133,762 research outputs found
Optimization of Parameters in the Menzerath–Altmann Law, II
No full textsummary:The paper continues our studies released under the same title [Andres, J., Kubáček, L., Machalová, J., Tučková, M.: Optimization of parameters in the Menzerath–Altmann law Acta Univ. Palacki. Olomuc., Fac. rer. nat., Math. 51, 1 (2012), 5–27.]. As the main result justifying the conclusions in [Andres, J., Kubáček, L., Machalová, J., Tučková, M.: Optimization of parameters in the Menzerath–Altmann law Acta Univ. Palacki. Olomuc., Fac. rer. nat., Math. 51, 1 (2012), 5–27.], the theorem is presented enunciating that the English original of Poe’s celebrated poem Raven is a language fractal only w.r.t. the application of the simplest truncated formulas of the Menzerath–Altmann law, but not w.r.t. other applied formulas under our consideration. Moreover, the related degree of semanticity is calculated in these cases, including the naive intervals of such a degree. A suitability of the applied formulas is discussed from the point of view of a verbal version of the Menzerath–Altmann law (i.e. the tendency of the approximating functions is to be decreasing) and by means of quantitative criteria characterizing the accuracy of fitted data. Our discussion extends the traditional approaches to the Menzerath–Altmann law
Natural products from higher plants and marine organisms as sources of new anticancer agents: synthesis and biological evaluation
No full textAbstract part A: The dysregulation of the Hedgehog (Hh) signaling pathway plays a pivotal role in the generation and cell-manteinance of many human cancers. Gli transcription factors, the final effectors of the pathway, represent the most promising target for the development of new drugs targeting the Hh pathway in tumors. In a previous work, a natural isoflavone, glabrescione B (GlaB) (I), was identified as the first small molecule binding Gli1. It is able to inhibit the transcriptional activity of Gli1, by interfering with its interaction with DNA. In order to perform further studies on the mechanism of action of GlaB (I) we developed a total synthesis, while NMR studies demonstrated the interaction of GlaB with Gli1
Biological studies have demonstrated its ability to interfere with the activity of Gli1 by inhibiting the growth of Gli-dependent-Hh-dependent tumor cells such as medulloblastoma (MB) and basal cell carcinoma (BCC) both in vitro and in allograft mouse models.
In addition, our new synthetic route, which encompasses just three steps with an overall yield of 15%, provided an efficient synthetic means to enable the investigation of the role of GlaB ring-B in the interaction Gli1-GlaB. In fact, our synthetic strategy allowed the preparation of several GlaB derivativesin order to elucidate the structure-activity relationships (SARs) and to clarify the molecular mechanism underlying its Hedgehog signalling modulation.Abstract part B: The second part of this PhD thesis describes the work I have carried out during my research stay abroad at Swiss Federal Institute of Technology (ETH) in Zürich (Switzerland) in Prof. Dr. Karl-Heinz Altmann's laboratory. Marine natural products show higher incidence of bioactivity compared to terrestrial natural products. This is due to a high degree of chemical novelty and their high dilution in ocean water. (+)-Dactylolide (I) was isolated by Riccio and co-workers from a sponge of the genus Dactylospongia, collected off the coast of Vanuatu islands, in the South Pacific Ocean. The absolute and the relative configuration at C19 of the compound remained unassigned. The assignment of the relative and absolute configuration of (+)-dactylolide (I) is based on its first total synthesis by Smith and co-workers. As had been described for the natural product, synthetic dactylolide has been found to be dextrorotatory, but the magnitude of the specific rotation reported for the natural product and synthetic I were significantly different from each other. In addition, the discrepancies between the 13C-NMR spectra of synthetic and natural (+)-dactylolide (if ever so slight), also leave open the possibility that the configuration of C19 in natural (+)-dactylolide is R and not S (i. e. natural dactylolide could have the structure II instead of I). In order to demonstrate that, a total synthesis of both compounds was established.
(+)-Dactylolide (I) is related to (-)-zampanolide (III), another marine macrolide. The latter shows low nanomolar cytotoxicity against both drug-sensitive and multi-drug resistant cancer cell lines, and induces microtubule bundle formation. While (-)-zampanolide (III) is a nM inhibitor of cancer cell growth in vitro, not many data about the activity of (+)-dactylolide (I) have been published. On the other hand, the biological activity of synthetic (-)-dactylolide (ent-I) is well known. This compound exhibits sub-μM IC50 values against a multitude of cancer cell lines, although (–)-zampanolide (III) is still 100- to 300-fold more potent. At the same time, not even synthetic (+)-zampanolide (ent-III) has ever been tested and the importance of the configuration of the macrocycle for the potency of dextrorotatory compounds remains unclear. Our goal was to synthesize (+)-dactylolide (I) and (+)-zampanolide (ent-III), in order to investigate how the macrocycle configuration would affect the biological activity of the compounds
Optimization of parameters in the Menzerath–Altmann law
No full textsummary:Four formulas of the Menzerath–Altmann law are tested from the point of view of their applicability and suitability. The accuracy of related approximations of measured data is examined by the least square method at first. Then the accuracy of calculated parameters in the formulas under consideration is compared statistically. The influence of neglecting parameter is investigated as well. Finally, the obtained results are discussed by means of an illustrative example from quantitative linguistics
Disturbance of cerebral function in people exposed to drinking water contaminated with aluminium sulphate: retrospective study of the Camelford water incident
No full textObjective: To establish whether people exposed to drinking water contaminated with 20 tonnes of aluminium sulphate in the Camelford area of Cornwall in the south west of England in July 1988 had suffered organic brain damage as opposed to psychological trauma only.
Design: Retrospective study of affected people.
Participants: 55 affected people and 15 siblings nearest in age to one of the group but who had not been exposed to the contaminated water were studied.
Main outcome measures: Various clinical and psychological tests to determine medical condition and anxiety levels in affected people. Assessment of premorbid IQ (pFSIQ) with the national adult reading test, a computerised battery of psychomotor testing, and measurement of the difference in latencies between the flash and pattern visual evoked potentials in all participants.
Results: The mean (SE) pFSIQ was above average at 114.4 (1.1). The most sensitive of the psychomotor tests for organic brain disease was the symbol digit coding (SDC) test (normal score 100, abnormal less than 85). Participants performed less well on this test (54.5 (6.0)) than expected from their pFSIQ (Pless than 0.0001) and a little less poorly on the averaged less discriminating tests within the battery (86.1 (2.5), Pless than 0.0001). In a comparison with the 15 sibling pairs (affected people's age 41.0 (3.3) years vsibling age of 42.7 (3.1) years (P=0.36) the exposed people had similar pFSIQ (114.7 (2.1)) to their siblings (116.3 (2.1), (P=0.59) but performed badly on the symbol digit coding test (51.8 (16.6)) v(87.5 (4.9) for siblings, P=0.03). The flash-pattern differences in exposed people were greater than in 42 unrelated control subjects of similar age (27.33 (1.64) ms v18.57 (1.47) ms, P=0.0002). The 15 unexposed siblings had significantly better flash-pattern differences than their affected siblings (13.4 (2.4) ms v29.6 (2.9) ms, P=0.0002). No effect of anxiety could be shown on these measurements from the analysis of the anxiety scores of exposed people.
Conclusion: People who were exposed to the contaminated water at Camelford suffered considerable damage to cerebral function, which was not related to anxiety. Follow up studies would be required to determine the longer term prognosis for affected individuals
Nontwist non-Hamiltonian systems
No full textWe show that the nontwist phenomena previously observed in Hamiltonian systems exist also in time-reversible non-Hamiltonian systems. In particular, we study the two standard collision-reconnection scenarios and we compute the parameter space breakup diagram of the shearless torus. Besides the Hamiltonian routes, the breakup may occur due to the onset of attractors. We study these phenomena in coupled phase oscillators and in non-area-preserving maps
Stolen Art and Sovereign Immunity: The Case of Altmann v. Austria
No full textPart I of this Article will briefly recount the principal facts of Altmann v. Republic ofAustria. Parts II through IV will then address the principal arguments that Austria has raised against the application of the Foreign Sovereign Immunities Act, namely: 1. That the FSIA would have an impermissible retroactive effect if it were to be applied to Altmann\u27s claims arising from operative facts that occurred before both the effective date of the FSIA and the 1952 Tate Letter; 2. That the conduct of the Nazi regime and its agencies and instrumentalities in World War II, including Austria, in no way would have defeated the expectations of these state parties that they would receive immunity from prosecution in foreign courts; 3. That application of the FSIA in Altmann will open the door to subjective, inconsistent, and unpredictable applications of the FSIA in future cases
MeSH term explosion and author rank improve expert recommendations
No full textInformation overload is an often-cited phenomenon that reduces the productivity, efficiency and efficacy of scientists. One challenge for scientists is to find appropriate collaborators in their research. The literature describes various solutions to the problem of expertise location, but most current approaches do not appear to be very suitable for expert recommendations in biomedical research. In this study, we present the development and initial evaluation of a vector space model-based algorithm to calculate researcher similarity using four inputs: 1) MeSH terms of publications; 2) MeSH terms and author rank; 3) exploded MeSH terms; and 4) exploded MeSH terms and author rank. We developed and evaluated the algorithm using a data set of 17,525 authors and their 22,542 papers. On average, our algorithms correctly predicted 2.5 of the top 5/10 coauthors of individual scientists. Exploded MeSH and author rank outperformed all other algorithms in accuracy, followed closely by MeSH and author rank. Our results show that the accuracy of MeSH term-based matching can be enhanced with other metadata such as author rank
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Synthesis and evaluation of glycomimetic antagonists for the lectins DC-SIGN and FimH
No full textLectins are carbohydrate-binding proteins that are widely spread in nature and crucially involved in a multitude of biological processes. This thesis addresses the design of glycomimetic antagonists for the human lectin DC-SIGN (chapter 2) and the bacterial lectin FimH (chapter 3), which are both involved in infectious diseases.
Dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) is a C-type lectin expressed on immature dendritic cells (DCs) prevalent in mucosal tissue. Besides its function as an adhesion molecule enabling the migration of DCs and binding to T cells, DC-SIGN is one of the major pathogen recognition receptors on DCs. In general, pathogen binding leads to phagocytosis, DC maturation, and migration to the lymph nodes, where antigenic fragments are presented to resting T cells which finally initiate a specific immune response. However, a variety of pathogens, such as viruses (e.g. HIV-1), bacteria (e.g. Mycobacterium tuberculosis), and parasites (e.g. Schistosoma mansoni), exploit this initial interaction with DC-SIGN to evade the immune system and, instead, efficiently infect the host. With its Ca2+-dependent carbohydrate recognition domain (CRD), DC-SIGN binds oligomannosides or fucose-containing Lewis antigens such as Lewisx (Lex = Gal(1-4)[Fuc(1-3)]GlcNAc) present on the surface of microbial cells or on viral envelop proteins. Blocking the first interaction between the microorganisms and DC-SIGN by suitable antagonists is therefore a promising therapeutic approach towards the prevention of infectious diseases.
The first part of this thesis addresses the development of fucose-based glycomimetic antagonists for DC-SIGN. To this end, the interaction of Lewis-type structures with DC-SIGN was elucidated. STD NMR experiments were conducted to determine the binding epitopes of Lewis trisaccharides bearing different aglycones. This study revealed a switch of the binding mode upon introduction of aromatic aglycones as a result of an additional hydrophobic interaction (chapter 2.2).
A series of trisaccharide mimics of Lex was synthesized to elucidate the role of D-Gal and D-GlcNAc in Lewis-type structures for binding to DC-SIGN. For this purpose, the central D-GlcNAc was replaced with (1R,2R)-cyclohexane-1,2-diol based moieties and the D-Gal moiety was replaced with various deoxy analogues. Affinity data including thermodynamic binding parameters indicate that, first, D-Gal is not crucial for binding and, second, mimicking of one sugar moiety enhances binding affinity (chapters 2.3.1 and 2.3.2).
Based on the preliminary results, further glycomimetics were developed to enable the interaction with the hydrophobic area in the binding site and tested for their potential as DC-SIGN antagonists (chapter 2.3.3).
FimH is a bacterial, mannose-specific lectin expressed on the tip of filamentous surface organelles of uropathogenic Escherichia coli. The CRD of FimH interacts with glycoconjugates such as uroplakin Ia present on urothelial cells. This bacterial adhesion is the initial and most crucial step in the establishment of urinary tract infections (UTIs), since it prevents the bacteria from being washed out by the bulk flow of urine. UTIs are among the most common infectious diseases affecting millions of people every year. The treatment with antibiotics encounters increasing bacterial resistance and demands for alternative strategies to prevent and treat UTIs. The development of anti-adhesive agents that are able to inhibit the crucial interaction of FimH with the urothelial cells presents a promising, alternative therapeutic approach.
Intestinal absorption and renal clearance are key issues for orally dosed FimH antagonists to reach the therapeutic target in the human bladder. Besides high affinity and selectivity for the target, a potent FimH antagonist thus must exhibit favourable pharmacokinetic (PK) properties. The second part of this thesis covers three studies that aim at improving these characteristics in mannose-based FimH antagonists.
The first study was directed towards the replacement of a conserved water molecule within the CRD of FimH. For this purpose, an appropriately modified D-mannoside was synthesized and biologically evaluated. The unexpected loss in affinity towards FimH could be explained by detailed molecular dynamics studies (chapter 3.2.1).
A Topliss-based structure-activity relationship study was conducted for the investigation of biphenyl mannosides as FimH antagonists. The pi-pi stacking of the aromatic aglycone with Tyr48 at the rim of the binding site was elucidated and a group of high-affinity antagonists with promising physico-pharmacological properties was identified (chapter 3.2.2).
One of these compounds was further investigated as part of a bioisosteres study for its potential as orally available FimH antagonist. In addition to the optimal in vitro PK/PD profile, this antagonist showed an excellent PK profile in vivo (chapter 3.2.3)
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