Cardiac myocyte-specific knock-out of calcium-independent phospholipase A2γ (iPLA2γ) decreases oxidized fatty acids during ischemia/reperfusion and reduces infarct size

Calcium-independent phospholipase A(2)γ (iPLA(2)γ) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA(2)γ in cardiac myocytes, we generated cardiac myocyte-specific iPLA(2)γ knock-out (CMiPLA(2)γKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA(2)γKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA(2)γKO mice demonstrated attenuated Ca(2+)-induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA(2)γKO mice (30 min of ischemia followed by 30 min of reperfusion in vivo) dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA(2)γKO mice subjected to 30 min of ischemia followed by 24 h of reperfusion in vivo developed substantially less cardiac necrosis in the area-at-risk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca(2+) by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA(2)γ, these results are consistent with salvage of myocardium after I/R by iPLA(2)γ loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion

Helicity-Selective Enhancement and Polarization Control of Attosecond High Harmonic Waveforms Driven by Bichromatic Circularly Polarized Laser Fields

source of bright, circularly polarized, extreme ultraviolet, and soft x-ray beams, where the individual harmonics themselves are completely circularly polarized. Here, we demonstrate the ability to preferentially select either the right or left circularly polarized harmonics simply by adjusting the relative intensity ratio of the bichromatic circularly polarized driving laser field. In the frequency domain, this significantly enhances the harmonic orders that rotate in the same direction as the higher-intensity driving laser. In the time domain, this helicity-dependent enhancement corresponds to control over the polarization of the resulting attosecond waveforms. This helicity control enables the generation of circularly polarized high harmonics with a user-defined polarization of the underlying attosecond bursts. In the future, this technique should allow for the production of bright highly elliptical harmonic supercontinua as well as the generation of isolated elliptically polarized attosecond pulses.H. K. and M. M. graciously acknowledge support from the Department of Energy BES Award No. DE-FG02- 99ER14982 for the experimental implementation, as well as a MURI grant from the Air Force Office of Scientific Research under Award No. FA9550-16-1-0121 for the theory. J. E. and C. M. acknowledge support from National Science Foundation Graduate Research Fellowships (Grant No. DGE-1144083). C. H.-G. acknowl- edges support from the Marie Curie International Outgoing Fellowship within the EU Seventh Framework Programme for Research and Technological Development (2007-2013), under REA Grant No. 328334, from Junta de Castilla y León (Project No. SA046U16) and Spanish Ministerio de Economía y Competitividad, MINECO (Projects No. FIS2013-44174-P and No. FIS2016-75652-P). Part of this work utilized the Janus supercomputer, which is sup- ported by the U.S. National Science Foundation (Grant No. CNS-0821794) and the University of Colorado Boulder

Phase matching of noncollinear sum and difference frequency high harmonic generation above and below the critical ionization level

We investigate the macroscopic physics of noncollinear high harmonic generation (HHG) at high pressures. We make the first experimental demonstration of phase matching of noncollinear high-order-difference-frequency generation at ionization fractions above the critical ionization level, which normally sets an upper limit on the achievable cutoff photon energies. Additionally, we show that noncollinear high-order-sum-frequency generation requires much higher pressures for phase matching than single-beam HHG does, which mitigates the short interaction region in this geometry. We also dramatically increase the experimentally realized cutoff energy of noncollinear circularly polarized HHG, reaching photon energies of 90 eV. Finally, we achieve complete angular separation of high harmonic orders without the use of a spectrometer.Department of Energy BES Award DE-FG02-99ER14982. MURI grant from the Air Force Office of Scientific Research under Award Number FA9550-16-1-0121. National Science Foundation Graduate Research Fellowship (DGE-1144083). Junta de Castilla y León (Project SA046U16) and Spanish MINECO (FIS2013-44174-P, FIS2016-75652-P)

Ultraviolet surprise: Efficient soft x-ray high-harmonic generation in multiply ionized plasmas

High-harmonic generation is a universal response of matter to strong femtosecond laser fields, coherently upconverting light to much shorter wavelengths. Optimizing the conversion of laser light into soft x-rays typically demands a trade-off between two competing factors. Because of reduced quantum diffusion of the radiating electron wave function, the emission from each species is highest when a short-wavelength ultraviolet driving laser is used. However, phase matching—the constructive addition of x-ray waves from a large number of atoms—favors longer-wavelength mid-infrared lasers.We identified a regime of high-harmonic generation driven by 40-cycle ultraviolet lasers in waveguides that can generate bright beams in the soft x-ray region of the spectrum, up to photon energies of 280 electron volts. Surprisingly, the high ultraviolet refractive indices of both neutral atoms and ions enabled effective phase matching, even in a multiply ionized plasma.We observed harmonics with very narrow linewidths, while calculations show that the x-rays emerge as nearly time-bandwidth–limited pulse trains of ~100 attoseconds.The experimental work was done at JILA, supported by Army Research Office grant WN11NF-13-1-0259, an NSF PFI AIR award, and U.S. Department of Energy (DOE) grant DE-SC0008803 (M.M.M., T.P., and H.C.K.). Theory was supported by a Marie Curie International Outgoing Fellowship within the EU Seventh Framework Programme for Research and Technological Development (2007–2013) under REA grant agreement 328334 (C.H.-G.); Junta de Castilla y León (SA116U13, UIC016) and MINECO (FIS2013-44174-P) (C.H.-G. and L.P.); NSF grants PHY-1125844 and PHY-1068706 and AFOSR MURI “Mathematical Modeling and Experimental Validation of Ultrafast Light-Matter Coupling associated with Filamentation in Transparent Media” grant FA9550-10-1-0561 (A.J.-B., R.J.L., X.G., A.L.G., M.M.M., and H.C.K.); Ministry of Science and Technology, Taiwan, grant 102-2112-M-007-025-MY3 (M.-C.C.); U.S. Department of Energy, Division of Chemical Sciences, Atomic, Molecular and Optical Sciences Program (A.B.); and DOE Office of Fusion Energy, HED Laboratory Plasmas program, grant AT5015033 (S.B.L., M.F., and J.A.G.). Lawrence Livermore National Laboratory is operated by Lawrence Livermore National Security LLC for DOE, National Nuclear Security Administration, under contract DE-AC52-07NA27344, LLNL-JRNL-676693. T.P., D.P., M.M.M., and H.C.K. have filed a patent on “Generation of VUV, EUV, X-ray Light Using VUV-UV-VIS Lasers,” U.S. patent application 61873794 (2013)/US 20150063385 (2015)

Antibody Targeting of Cathepsin S Inhibits Angiogenesis and Synergistically Enhances Anti-VEGF

Angiogenesis is a key hallmark of tumourigenesis and its inhibition is a proven strategy for the development of novel anti-cancer therapeutics. An important aspect of early angiogenesis is the co-ordinated migration and invasion of endothelial cells through the hypoxic tumour tissue. Cathepsin S has been shown to play an important role in angiogenesis as has vascular endothelial growth factor (VEGF). We sought to assess the anti-angiogenic effect of Fsn0503, a novel cathepsin S inhibitory antibody, when combined with anti-VEGF on vascular development. where it significantly retarded the development of vasculature in human xenograft models. Furthermore, when Fsn0503 was combined with an anti-VEGF antibody, a synergistic inhibition of microvascular development was observed.Taken together, this data demonstrates that the antibody-mediated targeting of cathepsin S represents a novel method of inhibiting angiogenesis. Furthermore, when used in combination with anti-VEGF therapies, Fsn0503 has the potential to significantly enhance current treatments of tumour neovascularisation and may also be of use in the treatment of other conditions associated with inappropriate angiogenesis

Ischemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation

Objective: It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed. Methods: We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585). Interpretation: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group