The effects of external electric field: creating non-zero first hyperpolarizability for centrosymmetric benzene and strongly enhancing first hyperpolarizability for non-centrosymmetric edge-modified graphene ribbon H2N-(3,3)ZGNR-NO2

How to generate a non-zero first hyperpolarizability for a centrosymmetric molecule is a challenging question. In this paper, an external (pump) electric field is used to make a centrosymmetric benzene molecule generate a non-zero value of the electric field induced first hyperpolarizability (β ^F ). This comes from the centrosymmetry breaking of electron cloud. Two interesting rules are exhibited. (1) β ^F is anisotropic for different directional fields (F _i, i?=?X, Y, Z). (2) The field dependence of β ^F is a non-monotonic function, and an optimum external electric field causes the maximum value of β ^F . The largest first hyperpolarizability β ^F reaches the considerable level of 3.9?×?10⁵ a.u. under F _Y?=?330?×?10^?4 a.u. for benzene. The external electric field effects on non-centrosymmetric edge-modified graphene ribbon H₂N-(3,3)ZGNR-NO₂ was also studied in this work. The first hyperpolarizability reaches as much as 2.1?×?10⁷ a.u. under F _X?=?600?×?10^?4 a.u. for H₂N-(3,3)ZGNR-NO₂. We show that the external electric field can not only create a non-zero first hyperpolarizability for centrosymmetric molecule, but also remarkably enhance the first hyperpolarizability for a non-centrosymmetric molecule.     

At-line near-infrared spectroscopy for monitoring concentrations in temperature-triggered glutamate fermentation

Rapid development in the glutamate fermentation industry has dictated the need for effective fermentation monitoring by rapid and precise methods that provide real-time information for quality control of the end-product. In recent years, near-infrared (NIR) spectroscopy and multivariate calibration have been developed as fast, inexpensive, non-destructive and environmentally safe techniques for industrial applications. The purpose of this study was to develop models for monitoring glutamate, glucose, lactate and alanine concentrations in the temperature-triggered process of glutamate fermentation. NIR measurements of eight batches of samples were analyzed by partial least-squares regression with several spectral pre-processing methods. The coefficient of determination (R ²), model root-mean square error of calibration (RMSEC), root-mean square error of prediction (RMSEP) and residual predictive deviation (RPD) of the test calibration for the glutamate concentration were 0.997, 3.11 g/L, 2.56 g/L and 19.81, respectively. For the glucose concentration, R ², RMSEC, RMSEP and RPD were 0.989, 1.37 g/L, 1.29 g/L and 9.72, respectively. For the lactate concentration, R ², RMSEC, RMSEP and RPD were 0.975, 0.078 g/L, 0.062 g/L and 6.29, respectively. For the alanine concentration, R ², RMSEC, RMSEP and RPD were 0.964, 0.213 g/L, 0.243 g/L and 5.29, respectively. New batch fermentation as an external validation was used to check the models, and the results suggested that the predictive capacity of the models for the glutamate fermentation process was good.     

KSHV MicroRNAs Mediate Cellular Transformation and Tumorigenesis by Redundantly Targeting Cell Growth and Survival Pathways

Kaposi''s sarcoma-associated herpesvirus (KSHV) is causally linked to several human cancers, including Kaposi''s sarcoma, primary effusion lymphoma and multicentric Castleman''s disease, malignancies commonly found in HIV-infected patients. While KSHV encodes diverse functional products, its mechanism of oncogenesis remains unknown. In this study, we determined the roles KSHV microRNAs (miRs) in cellular transformation and tumorigenesis using a recently developed KSHV-induced cellular transformation system of primary rat mesenchymal precursor cells. A mutant with a cluster of 10 precursor miRs (pre-miRs) deleted failed to transform primary cells, and instead, caused cell cycle arrest and apoptosis. Remarkably, the oncogenicity of the mutant virus was fully restored by genetic complementation with the miR cluster or several individual pre-miRs, which rescued cell cycle progression and inhibited apoptosis in part by redundantly targeting IκBα and the NF-κB pathway. Genomic analysis identified common targets of KSHV miRs in diverse pathways with several cancer-related pathways preferentially targeted. These works define for the first time an essential viral determinant for KSHV-induced oncogenesis and identify NF-κB as a critical pathway targeted by the viral miRs. Our results illustrate a common theme of shared functions with hierarchical order among the KSHV miRs.     

A Novel PEGylated Liposome-Encapsulated SANT75 Suppresses Tumor Growth through Inhibiting Hedgehog Signaling Pathway

The Hedgehog (Hh) pathway inhibitors have shown great promise in cancer therapeutics. SANT75, a novel compound we previously designed to specially inhibit the Smoothened (SMO) protein in the Hh pathway, has greater inhibitory potency than many of commonly used Hh inhibitors. However, preclinical studies of SANT75 revealed water insolubility and acute toxicity. To overcome these limitations, we developed a liposomal formulation of SANT75 and investigated its antitumor efficacy in vitro and in vivo. We encapsulated SANT75 into PEGylated liposome and the mean particle size distribution and zeta-potential (ZP) of liposomes were optimized. Using the Shh-light2 cell and Gli-GFP or Flk-GFP transgenic reporter zebrafish, we confirmed that liposome-encapsulated SANT75 inhibited Hh activity with similar potency as the original SANT75. SANT75 encapsulated into liposome exerted strong tumor growth-inhibiting effects in vitro and in vivo. In addition, the liposomal SANT75 therapy efficiently improved the survival time of tumor-bearing mice without obvious systemic toxicity. The pathological morphology and immunohistochemistry staining revealed that liposomal SANT75 induced tumor cell apoptosis, inhibited tumor angiogenesis as assessed by CD31 and down-regulated the expression of Hh target protein Gli-1 in tumor tissues. Our findings suggest that liposomal formulated SANT75 has improved solubility and bioavailability and should be further developed as a drug candidate for treating tumors with abnormally high Hh activity.     

Decreased Extracellular Adenosine Levels Lead to Loss of Hypoxia-Induced Neuroprotection after Repeated Episodes of Exposure to Hypoxia

Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs) is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC) or 6 days (E6d HPC). Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO) was induced. The effects of these HPC protocols on hypoxia-inducible factor (HIF) regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC). Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1). An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF-regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection.     

Comparison of HER2 and Phospho-HER2 Expression between Biopsy and Resected Breast Cancer Specimens Using a Quantitative Assessment Method

Background

HER2/Neu (ErbB-2) overexpression, which occurs in 15–20% of breast cancer cases, is associated with better response to treatment with the drug trastuzumab. PhosphoHER2 (pHER2) has been evaluated for prediction of response to trastuzumab. Both markers are heterogeneously detected and are potentially subject to loss as a consequence of delayed time to fixation. Here, we quantitatively assess both markers in core needle biopsies (CNBs) and matched tumor resections to assess concordance between the core and the resection and between HER2 and pHER2.

Methods

A selected retrospective collection of archival breast cancer cases yielded 67 cases with both core and resection specimens. Both HER2 and pTyr¹²⁴⁸HER2 were analyzed by the AQUA® method of quantitative immunofluorescence on each specimen pair.

Results

Both HER2 immunoreactivity (P<0.0001) and pTyr¹²⁴⁸HER2 immunoreactivity (P<0.0001) were lower in resections relative to CNB specimens. However, clinical implications of this change may not be evident since no case changed from 3+ (CNB) to negative (resection). Assessment of pTyr¹²⁴⁸HER2 showed no direct correlation with HER2 in either CNB or resection specimens.

Conclusions

The data suggest that measurement of both HER2 and phospho- Tyr¹²⁴⁸HER2, in formalin-fixed tissue by immunological methods is significantly affected by pre-analytic variables. The current study warrants the adequate handling of resected specimens for the reproducible evaluation of HER2 and pHER2. The level of pTyr¹²⁴⁸HER2, was not correlated to total HER2 protein. Further studies are required to determine the significance of these observations with respect to response to HER2 directed therapies.