulse, data collection requires averaging over many different crystals and a Monte Carlo integration of the diffraction intensities, making the accurate determination of structure factors challenging. To investigate whether sufficient accuracy can be attained for the measurement of anomalous signal, a large data set was collected from lysozyme microcrystals at the newly established `multi‐purpose spectroscopy/imaging instrument' of the SPring‐8 Ångstrom Compact Free‐Electron Laser (SACLA) at RIKEN Harima. Anomalous difference density maps calculated from these data demonstrate that serial femtosecond crystallography using a free‐electron laser is sufficiently accurate to measure even the very weak anomalous signal of naturally occurring S atoms in a protein at a photon energy of 7.3 keV.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Inhibitors of DNA methyltransferases (DNMTis) or histone deacetylases (HDACis) are epigenetic drugs which are investigated since decades. Several have been approved and are applied in the treatment ...of hematopoietic and lymphatic malignancies, although their mode of action has not been fully understood. Two recent findings improved mechanistic insights: i) activation of human endogenous retroviral elements (HERVs) with concomitant synthesis of double-stranded RNAs (dsRNAs), and ii) massive activation of promoters from long terminal repeats (LTRs) which originated from past HERV invasions. These dsRNAs activate an antiviral response pathway followed by apoptosis. LTR promoter activation leads to synthesis of non-annotated transcripts potentially encoding novel or cryptic proteins. Here, we discuss the current knowledge of the molecular effects exerted by epigenetic drugs with a focus on DNMTis and HDACis. We highlight the role in LTR activation and provide novel data from both in vitro and in vivo epigenetic drug treatment.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Immobilization of proteins has been examined to improve implant surfaces. In this study, titanium surfaces were modified with nanofunctionalized denosumab (cDMAB), a human monoclonal anti-RANKL IgG. ...Noncoding DNA oligonucleotides (ODN) served as linker molecules between titanium and DMAB. Binding and release experiments demonstrated a high binding capacity of cDMAB and continuous release. Human peripheral mononuclear blood cells (PBMCs) were cultured in the presence of RANKL/MCSF for 28 days and differentiated into osteoclasts. Adding soluble DMAB to the medium inhibited osteoclast differentiation. On nanofunctionalized titanium specimens, the osteoclast-specific TRAP5b protein was monitored and showed a significantly decreased amount on cDMAB-titanium in PBMCs + RANKL/MCSF. PBMCs on cDMAB-titanium also changed SEM cell morphology. In conclusion, the results indicate that cDMAB reduces osteoclast formation and has the potential to reduce osteoclastogenesis on titanium surfaces.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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