47,031 research outputs found

    Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

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    Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed

    Chiroptical studies on brevianamide B : vibrational and electronic circular dichroism confronted

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    Chiroptical spectroscopy, such as electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) are highly sensitive techniques to probe molecular conformation, configuration, solvation and aggregation. Here we report the application of these techniques to study the fungal metabolite brevianamide B. Comparison of the experimental ECD and VCD spectra with the density functional theory (DFT) simulated counterparts establishes that VCD is the more reliable technique to assign absolute configuration due to the larger functional and dispersion dependence of computed ECD spectra. Despite a low amount of available material, and a relatively unusual example of using VCD carbonyl multiplets, the absolute configuration could be reliably predicted, strengthening the case for application of VCD in the study of complex natural products. Spectral and crystallographic evidence for or against the formation of a dimeric aggregate is discussed; in solution the VCD spectra strongly suggest only monomeric species are present

    Integrality in the Steinberg module and the top-dimensional cohomology of SL_n(O_K)

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    We prove a new structural result for the spherical Tits building attached to SL_n(K) for many number fields K, and more generally for the fraction fields of many Dedekind domains O: the Steinberg module St_n(K) is generated by integral apartments if and only if the ideal class group cl(O) is trivial. We deduce this integrality by proving that the complex of partial bases of O^n is Cohen-Macaulay. We apply this to prove new vanishing and nonvanishing results for H^{vcd}(SL_n(O_K); Q), where O_K is the ring of integers in a number field and vcd is the virtual cohomological dimension of SL_n(O_K). The (non)vanishing depends on the (non)triviality of the class group of O_K. We also obtain a vanishing theorem for the cohomology H^{vcd}(SL_n(O_K); V) with twisted coefficients V.Comment: 36 pages; final version; to appear in Amer. J. Mat

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    Pengaruh Penerapan Media Audiovisual dalam Pembelajaran Bercerita Bahasa Indonesia di MI Perguruan Mu’allimat Cukir Kabupaten Jombang

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    Penelitian ini bertujuan untuk: (1) mengetahui perbedaan pengaruh penerapan media audiovisual VCD cerita dan penerapan media konvensional terhadap pembelajaran bercerita, (2) mengetahui perbedaan kemampuan bercerita siswa laki-laki dan perempuan, dan (3) mengetahui interaksi jenis kelamin terhadap pembelajaran bercerita menggunakan media audiovisual VCD cerita. Jenis penelitian ini adalah quasi eksperimen dengan desain Non Equivalent Pretest Postest Control Group Design. Dalam proses eksperimen ini dilakukan pengamatan pada dua kelompok pembelajaran yaitu kelompok eksperimen yang diberi treatment/perlakuan dengan media VCD cerita, dan kelompok kontrol dengan media konvensional teks cerita. Populasi penelitian adalah semua peserta didik kelas V MI Perguruan Mu’allimat Cukir Kabupaten Jombang yang berjumlah 2 kelas. Kelas VA menjadi kelas eksperimen dan kelas VB menjadi kelas kontrol. Dalam penelitian ini tidak ada pengambilan sampel dari populasi karena semua populasi dijadikan sebagai subjek penelitian. Analisis data dalam penelitian ini menggunakan analisis Anava dua jalur, dan teknik pengumpulan datanya menggunakan tes bercerita. Hasil analisis dengan menggunakan analisis varian dua jalur menunjukkan bahwa (1) media audiovisual VCD cerita lebih berpengaruh dibandingkan dengan media konvensional dalam pembelajaran bercerita. Hal ini dibuktikan dengan diperolehnya Fhitung untuk perbandingan nilai pretes dan postes pada kelompok eksperimen sebesar 25,062 dengan taraf signifikansi 0,000, dan untuk kelompok kontrol diperoleh Fhitung 2,832 dengan taraf signifikansi 0,098. (2) terdapat perbedaan kemampuan bercerita siswa laki-laki dan perempuan pada kelompok eksperimen dan kontrol. Untuk kelompok eksperimen diperoleh Fhitung sebesar 35,91 dan untuk kelompok kontrol diperoleh Fhitung 48,27 dengan taraf signifikansi masing-masing 0,000. (3) terdapat interaksi variabel jenis kelamin dengan media yang digunakan. Hal ini terlihat dari Fhitung sebesar 8,78 dengan taraf signifikansi 0,004

    Dimension invariants of outer automorphism groups

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    The geometric dimension for proper actions gd(G)\underline{\mathrm{gd}}(G) of a group GG is the minimal dimension of a classifying space for proper actions EG\underline{E}G. We construct for every integer r1r\geq 1, an example of a virtually torsion-free Gromov-hyperbolic group GG such that for every group Γ\Gamma which contains GG as a finite index normal subgroup, the virtual cohomological dimension vcd(Γ)\mathrm{vcd}(\Gamma) of Γ\Gamma equals gd(Γ)\underline{\mathrm{gd}}(\Gamma) but such that the outer automorphism group Out(G)\mathrm{Out}(G) is virtually torsion-free, admits a cocompact model for EOut(G)\underline E\mathrm{Out}(G) but nonetheless has vcd(Out(G))gd(Out(G))r\mathrm{vcd}(\mathrm{Out}(G))\le\underline{\mathrm{gd}}(\mathrm{Out}(G))-r.Comment: 24 page

    Model Building of Metal Oxide Surfaces and Vibronic Coupling Density as a Reactivity Index: Regioselectivity of CO2_2 Adsorption on Ag-loaded Ga2_2O3_3

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    The step-by-step hydrogen-terminated (SSHT) model is proposed as a model for the surfaces of metal oxides. Using this model, it is found that the vibronic coupling density (VCD) can be employed as a reactivity index for surface reactions. As an example, the regioselectivity of CO2_2 adsorption on the Ag-loaded Ga2_2O3_3 photocatalyst surface is investigated based on VCD analysis. The cluster model constructed by the SSHT approach reasonably reflects the electronic structures of the Ga2_2O3_3 surface. The geometry of CO2_2 adsorbed on the Ag-loaded Ga2_2O3_3 cluster has a bent structure, which is favorable for its photocatalytic reduction to CO.Comment: 18 pages, 11 figure

    The α\alpha, β\beta and γ\gamma parameterizations of CP violating CKM phase

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    The CKM matrix describing quark mixing with three generations can be parameterized by three mixing angles and one CP violating phase. In most of the parameterizations, the CP violating phase chosen is not a directly measurable quantity and is parametrization dependent. In this work, we propose to use experimentally measurable CP violating quantities, α\alpha, β\beta or γ\gamma in the unitarity triangle as the phase in the CKM matrix, and construct explicit α\alpha, β\beta and γ\gamma parameterizations. Approximate Wolfenstein-like expressions are also suggested.Comment: 14 page, 1 figur
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