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By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC50 = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes. [ABSTRACT FROM AUTHOR]

Bis(1-butyl-1-methypyrrolidinium) perthiodicarbonate was obtained by the reaction of carbon disulfide with 1-butyl-1-methypyrrolidinium acetate ([BmPyrro][Ac]) in the liquid phase. Structural characterization of this original complex was achieved by single-crystal X-ray diffraction (SCXRD) analysis. The asymmetric unit of the title compound, C2S6·2C9H20N, consisted of two crystallographically 1-methyl-1-butyl pyrrolidinium cations and one perthiodicarbonate anion. The complex C2S6·2C9H20N crystallized in the monoclinic space group, C 2/c, and possessed the following cell parameters: a = 16.0970(10) Å, b = 14.7140(9) Å, c = 12.3280(8) Å, α = 90°, β = 112.3730(12)°, γ = 90°, V = 2700.11 Å3, and Z = 8, Z' = 0.5. [ABSTRACT FROM AUTHOR]

For many presentist philosophers, e.g. Zimmerman (Contemp Debates Metaphys 10:211–225, 2008), a central motivation in favour of presentism is that it is supposed to be part of common sense. But the fact that common-sense intuitions are indeed presentist is usually taken for granted (and sometimes also conceded by eternalists). As has been shown in other domains of philosophy (e.g. free will), we should be careful when attributing some supposed intuitions to common sense, and Torrengo (Phenomenology and Mind 12: 50–55, 2017) and Le Bihan (Igitur-Arguments Philos 9(1):1–23, 2018) have legitimately raised doubts about the assumption that common sense is presentist. In this paper, I take up this challenge and try to show that our common-sense intuitions do imply presentism. More precisely, the intuitions that I take to imply presentism are fundamental intuitions about our selves as conscious beings. The upshot is that presentism is so much embedded within our conception of our selves that if presentism is false, then I don’t exist! [ABSTRACT FROM AUTHOR]

The syntheses of novel 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazolines 12 and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinolines 13 are reported here in six steps starting from various halogeno-quinazoline-2,4-(1H,3H)-diones or substituted anilines. The antiproliferative activities of the products were determined in vitro against a panel of breast (MCF-7 and MDA-MB-231), human adherent cervical (HeLa and SiHa), and ovarian (A2780) cell lines. Disubstituted 6- and 7-phenyl-bis(3-dimethylaminopropyl)aminomethylphenyl-quinazolines 12b, 12f, and 12i displayed the most interesting antiproliferative activities against six human cancer cell lines. In the series of quinoline derivatives, 6-phenyl-bis(3-dimethylaminopropyl)aminomethylphenylquinoline 13a proved to be the most active. G-quadruplexes (G4) stacked non-canonical nucleic acid structures found in specific G-rich DNA, or RNA sequences in the human genome are considered as potential targets for the development of anticancer agents. Then, as small aza-organic heterocyclic derivatives are well known to target and stabilize G4 structures, their ability to bind G4 structures have been determined through FRET melting, circular dichroism, and native mass spectrometry assays. Finally, telomerase inhibition ability has been also assessed using the MCF-7 cell line. [ABSTRACT FROM AUTHOR]

Potassium 6-oxo-7,13,16,22-tetraazatetracyclo[12.6.2.18,12.017,21]tricosa-1(20),8(23),9,11,14,16,18,21-octaen-2-yne-15-carboxylate was synthesized through a multi-step pathway, starting from commercially available 3-iodo-1,2-phenylenediamine. Structure characterization of this new substituted macrocyclic quinoxaline compound was achieved using 1H NMR, 13C NMR, and HRMS spectral analysis. This new macrocyclic derivative demonstrated submicromolar potency on both Pim-1 and Pim-2 isoforms, with an interesting selectivity profile against a selected panel of human kinases. [ABSTRACT FROM AUTHOR]

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Copyright of Revue Thomiste is the property of Revue Thomiste and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay. [ABSTRACT FROM AUTHOR]

(E)-Pyrrolo[1,2-a]quinoxalin-4-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one was designed then synthesized using a multi-step pathway starting from commercially available 2-nitroaniline. Structure characterization of this original substituted pyrrolo[1,2-a]quinoxaline compound was achieved by using FT-IR, 1H-NMR, 13C-NMR, X-Ray and HRMS spectral analysis. This new pyrroloquinoxaline shows interesting cytotoxic potential against different human leukemia cell lines (MV4-11, K562, MOLM14 and Jurkat cells). [ABSTRACT FROM AUTHOR]

Common-sense philosophers typically maintain that common-sense propositions have a certain kind of epistemic privilege that allows them to evade the threats of skepticism or radical revisionism. But why do they have this special privilege? In response to this question, the "Common-Sense Tradition" contains many different strands of arguments. In this paper, I will develop a strategy that combines two of these strands of arguments. First, the "Dynamic Argument" (or the "starting-point argument"), inspired by Thomas Reid and Charles S. Peirce (but which will be strengthened with the help of Gilbert Harman's epistemology of belief revision). Second, G.E. Moore's "greater certainty argument" (interpreted along the lines of Soames' and Pollock's construal). This combined strategy, I will argue, is the strong core of Common-Sense Philosophy, and relies on extremely modest and widely held assumptions. [ABSTRACT FROM AUTHOR]

Skepticism has had a long-standing appeal for philosophers since the days of Pyrrho of Elis. This is based on the idea that skepticism, especially skepticism about other minds, is not restricted to epistemological matters but has important consequences for metaphysics and ethics. Troubled by this prospect, philosophers like Epicurus, the Stoics, Augustine, Descartes, Reid, Kant, Hegel, G.E. Moore and Wittgenstein dealt with some varieties of radical skepticism. According to de Peretti's interpretation, Descartes' response to skepticism relies on a particular kind of faith in reason that is never really put in doubt. [Extracted from the article]

Copyright of Pédagogie Médicale is the property of EDP Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

1,3-Dihydro-1-{1-[4-(4-phenylpyrrolo[1,2-a]quinoxalin-3-yl)benzyl]piperidin-4-yl}-2H-benzimidazol-2-one has been synthesized through a multi-step pathway starting from commercially available 2-nitroaniline. A structure characterization of this new substituted pyrrolo[1,2-a]quinoxaline compound was achieved by using FT-IR, 1H-NMR, 13C-NMR, X-Ray and HRMS spectral analysis. This new pyrroloquinoxaline derivative shows an interesting cytotoxic potential against several human leukemia cell lines (HL60, K562 and U937 cells). [ABSTRACT FROM AUTHOR]

There are three families of solutions to the traditional Amputation Paradox: Eliminativism, Contingent Identity Theories, and Theories of Coincident Entities. Theories of Coincident Entities challenge our common understanding of the relation between identity and parthood, since they accept that two things can be mereologically coincident without being identical. The contemporary discussion of the Amputation Paradox tends to mention only one theory of Coincident Entities, namely the Constitution View, which violates the mereological principle of Extensionality. But in fact, there is another theory, namely the Unique Part View, which violates another mereological principle (the Weak Supplementation Principle). In this paper, I argue that the contemporary focus on the Constitution View is unmotivated, at least when we are confronted with the Amputation Paradox, and that a balanced comparison of the two views (as solutions to this specific paradox) should favour the Unique Part View. [ABSTRACT FROM AUTHOR]

Copyright of Annals of Philosophy / Roczniki Filozoficzne is the property of John Paul II Catholic University of Lublin, Faculty of Philosophy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

When the meta-philosophies of Nominalism and Realism are compared, it is often said that Nominalism is motivated by a methodology of ontological economy, while Realism would be motivated by an appeal to Common Sense. In this paper, I argue that this association is misguided. After briefly comparing the meta-philosophy of Common Sense and the meta-philosophy of economy, I show that the core motivation in favour of Realism relies in fact in a principle of economy which violates the methodology of Common Sense. I conclude that Common Sense philosophers should endorse Nominalism (and more precisely Ostrich Nominalism). [ABSTRACT FROM AUTHOR]

Defining an appropriate and efficient assessment of drug‐induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc‐prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14‐based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B‐based "double‐negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high‐dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double‐negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development. [ABSTRACT FROM AUTHOR]

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays. [ABSTRACT FROM AUTHOR]

Copyright of Annals of Philosophy / Roczniki Filozoficzne is the property of John Paul II Catholic University of Lublin, Faculty of Philosophy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Temperature-dependent sex determination, or TSD, is a widespread phenomenon in reptiles. The shape of the relationship between constant incubation temperature and sex ratio defines the TSD pattern. The TSD pattern is considered a life-history parameter important for conservation because the wider the range of temperatures producing both sexes, the more resilient the species is to climate change impacts.Wereview the different published equations and methodologies that have been used to model TSD patterns. We describe a new flexible model that allows for an asymmetrical pattern around the pivotal temperature, which is the constant temperature producing both sexes in equal proportions. We show that Metropolis-Hastings with Markov chain produced by a Monte Carlo process has many advantages compared to maximum likelihood and is preferred. Finally, we apply the models to results from incubation experiments using eggs from the marine turtle Lepidochelys olivacea originating in Northeast Indian, East Pacific, and West Atlantic Regional Management Units (RMUs) and find large differences in pivotal temperatures but not in transitional ranges of temperatures. [ABSTRACT FROM AUTHOR]

The title compound 4-{4-[(4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)benzyl]}-3-phenyl-3H-pyrrolo[2,3-c]quinoline 1, a compound that showed cytotoxic potential against two leukemia cell lines, has been synthesized via a multi-step pathway. This compound was characterized by single-crystal X-ray diffraction, IR, MS, elemental analysis, 1H and 13C NMR. The crystal (C37H33H5O, Mr = 563.68) belongs to orthorhombic, space group Pbcn with cell parameters a = 30.198(2) Å, b = 12.5097(11) Å, c = 15.6648(13) Å, V = 5917.7(8) Å3, Z = 8, Dc = 1.265 g/cm3, CuKα radiation, λ = 1.54180 Å, µ = 0.611 mm−1, F(000) = 2384, the final R = 0.0491 and wR = 0.1585 for 5698 observed reflections with I > 2σ(I). The antileukemial 4-{4-[(4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl)benzyl]}-3-phenyl-3H-pyrrolo[2,3-c]quinoline was synthesized and characterized by X-ray crystallography. [ABSTRACT FROM AUTHOR]

Introduction: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the L-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. Methods: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). Results: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. Discussion: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment. [ABSTRACT FROM AUTHOR]

Descartes’s Evil Demon argument has been the subject of many reconstructions in recent analytic debates. Some have proposed a reconstruction with a principle of Infallibility, others with a principle of Closure of Knowledge, others with more original principles. In this paper, I propose a new reconstruction, which relies on the combination of two principles, namely the Meta-Coherence principle (defended by Huemer) and the principle of Closure of Justification (best defended by Hawthorne). I argue that the argument construed in this way is the best interpretation of what is really at play in the Evil Demon intuition, and also that this argument is dialectically much stronger than previous reconstructions. If this is right, then the “Closure plus Meta-Coherence” argument is what anti-sceptics should really be attacking. [ABSTRACT FROM AUTHOR]

Recent in vitro cardiac safety studies demonstrate the ability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to detect electrophysiologic effects of drugs. However, variability contributed by unique approaches, procedures, cell lines, and reagents across laboratories makes comparisons of results difficult, leading to uncertainty about the role of hiPSC-CMs in defining proarrhythmic risk in drug discovery and regulatory submissions. A blinded pilot study was conducted to evaluate the electrophysiologic effects of 8 well-characterized drugs on 4 cardiomyocyte lines using a standardized protocol across 3 microelectrode array platforms (18 individual studies). Drugs were selected to define assay sensitivity of prominent repolarizing currents (E-4031 for I Kr, JNJ303 for I Ks) and depolarizing currents (nifedipine for I CaL, mexiletine for I Na) as well as drugs affecting multichannel block (flecainide, moxifloxacin, quinidine, and ranolazine). Inclusion criteria for final analysis was based on demonstrated sensitivity to I Kr block (20% prolongation with E-4031) and L-type calcium current block (20% shortening with nifedipine). Despite differences in baseline characteristics across cardiomyocyte lines, multiple sites, and instrument platforms, 10 of 18 studies demonstrated adequate sensitivity to I Kr block with E-4031 and I CaL block with nifedipine for inclusion in the final analysis. Concentration-dependent effects on repolarization were observed with this qualified data set consistent with known ionic mechanisms of single and multichannel blocking drugs. hiPSC-CMs can detect repolarization effects elicited by single and multichannel blocking drugs after defining pharmacologic sensitivity to I Kr and I CaL block, supporting further validation efforts using hiPSC-CMs for cardiac safety studies. [ABSTRACT FROM AUTHOR]

Objective: Multi electrodes arrays (MEAs) combined with cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) can enable high- or medium-throughput drug screening in safety pharmacology. This technology has recently attracted a lot of attention, in particular from an international initiative named CiPA. But it is currently limited by the difficulty to analyze the measured signals. We propose a strategy to analyze the signals acquired by the MEA and to automatically deduce the channels affected by the drug. Methods: Our method is based on the bidomain equations, a model for the MEA electrodes, and an inverse problem strategy. Results: in silico MEA signals are obtained for two commercial devices and an example of early after depolarization is presented. Then, by processing real signals obtained for four different compounds, our algorithm was able to provide dose-response curves for potassium, sodium, and calcium channels. For ivabradine and moxifloxacin, the IC50 and dose-response curves are in very good agreement with known values. Significance: The proposed strategy offers a possible answer to a major question raised by the community of safety pharmacology. By allowing a more automated analysis of the signals, our approach could contribute to promote the technology based on MEA and hiPSC-CMs and, therefore, improve reliability and efficiency of drug screening. [ABSTRACT FROM AUTHOR]

A series of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μ m range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic‐to‐antiparasitic activities of 107 and 39 against a chloroquine‐sensitive and a chloroquine‐resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G‐quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence. [ABSTRACT FROM AUTHOR]

G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore considered as important targets for the development of anticancer agents. Small organic heterocyclic molecules are well known to target and stabilize G4 structures. In this article, we have designed and synthesized 2,6-di-(4-carbamoyl-2-quinolyl)pyridine derivatives and their ability to stabilize G4-structures have been determined through the FRET melting assay. It has been established that these ligands are selective for G4 over duplexes and show a preference for the parallel conformation. Next, telomerase inhibition ability has been assessed using three cell lines (K562, MyLa and MV-4-11) and telomerase activity is no longer detected at 0.1 µM concentration for the most potent ligand 1c. The most promising G4 ligands were also tested for antiproliferative activity against the two human myeloid leukaemia cell lines, HL60 and K562. [ABSTRACT FROM AUTHOR]

This article reminisces about the life and key scientific achievements of Jan Evangelista Purkinje (1787-1869), a versatile 19th century Czech pioneer of modern experimental physiology. In 1804, after completing senior high school, Purkinje joined the Piarist monk order, but, after a 3-yr novitiate, he gave up the religious calling "to deal more freely with science." In 1818, he earned a Medical Doctor degree from Prague University by defending a dissertation on intraocular phenomena observed in oneself. In 1823, Purkinje became a Physiology and Pathology professor at the Prussian Medical University in Breslau, where he innovated the traditional teaching methods of physiology. Purkinje's contributions to physiology were manifold: accurate descriptions of various visual phenomena (e.g., Purkinje-Sanson images, Purkinje phenomenon), discovery of the terminal network of the cardiac conduction system (Purkinje fibers), identification of cerebellar neuronal bodies (Purkinje cells), formulation of the vertigo law (Purkinje's law), discovery of criteria to classify human fingerprints, etc. In 1850, Purkinje accepted and held until his death the Physiology chair at Prague Medical Faculty. During this period, he succeeded in introducing the Czech idiom (in addition to long-established German and Latin) as a Medical Faculty teaching language. Additionally, as a zealous Czech patriot, he actively contributed to the naissance and consolidation of a national Czech identity conscience. Purkinje was a trend-setting scientist who, throughout his career, worked to pave the way for the renovation of physiology from a speculative discipline, ancilla of anatomy, into a factual, autonomous science committed to the discovery of mechanisms governing in-life functions. [ABSTRACT FROM AUTHOR]

Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives1were synthesized and tested forin vitroactivity upon the intraerythrocytic stage of W2 and 3D7Plasmodium falciparumstrains. Biological results showed good antimalarial activity with IC50in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties towardLeishmania donovaniwere also investigated and revealed their selective antiplasmodial profile. In parallel, thein vitrocytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure–activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines1nand1pwere identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targetingPlasmodiumtelomeres by stabilizing thePlasmodiumtelomeric G-quadruplexes through a FRET melting assay by our new compounds. [ABSTRACT FROM PUBLISHER]

In a heterogeneous environment, when the fitness of males and females are differently influenced by habitat quality, habitat-dependent sex ratios may evolve to favor the production of the sex that benefits more (or loses less) from the local habitat. Similarly, sex-biased dispersal favors the evolution of habitat-dependent sex ratios. The present study documents the convergence stable sex ratios expected in the presence of sex-specific fitness gains when dispersal is partial, sex-biased or costly, using a simple model with patches of two qualities. Results show that partial dispersal reduces the sex ratio bias expected with sex-specific fitness gains. The direction of the sex ratio bias can be reversed by sex-biased dispersal or the existence of sex-specific dispersal costs, provided that fitness gains for the two sexes are not too different. The reversal of the sex ratio bias is more readily observed when sex-specific dispersal rates are opposite and extreme. Both dispersal and fitness gains, especially when they are sex-specific, should thus be considered when making predictions about sex ratio evolution in a heterogeneous environment. [ABSTRACT FROM AUTHOR]

ABSTRACT The design and synthesis of novel peptides that inhibit angiogenesis is an important area for anti-angiogenic drug development. Cyclic and small peptides present several advantages for therapeutic application, including stability, solubility, increased bio-availability and lack of immune response in the host cell. We describe here the synthesis and biological evaluations of a new cyclic peptide analog of CBO-P11: cyclo(RIKPHE), designated herein as CBO-P23M, a hexamer peptide encompassing residues 82 to 86 of VEGF which are involved in the interaction with VEGF receptor-2. CBO-P23M was prepared using in solution cyclization, therefore reducing the peptide cyclodimerization occurred during solid-phase cyclization. The cyclic dimer of CBO-P23M, which was obtained as the main side product during synthesis of the corresponding monomer, was also isolated and investigated. Both peptides markedly reduce VEGF-A-induced phosphorylation of VEGFR-2 and Erk1/2. Moreover, they exhibit anti-angiogenic activity in an in vitro morphogenesis study. Therefore CBO-P23M and CBO-P23M dimer appear as attractive candidates for the development of novel angiogenesis inhibitors for the treatment of cancer and other angiogenesis-related diseases. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 368-375, 2016. [ABSTRACT FROM AUTHOR]

This work reports on the design and the synthesis of two short linear peptides both containing a few amino acids with disorder propensity and an allylic ester group at the C-terminal end. Their structural properties were firstly analyzed by means of experimental techniques in solution such as CD and NMR methods that highlighted peptide flexibility. These results were further confirmed by MD simulations that demonstrated the ability of the peptides to assume conformational ensembles. They revealed a network of transient and dynamic H-bonds and interactions with water molecules. Binding assays with a well-known drug-target, i.e., the CXCR4 receptor, were also carried out in an attempt to verify their biological function and the possibility to use the assays to develop new specific targets for CXCR4. Moreover, our data indicate that these peptides represent useful tools for molecular recognition processes in which a flexible conformation is required in order to obtain an interaction with a specific target. [ABSTRACT FROM AUTHOR]

Due to their system of annulated 6-5-5-6-membered rings, indenoindoles have sparked great interest for the design of ATP-competitive inhibitors of human CK2. In the present study, we prepared twenty-one indeno[1,2-b]indole derivatives, all of which were tested in vitro on human CK2. The indenoindolones 5a and 5b inhibited human CK2 with an IC50 of 0.17 and 0.61 μM, respectively. The indeno[1,2-b]indoloquinone 7a also showed inhibitory activity on CK2 at a submicromolar range (IC50 = 0.43 μM). Additionally, a large number of indenoindole derivatives was evaluated for their cytotoxic activities against the cell lines 3T3, WI-38, HEK293T and MEF. [ABSTRACT FROM AUTHOR]

Any philosopher who defends Free Will should have an answer to the epistemological question: 'how do we know that we have such a capacity?' A traditional answer to this question is that we have some form of introspective access to our own Free Will. In recent times though, many philosophers have considered any such introspectionist theory as so obviously wrong that it hardly needs discussion, especially when Free Will is understood in libertarian terms. One of the rare objections to appear as an explicit argument was proposed by van Inwagen in his Essay on Free Will. In this paper, I address van Inwagen's anti-introspection argument; I argue that it is both inconsistent with his overall treatment of the Existence Question (namely, with his defence of the existence of Free Will from reflections about morality), and inconclusive in itself (at least for anyone not ready to endorse general scepticism about perception). In passing, I give a clarification of the notion of Introspection, in the case of Freedom, that also sets a more favourable stage for the evaluation of further objections. [ABSTRACT FROM AUTHOR]

We recently synthesized from aconitine a series of drugs with in vitro and in vivo antitumor properties, among which bis[ O-(14-benzoylaconine-8-yl)]suberate (BBAS) was the most active (Eur J Med Chem ; 54: 343). In the present work, we used the NCI panel of 60 human tumor cell lines to identify the most sensitive cell lines and drugs with comparable cytotoxicity profiles. GI values of BBAS ranged between 0.12 and 6.5 μM. Activity was higher than average for leukemia and melanoma cell lines, especially SK-MEL-5 and SK-MEL-28, for the COLO-205 and HT-29 (colorectal) and MDA-MB-468 (breast) cancer cell lines. We evaluated the correlation between the GI of BBAS and those of 125 antiproliferative compounds with various mechanisms of action, using Bonferroni correction for multiple testing, and we observed a highly significant correlation with the GIs of nitrosoureas. Interestingly, BBAS cytotoxicity was inversely correlated with the expression levels of MGMT ( p = 0.009), an enzyme involved in the repair of nitrosourea-induced DNA damage. However, no correlation was found with the expression of 102 other genes involved in DNA repair. Antitumor activity was tested on immunodeficient mice with subcutaneously xenografted COLO-205, HT-29, MDA-MB-468, SK-MEL-5 and SK-MEL-28 cell lines. At 10 mg/kg, there was a significant reduction in tumor size with T/C values of 41 % and 43 % for COLO-205 and SK-MEL-28 cell lines, respectively. The drug was less active on HT-29 and SK-MEL-5 and inactive on MDA-MB-468 xenografts. Cell cycle studies showed an accumulation of BBAS-treated cells in G2/M phase after treatment at 20 μM. Together, our results allowed the identification of a potentially new class of anticancer agent displaying a mechanism of action related to that of nitrosoureas. [ABSTRACT FROM AUTHOR]

The complete 1H and 13C assignments of eight bioactive indeno[1,2- b]indole-10-one derivatives were accomplished by the combined use of one-dimensional and two-dimensional NMR experiments. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Mefloquine (MQ), an antimalarial drug, is used as a racemate of (−)‐ and (+)‐enantiomers, which display biological differences. The question concerning their exact configuration remains a matter of debate. The absolute configuration of the two MQ enantiomers as well as their biological activity has been established, thus confirming the importance of the stereochemistry in the design of MQ analogues that have fewer adverse side effects (see figure). [ABSTRACT FROM AUTHOR]

The PI3K/Akt-signaling pathway, associated with cancer development and disease progression, is recognized to be an anti-tumor drug target that could present important therapeutic benefit. However, no targeted Akt medicines have been commercialized yet, reflecting that drug selection procedures requires significant improvement from early research to clinical trials. Thus, new methods permitting both the evaluation of cytotoxic and proliferation inhibition effect on cancer cells but also to provide a global fingerprint of the drug action mechanism of new Akt inhibitor candidates are of major interest. Because it can detect very subtle molecular changes and could provide a global fingerprint of drug effects on cells, Fourier-transform infrared (FTIR) spectroscopy appears to be a promising method to develop new time- and cost-saving tools for chemical library screening improvements. In this study, we combine FTIR spectroscopy, advanced chemometrics analysis and cross-validation by standard biological assays to establish a basis of a mid-throughput methodology for rapid and automated assessment of cell response to Akt inhibitors and quantitative evaluation of their anti-proliferative effects. Our results shows that our methodology is able (1) to detect cell response to an Akt inhibitor exposure even for very low doses, (2) to provide biochemical information of interest about its effects on the cell metabolism, lipidome, and proteome, (3) to predict accurately resulting cell proliferation inhibition rate. Thus, further based on a large spectral data base, our methodology could contribute to facilitate preliminary screening of chemical libraries and improving the selection procedure of drug candidates in laboratory routine. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]