Ticking terahertz wave generation in attoseconds

We perform a joint measurement of terahertz waves and high-order harmonics generated from noble atoms driven by a fundamental laser pulse and its second harmonic. By correlating their dependence on the phase-delay of the two pulses, we determine the generation of THz waves in tens of attoseconds precision. Compared with simulations and models, we find that the laser-assisted soft-collision of the electron wave packet with the atomic core plays a key role. It is demonstrated that the rescattering process, being indispensable in HHG processes, dominant THz wave generation as well but in a more elaborate way. The new finding might be helpful for the full characterization of the rescattering dynamics.Comment: 4 figure

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases

The role of endoscopic ultrasound-guided fine-needle aspiration/biopsy in the diagnosis of mediastinal lesions

ObjectiveEndoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) is an accurate technique for sampling the pancreas and mediastinum. The aim of this study was to determine the value of EUS-FNA/FNB in the diagnosis of mediastinal lesions.MethodsData from 107 patients who underwent EUS-FNA/FNB for mediastinal lesions were evaluated.ResultsThe sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNA/FNB for mediastinal lesions were 92.00%, 100%, 100%, and 85%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNA for malignant mediastinal lesions were 92.00%, 100%, 100%, and 86.00%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNB for malignant mediastinal lesions were 92.00%, 100%, 100%, and 82.00%, respectively. Except for the discomfort caused by conventional gastroscopy, none of the patients had any complications, such as damage to surrounding large blood vessels or nerves.ConclusionEUS-FNA/FNB is an effective tool for diagnosing unknown mediastinal lesions, without any obvious complications

Crystal Structures of a Plant Trypsin Inhibitor from Enterolobium contortisiliquum (EcTI) and of Its Complex with Bovine Trypsin

A serine protease inhibitor from Enterolobium contortisiliquum (EcTI) belongs to the Kunitz family of plant inhibitors, common in plant seeds. It was shown that EcTI inhibits the invasion of gastric cancer cells through alterations in integrin-dependent cell signaling pathway. We determined high-resolution crystal structures of free EcTI (at 1.75 angstrom) and complexed with bovine trypsin (at 2 angstrom). High quality of the resulting electron density maps and the redundancy of structural information indicated that the sequence of the crystallized isoform contained 176 residues and differed from the one published previously. the structure of the complex confirmed the standard inhibitory mechanism in which the reactive loop of the inhibitor is docked into trypsin active site with the side chains of Arg64 and Ile65 occupying the S1 and S1' pockets, respectively. the overall conformation of the reactive loop undergoes only minor adjustments upon binding to trypsin. Larger deviations are seen in the vicinity of Arg64, driven by the needs to satisfy specificity requirements. A comparison of the EcTI-trypsin complex with the complexes of related Kunitz inhibitors has shown that rigid body rotation of the inhibitors by as much as 15 degrees is required for accurate juxtaposition of the reactive loop with the active site while preserving its conformation. Modeling of the putative complexes of EcTI with several serine proteases and a comparison with equivalent models for other Kunitz inhibitors elucidated the structural basis for the fine differences in their specificity, providing tools that might allow modification of their potency towards the individual enzymes.United States Department of Energy, Office of Science, Office of Basic Energy SciencesCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)National Institutes of Health, National Cancer Institute, Center for Cancer ResearchNCI, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21701 USAUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, BrazilInst Butantan, Lab Bioquim & Biofis, Unidade Sequenciamento Prot & Peptideos, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, BrazilUnited States Department of Energy, Office of Science, Office of Basic Energy Sciences: W-31-109-Eng-38FAPESP: 09/53766-5Web of Scienc

Localization of ASV Integrase-DNA Contacts by Site-Directed Crosslinking and their Structural Analysis

We applied crosslinking techniques as a first step in preparation of stable avian sarcoma virus (ASV) integrase (IN)-DNA complexes for crystallographic investigations. These results were then compared with the crystal structures of the prototype foamy virus (PFV) intasome and with published data for other retroviral IN proteins.Photoaffinity crosslinking and site-directed chemical crosslinking were used to localize the sites of contacts with DNA substrates on the surface of ASV IN. Sulfhydryl groups of cysteines engineered into ASV IN and amino-modified nucleotides in DNA substrates were used for attachment of photocrosslinkers. Analysis of photocrosslinking data revealed several specific DNA-protein contacts. To confirm contact sites, thiol-modified nucleotides were introduced into oligo-DNA substrates at suggested points of contact and chemically crosslinked to the cysteines via formation of disulfide bridges. Cysteines incorporated in positions 124 and 146 in the ASV IN core domain were shown to interact directly with host and viral portions of the Y-mer DNA substrate, respectively. Crosslinking of an R244C ASV IN derivative identified contacts at positions 11 and 12 on both strands of viral DNA. The most efficient disulfide crosslinking was observed for complexes of the ASV IN E157C and D64C derivatives with linear viral DNA substrate carrying a thiol-modified scissile phosphate.Analysis of our crosslinking results as well as published results of retroviral IN protein from other laboratories shows good agreement with the structure of PFV IN and derived ASV, HIV, and MuLV models for the core domain, but only partial agreement for the N- and C-terminal domains. These differences might be explained by structural variations and evolutionary selection for residues at alternate positions to perform analogous functions, and by methodological differences: i.e., a static picture of a particular assembly from crystallography vs. a variety of interactions that might occur during formation of functional IN complexes in solution

Characterization of domain distributions by second harmonic generation in ferroelectrics

Domain orientations and their volume ratios in ferroelectrics are recognized as a compelling topic recently for domain switching dynamics and domain stability in devices application. Here, an optimized second harmonic generation method has been explored for ferroelectric domain characterization. Combing a unique theoretical model with azimuth-polarization-dependent second harmonic generation response, the complex domain components and their distributions can be rigidly determined in ferroelectric thin films. Using the proposed model, the domain structures of rhombohedral BiFeO3 films with 71° and 109° domain wall, and, tetragonal BiFeO3, Pb(Zr0.2Ti0.8)O3, and BaTiO3 ferroelectric thin films are analyzed and the corresponding polarization variants are determined. This work could provide a powerful and all-optical method to track and evaluate the evolution of ferroelectric domains in the ferroelectric-based devices

Robust muscle activity onset detection using an unsupervised electromyogram learning framework.

Accurate muscle activity onset detection is an essential prerequisite for many applications of surface electromyogram (EMG). This study presents an unsupervised EMG learning framework based on a sequential Gaussian mixture model (GMM) to detect muscle activity onsets. The distribution of the logarithmic power of EMG signal was characterized by a two-component GMM in each frequency band, in which the two components respectively correspond to the posterior distribution of EMG burst and non-burst logarithmic powers. The parameter set of the GMM was sequentially estimated based on maximum likelihood, subject to constraints derived from the relationship between EMG burst and non-burst distributions. An optimal threshold for EMG burst/non-burst classification was determined using the GMM at each frequency band, and the final decision was obtained by a voting procedure. The proposed novel framework was applied to simulated and experimental surface EMG signals for muscle activity onset detection. Compared with conventional approaches, it demonstrated robust performance for low and changing signal to noise ratios in a dynamic environment. The framework is applicable for real-time implementation, and does not require the assumption of non EMG burst in the initial stage. Such features facilitate its practical application

Efficient and Selective Oxidation of 5-Hydroxymethylfurfural into 2, 5-Diformylfuran Catalyzed by Magnetic Vanadium-Based Catalysts with Air as Oxidant

In this study, a new kind of magnetic vanadium-based catalyst was successfully prepared and employed to produce 2, 5-diformylfuran (DFF) in the liquid phase through selective oxidation of biomass-derived 5-hydroxymethylfurfur (HMF) with air as oxidant. It was found that magnetic Fe3O4 nanoparticles supported NH4 center dot V3O8 showed excellent catalytic performance with the achievement of 95.5% HMF conversion along with 82.9% selectivity to DFF under optimal reaction conditions. More importantly, the catalyst could be readily separated from the reaction mixture by a permanent magnet, and recycled several times without the loss of its catalytic activity. Graphic The NH4 center dot V3O8/Fe3O4 catalyst showed high activity for selective oxidation of 5-hydroxymethylfurfural into 2, 5-diformylfuran

Simulated EMG bursts and the corresponding detection performance of the unsupervised learning framework.

<p>The detected segments with muscle activity were highlighted by the rectangular envelope built on the basis of the onset/offset estimates provided by the unsupervised learning framework. (a) Simulated clean EMG trial without added noise, which is composed of five EMG bursts with different durations and amplitudes. The corresponding actual onsets and offsets are marked by vertical dashed lines. (b) Simulated EMG signals at SNR level of 2 dB and the muscle activity onset detection performance. (c) Simulated EMG signals at SNR level of 10 dB and the muscle activity onset detection performance. (d) Simulated EMG signals with time-varying SNR levels and the muscle activity onset detection performance (the dashed lines indicate different signal segments for calculating SNRs).</p

Schematic illustration of logarithmic energy distribution of a frequency band.

<p>(a) Distribution of EMG signal contaminated by noise. (b) Distributions of EMG burst and non-burst. The shadow denotes the classification error.</p