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  • American Institute of Physics (AIP)  (4)
  • International Union of Crystallography (IUCr)  (3)
  • The American Society for Microbiology (ASM)  (2)
  • 1
    Publication Date: 2018-02-27
    Description: Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus ( Togaviridae ) which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells. IMPORTANCE Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 in vitro and in vivo . A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 2
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: We have observed an unusual hysteresis loop in rf power dependence of high-temperature superconductor (HTS) coplanar transmission lines. At 77 K and 1 GHz, the signal transmission was linear (insertion loss 〈0.1 dB) until the input power (Pin) reached a critical value of Pc=0.4 W. An abrupt drop by ∼37 dB in the transmitted power (Pout) was observed at Pin=Pc followed by a slow increase (Pout∝Pin0.62) for Pin(approximately-greater-than) Pc. As Pm was then decreased, it retraced the previous curve only until Pin=Pc. However, as Pin was reduced further Pout did not rise until Pin=158 mW, at which Pout started to increase rapidly and returned to the linear regime for Pin〈71 mW. Such a sharp transition and a strong hysteresis effect were unique to the HTS line whereas a gold line with an identical structure did not exhibit these characteristics. This behavior may be utilized for potential applications of new HTS microwave power (current) limiters and switches. Several possible origins for the hysteresis effect are proposed and discussed. © 1995 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 63 (1993), S. 2274-2276 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: The surface impedance of superconducting YBa2Cu3O7 films as a function of temperature at 10 GHz has been measured in a parallel plate resonator geometry. The penetration depth λ(T), complex microwave conductivity σ(T), and quasiparticle scattering rate 1/τ(T) were also determined. After a rapid fall as T is lowered below Tc, the surface resistance Rs exhibits a linear dependence from 65 K down to 6 K. As T drops below Tc, the real part of the conductivity σ1 has a rapid rise, which is attributed to the observed dramatic increase in τ. The normal-fluid density shows a linear behavior at low temperatures, which is inconsistent with s-wave BCS superconductivity.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 43 (1987), S. 754-756 
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 43 (1987), S. 2130-2132 
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 47 (1991), S. 459-461 
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
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  • 7
    Electronic Resource
    Electronic Resource
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 89 (2001), S. 4275-4281 
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Molecular dynamics has been employed to study the disordering and amorphization processes in SiC irradiated with Si and Au ions. The large disordered domains, consisting of interstitials and antisite defects, are created in the cascades produced by Au primary knock-on atoms (PKAs); whereas Si PKAs generate only small interstitial clusters, with most defects being single interstitials and vacancies distributed over a large region. No evidence of amorphization is found at the end of the cascades created by Si recoils. However, the structure analysis indicates that the large disordered domains generated by Au recoils can be defined as an amorphous cluster lacking long-range order. The driving force for amorphization in this material is due to the local accumulation of Frenkel pairs and antisite defects. These results are in good agreement with experimental evidence, i.e., the observed higher disordering rate and the residual disorder after annealing for irradiation with Au2+ are associated with a higher probability for the in-cascade amorphization or formation of a large disordered cluster. © 2001 American Institute of Physics.
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  • 8
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Chaos 5 (1995), S. 43-47 
    ISSN: 1089-7682
    Source: AIP Digital Archive
    Topics: Physics
    Notes: The movement disorder syndrome of tardive dyskinesia arises as a consequence of prolonged regimens of neuroleptic medication, and is characterized, although not exclusively, by jerky and sometimes rhythmical stereotypical motions in a wide range of muscle systems. It is well established that the degree and variability of tremor in tardive dyskinesia is greater than that in normal age-matched subjects. The findings from the current experiment show that the dimension of the tardive dyskinetic finger tremor time series is systematically lower than that evident in normal finger tremor. Furthermore, the variability of finger motion in both groups is inversely related to the dimension of the respective attractor dynamic. The neuroleptic medication appears to constrain the degrees of freedom regulated in organization of the motor system. © 1995 American Institute of Physics.
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  • 9
    Publication Date: 2018-08-01
    Description: Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurovirulent coronavirus and causes neurological dysfunction in the central nervous system (CNS), but the neuropathological mechanism of PHEV remains poorly understood. We report that Unc51-like kinase 1 (Ulk1/Unc51.1) is a pivotal regulator of PHEV-induced neurological disorders and functions to selectively control the initiation of nerve growth factor (NGF)/TrkA endosome trafficking. We first identified the function of Ulk1 by histopathologic evaluation in a PHEV-infected mouse model in which neuronal loss was accompanied by the suppression of Ulk1 expression. Morphogenesis assessments in the primary cortical neurons revealed that overexpression or mutations of Ulk1 modulated neurite outgrowth, collateral sprouting, and endosomal transport. Likewise, Ulk1 expression was decreased following PHEV infection, suggesting that there was a correlation between the neurodegeneration and functional Ulk1 deficiency. We then showed that Ulk1 forms a multiprotein complex with TrkA and the early endosome marker Rab5 and that Ulk1 defects lead to either blocking of NGF/TrkA endocytosis or premature degradation of pTrkA via constitutive activation of the Rab5 GTPase. Further investigation determined that the ectopic expression of Rab5 mutants induces aberrant endosomal accumulation of activated pTrkA, proving that targeting of Ulk1-TrkA-NGF signaling to the retrograde transport route in the neurodegenerative process that underlies PHEV infection is dependent on Rab5 GTPase activity. Therefore, we described a long-distance signaling mechanism of PHEV-driven deficits in neurons and suggested that such Ulk1 repression may result in limited NGF/TrkA retrograde signaling within activated Rab5 endosomes, explaining the progressive failure of neurite outgrowth and survival. IMPORTANCE Porcine hemagglutinating encephalomyelitis virus (PHEV) is a neurotropic coronavirus and targets neurons in the nervous system for proliferation, frequently leaving behind grievous neurodegeneration. Structural plasticity disorders occur in the axons, dendrites, and dendritic spines of PHEV-infected neurons, and dysfunction of this neural process may contribute to neurologic pathologies, but the mechanisms remain undetermined. Further understanding of the neurological manifestations underlying PHEV infection in the CNS may provide insights into both neurodevelopmental and neurodegenerative diseases that may be conducive to targeted approaches for treatment. The significance of our research is in identifying an Ulk1-related neurodegenerative mechanism, focusing on the regulatory functions of Ulk1 in the transport of long-distance trophic signaling endosomes, thereby explaining the progressive failure of neurite outgrowth and survival associated with PHEV aggression. This is the first report to define a mechanistic link between alterations in signaling from endocytic pathways and the neuropathogenesis of PHEV-induced CNS disease.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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