Femtosecond Covariance Spectroscopy

The success of non-linear optics relies largely on pulse-to-pulse consistency. In contrast, covariance based techniques used in photoionization electron spectroscopy and mass spectrometry have shown that wealth of information can be extracted from noise that is lost when averaging multiple measurements. Here, we apply covariance based detection to nonlinear optical spectroscopy, and show that noise in a femtosecond laser is not necessarily a liability to be mitigated, but can act as a unique and powerful asset. As a proof of principle we apply this approach to the process of stimulated Raman scattering in alpha-quartz. Our results demonstrate how nonlinear processes in the sample can encode correlations between the spectral components of ultrashort pulses with uncorrelated stochastic fluctuations. This in turn provides richer information compared to the standard non-linear optics techniques that are based on averages over many repetitions with well-behaved laser pulses. These proof-of-principle results suggest that covariance based nonlinear spectroscopy will improve the applicability of fs non-linear spectroscopy in wavelength ranges where stable, transform limited pulses are not available such as, for example, x-ray free electron lasers which naturally have spectrally noisy pulses ideally suited for this approach

The integrated stress response in lung disease.

Lungs are repeatedly exposed to inhaled toxic insults, such as smoke, diesel exhaust, and microbes, which elicit cellular stress responses. The phosphorylation of eukaryotic translation initiation factor 2α by one of four stress-sensing kinases triggers a pathway called the integrated stress response that helps protect cellular reserves of nutrients and prevents the accumulation of toxic proteins. In this review, we discuss how activation of the integrated stress response has been shown to play an important role in pulmonary pathology, and how its study may help in the development of novel therapies for diverse conditions, from hypoxia to cancer

Staeckel systems generating coupled KdV hierarchies and their finite-gap and rational solutions

We show how to generate coupled KdV hierarchies from Staeckel separable systems of Benenti type. We further show that solutions of these Staeckel systems generate a large class of finite-gap and rational solutions of cKdV hierarchies. Most of these solutions are new.Comment: 15 page

Tissue expression of lactate transporters (MCT1 and MCT4) and prognosis of malignant pleural mesothelioma (brief report)

Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly related to asbestos exposure. As in other solid tumors, malignant cells exhibit high glucose uptake and glycolytic rates with increased lactic acid efflux into the interstitial space. Lactate transport into and out of cells, crucial to maintaining intracellular pH homeostasis and glycolysis, is carried out by monocarboxylate transporters (MCTs) and the chaperone basigin (CD147). We set out to examine the clinical significance of basigin, MCT1 and MCT4 in the context of MPM and to evaluate their expression in relation to the evolution of the disease. Methods: We used immunohistochemistry to measure the expression of basigin, MCT1 and MCT4 in a cohort of 135 individuals with MPM compared to a series of 15 non-MPM pleura specimens. Moreover, by Kaplan-Meier and Cox analyses we evaluated whether an expression over the average of these markers could be associated with the patients' overall survival (OS). Results: We detected positive staining of basigin, MCT1, and MCT4 in most MPM specimens. In particular, MCT4 was always positive in malignant tissues but undetectable in the 4 normal pleural specimens incorporated within the tissue microarray. This was confirmed in the additional series of 15 normal pleural samples. Moreover, MCT4 expression was significantly associated with reduced OS. Conclusion: In this study, the tissue expression of basigin did not prove to be exploitable as a diagnostic or prognostic marker for MPM patients. The expression of MCT1 was not informative either, being tightly correlated with that of basigin. However, the expression of MCT4 showed promise as a diagnostic/therapeutic and prognostic biomarker

Mapping the X-Ray Emission Region in a Laser-Plasma Accelerator

The x-ray emission in laser-plasma accelerators can be a powerful tool to understand the physics of relativistic laser-plasma interaction. It is shown here that the mapping of betatron x-ray radiation can be obtained from the x-ray beam profile when an aperture mask is positioned just beyond the end of the emission region. The influence of the plasma density on the position and the longitudinal profile of the x-ray emission is investigated and compared to particle-in-cell simulations. The measurement of the x-ray emission position and length provides insight on the dynamics of the interaction, including the electron self-injection region, possible multiple injection, and the role of the electron beam driven wakefield.Comment: 5 pages, 4 figure

Transient measurement of phononic states with covariance-based stochastic spectroscopy

We present a novel approach to transient Raman spectroscopy, which combines stochastic probe pulses and a covariance-based detection to measure stimulated Raman signals in alpha-quartz. A coherent broadband pump is used to simultaneously impulsively excite a range of different phonon modes, and the phase, amplitude, and energy of each mode are independently recovered as a function of the pump–probe delay by a noisy-probe and covariance-based analysis. Our experimental results and the associated theoretical description demonstrate the feasibility of 2D-Raman experiments based on the stochastic-probe schemes, with new capabilities not available in equivalent mean-value-based 2D-Raman techniques. This work unlocks the gate for nonlinear spectroscopies to capitalize on the information hidden within the noise and overlooked by a mean-value analysis

2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors

Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar K(I) values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the S ( N )Ar reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog

Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency.

α1-antitrypsin deficiency is the most widely recognised genetic disorder causing chronic obstructive pulmonary disease (COPD). Mutant Z α1-antitrypsin expression has previously been linked to intracellular accumulation and polymerisation of this proteinase inhibitor. Subsequently, this has been described to underlie an exaggerated endoplasmic reticulum stress response and enhanced nuclear factor-κB signalling. However, whether monocyte-derived macrophages display the same features remains unknown. Monocytes from homozygous PiZZ α1-antitrypsin deficiency patients and PiMM controls were cultured for 6 days in the presence of granulocyte-macrophage or macrophage colony-stimulating factor to obtain pro- and anti-inflammatory macrophages (mφ-1 and mφ-2, respectively). We first showed that, in contrast to monocytes, pre-stressed mφ-1 and mφ-2 from healthy blood donors display an enhanced endoplasmic reticulum stress response upon a lipopolysaccharide trigger (XBP1 splicing, CHOP, GADD34 and GRP78 mRNA). However, this endoplasmic reticulum stress response did not differ between monocyte-derived macrophages and monocytes from ZZ patients compared to MM controls. Furthermore, these ZZ cells do not secrete higher cytokine levels, and α1-antitrypsin polymers were not detectable by ELISA. These data suggest that monocyte-derived macrophages are not the local source of Z α1-antitrypsin polymers found in the lung and that endoplasmic reticulum stress and pro-inflammatory cytokine release is not altered.This study was supported by a grant from the Netherlands Asthma Foundation (grant no. 3.2.08.0032). E.F.A. van't Wout is an European Alpha-1-Antitrypsin Laurell’s Training Awardee (sponsored by Grifols, Barcelona, Spain). D.A. Lomas is supported by the Medical Research Council (London, UK) and the NIHR UCLH Biomedical Research Centre (London). S.J. Marciniak is a Medical Research Council Senior Clinical Research Fellow (grant no. G1002610)

A class of Poisson-Nijenhuis structures on a tangent bundle

Equipping the tangent bundle TQ of a manifold with a symplectic form coming from a regular Lagrangian L, we explore how to obtain a Poisson-Nijenhuis structure from a given type (1,1) tensor field J on Q. It is argued that the complete lift of J is not the natural candidate for a Nijenhuis tensor on TQ, but plays a crucial role in the construction of a different tensor R, which appears to be the pullback under the Legendre transform of the lift of J to co-tangent manifold of Q. We show how this tangent bundle view brings new insights and is capable also of producing all important results which are known from previous studies on the cotangent bundle, in the case that Q is equipped with a Riemannian metric. The present approach further paves the way for future generalizations.Comment: 22 page