Convergence Step Research Articles

Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

Plasmodium falciparum is unable to synthesize purine bases and relies upon purine salvage and purine recycling to meet its purine needs. We report that purines formed as products of polyamine synthesis are recycled in a novel pathway in which 5'-methylthioinosine is generated by adenosine deaminase. The action of P. falciparum purine nucleoside phosphorylase is a convergent step of purine salvage, converting both 5'-methylthioinosine and inosine to hypoxanthine. We used accelerator mass spectrometry to verify that 5'-methylthioinosine is an active nucleic acid precursor in P. falciparum. Prior studies have shown that inhibitors of purine salvage enzymes kill malaria, but potent malaria-specific inhibitors of these enzymes have not been described previously. 5'-Methylthio-immucillin-H, a transition state analogue inhibitor that is selective for malarial relative to human purine nucleoside phosphorylase, kills P. falciparum in culture. Immucillins are currently in clinical trials for other indications and may also have application as anti-malarials.

Mitomycin Synthetic Studies: Stereocontrolled and Convergent Synthesis of a Fully Elaborated Aziridinomitosane.

Full details of a stereocontrolled and convergent synthetic route to 9a-desmethoxymitomycin A (1) are reported. The target molecule possesses the parent tetrahydropyrrolo[1,2-a]indole ring system characteristic of the mitomycin family of antitumor agents. The synthesis was based on the diastereocontrolled addition of a fully elaborated cinnamylstannane to a pyrrolidine-based N-acyliminium ion as the key convergent step, which resulted in the installation of the C9 and C9a stereogenic centers.

Mitomycin synthetic studies: stereocontrolled and convergent synthesis of a fully elaborated aziridinomitosane.

Full details of a stereocontrolled and convergent synthetic route to 9a-desmethoxymitomycin A (1) are reported. The target molecule possesses the parent tetrahydropyrrolo[1,2-a]indole ring system characteristic of the mitomycin family of antitumor agents. The synthesis was based on the diastereocontrolled addition of a fully elaborated cinnamylstannane to a pyrrolidine-based N-acyliminium ion as the key convergent step, which resulted in the installation of the C9 and C9a stereogenic centers.

Relation between static and dynamic aspects of vergence, estimated with a subjective test using flashed dichoptic nonius lines.

The psychophysical technique for measuring vergence with dichoptic nonius lines was used to investigate dynamic responses to step vergence stimuli. Liquid crystal shutter glasses were operated with a cathode ray tube monitor to present convergent or divergent step stimuli of 32 min arc at t = 0. The resulting initial vergence response was estimated with nonius lines that appeared for 80 ms at a fixed delay of 400 ms after the vergence step stimulus. The vergence state reached 400 ms after the step depended on the vergence accuracy assumed before the step, i.e. baseline fixation disparity (FD). The following physiologically plausible results were found: (i) the amount of dynamic vergence changes within 400 ms tended to be negatively correlated between the convergent and divergent direction; (ii) subjects with a smaller convergent dynamic change had a steeper proximity-FD curve measured with static fusion targets as a function of viewing distance; (iii) FD was more eso or more exo depending on whether the vergence change was larger in the convergent or divergent direction respectively.

Gravity or translation: Central processing of vestibular signals to detect motion or tilt

The processing and detection of tilts relative to gravity from actual motion (translational accelerations) is one of the most fundamental issues for understanding vestibular sensorimotor control in altered gravity environments. In order to better understand the nature of multisensory signals in detecting motion and tilt, we summarize here our recent studies regarding the central processing of vestibular signals during multi-axis rotational and translational stimuli. Approximately one fourth of the cells in the vestibular nuclei exclusively encoded rotational movements (Canal-Only neurons) and were unresponsive to translation. The Canal-Only central neurons encoded head rotation in canal afferent coordinates, exhibited no orthogonal canal convergence and were characterized by significantly higher sensitivities to rotation as compared to canal afferents. Another fourth of the neurons modulated their firing rates during translation (Otolith-Only cells). During rotations, these neurons typically only responded when the axis of rotation was earth-horizontal and the head was changing orientation relative to gravity. The remaining cells (approximately half of total population) were sensitive to both rotations and translations (Otolith+Canal neurons). Maximum sensitivity vectors to rotation were distributed throughout the 3D space, suggesting strong convergence from multiple semicircular canals. Only a small subpopulation (approximately one third) of these Otolith+Canal neurons seems to encode a true estimate of the translational component of the imposed passive head and body movement. These results provide the first step in further understanding multisensory convergence in normal gravity, as this task is fundamental to our appreciation of neurovestibular adaptation to altered gravity.

Convergence properties and step size estimation for MLMS algorithm

According to the exact expression of the maladjustment, an equation for calculating the boundary of step-size in MLMS algorithm is derived and the relationship between the convergence rate and step-size is discussed in detail. It is shown that the threshold of the step-size is constrained by maladjustment. Three different properties are presented between the LMS and MLMS algorithms based on comparison. It is indicated that MLMS does not differ significantly from LMS when the given maladjustment is small.

High Order Uniformly Convergent Fractional Step RK Methods and HODIE Finite Difference Schemes for 2D Evolutionary Convection-Diffusion Problems

In this work we present a numerical method to solve linear time dependent two dimensional singularly perturbed problems of convection-diffusion type with dominat- ing convection term; this class of problems is characterized by the presence of a regular boundary layer in the output boundary of the spatial domain. The method combines the alternating direction technique, based on an A-stable third order RK method, with a third order HODIE finite difference scheme of classical type, i.e., exact only on polynomial functions, constructed on a special spatial mesh of Shishkin type. We show that, under appropriate restrictions between the discretization parameters, the method is uniformly convergent with respect to the diffusion parameter, having order three (except by a loga- rithmic factor) in the maximum norm. The method provides the computational advantages of the splitting technique and also the efficiency provided by high order methods, achieving good approximations of the solution in the whole domain, including the boundary layer region. We show some numerical results validating in practice the good properties of the method.

Distinct pathways of extracellular signal-regulated kinase activation by growth factors, fibronectin and parathyroid hormone 1–34

Growth factors, hormones, and matrix proteins regulate osteoblast proliferation and differentiation, acting through cognate receptors. Since each of the receptors are coupled to a variety of distinct signal transduction pathways, in this report we evaluated whether there is a common convergent intermediate step that allows cross-talk among the various pathways. Since extracellular signal-regulated kinases 1 and 2 (Erk1/2) play a role in mitogenesis and differentiation processes, we evaluated the effects of various osteotrophic factors on Erk1/2 phosphorylation in osteoblasts. Osteoblasts isolated from the metaphyseal marrow (MM) and diaphyseal marrow (DM) of 4–6 week old male rat longitudinal bones were grown to confluency and Erk1/2-phosphorylation was evaluated using antibodies that recognized either the total or the phosphorylated form of the kinase. There was very little Erk1/2 phosphorylation in cells kept in suspension. Both MM and DM cells attached to fibronectin (FN), demonstrated Erk1/2 phosphorylation that persisted for at least up to 8 h. Platelet-derived growth factor AB (PDGF-AB) induced a transient and robust Erk1/2 phosphorylation that was attenuated by 2 h. Studies with specific inhibitors indicated that the effects of these factors were mediated by protein kinase C, by receptor tyrosine kinase, as well as by protein phosphatases. Parathyroid hormone (PTH 1–34), a bone anabolic agent however, caused a down-regulation of FN stimulated Erk1/2 phosphorylation in MM derived cells. The inhibitory effect of PTH was mediated through cAMP-dependent protein kinase A (PKA) activation. The data collectively suggest that a combination of diverse extracellular stimuli regulates Erk1/2 phosphorylation that may ultimately influence osteoblast proliferation and/or differentiation.

Efficient synthesis of porphyrin-containing, benzoquinone-terminated, rigid polyphenylene dendrimers.

A series of rigid polyphenylene, free-base porphyrin-containing dendrimers terminated with either dimethoxybenzene or benzoquinone end-groups were prepared by a combined divergent and convergent synthesis. Unlike previous routes for preparing polyphenylene dendrimers that are incompatible with end-groups bearing certain functional moieties, the synthetic methodology chosen for this work enables incorporation of functional groups on the dendrimer end-groups during preparation of the dendrimer wedges and during synthesis of the final dendrimer. The basic strategy utilized a convergent preparation of dendrimer wedges using Suzuki coupling conditions, which were then either attached to a porphyrin core in a divergent coupling step or cyclized to form the porphyrin dendrimer in a convergent step. The latter approach was found to be more general and resulted in higher yields and more readily separated products. Steady-state absorption measurements for these dendrimers showed Soret and Q-band absorptions typical of free-base porphyrins. Preliminary steady-state fluorescence measurements of these dendrimers indicate quenching of the S1 state of the free-base porphyrin in all benzoquinone-containing dendrimers that is attributed to efficient electron-transfer from the excited porphyrin to the benzoquinone end-groups. The amount of fluorescence quenching was in good agreement with the number of benzoquinone groups at the dendrimer periphery and the distance between the porphyrin and benzoquinone groups as calculated by semiempirical (AM1) molecular orbital calculations.

The accuracy and efficiency of alternative option pricing approaches relative to a log-transformed trinomial model

This article presents a log-transformed trinomial approach to option pricing and finds that various numerical procedures in the option pricing literature are embedded in this approach with choices of different parameters. The unified view also facilitates comparisons of computational efficiency among numerous lattice approaches and explicit finite difference methods. We use the root-mean-squared relative error and the minimum convergence step to evaluate the accuracy and efficiency for alternative option pricing approaches. The numerical results show that the equal-probability trinomial specification of He (12) and Tian (25) and the sharpened trinomial specification of Omberg (21) outperform other lattice approaches and explicit finite difference methods. © 2002 Wiley Periodicals, Inc. Jrl Fut Mark 22:557–577, 2002

A new method of increasing the order of convergence step by step

In order to derive iterations for simultaneously finding all zeros of an algebraic polynomial with high order convergence, based on D–K method we construct some iterations of increasing the order of convergence step by step.

Ceramide and glucosamine antagonism of alternate signaling pathways regulating insulin- and osmotic shock-induced glucose transporter 4 translocation.

In addition to insulin, hyperosmolarity induces glucose transporter 4 (GLUT4) translocation in 3T3-L1 adipocytes. However, in contrast to insulin this stimulation is independent of PI3K/Akt. In this study we assessed whether ceramide and/or glucosamine, two known insulin-signaling antagonists, also affected the PI3K/Akt-independent signal. Insulin, but not hyperosmolarity, clearly increased the activities of PI3K and Akt. C2-ceramide did not alter insulin-stimulated PI3K activity, but did decrease the ability of insulin to activate Akt and GLUT4 translocation. Consistent with osmotic shock-mediated GLUT4 translocation being independent of PI3K/Akt, GLUT4 translocation induced by hyperosmolarity was not altered by C2-ceramide. In contrast to the specific C2-ceramide-induced attenuation of insulin-stimulated GLUT4 translocation, overexpression of glutamine:fructose-6-phosphate amidotransferase, the rate-limiting enzyme in the synthesis of UDP-N-acetylglucosamine, and/or pretreatment of cells with glucosamine, a precursor of UDP-N-acetylglucosamine, inhibited both insulin- and hyperosmolarity-stimulated GLUT4 translocation. Glucosamine did not alter any of the known proximal insulin signal transduction events. These data suggest that although the hyperosmolarity-induced signal bypasses the initial insulin signal transduction steps, it is likely to induce GLUT4 translocation through activation of a common convergent signal transduction step, targeted by UDP-N-acetylglucosamine, downstream of and/or in parallel to PI3K/Akt.

Ceramide and Glucosamine Antagonism of Alternate Signaling Pathways Regulating Insulin- and Osmotic Shock-Induced Glucose Transporter 4 Translocation

In addition to insulin, hyperosmolarity induces glucose transporter 4 (GLUT4) translocation in 3T3-L1 adipocytes. However, in contrast to insulin this stimulation is independent of PI3K/Akt. In this study we assessed whether ceramide and/or glucosamine, two known insulin-signaling antagonists, also affected the PI3K/Akt-independent signal. Insulin, but not hyperosmolarity, clearly increased the activities of PI3K and Akt. C2-ceramide did not alter insulin-stimulated PI3K activity, but did decrease the ability of insulin to activate Akt and GLUT4 translocation. Consistent with osmotic shock- mediated GLUT4 translocation being independent of PI3K/Akt, GLUT4 translocation induced by hyperosmolarity was not altered by C2-ceramide. In contrast to the specific C2-ceramide-induced attenuation of insulin-stimulated GLUT4 translocation, overexpression of glutamine:fructose-6-phosphate amidotransferase, the rate-limiting enzyme in the synthesis of UDP-N-acetylglucosamine, and/or pretreatment of cells with glucosamine, a precursor of UDP-N-acetylglucosamine, inhibited both insulin- and hyperosmolarity-stimulated GLUT4 translocation. Glucosamine did not alter any of the known proximal insulin signal transduction events. These data suggest that although the hyperosmolarity-induced signal bypasses the initial insulin signal transduction steps, it is likely to induce GLUT4 translocation through activation of a common convergent signal transduction step, targeted by UDP-N-acetylglucosamine, downstream of and/or in parallel to PI3K/Akt.

Isolation and characterization of a rat nitric oxide synthase type I gene promoter that confers expression and regulation in pituitary gonadotrope cells.

Nitric oxide synthase type I (NOS I) is expressed and up-regulated in rat pituitary gonadotrophs. Using rapid amplification of cDNA ends-PCR, 2 major transcripts with 5' ends corresponding to exon 1a but truncated of its first 369 or 384 nucleotides, indicative of two pituitary-specific transcription start sites, were identified. By chromosome walking, we isolated 5'-upstream of this truncated exon termed 1p, a novel -1653/+384-bp genomic region. Transient transfections, using the gonadotrope-derived alpha T3-1 and L beta T2 cell lines and the full-length or 5'-deleted sequences fused to a luciferase reporter gene, demonstrated that cell-specific positive and negative regions were present especially within the -246/-73 region, whereas the +12/+384 region was crucial for transcription. Moreover, in L beta T2 cells, the luciferase activity was increased by GnRH, with the full-length sequence being the most efficient and the -73/+60 region corresponding to the essential zone. The latter region was also crucial for cholera toxin-induced activation. Interestingly, GnRH and cAMP effects were not additive, implying a convergent step in the transduction cascade. These data provide evidence for the presence of several elements controlling NOS I expression in gonadotrophs and demonstrate that GnRH, the prime regulator of gonadotrope function, and cAMP may induce the transcription of NOS I in these cells.

Nonlinear convergence, accuracy, and time step control in nonequilibrium radiation diffusion

We study the interaction between converging the nonlinearities within a time step and time step control, on the accuracy of nonequilibrium radiation diffusion calculations. Typically, this type of calculation is performed using operator-splitting where the nonlinearities are lagged one time step. This method of integrating the nonlinear system results in an “effective” time-step constraint to obtain accuracy. A time-step control that limits the change in dependent variables (usually energy) per time step is used. We investigate the possibility that converging the nonlinearities within a time step may allow significantly larger time-step sizes and improved accuracy as well. The previously described Jacobian-free Newton–Krylov method (JQSRT 63 (1999) 15) is used to converge all nonlinearities within a time step. In addition, a new time-step control method, based on the hyperbolic model of a thermal wave (J. Comput. Phys. 152 (1999) 790), is employed. The benefits and cost of a second-order accurate time step are considered. It is demonstrated that for a chosen accuracy, significant increases in solution efficiency can be obtained by converging nonlinearities within a time step.

On flow and heat transfer of a viscous incompressible fluid past an impulsively started vertical isothermal plate

Numerical technique is employed to derive a solution to the transient natural convection flow of an incompressible viscous fluid past an impulsively started semi-infinite isothermal vertical plate. Heat transfer effects are taken into account and the governing equations are solved using implicit finite-difference method. Transient and steady-state velocity and temperature profiles, the local as well as average skin friction and the Nusselt number are shown graphically. The velocity and temperature profiles at small values of time t are shown to agree with the exact solution of the flow past an impulsively started infinite vertical isothermal plate. The heat transfer effects of different parameters Pr (the Prandtl number) and Gr (the Grashof number) are discussed. It is observed that the number of time steps for convergence to steady state depends strongly on Gr.

The Preparation and Evaluation of Electron Poor Benzylidene Fischer Carbene Complexes: Studies Toward the Total Synthesis of (+)-Olivin

The continued exploration into the fate of the benzannulation reaction is put forth using the electronic nature of substituents on the aryl ring of benzylidene Fischer carbene complexes as a handle to predict, using σ- para values as a guide, the outcome of the reaction based on the accepted mechanism. The design of this work focuses on evaluation of the synthetic utility of the benzannulation reaction and the means by which this reaction may be improved to be a better synthetic tool in the preparation of complex natural products as this is illustrated in our ongoing total synthesis of (+)-olivin which uses the benzannulation reaction as the key convergent synthetic step. To accomplish these tasks, the preparation of several electron poor benzylidene Fischer carbene complexes was carried out and their reaction with simple alkyne substrates studied. While much is known about the preparation of electron rich benzylidene Fischer carbene complexes, little is known about the preparation of their electron poor counterparts. Thus efforts toward developing useful preparative methods of these elusive targets has also been studied. While the use of both carbon and oxygen based aryl substituents has been explored, to date the preparation of benzylidene carbene complexes containing oxygen based aryl substituents has been exploited to a greater degree since these systems carry more immediate synthetic importance. This is so because the skeletal core of many of the natural products that have been targeted with the benzannulation reaction including (+)-olivin contain a highly oxygenated polycyclic aromatic core. The enhancement in efficiency of the benzannulation reaction using this synthetic methodology is demonstrated by the successful completion of the convergent synthetic step in the total synthesis of (+)-olivin.

Stereocontrolled Synthesis of Heteroannular Acetals from Functionalized 1,5-Enynes via Radical Cascades—Construction of Quaternary and 1,2-Diquaternary Centres in Polycyclic Systems

Sequential, radical-mediated cyclizations of 1,5-enynes have been evaluated with respect to structure, stereochemistry and reactivity. In series A 5- exo-trig, 6- endo-dig cascades are favoured. The unusual 6- endo-dig cyclization is dictated by ring strain. Diastereomeric series B tolerates leakage into the 5- exo-trig, 5- exo-dig sequence, especially if a quaternary carbon centre is established during the first five-ring cyclization. The cascade allows construction of four and more chiral centres in a single convergent step. The influence of E/ Z geometry of the olefinic component is also evaluated.

Modular construction of dendritic carbosilanes. Organization Of dendrimer connectivity around bifunctional precursors that are adapted for sequential convergent and divergent propagative steps

Regiospecific hydrosilylation of 1-bromo-4-(prop-2-enyl)benzene offers an efficient route to molecular building block precursors that can accommodate sequential divergent and convergent steps for dendritic extension, establishing a modular methodology for assembly and organization of connectivity used for synthesis of modified carbosilane dendrimers including 14.

Rapid assembly of rigid rods by metal complexation of bis(terpyridyl) ligands

The synthesis of rigid rods by a route involving alternating metal and bis(terpyridyl) ligand addition steps is described; and when combined with a final convergent step, this strategy rapidly produces species containing multiple metal centers.