Tryptophan is an essential nutrient required to generate vitamin B3 (niacin), which is mainly involved in energy metabolism and DNA production. Alterations in tryptophan metabolism could have ...significant effects on aging and musculoskeletal health. The kynurenine pathway, essential in tryptophan catabolism, is modulated by inflammatory factors that are increased in older persons, a process known as inflammaging. Osteoporosis, sarcopenia, osteosarcopenia, and frailty have also been linked with chronically increased levels of inflammatory factors. Due to the disruption of the kynurenine pathway by chronic inflammation and/or changes in the gut microbiota, serum levels of toxic metabolites are increased and are associated with the pathophysiology of those conditions. In contrast, anabolic products of this pathway, such as picolinic acid, have demonstrated a positive effect on skeletal muscle and bone. In addition, physical activity can modulate this pathway by promoting the secretion of anabolic kynurenines. According to the evidence collected, kynurenines could have a promising role as biomarkers for osteoporosis sarcopenia, osteosarcopenia, and frailty in older persons. In addition, some of these metabolites could become important targets for developing new pharmacological treatments for these conditions.
Una de las características propias del derecho internacional de las inversiones es la forma en la que, a partir de su lenguaje, su estructura y su funcionamiento, está pensado para ofrecer mayores ...herramientas para los inversionistas extranjeros. De allí que en realidad, las relaciones que de él se derivan sean asimétricas, beneficiando en buena medida a los particulares y dejando con pocas herramientas a los Estados; en particular, en el marco de los arbitrajes internacionales de inversión. Ahora bien, un concepto que ha sido utilizado en algunas oportunidades y que ha servido como herramienta para la defensa de los Estados es el de la debida diligencia de los inversionistas. No obstante, se trata de una noción disímil y en buena medida indeterminada. Este artículo propone, a partir de un estudio teórico, doctrinario y “jurisprudencial”, definir la debida diligencia –de los inversionistas- como un concepto híbrido multinivel del que se derivan obligaciones claras y exigibles para los inversionistas respecto de sí mismos, los Estados receptores y los individuos a los que afectan con sus inversiones.
We committed MSCs to differentiate into either osteoblasts or adipocytes and examined the effect of ALN on both adipogenesis and osteoblastogenesis. ALN inhibited adipogenesis while promoting ...osteoblast differentiation and activity. Our results reveal a new anabolic effect of ALN in differentiating bone marrow cells.
Introduction: Alendronate (ALN) prevents bone loss in postmenopausal patients through the regulation of osteoclastic activity. However, it has also proven to be effective in older adults where the pathophysiological mechanism is the predominance of adipogenesis over osteoblastogenesis. The aim of this study is to determine the in vitro effect of ALN on both osteoblastogenesis and adipogenesis.
Materials and Methods: Human mesenchymal stem cells (MSCs) were plated at a density of 5 × 105 cells/well in 100‐cm 2 dishes containing MSC growth media. After confluence, cells were committed to differentiate adding either adipogenic or osteogenic media with and without 1,25(OH)2D3 (10−8 M) and supplemented with ALN at increasing concentrations (10−9 to 10−7 M). Untreated differentiating MSCs were used as control. Alkaline phosphatase (ALP), oil red O, and Alizarin red staining were performed at timed intervals (weeks 1 and 2). Additionally, levels of expression of both osteogenesis and adipogenesis transcription factors were measured in protein extracts. Finally, the effect of ALN on PPARγ2 nuclear activation complex was assessed.
Results: We found that ALN has a significant and dose‐dependent effect on osteoblastogenesis. This effect was not modified by the presence of 1,25(OH)2D3 in the medium. Furthermore, adipogenic differentiation of MSCs was affected by addition of both ALN and 1,25(OH)2D3 to the media as confirmed by phenotype changes and lower number of lipid droplets. Finally, expression of adipogenic transcription factors and PPARγ2 activation were reduced in adipose differentiating MSCs treated with either ALN or ALN + 1,25(OH)2D3.
Conclusions: This study shows a potential anabolic effect of ALN in vitro through the stimulation of osteogenic differentiation of MSCs. Additionally, a previously unknown inhibitory effect of ALN on bone marrow adipogenesis was also found.
In this work, we report on the nonlinear ionization of argon atoms in the short wavelength regime using ultraintense x rays from the European XFEL. After sequential multiphoton ionization, high ...charge states are obtained. For photon energies that are insufficient to directly ionize a 1s electron, a different mechanism is required to obtain ionization to Ar17+. We propose this occurs through a two-color process where the second harmonic of the FEL pulse resonantly excites the system via a 1s→2p transition followed by ionization by the fundamental FEL pulse, which is a type of x-ray resonance-enhanced multiphoton ionization (REMPI). This resonant phenomenon occurs not only for Ar16+, but also through lower charge states, where multiple ionization competes with decay lifetimes, making x-ray REMPI distinctive from conventional REMPI. With the aid of state-of-the-art theoretical calculations, we explain the effects of x-ray REMPI on the relevant ion yields and spectral profile.
Abstract
Understanding the interaction of intense, femtosecond X-ray pulses with heavy atoms is crucial for gaining insights into the structure and dynamics of matter. One key aspect of nonlinear ...light–matter interaction was, so far, not studied systematically at free-electron lasers—its dependence on the photon energy. Here, we use resonant ion spectroscopy to map out the transient electronic structures occurring during the complex charge-up pathways of xenon. Massively hollow atoms featuring up to six simultaneous core holes determine the spectra at specific photon energies and charge states. We also illustrate how different X-ray pulse parameters, which are usually intertwined, can be partially disentangled. The extraction of resonance spectra is facilitated by the possibility of working with a constant number of photons per X-ray pulse at all photon energies and the fact that the ion yields become independent of the peak fluence beyond a saturation point. Our study lays the groundwork for spectroscopic investigations of transient atomic species in exotic, multiple-core-hole states that have not been explored previously.
The emerging concept of `beam by design' in free‐electron laser (FEL) accelerator physics aims for accurate manipulation of the electron beam to tailor spectral and temporal properties of the ...radiation for specific experimental purposes, such as X‐ray pump/X‐ray probe and multiple wavelength experiments. `Beam by design' requires fast, efficient, and detailed feedback on the spectral and temporal properties of the generated X‐ray radiation. Here a simple and cost‐efficient method to extract information on the longitudinal Wigner distribution function of emitted FEL pulses is proposed. The method requires only an ensemble of measured FEL spectra and is rather robust with respect to accelerator fluctuations. The method is applied to both the simulated SASE spectra with known radiation properties as well as to the SASE spectra measured at the European XFEL revealing underlying non‐linear chirp of the generated radiation. In the Appendices an intuitive understanding of time–frequency representations of chirped SASE radiation is provided.
An ensemble‐averaged Wigner distribution is a useful tool for time–frequency analysis of simulated SASE FEL pulses. Here it is shown how to calculate its frequency‐wise autocorrelation based on a set of measured single‐shot SASE spectra.
Abstract
The dispersion scan (d-scan) technique is extended to measurement of the time-dependent polarization state of ultrashort laser pulses. In the simplest implementation for linearly polarized ...ultrashort pulses, the d-scan technique records the second harmonic generation spectrum as a function of a known spectral phase manipulation. By applying this method to two orthogonally polarized projections of an arbitrary polarized electric field and by measuring the spectrum at an intermediate angle, we can reconstruct the evolution over time of the polarization state. We demonstrate the method by measuring a polarization gate generated from
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pulses with a combination of waveplates. The measurements are compared to simulations, showing an excellent agreement.
A novel interferometric technique to measure small wedge angle of transparent windows is proposed. The technique is based on the measurement of the shift of the interference pattern generated by two ...sheared copies of a laser beam after crossing the optical wedge. A simple lens is used to combine the two beams in their focal plane and measurements are taken for different shears. It is not necessary to perform a spatial filtering of the laser beam since correlations are used to determine the parameters of the experiment. A sample with a wedge slightly greater than one minute is used to illustrate the method.
Network-based approaches are becoming increasingly popular for drug discovery as they provide a systems-level overview of the mechanisms underlying disease pathophysiology. They have demonstrated ...significant early promise over other methods of biological data representation, such as in target discovery, side effect prediction and drug repurposing. In parallel, an explosion of -omics data for the deep characterization of biological systems routinely uncovers molecular signatures of disease for similar applications. Here, we present RPath, a novel algorithm that prioritizes drugs for a given disease by reasoning over causal paths in a knowledge graph (KG), guided by both drug-perturbed as well as disease-specific transcriptomic signatures. First, our approach identifies the causal paths that connect a drug to a particular disease. Next, it reasons over these paths to identify those that correlate with the transcriptional signatures observed in a drug-perturbation experiment, and anti-correlate to signatures observed in the disease of interest. The paths which match this signature profile are then proposed to represent the mechanism of action of the drug. We demonstrate how RPath consistently prioritizes clinically investigated drug-disease pairs on multiple datasets and KGs, achieving better performance over other similar methodologies. Furthermore, we present two case studies showing how one can deconvolute the predictions made by RPath as well as predict novel targets.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Small Quantum Systems instrument is one of the six operating instruments of the European XFEL, dedicated to the atomic, molecular and cluster physics communities. The instrument started its user ...operation at the end of 2018 after a commissioning phase. The design and characterization of the beam transport system are described here. The X‐ray optical components of the beamline are detailed, and the beamline performances, transmission and focusing capabilities are reported. It is shown that the X‐ray beam can be effectively focused as predicted by ray‐tracing simulations. The impact of non‐ideal X‐ray source conditions on the focusing performances is discussed.
The soft X‐ray beam from the SASE3 source at the European XFEL is delivered to the SQS instrument by a beam transport system. The system layout and performances are reported.
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