Systemic inhibition or global deletion of CaMKK2 protects against post-traumatic osteoarthritis.

OBJECTIVE: To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). METHODS: Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2-/- mice. Half of the DMM-WT mice and all other cohorts (n = 6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n = 6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033 mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4-6-day-old WT and Camkk2-/- mice, and treated with 10 ng/ml interleukin-1ß (IL)-1ß for 24 or 48 h to investigate gene and protein expression. RESULTS: CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1ß treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1ß, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1ß-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. CONCLUSIONS: Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.

Spectral filtering of high-order harmonics via optics-free focusing.

Controlling the wavefront of an extreme ultraviolet (XUV) high-order harmonic beam during the generation process offers the capability of modifying the beam properties without resorting to any XUV optics. By characterizing the XUV intensity profile and wavefront, we quantitatively retrieve both the size and the position of the waist of each harmonic generated in an argon jet. We show that optics-free focusing can occur under specific generating conditions leading to XUV focii of micrometer size. We also demonstrate that each focus is located at distinct longitudinal positions. Using this remarkable XUV wavefront control combined with near focus spatial selection, we experimentally demonstrate efficient and adjustable spectral filtering of the XUV beam, along with a strong rejection of the fundamental beam, without using any XUV optics. The experimental results are compared with simulations providing the impact of the filtering on the temporal profile of the XUV field. It shows that the attosecond structure is preserved and that the beam is more homogeneous after the filtering, thereby reducing the longitudinal focii shift. This is a major step to achieve high XUV intensity and probing ultrafast processes with an improved resolution.

High-order parametric generation of coherent XUV radiation.

Extreme ultraviolet (XUV) radiation finds numerous applications in spectroscopy. When the XUV light is generated via high-order harmonic generation (HHG), it may be produced in the form of attosecond pulses, allowing access to unprecedented ultrafast phenomena. However, the HHG efficiency remains limited. Here we present an observation of a new regime of coherent XUV emission which has a potential to provide higher XUV intensity, vital for applications. We explain the process by high-order parametric generation, involving the combined emission of THz and XUV photons, where the phase matching is very robust against ionization. This introduces a way to use higher-energy driving pulses, thus generating more XUV photons.

Optics-less focusing of XUV high-order harmonics.

By experimentally studying high-order harmonic beams generated in gases, we show how the spatial characteristics of these ultrashort extreme-ultraviolet (XUV) beams can be finely controlled when a single fundamental beam generates harmonics in a thin gas medium. We demonstrate that these XUV beams can be emitted as converging beams and thereby get focused after generation. We study this optics-less focusing using a spatially chirped beam that acts as a probe located inside the harmonic generation medium. We analyze the XUV beam evolution with an analytical model and obtain very good agreement with experimental measurements. The XUV foci sizes and positions vary strongly with the harmonic order, and the XUV waist can be located at arbitrarily large distances from the generating medium. We discuss how intense XUV fields can be obtained with optics-less focusing and how the order-dependent XUV beam characteristics are compatible with broadband XUV irradiation and attosecond science.

Two-Dimensional Frequency Resolved Optomolecular Gating of High-Order Harmonic Generation.

Probing electronic wave functions of polyatomic molecules is one of the major challenges in high-harmonic spectroscopy. The extremely nonlinear nature of the laser-molecule interaction couples the multiple degrees of freedom of the probed system. We combine two-dimensional control of the electron trajectories and vibrational control of the molecules to disentangle the two main steps in high-harmonic generation-ionization and recombination. We introduce a new measurement scheme, frequency-resolved optomolecular gating, which resolves the temporal amplitude and phase of the harmonic emission from excited molecules. Focusing on the study of vibrational motion in N_{2}O_{4}, we show that such advanced schemes provide a unique insight into the structural and dynamical properties of the underlying mechanism.

Spatio-spectral structures in high-order harmonic beams generated with Terawatt 10-fs pulses.

A large international effort is nowadays devoted to increase the energy of the extreme ultraviolet pulses by using high-peak power ultrashort fundamental pulses (Terawatt level). Using such fundamental pulses brings specific constraints that need to be addressed. Here we study high-order harmonic generation in gases with 10 fs pulses at Terawatt peak power and demonstrate that extreme ultraviolet beams can be highly structured and complex in various conditions. We use a single-shot spatially resolved spectral detection and demonstrate direct observation of the spatio-temporal coupling occurring in the generating medium. Clear and reproducible complex spatio-spectral structures are observed in the far field. Similar structures are reproduced with simulations and we show that they are intimately associated to the high nonlinearity of high-order harmonic generation. Those findings are of prime importance for the generation of high-energy attosecond pulses and reveal important issues for their applications.

Short pulse carrier-envelope phase absolute single-shot measurement by photoionization of gases with a guided laser beam.

We present an all optical approach to measure the value of the carrier-envelope phase (CEP) of a short intense laser pulse. This method relies on photo-ionization of gases with a guided laser beam. This approach that provides the absolute value of the CEP, is compatible with single shot characterization, is scalable in wavelength, does not suffer from bandwidth limitation and is largely intensity independent. It has also the potential to provide a full characterization of the pulse profile via high order autocorrelation on a single shot basis.

Inhomogeneous high harmonic generation in krypton clusters.

High order harmonic generation from clusters is a controversial topic: conflicting theories exist, with different explanations for similar experimental observations. From an experimental point of view, separating the contributions from monomers and clusters is challenging. By performing a spectrally and spatially resolved study in a controlled mixture of clusters and monomers, we are able to isolate a region of the spectrum where the emission purely originates from clusters. Surprisingly, the emission from clusters is depolarized, which is the signature of statistical inhomogeneous emission from a low-density source. The harmonic response to laser ellipticity shows that this generation is produced by a new recollisional mechanism, which opens the way to future theoretical studies.

High-harmonic transient grating spectroscopy of NO2 electronic relaxation.

We study theoretically and experimentally the electronic relaxation of NO(2) molecules excited by absorption of one ∼400 nm pump photon. Semiclassical simulations based on trajectory surface hopping calculations are performed. They predict fast oscillations of the electronic character around the intersection of the ground and first excited diabatic states. An experiment based on high-order harmonic transient grating spectroscopy reveals dynamics occurring on the same time scale. A systematic study of the detected transient is conducted to investigate the possible influence of the pump intensity, pump wavelength, and rotational temperature of the molecules. The quantitative agreement between measured and predicted dynamics shows that, in NO(2), high harmonic transient grating spectroscopy encodes vibrational dynamics underlying the electronic relaxation.

Role of the ionic potential in high harmonic generation.

Recollision processes provide direct insight into the structure and dynamics of electronic wave functions. However, the strength of the process sets its basic limitations--the interaction couples numerous degrees of freedom. In this Letter we decouple the basic steps of the process and resolve the role of the ionic potential which is at the heart of a broad range of strong field phenomena. Specifically, we measure high harmonic generation from argon atoms. By manipulating the polarization of the laser field we resolve the vectorial properties of the interaction. Our study shows that the ionic core plays a significant role in all steps of the interaction. In particular, Coulomb focusing induces an angular deflection of the electrons before recombination. A complete spatiospectral analysis reveals the influence of the potential on the spatiotemporal properties of the emitted light.

Conical intersection dynamics in NO2 probed by homodyne high-harmonic spectroscopy.

Conical intersections play a crucial role in the chemistry of most polyatomic molecules, ranging from the simplest bimolecular reactions to the photostability of DNA. The real-time study of the associated electronic dynamics poses a major challenge to the latest techniques of ultrafast measurement. We show that high-harmonic spectroscopy reveals oscillations in the electronic character that occur in nitrogen dioxide when a photoexcited wave packet crosses a conical intersection. At longer delays, we observe the onset of statistical dissociation dynamics. The present results demonstrate that high-harmonic spectroscopy could become a powerful tool to highlight electronic dynamics occurring along nonadiabatic chemical reaction pathways.

Phase characterization of the reflection on an extreme UV multilayer: comparison between attosecond metrology and standing wave measurements.

We characterize the phase shift induced by reflection on a multilayer mirror in the extreme UV range (80-93 eV) using two techniques: one based on high order harmonic generation and attosecond metrology (reconstruction of attosecond beating by interference of two-photon transitions), and a second based on synchrotron radiation and measurements of standing waves (total electron yield). We find an excellent agreement between the results from the two measurements and a flat group delay shift (±40 as) over the main reflectivity peak of the mirror.

Controlling high harmonics generation by spatial shaping of high-energy femtosecond beam.

We demonstrate controlled high-order harmonic generation in gas using high-energy femtosecond pulses (50 fs-50 mJ on target) by performing spatial shaping of the terrawatt fundamental laser beam. We have developed a two optical paths mirror that can withstand high power and shape the pump beam into a quasi-flat-top profile (super Gaussian) near focus. We observe clear signatures of the spatial shaping on the harmonic beam in terms of profile, divergence, level of signal, and spectrum. The harmonic generation in neon with a quasi-flat-top beam results in a broadband extreme UV beam with extremely low divergence (~340 µrad).

High harmonic spectroscopy of multichannel dynamics in strong-field ionization.

We perform high harmonic generation spectroscopy of aligned nitrogen molecules to characterize the attosecond dynamics of multielectron rearrangement during strong-field ionization. We use the spectrum and ellipticity of the harmonic light to reconstruct the relative phase between different ionization continua participating in the ionization, and thus determine the shape and location of the hole left in the molecule by strong-field ionization. Our interferometric technique uses transitions between the ionic states, induced by the laser field on the subcycle time scale.

Post-compression of high-energy femtosecond pulses using gas ionization.

We present a new optical post-compression technique designed for high-energy ultrashort pulses. A large spectral broadening is achieved through rapid ionization of helium by an intense pulse (>10(15) W/cm(2)) propagating in a capillary filled with low-pressure helium. The blueshifted pulses are re-compressed with chirped mirrors and silica plates. From a terawatt Ti:sapphire laser chain providing pulses of 40 fs, 70 mJ, we demonstrate the compression of pulses down to 11.4 fs (FWHM) with a total output energy of 13.7 mJ.