Divergent Class Research Articles

Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter

A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510nM at MDR-1. Three of the dimeric IDHPs possessed <1.5µM activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole – incorporated as part of the click assembly as a spacer – contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n=2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity.

Vested Interests and the Common Man as Seen Through Monetary and Fiscal Policy: Flooding Wall Street or Main Street?

:There are many angles through which a critical observer can analyze the divergent class interests in most aspects of macroeconomic management. We examine the insistence of financial authorities of all major economies on reviving economic activity through monetary — and not fiscal — policy as a particularly clear example of favoring vested interests over the interests of the common man. Nearly a century after Thorstein Veblen wrote on the subject, one can find many parallel elements to the political landscape of the times. Today, the common man is often expressed by the “99%,” and many accept that the dominant vested interest is that of global banks. Unlike in Veblen’s times, economists today have many historical experiments in economic management that they can consult. By employing logic, historical experience, and an understanding of our current global finance-led capitalism, we offer a preliminary institutionalist analysis of the mechanisms of current monetary policy that “flood” Wall Street, while leaving employment, production, and investment — Main Street — all but forgotten. We then explain how vested interests have abandoned fiscal policy and left a deflationary macroeconomic environment.

Bacterial lipids activate, synergize, and inhibit a developmental switch in choanoflagellates

In choanoflagellates, the closest living relatives of animals, multicellular rosette development is regulated by environmental bacteria. The simplicity of this evolutionarily relevant interaction provides an opportunity to identify the molecules and regulatory logic underpinning bacterial regulation of development. We find that the rosette-inducing bacterium Algoriphagus machipongonensis produces three structurally divergent classes of bioactive lipids that, together, activate, enhance, and inhibit rosette development in the choanoflagellate Salpingoeca rosetta. One class of molecules, the lysophosphatidylethanolamines (LPEs), elicits no response on its own but synergizes with activating sulfonolipid rosette-inducing factors (RIFs) to recapitulate the full bioactivity of live Algoriphagus. LPEs, although ubiquitous in bacteria and eukaryotes, have not previously been implicated in the regulation of a host-microbe interaction. This study reveals that multiple bacterially produced lipids converge to activate, enhance, and inhibit multicellular development in a choanoflagellate.

On Conformal Divergences and Their Population Minimizers

Total Bregman divergences are a recent tweak of ordinary Bregman divergences originally motivated by applications that required invariance by rotations. They have displayed superior results compared to ordinary Bregman divergences on several clustering, computer vision, medical imaging and machine learning tasks. These preliminary results raise two important problems : First, report a complete characterization of the left and right population minimizers for this class of total Bregman divergences. Second, characterize a principled superset of total and ordinary Bregman divergences with good clustering properties, from which one could tailor the choice of a divergence to a particular application. In this paper, we provide and study one such superset with interesting geometric features, that we call conformal divergences, and focus on their left and right population minimizers. Our results are obtained in a recently coined $(u, v)$-geometric structure that is a generalization of the dually flat affine connections in information geometry. We characterize both analytically and geometrically the population minimizers. We prove that conformal divergences (resp. total Bregman divergences) are essentially exhaustive for their left (resp. right) population minimizers. We further report new results and extend previous results on the robustness to outliers of the left and right population minimizers, and discuss the role of the $(u, v)$-geometric structure in clustering. Additional results are also given.

Comparative analysis of genetic diversity and its relation to heterosis in early and mid-maturity Indian cauliflower (Brassica oleracea var. botrytis L.)

An experiment involving self-incompatible line based 80 F1 hybrids in early and 54 F1 hybrids in mid-maturity groups derived from line × tester design were studied with an aim of relating genetic divergence among the parents with the magnitude of heterosis in the F1 generations and to identify suitable hybrids. The significant improvements in mean of the hybrids were observed over the parents for all the traits in both maturity groups. Mean performance of all growth and yield contributing traits of parents and hybrids were higher in mid-maturity group over early maturity. Based on cluster analysis in early maturity group six (cc-13, cc-14, 14-4-17, 351aa, Pusa Deepali and SL-7) out of eighteen inbred lines were least diverse. Line vv of cluster VI was found most diverse from the lines xx-2-6, cc-32E and cc-12 of cluster VII with inter-cluster distance of 3.88. However, in mid-maturity group the most diverse lines were ccm-8 (II) and Palam Uphar (VI) with inter-cluster distance of 5.48. The combination of heterosis and diversity analysis indicated the higher fre quency and magnitude of heterosis of hybrids derived from the parental divergence class DC3 in early maturity and DC2 in mid-maturity group suggesting moderate genetic diversity is most desirable to produce highly heterotic hybrids in Indian cauliflower. The correlation between genetic distance and the level of mid-parent heterosis was not reliable for all the quantitative traits in both early and mid-maturity group of the cauliflower. Identified hybrids 395aa x Pusa Deepali and cc-32E × 23000 in early maturity and cc-22 × Sarju Maghi and cc-22 × Palam Uphar of mid-maturity group having higher magnitude of heterosis for maximum number of desirable traits may be selected for further evaluation and commercialization.

Evaluation of upper and lower pharyngeal airway in hypo and hyper divergent Class I, II and III malocclusions in a group of Egyptian patients

IntroductionSignificant relationships between the pharyngeal structures and both dento-facial and craniofacial structures have been reported. Hyper-divergent patients may lead to narrower antero-posterior dimensions of the airway. Some authors associated vertical growth pattern with obstruction of the upper and lower pharyngeal airways others associated mouth breathing and Class II malocclusion. So the aim of this study was to assess the upper and lower pharyngeal airway width in different antero-posterior and vertical growth patterns and to evaluate sexual dimorphism in a group of Egyptian patients. Patients and methodA sample of 300 Egyptian patients had divided into (5) groups (each group 60 patients) group 1 Class I, group 2 and 3 Class II division 1 (maxillary prognathism and mandibular deficiency), group 4 and 5 Class III (maxillary deficiency and mandibular prognathism). Each group was divided into three sub groups (hypo-hyper and normal divergent) vertical growth pattern. Each subgroup consists of 10 male and 10 female. The upper and lower pharyngeal airway widths were measured and compared for all groups. ResultsSignificant differences had exist regarding lower pharyngeal airway between Class I and class II division 1, Class I and Class III mandibular prognathism, Class II and Class III maxillary deficiency, Class II and Class III mandibular prognathism. Significant differences between hypo, hyper and normal vertical growth pattern. ConclusionsIn all groups hyper-divergent growth had narrower airway than normal and hypo-divergent growth. Class III had wider airway than Class I malocclusion. Class I had wider airway than Class II division 1 malocclusion. Lower pharyngeal airway in class II division 1 had the narrowest width in all groups. Lower pharyngeal airway in class III mandibular prognathism had the widest width in all groups. Males have wider pharyngeal airway than females.

The Plasmodium gaboni genome illuminates allelic dimorphism of immunologically important surface antigens in P. falciparum

In the deadly human malaria parasite Plasmodium falciparum, several major merozoite surface proteins (MSPs) show a striking pattern of allelic diversity called allelic dimorphism (AD). In AD, the vast majority of observed alleles fall into two highly divergent allelic classes, with recombinant alleles being rare or not observed, presumably due to repression by natural selection (recombination suppression, or RS). The three AD loci, merozoite surface proteins (MSPs) 1, 2, and 6, along with MSP3, which also exhibits RS among four allelic classes, can be collectively called AD/RS. The causes of AD/RS and the evolutionary history of allelic diversity at these loci remain mysterious. The few available sequences from a single closely related chimpanzee parasite, P. reichenowi, have suggested that for 3/4 loci, AD/RS is an ancient state that has been retained in P. falciparum since well before the P. falciparum–P. reichenowi ancestor. On the other hand, based on comparative sequence analysis, we recently suggested that (i) AD/RS P. falciparum loci have undergone interallelic recombination over longer evolutionary times (on the timescale of recent speciation events), and thus (ii) AD/RS may be a recent phenomenon. The recent publication of genomic sequencing efforts for P. gaboni, an outgroup to P. falciparum and P. reichenowi, allows for improved reconstruction of the evolutionary history of these loci. In this work, I report genic sequence for P. gaboni for all four AD/RS P. falciparum loci (MSP1, 2, 3, and 6). Comparison of these sequences with available P. falciparum and P. reichenowi data strengthens the evidence for interallelic recombination over the evolutionary history of these species and also strengthens the case that AD/RS at these loci is ancient. Combined with previous results, these data provide evidence that AD/RS at different loci has evolved at several different times in the evolutionary history of P. falciparum: (i) before the P. gaboni–P. falciparum divergence, for much of MSP1 and MSP3; (ii) between the P. gaboni–P. falciparum and P. reichenowi–P. falciparum divergences, for the 5′ end of the AD region of MSP6 and block 3 of MSP1; (iii) near the P. reichenowi–P. falciparum divergence, for the 3′ end of the AD region of MSP6; and (iv) after the P. reichenowi–P. falciparum divergence, for MSP2. Based on these results, I suggest a new hypothesis for long-term evolutionary maintenance of AD/RS by recombination within allelic groups.

On local divergences between two probability measures

A broad class of local divergences between two probability measures or between the respective probability distributions is proposed in this paper. The introduced local divergences are based on the classic Csiszar $$\phi $$ -divergence and they provide with a pseudo-distance between two distributions on a specific area of their common domain. The range of values of the introduced class of local divergences is derived and explicit expressions of the proposed local divergences are also derived when the underlined distributions are members of the exponential family of distributions or they are described by multivariate normal models. An application is presented to illustrate the behavior of local divergences.

Marsupials and monotremes possess a novel family of MHC class I genes that is lost from the eutherian lineage

BackgroundMajor histocompatibility complex (MHC) class I genes are found in the genomes of all jawed vertebrates. The evolution of this gene family is closely tied to the evolution of the vertebrate genome. Family members are frequently found in four paralogous regions, which were formed in two rounds of genome duplication in the early vertebrates, but in some species class Is have been subject to additional duplication or translocation, creating additional clusters. The gene family is traditionally grouped into two subtypes: classical MHC class I genes that are usually MHC-linked, highly polymorphic, expressed in a broad range of tissues and present endogenously-derived peptides to cytotoxic T-cells; and non-classical MHC class I genes generally have lower polymorphism, may have tissue-specific expression and have evolved to perform immune-related or non-immune functions. As immune genes can evolve rapidly and are subject to different selection pressure, we hypothesised that there may be divergent, as yet unannotated or uncharacterised class I genes.ResultsApplication of a novel method of sensitive genome searching of available vertebrate genome sequences revealed a new, extensive sub-family of divergent MHC class I genes, denoted as UT, which has not previously been characterized. These class I genes are found in both American and Australian marsupials, and in monotremes, at an evolutionary chromosomal breakpoint, but are not present in non-mammalian genomes and have been lost from the eutherian lineage. We show that UT family members are expressed in the thymus of the gray short-tailed opossum and in other immune tissues of several Australian marsupials. Structural homology modelling shows that the proteins encoded by this family are predicted to have an open, though short, antigen-binding groove.ConclusionsWe have identified a novel sub-family of putatively non-classical MHC class I genes that are specific to marsupials and monotremes. This family was present in the ancestral mammal and is found in extant marsupials and monotremes, but has been lost from the eutherian lineage. The function of this family is as yet unknown, however, their predicted structure may be consistent with presentation of antigens to T-cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1745-4) contains supplementary material, which is available to authorized users.

Differential expression of four soybean bZIP genes during Phakopsora pachyrhizi infection.

Asian soybean rust (ASR), caused by the obligate biotrophic fungus Phakopsora pachyrhizi, is one of most important diseases in the soybean (Glycine max (L.) Merr.) agribusiness. The identification and characterization of genes related to plant defense responses to fungal infection are essential to develop ASR-resistant plants. In this work, we describe four soybean genes, GmbZIP62, GmbZIP105, GmbZIPE1, and GmbZIPE2, which encode transcription factors containing a basic leucine zipper (bZIP) domain from two divergent classes, and that are responsive to P. pachyrhizi infection. Molecular phylogenetic analyses demonstrated that these genes encode proteins similar to bZIP factors responsive to pathogens. Yeast transactivation assays showed that only GmbZIP62 has strong transactivation activity in yeast. In addition, three of the bZIP transcription factors analyzed were also differentially expressed by plant defense hormones, and all were differentially expressed by fungal attack, indicating that these proteins might participate in response to ASR infection. The results suggested that these bZIP proteins are part of the plant defense response to P. pachyrhizi infection, by regulating the gene expression related to ASR infection responses. These bZIP genes are potential targets to obtain new soybean genotypes resistant to ASR.

Log-Determinant Divergences Revisited: Alpha-Beta and Gamma Log-Det Divergences

This work reviews and extends a family of log-determinant (log-det) divergences for symmetric positive definite (SPD) matrices and discusses their fundamental properties. We show how to use parameterized Alpha-Beta (AB) and Gamma log-det divergences to generate many well-known divergences; in particular, we consider the Stein’s loss, the S-divergence, also called Jensen-Bregman LogDet (JBLD) divergence, Logdet Zero (Bhattacharyya) divergence, Affine Invariant Riemannian Metric (AIRM), and other divergences. Moreover, we establish links and correspondences between log-det divergences and visualise them on an alpha-beta plane for various sets of parameters. We use this unifying framework to interpret and extend existing similarity measures for semidefinite covariance matrices in finite-dimensional Reproducing Kernel Hilbert Spaces (RKHS). This paper also shows how the Alpha-Beta family of log-det divergences relates to the divergences of multivariate and multilinear normal distributions. Closed form formulas are derived for Gamma divergences of two multivariate Gaussian densities; the special cases of the Kullback-Leibler, Bhattacharyya, Rényi, and Cauchy-Schwartz divergences are discussed. Symmetrized versions of log-det divergences are also considered and briefly reviewed. Finally, a class of divergences is extended to multiway divergences for separable covariance (or precision) matrices.

Differential Operators on the Projective Plane

A formula for the addition of even spherical harmonics was obtained. This formula became the starting point for the derivation of the first regularized trace for the Laplace -- Beltrami operator with potential on the projective plane. Due to this formula, it is not need to find asymptotic formulas for the associated Legendre polynomials by the three parameters, which was an impossible problem for a long time. The obtained results are the basis for the calculation of the perturbation theory corrections and allow the following application for the formulas for regularized traces of elliptic differential operators. In this paper we consider the problem of summation of divergent series class. We propose a method for calculating of the corrections of perturbation theory for a differential operator with potential on the real projective plane. The method is applicable, in particular, to take sum of series with factorial growth of its members.

Identification and characterization of genetic structures coding for carbapenemases in enterobacteria from Central Greece

The dissemination of carbapenemases among different species of Enterobacteriaceae was investigated in the University Hospital of Larissa, Central Greece. The presence of the isoform (Tn4401a) of the transponson carrying blaKPC-2 and 5 divergent blaVIM-carrying class I integrons, including a novel structure, suggests interspecies transfer of these mobile elements and underscores their ongoing evolution.

LRRsearch: An asynchronous server-based application for the prediction of leucine-rich repeat motifs and an integrative database of NOD-like receptors

The leucine-rich repeat (LRR) motifs of the nucleotide-binding oligomerization domain like receptors (NLRs) play key roles in recognizing and binding various pathogen associated molecular patterns (PAMPs) resulting in the activation of downstream signaling and innate immunity. Therefore, identification of LRR motifs is very important to study ligand–receptor interaction. To date, available resources pose restrictions including both false negative and false positive prediction of LRR motifs from the primary protein sequence as their algorithms are relied either only on sequence based comparison or alignment techniques or are over biased for a particular LRR containing protein family. Therefore, to minimize the error (≤5%) and to identify a maximum number of LRR motifs in the wide range of proteins, we have developed “LRRsearch” web-server using position specific scoring matrix (PSSM) of 11 residue LRR-HCS (highly conserved segment) which are frequently observed motifs in the most divergent classes of LRR containing proteins. A data library of 421 proteins, distributed among five known NLR families has also been integrated with the “LRRsearch” for the rich user experience. The access to the “LRRsearch” program is freely available at http://www.lrrsearch.com/.

Structural and enzymatic insights into Lambda glutathione transferases from Populus trichocarpa, monomeric enzymes constituting an early divergent class specific to terrestrial plants.

GSTs represent a superfamily of multifunctional proteins which play crucial roles in detoxification processes and secondary metabolism. Instead of promoting the conjugation of glutathione to acceptor molecules as do most GSTs, members of the Lambda class (GSTLs) catalyse deglutathionylation reactions via a catalytic cysteine residue. Three GSTL genes (Pt-GSTL1, Pt-GSTL2 and Pt-GSTL3) are present in Populus trichocarpa, but two transcripts, differing in their 5' extremities, were identified for Pt-GSTL3. Transcripts for these genes were primarily found in flowers, fruits, petioles and buds, but not in leaves and roots, suggesting roles associated with secondary metabolism in these organs. The expression of GFP-fusion proteins in tobacco showed that Pt-GSTL1 is localized in plastids, whereas Pt-GSTL2 and Pt-GSTL3A and Pt-GSTL3B are found in both the cytoplasm and the nucleus. The resolution of Pt-GSTL1 and Pt-GSTL3 structures by X-ray crystallography indicated that, although these proteins adopt a canonical GST fold quite similar to that found in dimeric Omega GSTs, their non-plant counterparts, they are strictly monomeric. This might explain some differences in the enzymatic properties of both enzyme types. Finally, from competition experiments between aromatic substrates and a fluorescent probe, we determined that the recognition of glutathionylated substrates is favoured over non-glutathionylated forms.

Scale-Invariant Divergences for Density Functions

Divergence is a discrepancy measure between two objects, such as functions, vectors, matrices, and so forth. In particular, divergences defined on probability distributions are widely employed in probabilistic forecasting. As the dissimilarity measure, the divergence should satisfy some conditions. In this paper, we consider two conditions: The first one is the scale-invariance property and the second is that the divergence is approximated by the sample mean of a loss function. The first requirement is an important feature for dissimilarity measures. The divergence will depend on which system of measurements we used to measure the objects. Scale-invariant divergence is transformed in a consistent way when the system of measurements is changed to the other one. The second requirement is formalized such that the divergence is expressed by using the so-called composite score. We study the relation between composite scores and scale-invariant divergences, and we propose a new class of divergences called H¨older divergence that satisfies two conditions above. We present some theoretical properties of H¨older divergence. We show that H¨older divergence unifies existing divergences from the viewpoint of scale-invariance.

Contrasting actions of group I metabotropic glutamate receptors in distinct mouse striatal neurones

In mouse striatum, metabotropic glutamate receptor (mGluR) activation leads to several modulatory effects in synaptic transmission. These effects range from dampening of glutamate release from excitatory terminals to depolarization of divergent classes of interneurones. We compared the action of group I mGluR activation on several populations of striatal neurones using a combination of genetic identification, electrophysiology, and Ca(2+) imaging techniques. Patch-clamp recordings from spiny projection neurones (SPNs) and various interneurone populations demonstrated that the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) robustly depolarizes several interneurone classes that form GABAergic synapses onto SPNs. We further utilized the genetic reporter mouse strain Ai38, which expresses the calcium indicator protein GCaMP3 in a Cre-dependent manner. Breeding Ai38 mice with various neurone selective, promoter-driven Cre recombinase mice resulted in GCaMP3 expression in defined cell populations in striatum. Consistent with our electrophysiological findings, group I agonist applications increased intracellular levels of calcium ([Ca(2+)]i) in all interneurone populations tested. We also found that acute DHPG application evoked a transient, rapid increase in [Ca(2+)]i from only a small percentage of identifiable SPNs. Surprisingly, this fast [Ca(2+)]i response exhibited a robust enhancement or sensitization, in a calcium-dependent fashion. Following several procedures to increase [Ca(2+)]i, the vast majority of SPNs responded with rapid changes in [Ca(2+)]i to mGluR agonists in a time-dependent fashion. These findings extend our understanding on group I mGluR influence of striatal output via powerful, local GABAergic connections in addition to [Ca(2+)]i dynamics that impact on activity or spike-timing-dependent forms of synaptic plasticity.

Lipid-metabolizing CYPs in the regulation and dysregulation of metabolism.

The cytochrome P450s (CYPs) represent a highly divergent class of enzymes involved in the oxidation of organic compounds. A subgroup of CYPs metabolize ω3-arachidonic and linoleic acids and ω6-docosahexaenoic and eicosapentaenoic polyunsaturated fatty acids (PUFAs) into a series of related biologically active mediators. Over the past 20 years, increasing evidence has emerged for a role of these PUFA-derived mediators in physiological and pathophysiological processes in the vasculature, during inflammation, and in the regulation of metabolism. With recent technological advances and increased availability of lipid mass spectroscopy, we are now starting to discern the patterns of these CYP-PUFA products in health and disease. These analyses not only are revealing the diverse spectrum of lipid nutrients regulated by CYPs, but also clearly indicate that the balance of these mediators changes with dietary intake of different PUFA classes. These findings suggest that we are only just beginning to understand all of the relevant lipid species produced by CYP pathways. Moreover, we are still a long way from understanding the nature and presence of their receptors, their tissue expression, and the pathophysiological processes they regulate. This review highlights these future issues in the context of lipid-metabolizing CYP enzymes, focusing particularly on the CYP450 family of epoxygenases and the lipid mediators they produce.

Information Geometry of Positive Measures and Positive-Definite Matrices: Decomposable Dually Flat Structure

Information geometry studies the dually flat structure of a manifold, highlighted by the generalized Pythagorean theorem. The present paper studies a class of Bregman divergences called the (ρ,τ)-divergence. A (ρ,τ) -divergence generates a dually flat structure in the manifold of positive measures, as well as in the manifold of positive-definite matrices. The class is composed of decomposable divergences, which are written as a sum of componentwise divergences. Conversely, a decomposable dually flat divergence is shown to be a (ρ,τ) -divergence. A (ρ,τ) -divergence is determined from two monotone scalar functions, ρ and τ. The class includes the KL-divergence, α-, β- and (α, β)-divergences as special cases. The transformation between an affine parameter and its dual is easily calculated in the case of a decomposable divergence. Therefore, such a divergence is useful for obtaining the center for a cluster of points, which will be applied to classification and information retrieval in vision. For the manifold of positive-definite matrices, in addition to the dually flatness and decomposability, we require the invariance under linear transformations, in particular under orthogonal transformations. This opens a way to define a new class of divergences, called the (ρ,τ) -structure in the manifold of positive-definite matrices.

"Common People": Realism, Class Difference, and the Male Domestic Sphere in Nick Hornby's Collision with Britpop

My essay analyzes both High Fidelity and selected Britpop songs and videos, and reads these texts within the highly contested field of realism's larger relationship to "what's out there." The essay examines the ways in which Hornby's novel articulates a male domestic sphere and explores values typically associated with the British working class—ones regularly reinforced in 1990s (or "Cool Britannia"-era) texts such as Loaded magazine. Ultimately, I analyze how High Fidelity , like many canonical realist novels, imagines a form of social unity that supersedes the divergent social class "realities" depicted.