C\u3csub\u3e60\u3c/sub\u3e fullerenes selectively inhibit BK\u3csub\u3eCa\u3c/sub\u3e but not K\u3csub\u3ev\u3c/sub\u3e channels in pulmonary artery smooth muscle cells

© 2019 Elsevier Inc. Possessing unique physical and chemical properties, C60 fullerenes are arising as a potential nanotechnological tool that can strongly affect various biological processes. Recent molecular modeling studies have shown that C60 fullerenes can interact with ion channels, but there is lack of data about possible effects of C60 molecule on ion channels expressed in smooth muscle cells (SMC). Here we show both computationally and experimentally that water-soluble pristine C60 fullerene strongly inhibits the large conductance Ca2+-dependent K+ (BKCa), but not voltage-gated K+ (Kv) channels in pulmonary artery SMC. Both molecular docking simulations and analysis of single channel activity indicate that C60 fullerene blocks BKCa channel pore in its open state. In functional tests, C60 fullerene enhanced phenylephrine-induced contraction of pulmonary artery rings by about 25% and reduced endothelium-dependent acetylcholine-induced relaxation by up to 40%. These findings suggest a novel strategy for biomedical application of water-soluble pristine C60 fullerene in vascular dysfunction

Small Molecules Targeted to a Non-Catalytic “RVxF” Binding Site of Protein Phosphatase-1 Inhibit HIV-1

HIV-1 Tat protein recruits host cell factors including CDK9/cyclin T1 to HIV-1 TAR RNA and thereby induces HIV-1 transcription. An interaction with host Ser/Thr protein phosphatase-1 (PP1) is critical for this function of Tat. PP1 binds to a Tat sequence, Q35VCF38, which resembles the PP1-binding “RVxF” motif present on PP1-binding regulatory subunits. We showed that expression of PP1 binding peptide, a central domain of Nuclear Inhibitor of PP1, disrupted the interaction of HIV-1 Tat with PP1 and inhibited HIV-1 transcription and replication. Here, we report small molecule compounds that target the “RVxF”-binding cavity of PP1 to disrupt the interaction of PP1 with Tat and inhibit HIV-1 replication. Using the crystal structure of PP1, we virtually screened 300,000 compounds and identified 262 small molecules that were predicted to bind the “RVxF”-accommodating cavity of PP1. These compounds were then assayed for inhibition of HIV-1 transcription in CEM T cells. One of the compounds, 1H4, inhibited HIV-1 transcription and replication at non-cytotoxic concentrations. 1H4 prevented PP1-mediated dephosphorylation of a substrate peptide containing an RVxF sequence in vitro. 1H4 also disrupted the association of PP1 with Tat in cultured cells without having an effect on the interaction of PP1 with the cellular regulators, NIPP1 and PNUTS, or on the cellular proteome. Finally, 1H4 prevented the translocation of PP1 to the nucleus. Taken together, our study shows that HIV- inhibition can be achieved through using small molecules to target a non-catalytic site of PP1. This proof-of-principle study can serve as a starting point for the development of novel antiviral drugs that target the interface of HIV-1 viral proteins with their host partners

Testing of numerical simulation technique of concentrated suspensions agitation

The paper presents testing results of the numerical technique to simulate the agitation process of concentrated suspensions. The simulating technique is based on Eulerian two-fluid model of granular media, k-w SST URANS turbulence model, and sliding mesh approach. The results obtained show a good qualitative and quantitative agreement between calculation and experiment in terms of the shape and location of the phase interface and the distribution of the solid phase along the height

Testing of numerical simulation technique of concentrated suspensions agitation

The paper presents testing results of the numerical technique to simulate the agitation process of concentrated suspensions. The simulating technique is based on Eulerian two-fluid model of granular media, k-w SST URANS turbulence model, and sliding mesh approach. The results obtained show a good qualitative and quantitative agreement between calculation and experiment in terms of the shape and location of the phase interface and the distribution of the solid phase along the height

Testing of numerical simulation technique of concentrated suspensions agitation

The paper presents testing results of the numerical technique to simulate the agitation process of concentrated suspensions. The simulating technique is based on Eulerian two-fluid model of granular media, k-w SST URANS turbulence model, and sliding mesh approach. The results obtained show a good qualitative and quantitative agreement between calculation and experiment in terms of the shape and location of the phase interface and the distribution of the solid phase along the height

Периодические элементы f\sqrt f в эллиптических полях с полем констант нулевой характеристики

A study of the periodicity problem of functional continued fractions of elements of elliptic and hyperelliptic fields was begun about 200 years ago in the classical papers of N.~Abel and P.~L.~Chebyshev. In 2014 V.~P.~Platonov proposed a general conceptual method based on the deep connection between three classical problems: the problem of the existence and construction of fundamental $S$-units in hyperelliptic fields, the torsion problem in Jacobians of hyperelliptic curves, and the periodicity problem of continued fractions of elements of hyperelliptic fields. In 2015-2019, in the papers of V.~P.~Platonov et al. was made great progress in studying the problem of periodicity of elements in hyperelliptic fields, especially in the effective classification of such periodic elements.In the papers of V.~P.~Platonov et al, all elliptic fields $\mathbb{Q}(x)(\sqrt{f})$ were found such that $\sqrt{f}$ decomposes into a periodic continued fraction in $\mathbb{Q}((x))$, and also futher progress was obtained in generalizing the indicated result, as to other fields of constants, and to hyperelliptic curves of genus $2$ and higher. In this article, we provide a complete proof of the result announced by us in 2019 about the finiteness of the number of elliptic fields $k(x)(\sqrt{f})$ over an arbitrary number field $k$ with periodic decomposition of $\sqrt{f}$, for which the corresponding elliptic curve contains a $k$-point of even order not exceeding $18$ or a $k$-point of odd order not exceeding $11$. For an arbitrary field $k$ being quadratic extension of $\mathbb{Q}$ all such elliptic fields are found, and for the field $k = \mathbb{Q}$ we obtained new proof about of the finiteness of the number of periodic $\sqrt{f}$, not using the parameterization of elliptic curves and points of finite order on them.Исследование проблемы периодичности функциональных непрерывных дробей элементов эллиптических и гиперэллиптических полей было начато около 200 лет назад в классических работах Н.~Абеля и П.~Л.~Чебышева. В 2014 году В.~П.~Платоновым был предложен общий концептуальный метод, базирующийся на глубокой связи трех классических проблем: проблема существования и построения фундаментальных $S$-единиц в гиперэллиптических полях, проблема кручения в якобианах гиперэллиптических кривых и проблема периодичности непрерывных дробей элементов в гиперэллиптических полях. В 2015-2019 годах в работах В. П. Платонова с соавторами был достигнут большой прогресс в исследовании проблемы периодичности элементов в гиперэллиптических полях, в особенности в эффективной классификации таких периодических элементов. Так, например, в указанных работах В.~П.~Платонова с соавторами были найдены все эллиптические поля $\mathbb{Q}(x)(\sqrt{f})$ такие, что $\sqrt{f}$ разлагается в периодическую непрерывную дробь в $\mathbb{Q}((x))$, а также были получены дальнейшие продвижения в обобщении указанного результата, как на другие числовые поля констант, так и на гиперэллиптические кривые рода $2$ и выше. В настоящей статье мы приводим полное доказательство анонсированного нами в 2019 году результата о конечности числа эллиптических полей $k(x)(\sqrt{f})$ над произвольным числовым полем $k$ с периодическим разложением $\sqrt{f}$, для которых соответствующая эллиптическая кривая содержит $k$-точку четного порядка не превосходящего $18$ или $k$-точку нечетного порядка не превосходящего $11$. Для произвольного поля $k$ являющегося квадратичным расширением $\mathbb Q$ найдены все такие эллиптические поля, а для поля $k=\mathbb Q$ было получено новое доказательство конечности числа периодических $\sqrt{f}$, не использующее параметризацию эллиптических кривых и точек конечного порядка на них

1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription

Background and purpose: HIV-1 transcription is activated by the Tat protein which recruits the cyclin-dependent kinase CDK9/cyclin T1 to TAR RNA. Tat binds to protein phosphatase-1 (PP1) through the Q35VCF38 sequence and translocates PP1 to the nucleus. PP1 dephosphorylates CDK9 and activates HIV-1 transcription. We have synthesized a low MW compound 1H4, that targets PP1 and prevents HIV-1 Tat interaction with PP1 and inhibits HIV-1 gene transcription. Here, we report our further work with the 1H4-derived compounds and analysis of their mechanism of action

Small Molecules Targeted to a Non-Catalytic ‘‘RVxF’’ Binding Site of Protein Phosphatase-1 Inhibit HIV-1

HIV-1 Tat protein recruits host cell factors including CDK9/cyclin T1 to HIV-1 TAR RNA and thereby induces HIV-1 transcription. An interaction with host Ser/Thr protein phosphatase-1 (PP1) is critical for this function of Tat. PP1 binds to a Tat sequence, Q35VCF38, which resembles the PP1-binding ‘‘RVxF’’ motif present on PP1-binding regulatory subunits. We showed that expression of PP1 binding peptide, a central domain of Nuclear Inhibitor of PP1, disrupted the interaction of HIV-1 Tat with PP1 and inhibited HIV-1 transcription and replication. Here, we report small molecule compounds that target the ‘‘RVxF’’-binding cavity of PP1 to disrupt the interaction of PP1 with Tat and inhibit HIV-1 replication. Using the crystal structure of PP1, we virtually screened 300,000 compounds and identified 262 small molecules that were predicted to bind the ‘‘RVxF’’-accommodating cavity of PP1. These compounds were then assayed for inhibition of HIV-1 transcription in CEM T cells. One of the compounds, 1H4, inhibited HIV-1 transcription and replication at non-cytotoxic concentrations. 1H4 prevented PP1-mediated dephosphorylation of a substrate peptide containing an RVxF sequence in vitro. 1H4 also disrupted the association of PP1 with Tat in cultured cells without having an effect on the interaction of PP1 with the cellular regulators, NIPP1 and PNUTS, or on the cellular proteome. Finally, 1H4 prevented the translocation of PP1 to the nucleus. Taken together, our study shows that HIV- inhibition can be achieved through using small molecules to target a non-catalytic site of PP1. This proof-of-principle study can serve as a starting point for the development of novel antiviral drugs that target the interface of HIV-1 viral proteins with their host partners