ARHI (DIRAS 3), an Imprinted Tumor Suppressor Gene, Binds to Importins, and Blocks Nuclear Translocation of Stat3

ARHI (DIRAS3) is an imprinted tumor suppressor gene whose expression is lost in the majority of breast and ovarian cancers. Unlike its homologs Ras and Rap, ARHI functions as a tumor suppressor. Our previous study showed that ARHI can interact with transcription activator Stat3 and inhibit its nuclear translocation in human breast and ovarian cancer cells. To identify proteins that interact with ARHI in nuclear translocation, we have performed proteomic analysis and identified several importins that can associate with ARHI. To further explore this novel finding, we have purified 10 GST-importin fusion proteins (importin 7, 8, 13, b1, a1, a3, a5, a6, a7 as well as mutant a1). Using a GST-pull down assay, we found that ARHI can bind strongly to most importins; however, its binding is significantly reduced with an importin a1 mutant which contains an altered nuclear localization signal (NLS) domain. In addition, an ARHI N-terminal deletion mutant (NTD) exhibits much less binding to all importins than does wild type ARHI ARHI and NTD proteins were purified and tested for their ability to inhibit nuclear importation of proteins in HeLa cells. ARHI protein inhibits interaction of Ran-importin complexes with GFP fusion proteins that contain an NLS domain and a beta-like import receptor binding domain, blocking their nuclear localization. Addition of ARHI also blocked nuclear localization of phosphorylated Stat3β. By GST-pull down assays, we found that ARHI could compete for Ran-importins binding. Thus, ARHI-induced disruption of importin binding to cargo proteins including Stat3 could serve as an important regulatory mechanism that contributes to the tumor suppressor function of ARHI

Three classes of inhibitory amino acid terminals in the cochlear nucleus of the guinea pig

Electron microscopic postembedding immunocytochemistry was used to analyze and assess the synaptic distribution of glycine (GLY) and γ-amino butyric acid (GABA) immunoreactivities in the guinea pig cochlear nucleus (CN). Three classes of endings were identified containing immunolabeling for glycine, GABA, or both glycine and GABA (GLY/GABA). All classes were similar in that the terminals contained pleomorphic vesicles and formed symmetric synapses with their postsynaptic targets. A fourth class, which labeled with neither antibody, contained round vesicles and formed asymmetric synapses. Glycine endings predominated in the ventral CN, while GLY/GABA endings were prevalent in the dorsal CN. GABA endings were the least common and smallest in size. Glycine, GLY/GABA, and GABA endings differed in their proportions and patterns of distribution on the different classes of projection neurons in the CN, including spherical bushy, type I stellate/multipolar, and octopus cells in the ventral CN and fusiform cells in the dorsal CN. The vast majority of anatomically-defined, putative inhibitory endings contain GLY, GABA, or both, suggesting that most of the inhibition in the cochlear nucleus is mediated by these three cytochemically and, probably, functionally distinct classes of endings. The results of this study also suggest that a large proportion of the GABA available for inhibition in the CN coexists in terminals with glycine. © 1996 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50069/1/2_ftp.pd

A novel Big Data analytics and intelligent technique to predict driver's intent

Modern age offers a great potential for automatically predicting the driver's intent through the increasing miniaturization of computing technologies, rapid advancements in communication technologies and continuous connectivity of heterogeneous smart objects. Inside the cabin and engine of modern cars, dedicated computer systems need to possess the ability to exploit the wealth of information generated by heterogeneous data sources with different contextual and conceptual representations. Processing and utilizing this diverse and voluminous data, involves many challenges concerning the design of the computational technique used to perform this task. In this paper, we investigate the various data sources available in the car and the surrounding environment, which can be utilized as inputs in order to predict driver's intent and behavior. As part of investigating these potential data sources, we conducted experiments on e-calendars for a large number of employees, and have reviewed a number of available geo referencing systems. Through the results of a statistical analysis and by computing location recognition accuracy results, we explored in detail the potential utilization of calendar location data to detect the driver's intentions. In order to exploit the numerous diverse data inputs available in modern vehicles, we investigate the suitability of different Computational Intelligence (CI) techniques, and propose a novel fuzzy computational modelling methodology. Finally, we outline the impact of applying advanced CI and Big Data analytics techniques in modern vehicles on the driver and society in general, and discuss ethical and legal issues arising from the deployment of intelligent self-learning cars

The Mesozoic along-strike tectono-metamorphic segmentation of Longmen Shan (eastern Tibetan plateau)

The Longmen Shan belt (eastern border of the Tibetan plateau) constitutes a tectonically active region as demonstrated by the occurrence of the unexpected 2008 Mw 7.9 Wenchuan and 2013 Mw 6.6 Lushan earthquakes in the central and southern parts of the belt respectively. These events revealed the necessity of a better understanding of the long‐term geological evolution of the belt and its effect on the present dynamics and crustal structure. New structural and thermobarometric data offer a comprehensive dataset of the paleo‐temperatures across the belt and P‐T estimates for low‐grade metamorphic domains. In the central Longmen Shan, two metamorphic jumps of 150‐200°C, 5‐6 kbar and ~50 °C, 3‐5 kbar acquired during the Early Mesozoic are observed across the Wenchuan and Beichuan faults respectively, attesting to their thrusting movement and unrevealing a major decollement between the allochtonous Songpan‐Garze metasedimentary cover (at T > 500°C) and the autochtonous units and the basement (T < 400°C). In the southern Longmen Shan, the only greenschist‐facies metamorphism is observed both in the basement (360 ± 30°C, 6 ± 2 kbar) and in the metasedimentary cover (350 ± 30°C, 3 ± 1 kbar). Peak conditions were reached at c. 80‐60 Ma in the basement and c. 55‐33 Ma in the cover, c. 50 Ma after the greenschist‐facies metamorphic overprint observed in the central Longmen Shan (c. 150‐120 Ma). This along‐strike metamorphic segmentation coincides well with the present fault segmentation and reveals that the central and southern Longmen Shan experienced different tectono‐metamorphic histories since the Mesozoic

Influence of dissolution/reprecipitation reactions on metamorphic greenschist to amphibolite-facies mica ⁴⁰Ar/³⁹Ar ages in the Longmen Shan (eastern Tibet)

Linking ages to metamorphic stages in rocks that have experienced low to medium‐grade metamorphism can be particularly tricky due to the rarity of index minerals and the preservation of mineral or compositional relicts. The timing of metamorphism and the Mesozoic exhumation of the metasedimentary units and crystalline basement that form the internal part of the Longmen Shan (eastern Tibet, Sichuan, China), is, for these reasons, still largely unconstrained, but crucial for understanding the regional tectonic evolution of the eastern Tibet. In‐situ core‐rim 40Ar/39Ar biotite and U‐Th/Pb allanite data show that amphibolite‐facies conditions (~10‐11 kbar, 530 °C to 6‐7 kbar, 580 °C) were reached at 210‐180 Ma and that biotite records crystallization, rather than cooling, ages. These conditions are mainly recorded in the metasedimentary cover. The 40Ar/39Ar ages obtained from matrix muscovite that partially re‐equilibrated during the post peak‐P metamorphic history comprise a mixture of ages between that of early prograde muscovite relicts and the timing of late muscovite recrystallization at c. 140‐120 Ma. This event marks a previously poorly documented greenschist facies metamorphic overprint. This latest stage is also recorded in the crystalline basement, and defines the timing of the greenschist‐overprint (7 ± 1 kbar, 370 ± 35 °C). Numerical models of Ar diffusion show that the difference between 40Ar/39Ar biotite and muscovite ages cannot be explained by a slow and protracted cooling in an open system. The model and petrological results rather suggest that biotite and muscovite experienced different Ar retention and resetting histories. The Ar record in mica of the studied low to medium grade rocks seems to be mainly controlled by dissolution‐reprecipitation processes rather than by diffusive loss, and by different microstructural positions in the sample. Together, our data show that the metasedimentary cover was thickened and cooled independently from the basement prior to c. 140 Ma (with a relatively fast cooling at 4.5 ± 0.5 °C/Ma between 185 and 140 Ma). Since the Lower Cretaceous the metasedimentary cover and the crystalline basement experienced a coherent history during which both were partially exhumed. The Mesozoic history of the Eastern border of the Tibetan plateau is therefore complex, polyphase, and the basement was actively involved at least since the Early Cretaceous, changing our perspective on the contribution of the Cenozoic geology

Anti-UVC Irradiation and Metal Chelation Properties of 6-Benzoyl-5,7-dihydroxy-4-phenyl-chromen-2-one: An Implications for Anti-Cataract Agent

Coumarin derivative 1, 5,7-dihydroxy-6-(3-methyl-1-butyryl)-4-phenyl-chromen- 2-one, has been reported to possess radical scavenging activity and DNA protection. We have synthesized a series of coumarins with structural modifications at positions C4, C5, C6 and C7 and evaluated them for their anti-UVC properties. Coumarin 7, 6-benzoyl-5,6-dihydroxy-4-phenyl-chromen-2-one, was found to have the most potent activity in protecting porcine γ-crystallin against UVC insults. Results of fluorescence assays indicated that compound 7 was capable of decreasing the loss of intensity while lens crystallins and DNA PUC19 were irradiated with UVC. Presence of compound 7 decreased hydroxyl radical levels determined by probe 1b and the free iron concentrations determined by Ferrozine reagent. The chelation assay showed that compound 7 was chelated to metal via 6-CO and 5-OH on the benzopyrone ring. The observed protective effects of compound 7 towards crystallins from insults of UVC and free radicals may be due to its iron-chelating activity and its peak absorption at 254 nm