Leukemia inhibitory factor (LIF)/STAT3 signalling is a hallmark of naive pluripotency in rodent pluripotent stem cells (PSCs), whereas fibroblast growth factor (FGF)-2 and activin/nodal signalling is ...required to sustain self-renewal of human PSCs in a condition referred to as the primed state. It is unknown why LIF/STAT3 signalling alone fails to sustain pluripotency in human PSCs. Here we show that the forced expression of the hormone-dependent STAT3-ER (ER, ligand-binding domain of the human oestrogen receptor) in combination with 2i/LIF and tamoxifen allows human PSCs to escape from the primed state and enter a state characterized by the activation of STAT3 target genes and long-term self-renewal in FGF2- and feeder-free conditions. These cells acquire growth properties, a gene expression profile and an epigenetic landscape closer to those described in mouse naive PSCs. Together, these results show that temporarily increasing STAT3 activity is sufficient to reprogramme human PSCs to naive-like pluripotent cells.
We discuss the multiscale modeling of a granular material trapped between continuum elastic domains. The amorphous granular region, usually termed “gouge,” is under high confinement pressure, to ...represent the loading of faults at depth. We model the granularity of gouge using the discrete element method (DEM), while the elastic regions surrounding it are represented with two continuum domains modeled with the finite element method (FEM). We resort to a concurrent coupling of the discrete and continuum domains for a proper transmission of waves between the discrete and continuum domains. The confinement pressure results in the appearance of a new kind of ghost forces, which we address via two different overlapping coupling strategies. The first one is a generalization to granular materials of the bridging method, which was originally introduced to couple continuum domains to regular atomic lattices. This method imposes a strong formulation for the Lagrange constraints at the coupling interface. The second strategy considers a weak formulation. Different DEM samples sizes are tested in order to determine at which scale a convergence of the elastic properties is reached. This scale sets the minimal mesh element size in the DEM/FEM interface necessary to avoid undesirable effects due to an elastic properties mismatch. Then, the two DEM/FEM strategies are compared for a system initially at equilibrium. While the performance of both strategies is adequate, we show that the strong coupling is the most stable one as it generates the least spurious numerical noise. Finally, as a practical example for the strong coupling approach, we analyze the propagation of pressure and shear waves through the FEM/DEM interface and discuss dispersion as function of the incoming wave frequency.
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► Control of the temperature during Spark Plasma Sintering in three different facilities. ► We use a phase transformation as a marker of the temperature. ► Finite Element Simulations ...are used as a predictive tool. ► We sinter large specimens with controlled microstructure. ► We sinter complex shapes with controlled microstructure.
The determination and the homogeneity of the sample temperature during consolidation of powders by Spark Plasma Sintering (SPS) are addressed. Densifications were carried out in three different facilities differing by their constructors and their size. A structural transformation activated in a TiAl alloy was used as a marker of the sample temperature and finite element modeling were performed to evaluate the temperature at each point of the set-up. A good agreement between experimental and simulated data is exhibited. Alloys with identical microstructures were sintered and the homogeneity of the microstructure was better in the largest machines or when the sample was isolated by alumina disks.
Large specimens with a diameter of 100mm and a height of 60mm were sintered, with the aim to achieve full densification and good microstructural control. On the basis of this temperature mastering, samples with complex shape were successfully densified. SEM post mortem observations confirmed the absence of porosities, and the expected microstructure as predicted by FEM calculations.
Extracellular adenosine triphosphate (ATP) can activate purinergic receptors of the plasma membrane and modulate multiple cellular functions. We report that ATP is released from HIV-1 target cells ...through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with new therapeutic approaches.
Most studies that aim to understand the interactions between different types of photon radiation and cellular DNA assume homogeneous cell irradiation, with all cells receiving the same amount of ...energy. The level of DNA damage is therefore generally determined by averaging it over the entire population of exposed cells. However, evaluating the molecular consequences of a stochastic phenomenon such as energy deposition of ionizing radiation by measuring only an average effect may not be sufficient for understanding some aspects of the cellular response to this radiation. The variance among the cells associated with this average effect may also be important for the behaviour of irradiated tissue. In this study, we accurately estimated the distribution of the number of radiation-induced γH2AX foci (RIF) per cell nucleus in a large population of endothelial cells exposed to 3 macroscopic doses of gamma rays from 60Co. The number of RIF varied significantly and reproducibly from cell to cell, with its relative standard deviation ranging from 36% to 18% depending on the macroscopic dose delivered. Interestingly, this relative cell-to-cell variability increased as the dose decreased, contrary to the mean RIF count per cell. This result shows that the dose effect, in terms of the number of DNA lesions indicated by RIF is not as simple as a purely proportional relation in which relative SD is constant with dose. To analyse the origins of this observed variability, we calculated the spread of the specific energy distribution for the different target volumes and subvolumes in which RIF can be generated. Variances, standard deviations and relative standard deviations all changed similarly from dose to dose for biological and calculated microdosimetric values. This similarity is an important argument that supports the hypothesis of the conservation of the association between the number of RIF per nucleus and the specific energy per DNA molecule. This comparison allowed us to calculate a volume of 1.6 μm3 for which the spread of the specific energy distribution could explain the entire variability of RIF counts per cell in an exposed cell population. The definition of this volume may allow to use a microdosimetric quantity to predict heterogeneity in DNA damage. Moreover, this value is consistent with the order of magnitude of the volume occupied by the hydrated sugar-phosphate backbone of the DNA molecule, which is the part of the DNA molecule responsible for strand breaks.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Monocyte Chemoattractant Protein-1 (MCP-1), a glial-derived chemokine, mediates neuroinflammation and may regulate memory outcomes among older adults. We aimed to explore the associations of plasma ...MCP-1 levels (alone and in combination with β-amyloid deposition-Aβ
) with overall and domain-specific cognitive evolution among older adults.
Secondary analyses including 1097 subjects (mean age = 75.3 years ± 4.4; 63.8% women) from the Multidomain Alzheimer Preventive Trial (MAPT). MCP-1 (higher is worse) and Aβ
(lower is worse) were measured in plasma collected at year 1. MCP-1 in continuous and as a dichotomy (values in the highest quartile (MCP-1
)) were used, as well as a dichotomy of Aβ
. Outcomes were measured annually over 4 years and included the following: cognitive composite z-score (CCS), the Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) sum of boxes (overall cognitive function); composite executive function z-score, composite attention z-score, Free and Cued Selective Reminding Test (FCSRT - memory).
Plasma MCP-1 as a continuous variable was associated with the worsening of episodic memory over 4 years of follow-up, specifically in measures of free and cued delayed recall. MCP-1
was associated with worse evolution in the CCS (4-year between-group difference: β = -0.14, 95%CI = -0.26, -0.02) and the CDR sum of boxes (2-year: β = 0.19, 95%CI = 0.06, 0.32). In domain-specific analyses, MCP-1
was associated with declines in the FCSRT delayed recall sub-domains. In the presence of low Aβ
, MCP-1
was not associated with greater declines in cognitive functions. The interaction with continuous biomarker values Aβ
× MCP-1 × time was significant in models with CDR sum of boxes and FCSRT DTR as dependent variables.
Baseline plasma MCP-1 levels were associated with longitudinal declines in overall cognitive and episodic memory performance in older adults over a 4-year follow-up. How plasma MCP-1 interacts with Aβ
to determine cognitive decline at different stages of cognitive decline/dementia should be clarified by further research. The MCP-1 association on cognitive decline was strongest in those with amyloid plaques, as measured by blood plasma Aβ
Aerosol-cloud interaction contributes to the largest uncertainties in the estimation and interpretation of the Earth’s changing energy budget. The present study explores experimentally the impacts of ...water condensation-evaporation events, mimicking processes occurring in atmospheric clouds, on the molecular composition of secondary organic aerosol (SOA) from the photooxidation of methacrolein. A range of on- and off-line mass spectrometry techniques were used to obtain a detailed chemical characterization of SOA formed in control experiments in dry conditions, in triphasic experiments simulating gas-particle-cloud droplet interactions (starting from dry conditions and from 60% relative humidity (RH)), and in bulk aqueous-phase experiments. We observed that cloud events trigger fast SOA formation accompanied by evaporative losses. These evaporative losses decreased SOA concentration in the simulation chamber by 25–32% upon RH increase, while aqueous SOA was found to be metastable and slowly evaporated after cloud dissipation. In the simulation chamber, SOA composition measured with a high-resolution time-of-flight aerosol mass spectrometer, did not change during cloud events compared with high RH conditions (RH > 80%). In all experiments, off-line mass spectrometry techniques emphasize the critical role of 2-methylglyceric acid as a major product of isoprene chemistry, as an important contributor to the total SOA mass (15–20%) and as a key building block of oligomers found in the particulate phase. Interestingly, the comparison between the series of oligomers obtained from experiments performed under different conditions show a markedly different reactivity. In particular, long reaction times at high RH seem to create the conditions for aqueous-phase processing to occur in a more efficient manner than during two relatively short cloud events.
A neotype is designated for Pelecanus aquilus Linnaeus, 1758 (currently Fregata aquila ; Aves, Fregatidae) to fix the identity of this nominal species.
Protein–protein interactions are central to many biological processes, from intracellular communication to cytoskeleton assembly, and therefore represent an important class of targets for new ...therapeutics. The most common secondary structure in natural proteins is an α-helix. Small molecules seem to be attractive candidates for stabilizing or disrupting protein–protein interactions based on α-helices. In our study, we assessed the ability of oligopyridyl scaffolds to mimic the α-helical twist. The theoretical as well as experimental studies (X-ray diffraction and NMR) on conformations of bipyridines in the function of substituent and pyridine nitrogen positions were carried out. Furthermore, the experimental techniques showed that the conformations observed in bipyridines are maintained within a longer oligopyridyl scaffold (quaterpyridines). The alignment of the synthesized quaterpyridine with two methyl substituents showed that it is an α-helix foldamer; their methyl groups overlap very well with side chain positions, i and i + 3, of an ideal α-helix.
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