Mid-IR Multiwavelength Difference Frequency Generation Based on Fiber Lasers

A mid-IR multiwavelength difference frequency generation (DFG) laser source with fiber laser fundamental lights is demonstrated by using the dispersion property of PPLN to broaden the quasi-phase-matching (QPM) acceptance bandwidth (BW). Our results show that the QPM BW for the pump YDFL is much larger than that for the signal EDFL. Using a multiwavelength YDFL and a single-wavelength EDFL as the pump and the signal lights, the DFG laser source can simultaneously emit 14 mid-IR wavelengths with the spacing of 14nm at a fixed PPLN temperature. Moreover, mid-IR multiwavelength lasing lines can be synchronously tuned between 3.28 and 3.47μm

Strong Convergence Theorem for Bregman Strongly Nonexpansive Mappings and Equilibrium Problems in Reflexive Banach Spaces

By using a new hybrid method, a strong convergence theorem for finding a common element of the set of solutions of an equilibrium problem and the set of fixed points of Bregman strongly nonexpansive mappings in a reflexive Banach space is proved

Mapping the Interaction of Talin:RIAM Complex in Inside-Out Integrin Activation Pathway

Integrin signaling plays important roles in numerous biological processes including maintenance of normal cellular function and essential homeostasis. In addition, integrin signaling is also involved in the metastasis of cancer cells by changes in normal cell adhesion and migration regulation. Studies have shown that Rap1-interacting adaptor molecule (RIAM), an MRL-family protein, recruits the cytoskeletal protein talin to the plasma membrane, thereby mediating the inside-out integrin signaling. The R8 domain of talin has been identified as the RIAM binding site. Recent knock-out studies have shown that talin does not translocate to the plasma membrane without RIAM recruitment. The goal of this project is to elucidate the mechanism of the interaction between the talin R8 domain and RIAM’s talin-binding (TB) region via structural and molecular studies. We will first determine the structure of the RIAM(TB):talin(R8) complex by X-ray crystallography, then perform functional studies in integrin-mediated cell adhesion. Exposing the structural properties of such an interaction is necessary in understanding the mechanism of integrin activation, and will facilitate the development of anticancer compounds

Proteomic characterization of an isolated fraction of synthetic proteasome inhibitor (PSI)-induced inclusions in PC12 cells might offer clues to aggresomes as a cellular defensive response against proteasome inhibition by PSI

<p>Abstract</p> <p>Background</p> <p>Cooperation of constituents of the ubiquitin proteasome system (UPS) with chaperone proteins in degrading proteins mediate a wide range of cellular processes, such as synaptic function and neurotransmission, gene transcription, protein trafficking, mitochondrial function and metabolism, antioxidant defence mechanisms, and apoptotic signal transduction. It is supposed that constituents of the UPS and chaperone proteins are recruited into aggresomes where aberrant and potentially cytotoxic proteins may be sequestered in an inactive form.</p> <p>Results</p> <p>To determinate the proteomic pattern of synthetic proteasome inhibitor (PSI)-induced inclusions in PC12 cells after proteasome inhibition by PSI, we analyzed a fraction of PSI-induced inclusions. A proteomic feature of the isolated fraction was characterized by identification of fifty six proteins including twenty previously reported protein components of Lewy bodies, twenty eight newly identified proteins and eight unknown proteins. These proteins, most of which were recognized as a profile of proteins within cellular processes mediated by the UPS, a profile of constituents of the UPS and a profile of chaperone proteins, are classed into at least nine accepted categories. In addition, prolyl-4-hydroxylase beta polypeptide, an endoplasmic reticulum member of the protein disulfide isomerase family, was validated in the developmental process of PSI-induced inclusions in the cells.</p> <p>Conclusions</p> <p>It is speculated that proteomic characterization of an isolated fraction of PSI-induced inclusions in PC12 cells might offer clues to appearance of aggresomes serving as a cellular defensive response against proteasome inhibition.</p

Design and evaluation of rhubarb total free anthraquinones oral colon-specific drug delivery granules to improve the purgative effect

Rhubarb is commonly used as a cathartic in Asian countries. However, researchers have devotedextensive concerns to the quality control and safety of rhubarb and traditional Chinese preparations composed of rhubarb due to the instable purgative effect and potential nephrotoxicity of anthraquinones. In this study, we aimed to prepare rhubarb total free anthraquinones (RTFA) oral colon-specific drug delivery granules (RTFA-OCDD-GN) to delivery anthraquinones to colon to produce purgative effect. RTFAOCDD-GN were prepared using chitosan and Eudragit S100 through a double-layer coating process and the formulation was optimized. Continuous release studies were performed in a simulated gastric fluid (pH 1.2), followed by a small-intestinal fluid (pH 6.8) and a colonic fluid (pH 7.4, containing rat cecal contents). The purgative effect test was performed in rats. The dissolution profile of RTFA-OCDD-GN showed that the accumulative dissolution rate of RTFA was about 83.0% in the simulated colonic fluid containing rat cecal contents and only about 9.0% in the simulated gastrointestinal fluids. And the RTFAOCDD-GN could produce the comparative purgative activity as rhubarb, suggesting it could deliver the free AQs to the colon. The RTFA-OCDD-GN was a useful media to enhance the purgative activity of free anthraquinones after administered orally

Insolation driven biomagnetic response to the Holocene Warm Period in semi-arid East Asia

The Holocene Warm Period (HWP) provides valuable insights into the climate system and biotic responses to environmental variability and thus serves as an excellent analogue for future global climate changes. Here we document, for the first time, that warm and wet HWP conditions were highly favourable for magnetofossil proliferation in the semi-arid Asian interior. The pronounced increase of magnetofossil concentrations at ~9.8 ka and decrease at ~5.9 ka in Dali Lake coincided respectively with the onset and termination of the HWP, and are respectively linked to increased nutrient supply due to postglacial warming and poor nutrition due to drying at ~6 ka in the Asian interior. The two-stage transition at ~7.7 ka correlates well with increased organic carbon in middle HWP and suggests that improved climate conditions, leading to high quality nutrient influx, fostered magnetofossil proliferation. Our findings represent an excellent lake record in which magnetofossil abundance is, through nutrient availability, controlled by insolation driven climate changes.This research was supported by the NSFC grant 41330104 and the 973 program grant 2012CB821900. J.X. was supported by the 973 program grant 2010CB833400 and the NSFC grant 41130101. J.L. received support from the NSFC grant 41374004. C.D. acknowledges further support from the NSFC grant 40925012 and the CAS Bairen Program

PA-X is a virulence factor in avian H9N2 influenza virus

H9N2 influenza viruses have been circulating worldwide in multiple avian species, and regularly infect pigs and humans. Recently, a novel protein, PA-X, produced from the PA gene by ribosomal frameshifting, was demonstrated to be an antivirulence factor in pandemic 2009 H1N1, highly pathogenic avian H5N1 and 1918 H1N1 viruses. However, a similar role of PA-X in the prevalent H9N2 avian influenza viruses has not been established. In this study, we compared the virulence and cytopathogenicity of H9N2 WT virus and H9N2 PA-X-deficient virus. Loss of PA-X in H9N2 virus reduced apoptosis and had a marginal effect on progeny virus output in human pulmonary adenocarcinoma (A549) cells. Without PA-X, PA was less able to suppress co-expressed GFP in human embryonic kidney 293T cells. Furthermore, absence of PA-X in H9N2 virus attenuated viral pathogenicity in mice, which showed no mortality, reduced progeny virus production, mild-to-normal lung histopathology, and dampened proinflammatory cytokine and chemokine response. Therefore, unlike previously reported H1N1 and H5N1 viruses, we show that PA-X protein in H9N2 virus is a pro-virulence factor in facilitating viral pathogenicity and that the pro- or antivirulence role of PA-X in influenza viruses is virus strain-dependent

Thapsigargin at non-cytotoxic levels induces a potent host antiviral response that blocks influenza a virus replication

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Influenza A virus is a major global pathogen of humans, and there is an unmet need for effective antivirals. Current antivirals against influenza A virus directly target the virus and are vulnerable to mutational resistance. Harnessing an effective host antiviral response is an attractive alternative. We show that brief exposure to low, non-toxic doses of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, promptly elicits an extended antiviral state that dramatically blocks influenza A virus production. Crucially, oral administration of TG protected mice against lethal virus infection and reduced virus titres in the lungs of treated mice. TG-induced ER stress unfolded protein response appears as a key driver responsible for activating a spectrum of host antiviral defences that include an enhanced type I/III interferon response. Our findings suggest that TG is potentially a viable host-centric antiviral for the treatment of influenza A virus infection without the inherent problem of drug resistance

Prevailing PA mutation K356R in avian influenza H9N2 virus increases mammalian replication and pathogenicity

Adaptation of the viral polymerase complex comprising PB1, PB2, and PA is necessary for efficient influenza A virus replication in new host species. We found that PA mutation K356R (PA-K356R) has become predominant since 2014 in avian H9N2 viruses in China as with seasonal human H1N1 viruses. The same mutation is also found in most human isolates of emergent avian H7N9 and H10N8 viruses whose six internal gene segments are derived from the H9N2 virus. We further demonstrated the mammalian adaptive functionality of the PA-K356R mutation. Avian H9N2 virus with the PA-K356R mutation in human A549 cells showed increased nuclear accumulation of PA and increased viral polymerase activity that resulted in elevated levels of viral transcription and virus output. The same mutant virus in mice also enhanced virus replication and caused lethal infection. In addition, combined mutation of PA-K356R and PB2-E627K, a well-known mammalian adaptive marker, in the H9N2 virus showed further cooperative increases in virus production and severity of infection in vitro and in vivo. In summary, PA-K356R behaves as a novel mammalian tropism mutation, which, along with other mutations such as PB2-E627K, might render avian H9N2 viruses adapted for human infection

M gene reassortment in H9N2 influenza virus promotes early infection and replication: contribution to rising virus prevalence in chickens in China

Segment reassortment and base mutagenesis of influenza A viruses are the primary routes to the rapid evolution of high fitness virus genotypes. We recently described a predominant G57 genotype of avian H9N2 viruses that caused country-wide outbreaks in chickens in China during 2010-2013 which led to the zoonotic emergence of H7N9 viruses. One of the key features of the G57 genotype is the substitution of the earlier BJ/94-like M gene with the G1-like M gene of quail origin. We report here on the functional significance of the G1-like M gene in H9N2 viruses in conferring increased infection severity and infectivity in primary chicken embryonic fibroblasts and chickens. H9N2 virus housing the G1-like M gene, in place of BJ/94-like M gene, showed early surge in viral mRNA and vRNA transcription that were associated with enhanced viral protein production, and with early elevated release of progeny virus comprising largely spherical rather than filamentous virions. Importantly, H9N2 virus with G1-like M gene conferred extrapulmonary virus spread in chickens. Five highly represented signature amino acid residues (37A, 95K, 224N and 242N in M1 protein, and 21G in M2 protein) encoded by the prevalent G1-like M gene were demonstrated as prime contributors to enhanced infectivity. Therefore, the genetic evolution of M gene in H9N2 virus increases reproductive virus fitness, indicating its contribution to rising virus prevalence in chickens in China. Importance We recently described the circulation of a dominant genotype (G57) of H9N2 viruses in country-wide outbreaks in chickens in China, which was responsible through reassortment for the emergence of H7N9 viruses that cause severe human infections. A key feature of the G57 genotype H9N2 virus is the presence of quail origin G1-like M gene which had replaced the earlier BJ/94-like M gene. We found that H9N2 virus with G1-like M gene, but not BJ/94-like M gene, showed early surge in progeny virus production, more severe pathology and extrapulmonary virus spread in chickens. Five highly represented amino acid residues in M1 and M2 proteins derived from G1-like M gene were shown to mediate enhanced virus infectivity. These observations enhance what we currently know about the roles of reassortment and mutations on virus fitness and have implications for assessing the potential of variant influenza viruses that can cause rising prevalence in chickens