WorldWideScience

Sample records for rank ligand inhibitors

  1. [Biotechnological advances in monoclonal antibody therapy: the RANK ligand inhibitor antibody].

    Science.gov (United States)

    Kiss, Emese; Kuluncsics, Zénó; Kiss, Zoltán; Poór, Gyula

    2010-12-26

    Biological drugs have been used since the middle of the last century in medicine. Nowadays we are witnesses of the intensive development and wider administration of these drugs in clinical practice. Around 250 biological drugs are available and more than 350 million patients have been treated since their marketed authorization. Among the biologics there are protein based macromolecules, which mass production can be performed with the help of biotechnology. This term referring to the use of living organisms for production of molecules, was introduced by the Hungarian engineer, Károly Ereky. The present review focuses on the research, production and development of monoclonal antibodies manufactured by biotechnology. Some steps of this development have changed our immunological knowledge and the outcome of several diseases. The development of antibodies was highly recognized by two Nobel prizes. Authors detail the structure and functions of immunoglobulins, and their development, including fully human monoclonal antibodies. The RANKL inhibitor denosumab, a fully human IgG2 monoclonal antibody belongs to this latter group and it is available for treatment of osteoporosis. Authors also summarize the basic process of bone metabolism and the benefits of RANK ligand inhibition.

  2. The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review

    NARCIS (Netherlands)

    Groenen, K.H.J.; Pouw, M.H.; Hannink, G.; Hosman, A.J.; van der Linden, Y.M.; Verdonschot, Nicolaas Jacobus Joseph; Tanck, E.

    2016-01-01

    Purpose The role of radiotherapy in stabilizing metastatic bones is unclear. This systematic review assessed the effects of (1) radiotherapy, (2) radiotherapy combined with bisphosphonates, and (3) radiotherapy combined with RANK ligand (RANKL) inhibitors on bone quality and bone strength in bone

  3. RANK and RANK ligand expression in primary human osteosarcoma

    Directory of Open Access Journals (Sweden)

    Daniel Branstetter

    2015-09-01

    Our results demonstrate RANKL expression was observed in the tumor element in 68% of human OS using IHC. However, the staining intensity was relatively low and only 37% (29/79 of samples exhibited≥10% RANKL positive tumor cells. RANK expression was not observed in OS tumor cells. In contrast, RANK expression was clearly observed in other cells within OS samples, including the myeloid osteoclast precursor compartment, osteoclasts and in giant osteoclast cells. The intensity and frequency of RANKL and RANK staining in OS samples were substantially less than that observed in GCTB samples. The observation that RANKL is expressed in OS cells themselves suggests that these tumors may mediate an osteoclastic response, and anti-RANKL therapy may potentially be protective against bone pathologies in OS. However, the absence of RANK expression in primary human OS cells suggests that any autocrine RANKL/RANK signaling in human OS tumor cells is not operative, and anti-RANKL therapy would not directly affect the tumor.

  4. Histological Regression of Giant Cell Tumor of Bone Following RANK Ligand Inhibition

    Directory of Open Access Journals (Sweden)

    Martin F. Dietrich MD, PhD

    2014-11-01

    Full Text Available Lung metastases are a rare complication of giant cell tumors of bone. We herein describe an interesting case of histological regression and size reduction of lung metastases originating from a primary giant cell tumor of bone in response to the RANK ligand inhibitor denosumab.

  5. RANK/RANK-Ligand/OPG: Ein neuer Therapieansatz in der Osteoporosebehandlung

    Directory of Open Access Journals (Sweden)

    Preisinger E

    2007-01-01

    Full Text Available Die Erforschung der Kopplungsmechanismen zur Osteoklastogenese, Knochenresorption und Remodellierung eröffnete neue mögliche Therapieansätze in der Behandlung der Osteoporose. Eine Schlüsselrolle beim Knochenabbau spielt der RANK- ("receptor activator of nuclear factor (NF- κB"- Ligand (RANKL. Durch die Bindung von RANKL an den Rezeptor RANK wird die Knochenresorption eingeleitet. OPG (Osteoprotegerin sowie der für den klinischen Gebrauch entwickelte humane monoklonale Antikörper (IgG2 Denosumab blockieren die Bindung von RANK-Ligand an RANK und verhindern den Knochenabbau.

  6. Quantum probability ranking principle for ligand-based virtual screening

    Science.gov (United States)

    Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

    2017-04-01

    Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

  7. Quantum probability ranking principle for ligand-based virtual screening.

    Science.gov (United States)

    Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

    2017-04-01

    Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

  8. Die Rolle von RANK-Ligand und Osteoprotegerin bei Osteoporose

    Directory of Open Access Journals (Sweden)

    Hofbauer LC

    2004-01-01

    Full Text Available Receptor activator of nuclear factor (NF- κB ligand (RANKL, sein zellulärer Rezeptor RANK und der Decoy-Rezeptor Osteoprotegerin (OPG stellen ein essentielles Zytokinsystem für die Zellbiologie von Osteoklasten dar. Verschiedene Untersuchungen belegen die Bedeutung von Störungen des OPG/RANKL/RANK-Systems bei der Pathogenese metabolischer Knochenerkrankungen. In dieser Arbeit werden die wichtigsten Störungen des OPG/RANKL/RANK-Systems bei verschiedenen Osteoporoseformen dargestellt. Östrogenrezeptor- (ER- Agonisten wie 17 β-Östradiol, Raloxifen und Genistein stimulieren die osteoblastäre Produktion von OPG durch Aktivierung von ER- α in vitro, während Lymphozyten von Patientinnen mit Östrogenmangel RANKL überexprimieren. Die parenterale Gabe von OPG vermag den mit Östrogenmangel assoziierten Knochenverlust im Tiermodell und in einer kleineren klinischen Studie zu verhindern. Glukokortikoide und Immunsuppressiva steigern gleichzeitig die RANKL-Expression und hemmen die OPG-Produktion in osteoblastären Zellen in vitro. Glukokortikoide sind auch in vivo imstande, die OPG-Serumspiegel deutlich zu reduzieren. Dagegen hemmen biomechanische Reize in vitro die RANKL-Produktion und steigern die OPG-Produktion. Ein Fehlen dieser biomechanischen Reize bei längerer Immobilisierung kann daher den RANKL/OPG-Quotienten steigern, während die tierexperimentelle Immobilisierungs-Osteoporose durch die parenterale Gabe von OPG gemildert werden kann.

  9. Virtual Lead Identification of Farnesyltransferase Inhibitors Based on Ligand and Structure-Based Pharmacophore Techniques

    Directory of Open Access Journals (Sweden)

    Nizar M. Mhaidat

    2013-05-01

    Full Text Available Farnesyltransferase enzyme (FTase is considered an essential enzyme in the Ras signaling pathway associated with cancer. Thus, designing inhibitors for this enzyme might lead to the discovery of compounds with effective anticancer activity. In an attempt to obtain effective FTase inhibitors, pharmacophore hypotheses were generated using structure-based and ligand-based approaches built in Discovery Studio v3.1. Knowing the presence of the zinc feature is essential for inhibitor’s binding to the active site of FTase enzyme; further customization was applied to include this feature in the generated pharmacophore hypotheses. These pharmacophore hypotheses were thoroughly validated using various procedures such as ROC analysis and ligand pharmacophore mapping. The validated pharmacophore hypotheses were used to screen 3D databases to identify possible hits. Those which were both high ranked and showed sufficient ability to bind the zinc feature in active site, were further refined by applying drug-like criteria such as Lipiniski’s “rule of five” and ADMET filters. Finally, the two candidate compounds (ZINC39323901 and ZINC01034774 were allowed to dock using CDOCKER and GOLD in the active site of FTase enzyme to optimize hit selection.

  10. Bivalent ligands derived from Huperzine A as acetylcholinesterase inhibitors.

    Science.gov (United States)

    Haviv, H; Wong, D M; Silman, I; Sussman, J L

    2007-01-01

    The naturally occurring alkaloid Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor that has been used for centuries as a Chinese folk medicine in the context of its source plant Huperzia Serrata. The potency and relative safety of HupA rendered it a promising drug for the ameliorative treatment of Alzheimer's disease (AD) vis-à-vis the "cholinergic hypothesis" that attributes the cognitive decrements associated with AD to acetylcholine deficiency in the brain. However, recent evidence supports a neuroprotective role for HupA, suggesting that it could act as more than a mere palliative. Biochemical and crystallographic studies of AChE revealed two potential binding sites in the active-site gorge of AChE, one of which, the "peripheral anionic site" at the mouth of the gorge, was implicated in promoting aggregation of the beta amyloid (Abeta) peptide responsible for the neurodegenerative process in AD. This feature of AChE facilitated the development of dual-site binding HupA-based bivalent ligands, in hopes of concomitantly increasing AChE inhibition potency by utilizing the "chelate effect", and protecting neurons from Abeta toxicity. Crystal structures of AChE allowed detailed modeling and docking studies that were instrumental in enhancing the understanding of underlying principles of bivalent inhibitor-enzyme dynamics. This monograph reviews two categories of HupA-based bivalent ligands, in which HupA and HupA fragments serve as building blocks, with a focus on the recently solved crystallographic structures of Torpedo californica AChE in complex with such bifunctional agents. The advantages and drawbacks of such structured-based drug design, as well as species differences, are highlighted and discussed.

  11. D3R Grand Challenge 2: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies

    Science.gov (United States)

    Gaieb, Zied; Liu, Shuai; Gathiaka, Symon; Chiu, Michael; Yang, Huanwang; Shao, Chenghua; Feher, Victoria A.; Walters, W. Patrick; Kuhn, Bernd; Rudolph, Markus G.; Burley, Stephen K.; Gilson, Michael K.; Amaro, Rommie E.

    2018-01-01

    The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 subchallenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 subchallenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarizes all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank (http://www.pdb.org), and in affinity ranking and scoring of bound ligands.

  12. In Silico target fishing: addressing a "Big Data" problem by ligand-based similarity rankings with data fusion.

    Science.gov (United States)

    Liu, Xian; Xu, Yuan; Li, Shanshan; Wang, Yulan; Peng, Jianlong; Luo, Cheng; Luo, Xiaomin; Zheng, Mingyue; Chen, Kaixian; Jiang, Hualiang

    2014-01-01

    Ligand-based in silico target fishing can be used to identify the potential interacting target of bioactive ligands, which is useful for understanding the polypharmacology and safety profile of existing drugs. The underlying principle of the approach is that known bioactive ligands can be used as reference to predict the targets for a new compound. We tested a pipeline enabling large-scale target fishing and drug repositioning, based on simple fingerprint similarity rankings with data fusion. A large library containing 533 drug relevant targets with 179,807 active ligands was compiled, where each target was defined by its ligand set. For a given query molecule, its target profile is generated by similarity searching against the ligand sets assigned to each target, for which individual searches utilizing multiple reference structures are then fused into a single ranking list representing the potential target interaction profile of the query compound. The proposed approach was validated by 10-fold cross validation and two external tests using data from DrugBank and Therapeutic Target Database (TTD). The use of the approach was further demonstrated with some examples concerning the drug repositioning and drug side-effects prediction. The promising results suggest that the proposed method is useful for not only finding promiscuous drugs for their new usages, but also predicting some important toxic liabilities. With the rapid increasing volume and diversity of data concerning drug related targets and their ligands, the simple ligand-based target fishing approach would play an important role in assisting future drug design and discovery.

  13. RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation

    International Nuclear Information System (INIS)

    Sundaram, Kumaran; Nishimura, Riko; Senn, Joseph; Youssef, Rimon F.; London, Steven D.; Reddy, Sakamuri V.

    2007-01-01

    Osteoclast differentiation is tightly regulated by receptor activator of NF-κB ligand (RANKL) signaling. Matrix metalloproteinase-9 (MMP-9), a type IV collagenase is highly expressed in osteoclast cells and plays an important role in degradation of extracellular matrix; however, the molecular mechanisms that regulate MMP-9 gene expression are unknown. In this study, we demonstrate that RANKL signaling induces MMP-9 gene expression in osteoclast precursor cells. We further show that RANKL regulates MMP-9 gene expression through TRAF6 but not TRAF2. Interestingly, blockade of p38 MAPK activity by pharmacological inhibitor, SB203580 increases MMP-9 activity whereas ERK1/2 inhibitor, PD98059 decreases RANKL induced MMP-9 activity in RAW264.7 cells. These data suggest that RANKL differentially regulates MMP-9 expression through p38 and ERK signaling pathways during osteoclast differentiation. Transient expression of MMP-9 gene (+ 1 to - 1174 bp relative to ATG start codon) promoter-luciferase reporter plasmids in RAW264.7 cells and RANKL stimulation showed significant increase (20-fold) of MMP-9 gene promoter activity; however, there is no significant change with respect to + 1 bp to - 446 bp promoter region and empty vector transfected cells. These results indicated that MMP-9 promoter sequence from - 446 bp to - 1174 bp relative to start codon is responsive to RANKL stimulation. Sequence analysis of the mouse MMP-9 gene promoter region further identified the presence of binding motif (- 1123 bp to - 1153 bp) for the nuclear factor of activated T cells 1 (NFATc1) transcription factor. Inhibition of NFATc1 using siRNA and VIVIT peptide inhibitor significantly decreased RANKL stimulation of MMP-9 activity. We further confirm by oligonucleotide pull-down assay that RANKL stimuli enhanced NFATc1 binding to MMP-9 gene promoter element. In addition, over-expression of constitutively active NFAT in RAW264.7 cells markedly increased (5-fold) MMP-9 gene promoter activity in

  14. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.

    Science.gov (United States)

    Nolan, Emma; Vaillant, François; Branstetter, Daniel; Pal, Bhupinder; Giner, Göknur; Whitehead, Lachlan; Lok, Sheau W; Mann, Gregory B; Rohrbach, Kathy; Huang, Li-Ya; Soriano, Rosalia; Smyth, Gordon K; Dougall, William C; Visvader, Jane E; Lindeman, Geoffrey J

    2016-08-01

    Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.

  15. Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells

    International Nuclear Information System (INIS)

    McDonald, Elizabeth S.; Mankoff, Julia; Makvandi, Mehran; Chu, Wenhua; Chu, Yunxiang; Mach, Robert H.; Zeng, Chenbo

    2017-01-01

    The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines. We showed that the PARP inhibitor, YUN3-6, sensitized mouse breast cancer cell line, EMT6, to sigma-2 receptor ligand (SV119, WC-26, and RHM-138) induced cell death determined by cell viability assay and colony forming assay. The PARP inhibitor, olaparib, sensitized tumor cells to a different sigma-2 receptor ligand SW43-induced apoptosis and cell death in human triple negative cell line, MDA-MB-231. Olaparib inhibited PARP activity and cell proliferation, and arrested cells in G2/M phase of the cell cycle in MDA-MB-231 cells. Subsequently cells became sensitized to SW43 induced cell death. In conclusion, the combination of sigma-2 receptor ligands and PARP inhibitors appears to hold promise for synergistically triggering cell death in certain types of breast cancer cells and merits further investigation. - Highlights: • PARPi, YUN3-6 and olaparib, and σ2 ligands, SV119 and SW43, were evaluated. • Mouse and human breast cancer cells, EMT6 and MDA-MB-231 respectively, were used. • YUN3-6 and SV119 synergistically triggered cell death in EMT6 cells. • Olaparib and SW43 additively triggered cell death in MDA-MB-231 cells. • Olaparib arrested cells in G2/M in MDA-MB-231 cells.

  16. Transcriptional regulation of human RANK ligand gene expression by E2F1

    International Nuclear Information System (INIS)

    Hu Yan; Sun Meng; Nadiminty, Nagalakshmi; Lou Wei; Pinder, Elaine; Gao, Allen C.

    2008-01-01

    Receptor activator of nuclear factor kappa B ligand (RANKL) is a critical osteoclastogenic factor involved in the regulation of bone resorption, immune function, the development of mammary gland and cardiovascular system. To understand the transcriptional regulation of RANKL, we amplified and characterized a 1890 bp 5'-flanking sequence of human RANKL gene (-1782 bp to +108 bp relative to the transcription start site). Using a series of deletion mutations of the 1890 bp RANKL promoter, we identified a 72 bp region (-172 to -100 bp) mediating RANKL basal transcriptional activity. Sequence analysis revealed a putative E2F binding site within this 72 bp region in the human RANKL promoter. Overexpression of E2F1 increased RANKL promoter activity, while down-regulation of E2F1 expression by small interfering RNA decreased RANKL promoter activity. RT-PCR and enzyme linked immunosorbent assays (ELISA) further demonstrated that E2F1 induced the expression of RANKL. Electrophoretic gel mobility shift assays (EMSA) and antibody competition assays confirmed that E2F1 proteins bind to the consensus E2F binding site in the RANKL promoter. Mutation of the E2F consensus binding site in the RANKL promoter profoundly reduced the basal promoter activity and abolished the transcriptional modulation of RANKL by E2F1. These results suggest that E2F1 plays an important role in regulating RANKL transcription through binding to the E2F consensus binding site

  17. Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

    Science.gov (United States)

    Mor, Marco; Rivara, Silvia; Lodola, Alessio; Lorenzi, Simone; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Duranti, Andrea; Tontini, Andrea; Tarzia, Giorgio

    2005-11-01

    Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.

  18. Virtual screening using the ligand ZINC database for novel lipoxygenase-3 inhibitors.

    Science.gov (United States)

    Monika; Kour, Janmeet; Singh, Kulwinder

    2013-01-01

    The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. Epidermis-type lipoxygenase-3 (ALOXE3), a distinct subclass within the multigene family of mammalian lipoxygenases, is a novel isoenzyme involved in the metabolism of leukotrienes and plays a very important role in skin barrier functions. Lipoxygenase selective inhibitors such as azelastine and zileuton are currently used to reduce inflammatory response. Nausea, pharyngolaryngeal pain, headache, nasal burning and somnolence are the most frequently reported adverse effects of these drugs. Therefore, there is still a need to develop more potent lipoxygenase inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains over 21 million compounds) using the Molegro Virtual Docker software against the ALOXE3 protein. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 1N8Q bound ligand protocatechuic acid. The analysis resulted in 4319 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified four molecules ZINC84299674; ZINC76643455; ZINC84299122 & ZINC75626957 with MolDock score of -128.901, -120.22, -116.873 & - 102.116 kcal/mol, respectively. Their energy scores were better than the 1N8Q bound co-crystallized ligand protocatechuic acid (with MolDock score of -77.225 kcal/mol). All the ligands were docked within the binding pocket forming interactions with amino acid residues.

  19. Investigation of formation constant of complex of a new synthesized tripodal ligand with Cu2+ using rank annihilation factor analysis in surfactant media

    Directory of Open Access Journals (Sweden)

    R. Golbedaghi

    2014-01-01

    Full Text Available The complex formation between a newly synthesized tripodal ligand and the cation Cu2+ in water and surfactant media was studied spectrophotometrically using rank annihilation factor analysis (RAFA. According to molar ratio data the stoichiometry of complexation between the ligand and the cation Cu2+ was 1:1. Formation constant of this complex was derived using RAFA on spectrophotometric data. The performance of the method has been evaluated by using synthetic data. Also concentration and spectral profiles of ligand and complex can be obtained by using the stability constant and appropriate equations. The effect of surfactants such as sodium dodecyl sulfate (SDS, cetyltrimethylammonium bromide (CTAB and Triton X-100 on complex formation constant of Cu2+ with the ligand was investigated.

  20. Application of rank annihilation factor analysis to the spectrophotometric determination of the formation constant of complex of a new synthesized tripodal ligand with Co2+

    Directory of Open Access Journals (Sweden)

    Reza Golbedaghi

    2017-05-01

    Full Text Available The complex formation between a new synthesized tripodal ligand (L22py and the cation Co2+ in water was studied spectrophotometrically using rank annihilation factor analysis (RAFA. According to molar ratio data the stoichiometry of complexation between the ligand and the cation Co2+ was 1:1. Formation constant of this complex was derived using RAFA on spectrophotometric data. In this process the contribution of ligand is removed from the absorbance data matrix when the complex stability constant acts as an optimizing object and simply combined with the pure spectrum of ligand, the rank of original data matrix can be reduced by one by annihilating the information of the ligand from the original data matrix. The effect of ethanol, dimethylformamide (DMF and acetonitrile (AN was investigated on the formation constant of the Co2+ complex. Complex formation constant in water was estimated as log Kf = 5.09 ± 0.02. In mixtures of solvents of water and DMF and water and AN, the formation constant of the complex was increased because of lowering donor number of the solvent and in mixture of water and ethanol, the complex formation constant was decreased because of lowering of dielectric constant of the solvent.

  1. Ranking docking poses by graph matching of protein-ligand interactions: lessons learned from the D3R Grand Challenge 2

    Science.gov (United States)

    da Silva Figueiredo Celestino Gomes, Priscila; Da Silva, Franck; Bret, Guillaume; Rognan, Didier

    2018-01-01

    A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein-ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method. In agreement with results obtained during the previous 2015 docking challenge, we clearly show that GRIM rescoring improves the overall quality of top-ranked poses by prioritizing interaction patterns already visited in the PDB. Importantly, this challenge enables us to refine the applicability domain of the method by better defining the conditions of its success. We notably show that rescoring apolar ligands in hydrophobic pockets leads to frequent GRIM failures. In the second phase, 102 FXR agonists were ranked by decreasing affinity according to the Gibbs free energy of the corresponding GRIM-selected poses, computed by the HYDE scoring function. Interestingly, this fast and simple rescoring scheme provided the third most accurate ranking method among 57 contributions. Although the obtained ranking is still unsuitable for hit to lead optimization, the GRIM-HYDE scoring scheme is accurate and fast enough to post-process virtual screening data.

  2. Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo

    International Nuclear Information System (INIS)

    Franco, Gilson C.N.; Kajiya, Mikihito; Nakanishi, Tadashi; Ohta, Kouji; Rosalen, Pedro L.; Groppo, Francisco C.; Ernst, Cory W.O.; Boyesen, Janie L.; Bartlett, John D.; Stashenko, Philip; Taubman, Martin A.; Kawai, Toshihisa

    2011-01-01

    Tetracycline antibiotics, including doxycycli/e (DOX), have been used to treat bone resorptive diseases, partially because of their activity to suppress osteoclastogenesis induced by receptor activator of nuclear factor kappa B ligand (RANKL). However, their precise inhibitory mechanism remains unclear. Therefore, the present study examined the effect of Dox on osteoclastogenesis signaling induced by RANKL, both in vitro and in vivo. Although Dox inhibited RANKL-induced osteoclastogenesis and down-modulated the mRNA expression of functional osteoclast markers, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K, Dox neither affected RANKL-induced MAPKs phosphorylation nor NFATc1 gene expression in RAW264.7 murine monocytic cells. Gelatin zymography and Western blot analyses showed that Dox down-regulated the enzyme activity of RANKL-induced MMP-9, but without affecting its protein expression. Furthermore, MMP-9 enzyme inhibitor also attenuated both RANKL-induced osteoclastogenesis and up-regulation of TRAP and cathepsin K mRNA expression, indicating that MMP-9 enzyme action is engaged in the promotion of RANKL-induced osteoclastogenesis. Finally, Dox treatment abrogated RANKL-induced osteoclastogenesis and TRAP activity in mouse calvaria along with the suppression of MMP9 enzyme activity, again without affecting the expression of MMP9 protein. These findings suggested that Dox inhibits RANKL-induced osteoclastogenesis by its inhibitory effect on MMP-9 enzyme activity independent of the MAPK-NFATc1 signaling cascade.

  3. Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Franco, Gilson C.N. [Department of Immunology, Forsyth Institute, Cambridge, MA (United States); Department of Pharmacology, FOP/UNICAMP, Piracicaba, SP (Brazil); Kajiya, Mikihito [Department of Immunology, Forsyth Institute, Cambridge, MA (United States); Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA (United States); Nakanishi, Tadashi [Department of Immunology, Forsyth Institute, Cambridge, MA (United States); Ohta, Kouji [Department of Immunology, Forsyth Institute, Cambridge, MA (United States); Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA (United States); Rosalen, Pedro L.; Groppo, Francisco C. [Department of Pharmacology, FOP/UNICAMP, Piracicaba, SP (Brazil); Ernst, Cory W.O.; Boyesen, Janie L. [Department of Immunology, Forsyth Institute, Cambridge, MA (United States); Bartlett, John D.; Stashenko, Philip [Department of Cytokine Biology, Forsyth Institute, Cambridge, MA (United States); Taubman, Martin A. [Department of Immunology, Forsyth Institute, Cambridge, MA (United States); Kawai, Toshihisa, E-mail: tkawai@forsyth.org [Department of Immunology, Forsyth Institute, Cambridge, MA (United States); Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA (United States)

    2011-06-10

    Tetracycline antibiotics, including doxycycli/e (DOX), have been used to treat bone resorptive diseases, partially because of their activity to suppress osteoclastogenesis induced by receptor activator of nuclear factor kappa B ligand (RANKL). However, their precise inhibitory mechanism remains unclear. Therefore, the present study examined the effect of Dox on osteoclastogenesis signaling induced by RANKL, both in vitro and in vivo. Although Dox inhibited RANKL-induced osteoclastogenesis and down-modulated the mRNA expression of functional osteoclast markers, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K, Dox neither affected RANKL-induced MAPKs phosphorylation nor NFATc1 gene expression in RAW264.7 murine monocytic cells. Gelatin zymography and Western blot analyses showed that Dox down-regulated the enzyme activity of RANKL-induced MMP-9, but without affecting its protein expression. Furthermore, MMP-9 enzyme inhibitor also attenuated both RANKL-induced osteoclastogenesis and up-regulation of TRAP and cathepsin K mRNA expression, indicating that MMP-9 enzyme action is engaged in the promotion of RANKL-induced osteoclastogenesis. Finally, Dox treatment abrogated RANKL-induced osteoclastogenesis and TRAP activity in mouse calvaria along with the suppression of MMP9 enzyme activity, again without affecting the expression of MMP9 protein. These findings suggested that Dox inhibits RANKL-induced osteoclastogenesis by its inhibitory effect on MMP-9 enzyme activity independent of the MAPK-NFATc1 signaling cascade.

  4. Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.

    Science.gov (United States)

    Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

    2015-06-01

    By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Biophysical and physicochemical methods differentiate highly ligand-efficient human D-amino acid oxidase inhibitors.

    Science.gov (United States)

    Lange, Jos H M; Venhorst, Jennifer; van Dongen, Maria J P; Frankena, Jurjen; Bassissi, Firas; de Bruin, Natasja M W J; den Besten, Cathaline; de Beer, Stephanie B A; Oostenbrink, Chris; Markova, Natalia; Kruse, Chris G

    2011-10-01

    Many early drug research efforts are too reductionist thereby not delivering key parameters such as kinetics and thermodynamics of target-ligand binding. A set of human D-Amino Acid Oxidase (DAAO) inhibitors 1-6 was applied to demonstrate the impact of key biophysical techniques and physicochemical methods in the differentiation of chemical entities that cannot be adequately distinguished on the basis of their normalized potency (ligand efficiency) values. The resulting biophysical and physicochemical data were related to relevant pharmacodynamic and pharmacokinetic properties. Surface Plasmon Resonance data indicated prolonged target-ligand residence times for 5 and 6 as compared to 1-4, based on the observed k(off) values. The Isothermal Titration Calorimetry-derived thermodynamic binding profiles of 1-6 to the DAAO enzyme revealed favorable contributions of both ΔH and ΔS to their ΔG values. Surprisingly, the thermodynamic binding profile of 3 elicited a substantially higher favorable contribution of ΔH to ΔG in comparison with the structurally closely related fused bicyclic acid 4. Molecular dynamics simulations and free energy calculations of 1, 3, and 4 led to novel insights into the thermodynamic properties of the binding process at an atomic level and in the different thermodynamic signatures of 3 and 4. The presented holistic approach is anticipated to facilitate the identification of compounds with best-in-class properties at an early research stage. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  6. Predicting the affinity of Farnesoid X Receptor ligands through a hierarchical ranking protocol: a D3R Grand Challenge 2 case study

    Science.gov (United States)

    Réau, Manon; Langenfeld, Florent; Zagury, Jean-François; Montes, Matthieu

    2018-01-01

    The Drug Design Data Resource (D3R) Grand Challenges are blind contests organized to assess the state-of-the-art methods accuracy in predicting binding modes and relative binding free energies of experimentally validated ligands for a given target. The second stage of the D3R Grand Challenge 2 (GC2) was focused on ranking 102 compounds according to their predicted affinity for Farnesoid X Receptor. In this task, our workflow was ranked 5th out of the 77 submissions in the structure-based category. Our strategy consisted in (1) a combination of molecular docking using AutoDock 4.2 and manual edition of available structures for binding poses generation using SeeSAR, (2) the use of HYDE scoring for pose selection, and (3) a hierarchical ranking using HYDE and MM/GBSA. In this report, we detail our pose generation and ligands ranking protocols and provide guidelines to be used in a prospective computer aided drug design program.

  7. Combination Therapy of PPAR Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jordi Tauler

    2008-01-01

    Full Text Available Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPAR. Targeting LOX/COX enzymes and inducing activation of PPAR have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPAR activation through synthetic ligands (TZDs has revealed a great mechanistic complexity since effects are produced through PPAR-dependent and -independent mechanisms. Furthermore, PPAR could also be involved in regulation of COX-2. Overexpression of PPAR has reported to play a role in control of invasion and differentiation. Exploring the function of PPAR, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.

  8. "Flexible Ligand Docking Studies of Matrix Metalloproteinase Inhibitors Using Lamarckian Genetic Algorithm "

    Directory of Open Access Journals (Sweden)

    lOrkideh Ghorban Dadrass

    2004-06-01

    Full Text Available As important therapeutic drug targets, matrix metalloproteinases (MMPs have recently attracted great interest in the search for potent and selective inhibitors using computer-aided molecular modelling and docking techniques. Availability of more than 60 X-ray crystal structures or NMR solution structures related to MMPs in Protein Data Bank (PDB of which more than half of them are in complex with various MMP inhibitors (MMPIs, provides a great opportunity for docking studies. In this study AutoDock 3.0.5 along with its LGA algorithm were used for automated flexible ligand docking of 32 MMPI-MMP complexes and docking accuracy and reliability of the estimated inhibition constants were evaluated. Twenty-six out of 32 docks had RMSD less than 3.0 Å which is considered as well-docked, however, for the most of the cases (15 out of 27, predicted pKi values were considerably overestimated in comparison to experimental values. To improve pKi prediction regarding MMPI-MMP complexes, inclusion of at least one such a complex in calibration of empirical free energy function in the next release of AutoDock is highly recommended.

  9. Spherical harmonics coefficients for ligand-based virtual screening of cyclooxygenase inhibitors.

    Science.gov (United States)

    Wang, Quan; Birod, Kerstin; Angioni, Carlo; Grösch, Sabine; Geppert, Tim; Schneider, Petra; Rupp, Matthias; Schneider, Gisbert

    2011-01-01

    Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort.

  10. Checkpoint Inhibition: Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors in Hodgkin Lymphoma.

    Science.gov (United States)

    Villasboas, Jose Caetano; Ansell, Stephen

    2016-01-01

    Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by a reactive immune infiltrate surrounding relatively few malignant cells. In this scenario, active immune evasion seems to play a central role in allowing tumor progression. Immune checkpoint inhibitor pathways are normal mechanisms of T-cell regulation that suppress immune effector function following an antigenic challenge. Hodgkin lymphoma cells are able to escape immune surveillance by co-opting these mechanisms. The programmed cell death 1 (PD-1) pathway in particular is exploited in HL as the malignant Hodgkin and Reed-Sternberg cells express on their surface cognate ligands (PD-L1/L2) for the PD-1 receptor and thereby dampen the T-cell-mediated antitumoral response. Monoclonal antibodies that interact with and disrupt the PD-1:PD-L1/L2 axis have now been developed and tested in early-phase clinical trials in patients with advanced HL with encouraging results. The remarkable clinical activity of PD-1 inhibitors in HL highlights the importance of immune checkpoint pathways as therapeutic targets in HL. In this review, we discuss the rationale for targeting PD-1 and PD-L1 in the treatment of HL. We will evaluate the published clinical data on the different agents and highlight the safety profile of this class of agents. We discuss the available evidence on the use of biomarkers as predictors of response to checkpoint blockade and summarize the areas under active investigation in the use of PD-1/PD-L1 inhibitors for the treatment of HL.

  11. New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors.

    Science.gov (United States)

    Greig, Nigel H; Reale, Marcella; Tata, Ada M

    2013-08-01

    The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer' and Sjogren's diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic

  12. Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method.

    OpenAIRE

    Simonin Céline; Awale Mahendra; Brand Michael; van Deursen Ruud; Schwartz Julian; Fine Michael; Kovacs Gergely; Häfliger Pascal; Gyimesi Gergely; Sithampari Abilashan; Charles Roch-Philippe; Hediger Matthias A; Reymond Jean-Louis

    2015-01-01

    Herein we report the discovery of the first potent and selective inhibitor of TRPV6 a calcium channel overexpressed in breast and prostate cancer and its use to test the effect of blocking TRPV6 mediated Ca(2+) influx on cell growth. The inhibitor was discovered through a computational method xLOS a 3D shape and pharmacophore similarity algorithm a type of ligand based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule two successive rou...

  13. Discovering Small Molecule Inhibitors Targeted to Ligand-Stimulated RAGE-DIAPH1 Signaling Transduction

    Science.gov (United States)

    Pan, Jinhong

    The receptor of advanced glycation end product (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, which plays an important role in immune responses. Full-length RAGE includes three extracellular immunoglobulin domains, a transmembrane domain and an intracellular domain. It is a pattern recognition receptor that can bind diverse ligands. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. It is found that calgranulin binding to the C1C2 domain or AGEs binding to the V domain activates extracellular signaling, which triggers interactions of the RAGE cytoplasmic tail (ctRAGE) with intracellular effector, such as diaphanous 1 (DIAPH1), to initiate signal transduction cascades. ctRAGE is essential for RAGE-ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE is over-expressed in diseased tissues of most RAGE-associated pathogenic conditions, such as complications of Alzheimer's diseases, diabetes, vascular diseases, inflammation, cancers and neurodegeneration. They are the major diseases affecting a large population worldwide. RAGE can function as a biomarker or drug target for these diseases. The cytoplasmic tail of RAGE can be used as a drug target to inhibit RAGE-induced intracellular signaling by small molecule inhibitors to treat RAGE-associated diseases. We developed a high throughput screening assay with which we probed a small molecule library of 58,000 compounds to find that 777 small molecules displayed 50% inhibition and 97 compounds demonstrated dose-dependent inhibition of the binding of ctRAGE-DIAPH1. Eventually, there were 13 compounds which displayed dose-dependent inhibition of ctRAGE binding to DIAPH1 and direct binding to ctRAGE analyzed by 15N HSQC-NMR and native tryptophan fluorescence titration experiments; thus, they were

  14. Ligand-based virtual screening and inductive learning for identification of SIRT1 inhibitors in natural products.

    Science.gov (United States)

    Sun, Yunan; Zhou, Hui; Zhu, Hongmei; Leung, Siu-wai

    2016-01-25

    Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase, and its dysregulation can lead to ageing, diabetes, and cancer. From 346 experimentally confirmed SIRT1 inhibitors, an inhibitor structure pattern was generated by inductive logic programming (ILP) with DMax Chemistry Assistant software. The pattern contained amide, amine, and hetero-aromatic five-membered rings, each of which had a hetero-atom and an unsubstituted atom at a distance of 2. According to this pattern, a ligand-based virtual screening of 1 444 880 active compounds from Chinese herbs identified 12 compounds as inhibitors of SIRT1. Three compounds (ZINC08790006, ZINC08792229, and ZINC08792355) had high affinity (-7.3, -7.8, and -8.6 kcal/mol, respectively) for SIRT1 as estimated by molecular docking software AutoDock Vina. This study demonstrated a use of ILP and background knowledge in machine learning to facilitate virtual screening.

  15. Support vector regression scoring of receptor-ligand complexes for rank-ordering and virtual screening of chemical libraries.

    Science.gov (United States)

    Li, Liwei; Wang, Bo; Meroueh, Samy O

    2011-09-26

    The community structure-activity resource (CSAR) data sets are used to develop and test a support vector machine-based scoring function in regression mode (SVR). Two scoring functions (SVR-KB and SVR-EP) are derived with the objective of reproducing the trend of the experimental binding affinities provided within the two CSAR data sets. The features used to train SVR-KB are knowledge-based pairwise potentials, while SVR-EP is based on physicochemical properties. SVR-KB and SVR-EP were compared to seven other widely used scoring functions, including Glide, X-score, GoldScore, ChemScore, Vina, Dock, and PMF. Results showed that SVR-KB trained with features obtained from three-dimensional complexes of the PDBbind data set outperformed all other scoring functions, including best performing X-score, by nearly 0.1 using three correlation coefficients, namely Pearson, Spearman, and Kendall. It was interesting that higher performance in rank ordering did not translate into greater enrichment in virtual screening assessed using the 40 targets of the Directory of Useful Decoys (DUD). To remedy this situation, a variant of SVR-KB (SVR-KBD) was developed by following a target-specific tailoring strategy that we had previously employed to derive SVM-SP. SVR-KBD showed a much higher enrichment, outperforming all other scoring functions tested, and was comparable in performance to our previously derived scoring function SVM-SP.

  16. Discovering new PI3Kα inhibitors with a strategy of combining ligand-based and structure-based virtual screening.

    Science.gov (United States)

    Yu, Miao; Gu, Qiong; Xu, Jun

    2018-02-01

    PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits. The structural validated hits were examined by PI3Kα inhibitory assay. With this screening protocol, ten PI3Kα inhibitors with new scaffolds were discovered with IC 50 values ranging 0.44-31.25 μM. The binding affinities for the most active compounds 33 and 74 were estimated through molecular dynamics simulations and MM-PBSA analyses.

  17. Discovering new PI3Kα inhibitors with a strategy of combining ligand-based and structure-based virtual screening

    Science.gov (United States)

    Yu, Miao; Gu, Qiong; Xu, Jun

    2018-02-01

    PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits. The structural validated hits were examined by PI3Kα inhibitory assay. With this screening protocol, ten PI3Kα inhibitors with new scaffolds were discovered with IC50 values ranging 0.44-31.25 μM. The binding affinities for the most active compounds 33 and 74 were estimated through molecular dynamics simulations and MM-PBSA analyses.

  18. Electrostatic similarities between protein and small molecule ligands facilitate the design of protein-protein interaction inhibitors.

    Directory of Open Access Journals (Sweden)

    Arnout Voet

    Full Text Available One of the underlying principles in drug discovery is that a biologically active compound is complimentary in shape and molecular recognition features to its receptor. This principle infers that molecules binding to the same receptor may share some common features. Here, we have investigated whether the electrostatic similarity can be used for the discovery of small molecule protein-protein interaction inhibitors (SMPPIIs. We have developed a method that can be used to evaluate the similarity of electrostatic potentials between small molecules and known protein ligands. This method was implemented in a software called EleKit. Analyses of all available (at the time of research SMPPII structures indicate that SMPPIIs bear some similarities of electrostatic potential with the ligand proteins of the same receptor. This is especially true for the more polar SMPPIIs. Retrospective analysis of several successful SMPPIIs has shown the applicability of EleKit in the design of new SMPPIIs.

  19. Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors.

    Science.gov (United States)

    Frett, Brendan; McConnell, Nick; Smith, Catherine C; Wang, Yuanxiang; Shah, Neil P; Li, Hong-yu

    2015-04-13

    The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  20. Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

    Science.gov (United States)

    Giroud, Maude; Dietzel, Uwe; Anselm, Lilli; Banner, David; Kuglstatter, Andreas; Benz, Jörg; Blanc, Jean-Baptiste; Gaufreteau, Delphine; Liu, Haixia; Lin, Xianfeng; Stich, August; Kuhn, Bernd; Schuler, Franz; Kaiser, Marcel; Brun, Reto; Schirmeister, Tanja; Kisker, Caroline; Diederich, François; Haap, Wolfgang

    2018-04-26

    Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( K i < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC 50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.

  1. Constitutive expression of TNF-related activation-induced cytokine (TRANCE/receptor activating NF-κB ligand (RANK-L by rat plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Thomas Anjubault

    Full Text Available Plasmacytoid dendritic cells (pDCs are a subset of DCs whose major function relies on their capacity to produce large amount of type I IFN upon stimulation via TLR 7 and 9. This function is evolutionary conserved and place pDC in critical position in the innate immune response to virus. Here we show that rat pDC constitutively express TNF-related activation-induced cytokine (TRANCE also known as Receptor-activating NF-κB ligand (RANKL. TRANCE/RANKL is a member of the TNF superfamily which plays a central role in osteoclastogenesis through its interaction with its receptor RANK. TRANCE/RANK interaction are also involved in lymphoid organogenesis as well as T cell/DC cross talk. Unlike conventional DC, rat CD4(high pDC were shown to constitutively express TRANCE/RANKL both at the mRNA and the surface protein level. TRANCE/RANKL was also induced on the CD4(low subsets of pDC following activation by CpG. The secreted form of TRANCE/RANKL was also produced by rat pDC. Of note, levels of mRNA, surface and secreted TRANCE/RANKL expression were similar to that observed for activated T cells. TRANCE/RANKL expression was found on pDC in all lymphoid organs as well blood and BM with a maximum expression in mesenteric lymph nodes. Despite this TRANCE/RANKL expression, we were unable to demonstrate in vitro osteoclastogenesis activity for rat pDC. Taken together, these data identifies pDC as novel source of TRANCE/RANKL in the immune system.

  2. Identification of small molecular ligands as potent inhibitors of fatty acid metabolism in Mycobacterium tuberculosis

    Science.gov (United States)

    Malikanti, Ramesh; Vadija, Rajender; Veeravarapu, Hymavathi; Mustyala, Kiran Kumar; Malkhed, Vasavi; Vuruputuri, Uma

    2017-12-01

    Tuberculosis (Tb) is one of the major health challenges for the global scientific community. The 3-hydroxy butyryl-CoA dehydrogenase (Fad B2) protein belongs to 3-hydroxyl acetyl-CoA dehydrogenase family, which plays a key role in the fatty acid metabolism and β-oxidation in the cell membrane of Mycobacterium tuberculosis (Mtb). In the present study the Fad B2 protein is targeted for the identification of potential drug candidates for tuberculosis. The 3D model of the target protein Fad B2, was generated using homology modeling approach and was validated. The plausible binding site of the Fad B2 protein was identified from computational binding pocket prediction tools, which ranges from ASN120 to VAL150 amino acid residues. Virtual screening was carried out with the databases, Ligand box UOS and hit definder, at the binding site region. 133 docked complex structures were generated as an output. The identified ligands show good glide scores and glide energies. All the ligand molecules contain benzyl amine pharmacophore in common, which show specific and selective binding interactions with the SER122 and ASN146 residues of the Fad B2 protein. The ADME properties of all the ligand molecules were observed to be within the acceptable range. It is suggested from the result of the present study that the docked molecular structures with a benzyl amine pharmacophore act as potential ligands for Fad B2 protein binding and as leads in Tb drug discovery.

  3. Ligand and structure-based classification models for Prediction of P-glycoprotein inhibitors

    DEFF Research Database (Denmark)

    Klepsch, Freya; Poongavanam, Vasanthanathan; Ecker, Gerhard Franz

    2014-01-01

    an algorithm based on Euclidean distance. Results show that random forest and SVM performed best for classification of P-gp inhibitors and non-inhibitors, correctly predicting 73/75 % of the external test set compounds. Classification based on the docking experiments using the scoring function Chem...

  4. Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    O' Dowd, Bing [Department of Chemistry, University of Illinois, 600 South Mathews Avenue Urbana IL 61801 USA; Williams, Sarah [Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla CA 92093 USA; Wang, Hongxin [Department of Chemistry, University of California, 1 Shields Avenue Davis CA 95616 USA; Lawrence Berkeley National Laboratory, 1 Cyclotron Road Berkeley CA 94720 USA; No, Joo Hwan [Center for Biophysics and Computational Biology, Urbana, IL (United States); Rao, Guodong [Department of Chemistry, University of Illinois, 600 South Mathews Avenue Urbana IL 61801 USA; Wang, Weixue [Center for Biophysics and Computational Biology, Urbana, IL (United States); McCammon, J. Andrew [Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla CA 92093 USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla CA 92093 USA; National Biomedical Computation Resource, University of California at San Diego, La Jolla CA 92093 USA; Cramer, Stephen P. [Department of Chemistry, University of California, 1 Shields Avenue Davis CA 95616 USA; Lawrence Berkeley National Laboratory, 1 Cyclotron Road Berkeley CA 94720 USA; Oldfield, Eric [Department of Chemistry, University of Illinois, 600 South Mathews Avenue Urbana IL 61801 USA

    2017-04-07

    Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target described is (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H + /2e - reduction. IspH contains a 4 Fe-4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe-4 S clusters by η 1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H 2 O, O 2 ) binding. Based on these ideas, we used in silico methods to find drug-like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a K i value of ≈500 nm against Pseudomonas aeruginosa IspH.

  5. Ligand-based modeling of Akt3 lead to potent dual Akt1/Akt3 inhibitor.

    Science.gov (United States)

    Al-Sha'er, Mahmoud A; Taha, Mutasem O

    2018-02-13

    Akt1 and Akt3 are important serine/threonine-specific protein kinases involved in G2 phase required by cancer cells to maintain cell cycle and to prevent cell death. Accordingly, inhibitors of these kinases should have potent anti-cancer properties. This prompted us to use pharmacophore/QSAR modeling to identify optimal binding models and physicochemical descriptors that explain bioactivity variation within a set of 74 diverse Akt3 inhibitors. Two successful orthogonal pharmacophores were identified and further validated using receiver operating characteristic (ROC) curve analyses. The pharmacophoric models and associated QSAR equation were applied to screen the national cancer institute (NCI) list of compounds for new Akt3 inhibitors. Six hits showed significant experimental anti-Akt3 IC 50 values, out of which one compound exhibited dual low micromolar anti-Akt1 and anti-Akt3 inhibitory profiles. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands

    DEFF Research Database (Denmark)

    Pedersen, Katrine E; Einholm, Anja P; Christensen, Anni

    2003-01-01

    Negatively charged organochemical inactivators of the anti-proteolytic activity of plasminogen activator inhibitor-1 (PAI-1) convert it to inactive polymers. As investigated by native gel electrophoresis, the size of the PAI-1 polymers ranged from dimers to multimers of more than 20 units. As com...

  7. Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors.

    Science.gov (United States)

    Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J; Borges, Fernanda

    2018-01-01

    Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN 1 (catechol derivative), and AntiOxBEN 2 (pyrogallol derivative) and compounds 15-18 , which have longer spacers. Compounds AntiOxBEN 1 and 15 , with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC 50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC 50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17 , no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN 1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

  8. Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

    Directory of Open Access Journals (Sweden)

    Catarina Oliveira

    2018-04-01

    Full Text Available Alzheimer's disease (AD is a multifactorial age-related disease associated with oxidative stress (OS and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative, and AntiOxBEN2 (pyrogallol derivative and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively, while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively. Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y and human hepatocarcinoma (HepG2 cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

  9. Hydroxybenzoic acid derivatives as dual-target ligands: mitochondriotropic antioxidants and cholinesterase inhibitors

    Science.gov (United States)

    Oliveira, Catarina; Cagide, Fernando; Teixeira, José; Amorim, Ricardo; Sequeira, Lisa; Mesiti, Francesco; Silva, Tiago; Garrido, Jorge; Remião, Fernando; Vilar, Santiago; Uriarte, Eugenio; Oliveira, Paulo J.; Borges, Fernanda

    2018-04-01

    Alzheimer’s disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy towards AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15-18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a ten-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 nM, respectively). Interestingly, molecular modelling data pointed towards bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Αβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favourable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related disease

  10. De novo design of alpha-amylase inhibitor: A small linear mimetic of macromolecular proteinaceous ligands

    Czech Academy of Sciences Publication Activity Database

    Marešová, Lucie; Pavlík, Manfred; Horn, Martin; Mareš, Michael

    2005-01-01

    Roč. 12, č. 12 (2005), 1349-1357 ISSN 1074-5521 R&D Projects: GA ČR(CZ) GP203/02/P081; GA MŠk(CZ) OC D16.001 Institutional research plan: CEZ:AV0Z40550506 Keywords : amylase * peptide inhibitor * combinatorial chemistry Subject RIV: CE - Biochemistry Impact factor: 6.138, year: 2005

  11. Ligand and Structure-Based Approaches for the Identification of Peptide Deformylase Inhibitors as Antibacterial Drugs.

    Science.gov (United States)

    Gao, Jian; Liang, Li; Zhu, Yasheng; Qiu, Shengzhi; Wang, Tao; Zhang, Ling

    2016-07-15

    Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, which makes it an important antibacterial drug target. Given the importance of PDF inhibitors like actinonin in antibacterial drug discovery, several reported potent PDF inhibitors were used to develop pharmacophore models using the Galahad module of Sybyl 7.1 software. Generated pharmacophore models were composed of two donor atom centers, four acceptor atom centers and two hydrophobic groups. Model-1 was screened against the Zinc database and several compounds were retrieved as hits. Compounds with Qfit values of more than 60 were employed to perform a molecular docking study with the receptor Escherichia coli PDF, then compounds with docking score values of more than 6 were used to predict the in silico pharmacokinetic and toxicity risk via OSIRIS property explorer. Two known PDF inhibitors were also used to perform a molecular docking study with E. coli PDF as reference molecules. The results of the molecular docking study were validated by reproducing the crystal structure of actinonin. Molecular docking and in silico pharmacokinetic and toxicity prediction studies suggested that ZINC08740166 has a relatively high docking score of 7.44 and a drug score of 0.78.

  12. Measles Virus Nucleocapsid (MVNP) Gene Expression and RANK Receptor Signaling in Osteoclast Precursors, Osteoclast Inhibitors Peptide Therapy for Pagets Disease

    Science.gov (United States)

    2008-10-01

    PS, Zurbriggen A, Cosby SL, Dickson GR, Fraser WD, Ooi CG, Selby PL, Crisp AJ, Wallace RG, Kahn S, Ralston SH 2000 A negative search for a...Zurbriggen A, Cosby SL, Dickson GR, Fraser WD, Ooi CG, Selby PL, Crisp AJ, Wallace RG, Kahn S, Ralston SH. 2000. A negative search for a paramyxoviral...van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM . 2000. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile

  13. New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors

    Science.gov (United States)

    Greig, Nigel H.; Reale, Marcella; Tata, Ada Maria

    2016-01-01

    The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer’ and Sjogren’s diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic

  14. Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches

    Directory of Open Access Journals (Sweden)

    Adeena Tahir

    2018-06-01

    Full Text Available The bromodomain containing protein 4 (BRD4 recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA and comparative molecular similarity indices analysis (CoMSIA approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r2, leave-one-out (LOO cross validated correlation coefficient (q2, bootstrapping, and Fisher’s randomization test. The highly reliable and predictive CoMFA (q2 = 0.569, r2 = 0.979 and CoMSIA (q2 = 0.500, r2 = 0.982 models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94. The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein’s active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds.

  15. High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase I Chemical Library.

    Science.gov (United States)

    Wang, Jun; Hallinger, Daniel R; Murr, Ashley S; Buckalew, Angela R; Simmons, Steven O; Laws, Susan C; Stoker, Tammy E

    2018-05-01

    Thyroid uptake of iodide via the sodium-iodide symporter (NIS) is the first step in the biosynthesis of thyroid hormones that are critical for health and development in humans and wildlife. Despite having long been a known target of endocrine disrupting chemicals such as perchlorate, information regarding NIS inhibition activity is still unavailable for the vast majority of environmental chemicals. This study applied a previously validated high-throughput approach to screen for NIS inhibitors in the ToxCast phase I library, representing 293 important environmental chemicals. Here 310 blinded samples were screened in a tiered-approach using an initial single-concentration (100 μM) radioactive-iodide uptake (RAIU) assay, followed by 169 samples further evaluated in multi-concentration (0.001 μM-100 μM) testing in parallel RAIU and cell viability assays. A novel chemical ranking system that incorporates multi-concentration RAIU and cytotoxicity responses was also developed as a standardized method for chemical prioritization in current and future screenings. Representative chemical responses and thyroid effects of high-ranking chemicals are further discussed. This study significantly expands current knowledge of NIS inhibition potential in environmental chemicals and provides critical support to U.S. EPA's Endocrine Disruptor Screening Program (EDSP) initiative to expand coverage of thyroid molecular targets, as well as the development of thyroid adverse outcome pathways (AOPs).

  16. Combination Treatment with PPARγ Ligand and Its Specific Inhibitor GW9662 Downregulates BIS and 14-3-3 Gamma, Inhibiting Stem-Like Properties in Glioblastoma Cells.

    Science.gov (United States)

    Im, Chang-Nim

    2017-01-01

    PPAR γ is a nuclear receptor that regulates differentiation and proliferation and is highly expressed in many cancer cells. Its synthetic ligands, such as rosiglitazone and ciglitazone, and its inhibitor GW9662, were shown to induce cellular differentiation, inhibit proliferation, and lead to apoptosis. Glioblastoma is a common brain tumor with poor survival prospects. Recently, glioblastoma stem cells (GSCs) have been examined as a potential target for anticancer therapy; however, little is known about the combined effect of various agents on GSCs. In this study, we found that cotreatment with PPAR γ ligands and GW9662 inhibited stem-like properties in GSC-like spheres, which significantly express SOX2. In addition, this treatment decreased the activation of STAT3 and AKT and decreased the amounts of 14-3-3 gamma and BIS proteins. Moreover, combined administration of small-interfering RNA (siRNA) transfection with PPAR γ ligands induced downregulation of SOX2 and MMP2 activity together with inhibition of sphere-forming activity regardless of poly(ADP-ribose) polymerase (PARP) cleavage. Taken together, our findings suggest that a combination therapy using PPAR γ ligands and its inhibitor could be a potential therapeutic strategy targeting GSCs.

  17. Combination Treatment with PPARγ Ligand and Its Specific Inhibitor GW9662 Downregulates BIS and 14-3-3 Gamma, Inhibiting Stem-Like Properties in Glioblastoma Cells

    Directory of Open Access Journals (Sweden)

    Chang-Nim Im

    2017-01-01

    Full Text Available PPARγ is a nuclear receptor that regulates differentiation and proliferation and is highly expressed in many cancer cells. Its synthetic ligands, such as rosiglitazone and ciglitazone, and its inhibitor GW9662, were shown to induce cellular differentiation, inhibit proliferation, and lead to apoptosis. Glioblastoma is a common brain tumor with poor survival prospects. Recently, glioblastoma stem cells (GSCs have been examined as a potential target for anticancer therapy; however, little is known about the combined effect of various agents on GSCs. In this study, we found that cotreatment with PPARγ ligands and GW9662 inhibited stem-like properties in GSC-like spheres, which significantly express SOX2. In addition, this treatment decreased the activation of STAT3 and AKT and decreased the amounts of 14-3-3 gamma and BIS proteins. Moreover, combined administration of small-interfering RNA (siRNA transfection with PPARγ ligands induced downregulation of SOX2 and MMP2 activity together with inhibition of sphere-forming activity regardless of poly(ADP-ribose polymerase (PARP cleavage. Taken together, our findings suggest that a combination therapy using PPARγ ligands and its inhibitor could be a potential therapeutic strategy targeting GSCs.

  18. Prostate-specific membrane antigen targeted imaging and therapy of prostate cancer using a PSMA inhibitor as a homing ligand.

    Science.gov (United States)

    Kularatne, Sumith A; Wang, Kevin; Santhapuram, Hari-Krishna R; Low, Philip S

    2009-01-01

    Prostate cancer (PCa) is a major cause of mortality and morbidity in Western society today. Current methods for detecting PCa are limited, leaving most early malignancies undiagnosed and sites of metastasis in advanced disease undetected. Major deficiencies also exist in the treatment of PCa, especially metastatic disease. In an effort to improve both detection and therapy of PCa, we have developed a PSMA-targeted ligand that delivers attached imaging and therapeutic agents selectively to PCa cells without targeting normal cells. The PSMA-targeted radioimaging agent (DUPA-(99m)Tc) was found to bind PSMA-positive human PCa cells (LNCaP cell line) with nanomolar affinity (K(D) = 14 nM). Imaging and biodistribution studies revealed that DUPA-(99m)Tc localizes primarily to LNCaP cell tumor xenografts in nu/nu mice (% injected dose/gram = 11.3 at 4 h postinjection; tumor-to-muscle ratio = 75:1). Two PSMA-targeted optical imaging agents (DUPA-FITC and DUPA-rhodamine B) were also shown to efficiently label PCa cells and to internalize and traffic to intracellular endosomes. A PSMA-targeted chemotherapeutic agent (DUPA-TubH) was demonstrated to kill PSMA-positive LNCaP cells in culture (IC(50) = 3 nM) and to eliminate established tumor xenografts in nu/nu mice with no detectable weight loss. Blockade of tumor targeting upon administration of excess PSMA inhibitor (PMPA) and the absence of targeting to PSMA-negative tumors confirmed the specificity of each of the above targeted reagents for PSMA. Tandem use of the imaging and therapeutic agents targeted to the same receptor could allow detection, staging, monitoring, and treatment of PCa with improved accuracy and efficacy.

  19. Inhibitors

    Science.gov (United States)

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  20. Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Arun K.; Brindisi, Margherita; Nyalapatla, Prasanth R.; Takayama, Jun; Ella-Menye, Jean-Rene; Yashchuk, Sofiya; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

    2017-10-01

    Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

  1. Discovery of novel urokinase plasminogen activator (uPA) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis.

    Science.gov (United States)

    Al-Sha'er, Mahmoud A; Khanfar, Mohammad A; Taha, Mutasem O

    2014-01-01

    Urokinase plasminogen activator (uPA)-a serine protease-is thought to play a central role in tumor metastasis and angiogenesis and, therefore, inhibition of this enzyme could be beneficial in treating cancer. Toward this end, we explored the pharmacophoric space of 202 uPA inhibitors using seven diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, we employed genetic algorithm-based quantitative structure-activity relationship (QSAR) analysis as a competition arena to select the best possible combination of pharmacophoric models and physicochemical descriptors that can explain bioactivity variation within the training inhibitors (r (2) 162 = 0.74, F-statistic = 64.30, r (2) LOO = 0.71, r (2) PRESS against 40 test inhibitors = 0.79). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the uPA binding pocket. This conclusion was supported by receiver operating characteristic (ROC) curve analyses of the QSAR-selected pharmacophores. Moreover, the three pharmacophores were comparable with binding interactions seen in crystallographic structures of bound ligands within the uPA binding pocket. We employed the resulting pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds. The captured hits were tested in vitro. Overall, our modeling workflow identified new low micromolar anti-uPA hits.

  2. Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control

    Science.gov (United States)

    Raschka, Sebastian; Scott, Anne M.; Liu, Nan; Gunturu, Santosh; Huertas, Mar; Li, Weiming; Kuhn, Leslie A.

    2018-03-01

    While the advantage of screening vast databases of molecules to cover greater molecular diversity is often mentioned, in reality, only a few studies have been published demonstrating inhibitor discovery by screening more than a million compounds for features that mimic a known three-dimensional (3D) ligand. Two factors contribute: the general difficulty of discovering potent inhibitors, and the lack of free, user-friendly software to incorporate project-specific knowledge and user hypotheses into 3D ligand-based screening. The Screenlamp modular toolkit presented here was developed with these needs in mind. We show Screenlamp's ability to screen more than 12 million commercially available molecules and identify potent in vivo inhibitors of a G protein-coupled bile acid receptor within the first year of a discovery project. This pheromone receptor governs sea lamprey reproductive behavior, and to our knowledge, this project is the first to establish the efficacy of computational screening in discovering lead compounds for aquatic invasive species control. Significant enhancement in activity came from selecting compounds based on one of the hypotheses: that matching two distal oxygen groups in the 3D structure of the pheromone is crucial for activity. Six of the 15 most active compounds met these criteria. A second hypothesis—that presence of an alkyl sulfate side chain results in high activity—identified another 6 compounds in the top 10, demonstrating the significant benefits of hypothesis-driven screening.

  3. Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Arun K.; Takayama, Jun; Rao, Kalapala Venkateswar; Ratia, Kiira; Chaudhuri, Rima; Mulhearn, Debbie C.; Lee, Hyun; Nichols, Daniel B.; Baliji, Surendranath; Baker, Susan C.; Johnson, Michael E.; Mesecar, Andrew D. (Purdue); (UC); (UIC)

    2012-02-21

    The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC{sub 50} = 0.56 {mu}M; antiviral EC{sub 50} = 9.1 {mu}M) and the corresponding (R)-Me 15g (IC{sub 50} = 0.32 {mu}M; antiviral EC{sub 50} = 9.1 {mu}M) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.

  4. 18F-FDG PET/CT for Monitoring Response of Merkel Cell Carcinoma to the Novel Programmed Cell Death Ligand 1 Inhibitor Avelumab.

    Science.gov (United States)

    Eshghi, Naghmehossadat; Lundeen, Tamara F; MacKinnon, Lea; Avery, Ryan; Kuo, Phillip H

    2018-05-01

    An 85-year-old man with stage IIIA Merkel cell carcinoma of the left arm was initially treated with local excision and axillary node dissection followed by radiation therapy. Eight months after surgery, whole-body FDG PET/CT demonstrated intensely hypermetabolic hepatic metastases and abdominal lymphadenopathy. Given his age and comorbidities, he was considered a poor candidate for chemotherapy, and therefore the novel programmed cell death ligand 1 inhibitor avelumab was initiated. FDG PET/CT after 4 cycles showed complete resolution of hepatic and nodal metastases. Whole-body FDG PET/CT can be used for monitoring response of multisystem metastases from Merkel cell carcinoma to active immunotherapy.

  5. Impact of Stereochemistry on Ligand Binding: X-ray Crystallographic Analysis of an Epoxide-Based HIV Protease Inhibitor.

    Science.gov (United States)

    Benedetti, Fabio; Berti, Federico; Campaner, Pietro; Fanfoni, Lidia; Demitri, Nicola; Olajuyigbe, Folasade M; De March, Matteo; Geremia, Silvano

    2014-09-11

    A new pseudopeptide epoxide inhibitor, designed for irreversible binding to HIV protease (HIV-PR), has been synthesized and characterized in solution and in the solid state. However, the crystal structure of the complex obtained by inhibitor-enzyme cocrystallization revealed that a minor isomer, with inverted configuration of the epoxide carbons, has been selected by HIV-PR during crystallization. The structural characterization of the well-ordered pseudopeptide, inserted in the catalytic channel with its epoxide group intact, provides deeper insights into inhibitor binding and HIV-PR stereoselectivity, which aids development of future epoxide-based HIV inhibitors.

  6. Rank Dynamics

    Science.gov (United States)

    Gershenson, Carlos

    Studies of rank distributions have been popular for decades, especially since the work of Zipf. For example, if we rank words of a given language by use frequency (most used word in English is 'the', rank 1; second most common word is 'of', rank 2), the distribution can be approximated roughly with a power law. The same applies for cities (most populated city in a country ranks first), earthquakes, metabolism, the Internet, and dozens of other phenomena. We recently proposed ``rank diversity'' to measure how ranks change in time, using the Google Books Ngram dataset. Studying six languages between 1800 and 2009, we found that the rank diversity curves of languages are universal, adjusted with a sigmoid on log-normal scale. We are studying several other datasets (sports, economies, social systems, urban systems, earthquakes, artificial life). Rank diversity seems to be universal, independently of the shape of the rank distribution. I will present our work in progress towards a general description of the features of rank change in time, along with simple models which reproduce it

  7. Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation.

    Science.gov (United States)

    Więckowska, Anna; Kołaczkowski, Marcin; Bucki, Adam; Godyń, Justyna; Marcinkowska, Monika; Więckowski, Krzysztof; Zaręba, Paula; Siwek, Agata; Kazek, Grzegorz; Głuch-Lutwin, Monika; Mierzejewski, Paweł; Bienkowski, Przemysław; Sienkiewicz-Jarosz, Halina; Knez, Damijan; Wichur, Tomasz; Gobec, Stanislav; Malawska, Barbara

    2016-11-29

    As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT 6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT 6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT 6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT 6 receptor (K b  = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC 50 hAChE  = 12 nM, IC 50 hBuChE  = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade.

    LENUS (Irish Health Repository)

    Rooney, Terence

    2012-02-01

    The objective of the study was to evaluate synovial tissue receptor activator of nuclear factor-kappabeta ligand (RANKL) and osteoprotegerin (OPG) as biomarkers of disease activity, progressive joint damage, and therapeutic response, during cytokine blockade in rheumatoid arthritis (RA). Patients with active RA entered a randomized open-label 12-month study of anakinra 100 mg\\/day, administered as monotherapy or in combination with pegsunercept 800 mug\\/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline, at 4 weeks and at the final time point. Following immunohistochemical staining, RANKL and OPG expression was quantified using digital image analysis. Radiographic damage was evaluated using the van der Heijde modification of the Sharp scoring system. Twenty-two patients were randomized. Baseline expression of RANKL, but not OPG, correlated significantly with baseline CRP levels (r = 0.61, P < 0.01). While a significant reduction in OPG expression following treatment was observed in clinical responders at the final time point (P < 0.05 vs. baseline), RANKL levels did not change, and the RANKL:OPG ratio remained unaltered, even at the highest levels of clinical response. When potential predictors of radiographic outcome were evaluated, baseline RANKL expression correlated with erosive progression at 1 year (r = 0.71, P < 0.01). Distinct, though related, pathophysiologic processes mediate joint inflammation and destruction in RA. Elevated synovial tissue RANKL expression is associated with progressive joint erosion, and may be independent of the clinical response to targeted therapy. The potential therapeutic importance of modulating RANKL in RA is highlighted, if radiographic arrest is to be achieved.

  9. Gentamicin binds to the megalin receptor as a competitive inhibitor using the common ligand binding motif of complement type repeats

    DEFF Research Database (Denmark)

    Dagil, Robert; O'Shea, Charlotte; Nykjær, Anders

    2013-01-01

    megalin and investigated its interaction with gentamicin. Using NMR titration data in HADDOCK, we have generated a three-dimensional model describing the complex between megalin and gentamicin. Gentamicin binds to megalin with low affinity and exploits the common ligand binding motif previously described...... to megalin is highly similar to gentamicin binding to calreticulin. We discuss the impact of this novel insight for the future structure-based design of gentamicin antagonists....

  10. Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion.

    Science.gov (United States)

    Prescher, Horst; Frank, Martin; Gütgemann, Stephan; Kuhfeldt, Elena; Schweizer, Astrid; Nitschke, Lars; Watzl, Carsten; Brossmer, Reinhard

    2017-02-09

    Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar K d values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds.

  11. A Nonbactericidal Zinc-Complexing Ligand as a Biofilm Inhibitor: Structure-Guided Contrasting Effects on Staphylococcus aureus Biofilm.

    Science.gov (United States)

    Kapoor, Vidushi; Rai, Rajanikant; Thiyagarajan, Durairaj; Mukherjee, Sandipan; Das, Gopal; Ramesh, Aiyagari

    2017-08-04

    Zinc-complexing ligands are prospective anti-biofilm agents because of the pivotal role of zinc in the formation of Staphylococcus aureus biofilm. Accordingly, the potential of a thiosemicarbazone (compound C1) and a benzothiazole-based ligand (compound C4) in the prevention of S. aureus biofilm formation was assessed. Compound C1 displayed a bimodal activity, hindering biofilm formation only at low concentrations and promoting biofilm growth at higher concentrations. In the case of C4, a dose-dependent inhibition of S. aureus biofilm growth was observed. Atomic force microscopy analysis suggested that at higher concentrations C1 formed globular aggregates, which perhaps formed a substratum that favored adhesion of cells and biofilm formation. In the case of C4, zinc supplementation experiments validated zinc complexation as a plausible mechanism of inhibition of S. aureus biofilm. Interestingly, C4 was nontoxic to cultured HeLa cells and thus has promise as a therapeutic anti-biofilm agent. The essential understanding of the structure-driven implications of zinc-complexing ligands acquired in this study might assist future screening regimes for identification of potent anti-biofilm agents. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Fluorescent ligand fishing combination with in-situ imaging and characterizing to screen Hsp 90 inhibitors from Curcuma longa L. based on InP/ZnS quantum dots embedded mesoporous nanoparticles.

    Science.gov (United States)

    Hu, Yue; Fu, Anchen; Miao, Zhaoyi; Zhang, Xiaojing; Wang, Tianlin; Kang, An; Shan, Jinjun; Zhu, Dong; Li, Wei

    2018-02-01

    Although ligand fishing has been shown to be an efficient technique for the identification of bioactive components from complex mixtures such as natural products, it cannot be applied to biomedical image processing. Herein, a specific fluorescent ligand fishing combined with in situ imaging approach is presented for the identification of heat shock protein 90 (Hsp 90) inhibitors from complex matrixes, Curcuma longa L., using N-terminus immobilized Hsp 90α functionalized InP/ZnS quantum dots embedded mesoporous nanoparticles (i.e. Hsp 90α (NT)-FQDNs) as extraction sorbents and fluorescent tracer. The fished ligands were identified by liquid chromatography time-of-flight/mass spectrometry (LC-TOF/MS) and gas chromatography-mass spectrometry (GC-MS). Moreover, in situ imaging by confocal laser scanning microscopy (CLSM) was applied for evaluating the effect of fished-ligands on bioactivity-induced apoptosis morphologically in HeLa cells. MTT assay verified the bioactivity of the ligands and molecular docking results further provided convincing information to verify the feasible binding mode between ligands and protein. Twelve ligands as potential Hsp 90 inhibitors were ultimately fished and identified from Curcuma longa L. crude extracts. The proposed approach based on Hsp 90α functionalized nanocomposites is superior in the combination of highly specific screening efficiency and concurrent visual in situ imaging, which could have great promise for the development of other plant-derived Hsp 90 inhibitors, and providing a rapid and reliable platform for discovering biologically active molecules in natural products. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. University Rankings: The Web Ranking

    Science.gov (United States)

    Aguillo, Isidro F.

    2012-01-01

    The publication in 2003 of the Ranking of Universities by Jiao Tong University of Shanghai has revolutionized not only academic studies on Higher Education, but has also had an important impact on the national policies and the individual strategies of the sector. The work gathers the main characteristics of this and other global university…

  14. High-throughput screening using the differential radial capillary action of ligand assay identifies ebselen as an inhibitor of diguanylate cyclases.

    Science.gov (United States)

    Lieberman, Ori J; Orr, Mona W; Wang, Yan; Lee, Vincent T

    2014-01-17

    The rise of bacterial resistance to traditional antibiotics has motivated recent efforts to identify new drug candidates that target virulence factors or their regulatory pathways. One such antivirulence target is the cyclic-di-GMP (cdiGMP) signaling pathway, which regulates biofilm formation, motility, and pathogenesis. Pseudomonas aeruginosa is an important opportunistic pathogen that utilizes cdiGMP-regulated polysaccharides, including alginate and pellicle polysaccharide (PEL), to mediate virulence and antibiotic resistance. CdiGMP activates PEL and alginate biosynthesis by binding to specific receptors including PelD and Alg44. Mutations that abrogate cdiGMP binding to these receptors prevent polysaccharide production. Identification of small molecules that can inhibit cdiGMP binding to the allosteric sites on these proteins could mimic binding defective mutants and potentially reduce biofilm formation or alginate secretion. Here, we report the development of a rapid and quantitative high-throughput screen for inhibitors of protein-cdiGMP interactions based on the differential radial capillary action of ligand assay (DRaCALA). Using this approach, we identified ebselen as an inhibitor of cdiGMP binding to receptors containing an RxxD domain including PelD and diguanylate cyclases (DGC). Ebselen reduces diguanylate cyclase activity by covalently modifying cysteine residues. Ebselen oxide, the selenone analogue of ebselen, also inhibits cdiGMP binding through the same covalent mechanism. Ebselen and ebselen oxide inhibit cdiGMP regulation of biofilm formation and flagella-mediated motility in P. aeruginosa through inhibition of diguanylate cyclases. The identification of ebselen provides a proof-of-principle that a DRaCALA high-throughput screening approach can be used to identify bioactive agents that reverse regulation of cdiGMP signaling by targeting cdiGMP-binding domains.

  15. Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients.

    Science.gov (United States)

    Massi, Daniela; Romano, Emanuela; Rulli, Eliana; Merelli, Barbara; Nassini, Romina; De Logu, Francesco; Bieche, Ivan; Baroni, Gianna; Cattaneo, Laura; Xue, Gongda; Mandalà, Mario

    2017-06-01

    The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified. Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients. We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03-0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54-131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10-0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09-0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%. Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and

  16. Dissecting Orthosteric Contacts for a Reverse-Fragment-Based Ligand Design.

    Science.gov (United States)

    Chandramohan, Arun; Tulsian, Nikhil K; Anand, Ganesh S

    2017-08-01

    Orthosteric sites on proteins are formed typically from noncontiguous interacting sites in three-dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the local secondary structure. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD). In this study, we describe an approach of progressive unfolding of a target protein using a gradient of denaturant urea to reveal the individual energetic contributions of various ligand-functional groups to the affinity of the entire ligand. Through calibrated unfolding of two protein-ligand systems: cAMP-bound regulatory subunit of Protein Kinase A (RIα) and IBMX-bound phosphodiesterase8 (PDE8), monitored by amide hydrogen-deuterium exchange mass spectrometry, we show progressive disruption of individual orthosteric contacts in the ligand binding sites, allowing us to rank the energetic contributions of these individual interactions. In the two cAMP-binding sites of RIα, exocyclic phosphate oxygens of cAMP were identified to mediate stronger interactions than ribose 2'-OH in both the RIα-cAMP binding interfaces. Further, we have also ranked the relative contributions of the different functional groups of IBMX based on their interactions with the orthosteric residues of PDE8. This strategy for deconstruction of individual binding sites and identification of the strongest functional group interaction in enzyme orthosteric sites offers a rational starting point for FBDD.

  17. Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials.

    Science.gov (United States)

    Khunger, Monica; Rakshit, Sagar; Pasupuleti, Vinay; Hernandez, Adrian V; Mazzone, Peter; Stevenson, James; Pennell, Nathan A; Velcheti, Vamsidhar

    2017-08-01

    Programmed death 1 (PD-1) programmed death-ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune-mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD-1 and PD-L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use. MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors and between treatment naive and previously treated patients. Nineteen trials (12 with PD-1 inhibitors [n = 3,232] and 7 with PD-L1 inhibitors [n = 1,806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD-L1 inhibitors (3.6%; 95% CI, 2.4%-4.9% vs 1.3%; 95% CI, 0.8%-1.9%, respectively; P = .001). PD-1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%-1.7% vs 0.4%; 95% CI, 0%-0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%-6.3% vs 2.8%; 95% CI, 1.7%- 4%; P = .03). There was a higher incidence of pneumonitis with use of PD-1 inhibitors compared with PD-L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  18. Sparse structure regularized ranking

    KAUST Repository

    Wang, Jim Jing-Yan; Sun, Yijun; Gao, Xin

    2014-01-01

    Learning ranking scores is critical for the multimedia database retrieval problem. In this paper, we propose a novel ranking score learning algorithm by exploring the sparse structure and using it to regularize ranking scores. To explore the sparse

  19. Kinetic and Thermodynamic Rationale for SAHA Being a Preferential Human HDAC8 Inhibitor as Compared to the Structurally Similar Ligand, TSA

    Science.gov (United States)

    Singh, Raushan K.; Lall, Naveena; Leedahl, Travis S.; McGillivray, Abigail; Mandal, Tanmay; Haldar, Manas; Mallik, Sanku; Cook, Gregory; Srivastava, D.K.

    2013-01-01

    Of the different hydroxamate-based histone deacetylase (HDAC) inhibitors, Suberoylanilide hydroxamic acid (SAHA) has been approved by the FDA for treatment of T-cell lymphoma. Interestingly, a structurally similar inhibitor, Trichostatin A (TSA), which has a higher in vitro inhibitory-potency against HDAC8, reportedly shows a poor efficacy in clinical settings. In order to gain the molecular insight into the above discriminatory feature, we performed transient kinetic and isothermal titration calorimetric studies for the interaction of SAHA and TSA to the recombinant form of human HDAC8. The transient kinetic data revealed that the binding of both the inhibitors to the enzyme showed the biphasic profiles, which represented an initial encounter of enzyme with the inhibitor followed by the isomerization of the transient enzyme-inhibitor complexes. The temperature-dependent transient kinetic studies with the above inhibitors revealed that the bimolecular process is primarily dominated by favorable enthalpic changes, as opposed to the isomerization step; which is solely contributed by entropic changes. The standard binding-enthalpy (ΔH0) of SAHA, deduced from the transient kinetic as well as the isothermal titration calorimetric experiments, was 2–3 kcal/mol higher as compared to TSA. The experimental data presented herein suggests that SAHA serves as a preferential (target-specific/selective) HDAC8 inhibitor as compared to TSA. Arguments are presented that the detailed kinetic and thermodynamic studies may guide in the rational design of HDAC inhibitors as therapeutic agents. PMID:24079912

  20. Binding cooperativity between a ligand carbonyl group and a hydrophobic side chain can be enhanced by additional H-bonds in a distance dependent manner: A case study with thrombin inhibitors.

    Science.gov (United States)

    Said, Ahmed M; Hangauer, David G

    2015-01-01

    One of the underappreciated non-covalent binding factors, which can significantly affect ligand-protein binding affinity, is the cooperativity between ligand functional groups. Using four different series of thrombin inhibitors, we reveal a strong positive cooperativity between an H-bond accepting carbonyl functionality and the adjacent P3 hydrophobic side chain. Adding an H-bond donating amine adjacent to the P3 hydrophobic side chain further increases this positive cooperativity thereby improving the Ki by as much as 546-fold. In contrast, adding an amidine multiple H-bond/salt bridge group in the distal S1 pocket does not affect this cooperativity. An analysis of the crystallographic B-factors of the ligand groups inside the binding site indicates that the strong cooperativity is mainly due to a significant mutual reduction in the residual mobility of the hydrophobic side chain and the H-bonding functionalities that is absent when the separation distance is large. This type of cooperativity is important to encode in binding affinity prediction software, and to consider in SAR studies. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. Reduced Rank Regression

    DEFF Research Database (Denmark)

    Johansen, Søren

    2008-01-01

    The reduced rank regression model is a multivariate regression model with a coefficient matrix with reduced rank. The reduced rank regression algorithm is an estimation procedure, which estimates the reduced rank regression model. It is related to canonical correlations and involves calculating...

  2. Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Arun K.; Sean Fyvie, W.; Brindisi, Margherita; Steffey, Melinda; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

    2017-11-01

    Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

  3. Understanding the Molecular Determinant of Reversible Human Monoamine Oxidase B Inhibitors Containing 2H-Chromen-2-One Core: Structure-Based and Ligand-Based Derived Three-Dimensional Quantitative Structure-Activity Relationships Predictive Models.

    Science.gov (United States)

    Mladenović, Milan; Patsilinakos, Alexandros; Pirolli, Adele; Sabatino, Manuela; Ragno, Rino

    2017-04-24

    Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme's malfunction can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson's disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico-in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including the following: (1) definition of optimized and validated structure-based three-dimensional (3-D) quantitative structure-activity relationships (QSAR) models derived from available cocrystallized inhibitor-MAO B complexes; (2) elaboration of SAR features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61 ) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rule assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro. Due to the wide range of molecular diversity within the 3-D QSAR training set and derived features, the selected N probe-derived 3-D QSAR model proves to be a valuable tool for virtual screening (VS) of novel MAO B inhibitors and a platform for design, synthesis and evaluation of novel active structures. Accordingly, six highly active and selective MAO B inhibitors (picomolar to low nanomolar range of activity) were disclosed as a

  4. Structure-Based Design of Peptidic Inhibitors of the Interaction between CC Chemokine Ligand 5 (CCL5) and Human Neutrophil Peptides 1 (HNP1)

    NARCIS (Netherlands)

    Wichapong, Kanin; Alard, Jean-Eric; Ortega-Gomez, Almudena; Weber, Christian; Hackeng, Tilman M.; Soehnlein, Oliver; Nicolaes, Gerry A. F.

    2016-01-01

    Protein-protein interactions (PPIs) are receiving increasing interest, much sparked by the realization that they represent druggable targets. Recently, we successfully developed a peptidic inhibitor, RRYGTSKYQ ("SKY" peptide), that shows high potential in vitro and in vivo to interrupt a PPI between

  5. A Mixed-Ligand Approach Enables the Asymmetric Hydrogenation of an α-Isopropylcinnamic Acid en Route to the Renin Inhibitor Aliskiren

    NARCIS (Netherlands)

    Boogers, Jeroen A.F.; Felfer, Ulfried; Kotthaus, Martina; Lefort, Laurent; Steinbauer, Gerhard; Vries, André H.M. de; Vries, Johannes G. de

    2007-01-01

    An asymmetric hydrogenation process for an α-isopropyl dihydrocinnamic acid derivative, an intermediate for the renin inhibitor aliskiren, has been developed using a rhodium catalyst ligated with a chiral monodentate phosphoramidite and a nonchiral phosphine. Whereas catalysts based on two

  6. Ranking Operations Management conferences

    NARCIS (Netherlands)

    Steenhuis, H.J.; de Bruijn, E.J.; Gupta, Sushil; Laptaned, U

    2007-01-01

    Several publications have appeared in the field of Operations Management which rank Operations Management related journals. Several ranking systems exist for journals based on , for example, perceived relevance and quality, citation, and author affiliation. Many academics also publish at conferences

  7. Evaluation of the osteoclastogenic process associated with RANK / RANK-L / OPG in odontogenic myxomas

    Science.gov (United States)

    González-Galván, María del Carmen; Mosqueda-Taylor, Adalberto; Bologna-Molina, Ronell; Setien-Olarra, Amaia; Marichalar-Mendia, Xabier; Aguirre-Urizar, José-Manuel

    2018-01-01

    Background Odontogenic myxoma (OM) is a benign intraosseous neoplasm that exhibits local aggressiveness and high recurrence rates. Osteoclastogenesis is an important phenomenon in the tumor growth of maxillary neoplasms. RANK (Receptor Activator of Nuclear Factor κappa B) is the signaling receptor of RANK-L (Receptor activator of nuclear factor kappa-Β ligand) that activates the osteoclasts. OPG (osteoprotegerin) is a decoy receptor for RANK-L that inhibits pro-osteoclastogenesis. The RANK / RANKL / OPG system participates in the regulation of osteolytic activity under normal conditions, and its alteration has been associated with greater bone destruction, and also with tumor growth. Objectives To analyze the immunohistochemical expression of OPG, RANK and RANK-L proteins in odontogenic myxomas (OMs) and their relationship with the tumor size. Material and Methods Eighteen OMs, 4 small ( 3cm) and 18 dental follicles (DF) that were included as control were studied by means of standard immunohistochemical procedure with RANK, RANKL and OPG antibodies. For the evaluation, 5 fields (40x) of representative areas of OM and DF were selected where the expression of each antibody was determined. Descriptive and comparative statistical analyses were performed with the obtained data. Results There are significant differences in the expression of RANK in OM samples as compared to DF (p = 0.022) and among the OMSs and OMLs (p = 0.032). Also a strong association is recognized in the expression of RANK-L and OPG in OM samples. Conclusions Activation of the RANK / RANK-L / OPG triad seems to be involved in the mechanisms of bone balance and destruction, as well as associated with tumor growth in odontogenic myxomas. Key words:Odontogenic myxoma, dental follicle, RANK, RANK-L, OPG, osteoclastogenesis. PMID:29680857

  8. Acinetobacter baumannii FolD ligand complexes --potent inhibitors of folate metabolism and a re-evaluation of the structure of LY374571.

    Science.gov (United States)

    Eadsforth, Thomas C; Maluf, Fernando V; Hunter, William N

    2012-12-01

    The bifunctional N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase (DHCH or FolD), which is widely distributed in prokaryotes and eukaryotes, is involved in the biosynthesis of folate cofactors that are essential for growth and cellular development. The enzyme activities represent a potential antimicrobial drug target. We have characterized the kinetic properties of FolD from the Gram-negative pathogen Acinetobacter baumanni and determined high-resolution crystal structures of complexes with a cofactor and two potent inhibitors. The data reveal new details with respect to the molecular basis of catalysis and potent inhibition. A unexpected finding was that our crystallographic data revealed a different structure for LY374571 (an inhibitor studied as an antifolate) than that previously published. The implications of this observation are discussed. © 2012 The Authors Journal compilation © 2012 FEBS.

  9. Virtual drug screen schema based on multiview similarity integration and ranking aggregation.

    Science.gov (United States)

    Kang, Hong; Sheng, Zhen; Zhu, Ruixin; Huang, Qi; Liu, Qi; Cao, Zhiwei

    2012-03-26

    The current drug virtual screen (VS) methods mainly include two categories. i.e., ligand/target structure-based virtual screen and that, utilizing protein-ligand interaction fingerprint information based on the large number of complex structures. Since the former one focuses on the one-side information while the later one focuses on the whole complex structure, they are thus complementary and can be boosted by each other. However, a common problem faced here is how to present a comprehensive understanding and evaluation of the various virtual screen results derived from various VS methods. Furthermore, there is still an urgent need for developing an efficient approach to fully integrate various VS methods from a comprehensive multiview perspective. In this study, our virtual screen schema based on multiview similarity integration and ranking aggregation was tested comprehensively with statistical evaluations, providing several novel and useful clues on how to perform drug VS from multiple heterogeneous data sources. (1) 18 complex structures of HIV-1 protease with ligands from the PDB were curated as a test data set and the VS was performed with five different drug representations. Ritonavir ( 1HXW ) was selected as the query in VS and the weighted ranks of the query results were aggregated from multiple views through four similarity integration approaches. (2) Further, one of the ranking aggregation methods was used to integrate the similarity ranks calculated by gene ontology (GO) fingerprint and structural fingerprint on the data set from connectivity map, and two typical HDAC and HSP90 inhibitors were chosen as the queries. The results show that rank aggregation can enhance the result of similarity searching in VS when two or more descriptions are involved and provide a more reasonable similarity rank result. Our study shows that integrated VS based on multiple data fusion can achieve a remarkable better performance compared to that from individual ones and

  10. Sparse structure regularized ranking

    KAUST Repository

    Wang, Jim Jing-Yan

    2014-04-17

    Learning ranking scores is critical for the multimedia database retrieval problem. In this paper, we propose a novel ranking score learning algorithm by exploring the sparse structure and using it to regularize ranking scores. To explore the sparse structure, we assume that each multimedia object could be represented as a sparse linear combination of all other objects, and combination coefficients are regarded as a similarity measure between objects and used to regularize their ranking scores. Moreover, we propose to learn the sparse combination coefficients and the ranking scores simultaneously. A unified objective function is constructed with regard to both the combination coefficients and the ranking scores, and is optimized by an iterative algorithm. Experiments on two multimedia database retrieval data sets demonstrate the significant improvements of the propose algorithm over state-of-the-art ranking score learning algorithms.

  11. Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches.

    Science.gov (United States)

    Sabatino, Manuela; Rotili, Dante; Patsilinakos, Alexandros; Forgione, Mariantonietta; Tomaselli, Daniela; Alby, Fréderic; Arimondo, Paola B; Mai, Antonello; Ragno, Rino

    2018-03-01

    Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis. Although numerous DOT1L inhibitors have been several structural data published no pronounced computational efforts have been yet reported. In these studies a first tentative of multi-stage and LB/SB combined approach is reported in order to maximize the use of available data. Using co-crystallized ligand/DOT1L complexes, predictive 3-D QSAR and COMBINE models were built through a python implementation of previously reported methodologies. The models, validated by either modeled or experimental external test sets, proved to have good predictive abilities. The application of these models to an internal library led to the selection of two unreported compounds that were found able to inhibit DOT1L at micromolar level. To the best of our knowledge this is the first report of quantitative LB and SB DOT1L inhibitors models and their application to disclose new potential epigenetic modulators.

  12. Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches

    Science.gov (United States)

    Sabatino, Manuela; Rotili, Dante; Patsilinakos, Alexandros; Forgione, Mariantonietta; Tomaselli, Daniela; Alby, Fréderic; Arimondo, Paola B.; Mai, Antonello; Ragno, Rino

    2018-03-01

    Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis. Although numerous DOT1L inhibitors have been several structural data published no pronounced computational efforts have been yet reported. In these studies a first tentative of multi-stage and LB/SB combined approach is reported in order to maximize the use of available data. Using co-crystallized ligand/DOT1L complexes, predictive 3-D QSAR and COMBINE models were built through a python implementation of previously reported methodologies. The models, validated by either modeled or experimental external test sets, proved to have good predictive abilities. The application of these models to an internal library led to the selection of two unreported compounds that were found able to inhibit DOT1L at micromolar level. To the best of our knowledge this is the first report of quantitative LB and SB DOT1L inhibitors models and their application to disclose new potential epigenetic modulators.

  13. Ligand efficiency based approach for efficient virtual screening of compound libraries.

    Science.gov (United States)

    Ke, Yi-Yu; Coumar, Mohane Selvaraj; Shiao, Hui-Yi; Wang, Wen-Chieh; Chen, Chieh-Wen; Song, Jen-Shin; Chen, Chun-Hwa; Lin, Wen-Hsing; Wu, Szu-Huei; Hsu, John T A; Chang, Chung-Ming; Hsieh, Hsing-Pang

    2014-08-18

    Here we report for the first time the use of fit quality (FQ), a ligand efficiency (LE) based measure for virtual screening (VS) of compound libraries. The LE based VS protocol was used to screen an in-house database of 125,000 compounds to identify aurora kinase A inhibitors. First, 20 known aurora kinase inhibitors were docked to aurora kinase A crystal structure (PDB ID: 2W1C); and the conformations of docked ligand were used to create a pharmacophore (PH) model. The PH model was used to screen the database compounds, and rank (PH rank) them based on the predicted IC50 values. Next, LE_Scale, a weight-dependant LE function, was derived from 294 known aurora kinase inhibitors. Using the fit quality (FQ = LE/LE_Scale) score derived from the LE_Scale function, the database compounds were reranked (PH_FQ rank) and the top 151 (0.12% of database) compounds were assessed for aurora kinase A inhibition biochemically. This VS protocol led to the identification of 7 novel hits, with compound 5 showing aurora kinase A IC50 = 1.29 μM. Furthermore, testing of 5 against a panel of 31 kinase reveals that it is selective toward aurora kinase A & B, with <50% inhibition for other kinases at 10 μM concentrations and is a suitable candidate for further development. Incorporation of FQ score in the VS protocol not only helped identify a novel aurora kinase inhibitor, 5, but also increased the hit rate of the VS protocol by improving the enrichment factor (EF) for FQ based screening (EF = 828), compared to PH based screening (EF = 237) alone. The LE based VS protocol disclosed here could be applied to other targets for hit identification in an efficient manner. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting β(2-adrenoceptor [corrected] agonist and glucocorticoid receptor ligands.

    Directory of Open Access Journals (Sweden)

    Christopher F Rider

    Full Text Available Acting on the glucocorticoid receptor (NR3C1, glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2 × glucocorticoid response element (GRE reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-α (TNF or interleukin-1β inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3

  15. Discovery of novel benzopyranyl tetracycles that act as inhibitors of osteoclastogenesis induced by receptor activator of NF-κB ligand.

    Science.gov (United States)

    Zhu, Mingyan; Kim, Myung Hee; Lee, Sanghee; Bae, Su Jung; Kim, Seong Hwan; Park, Seung Bum

    2010-12-23

    A novel benzopyran-fused molecular framework 7ai was discovered as a specific inhibitor of RANKL-induced osteoclastogenesis using a cell-based TRAP activity assay from drug-like small-molecule libraries constructed by diversity-oriented synthesis. Its inhibitory activity was confirmed by in vitro evaluations including specific inhibition of RANKL-induced ERK phosphorylation and NF-κB transcriptional activation. 7ai can serve as a specific small-molecule modulator for mechanistic studies of RANKL-induced osteoclast differentiation as well as a potential lead for the development of antiresorptive drugs.

  16. Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.

    Science.gov (United States)

    Duffy, Bryan C; Liu, Shuang; Martin, Gregory S; Wang, Ruifang; Hsia, Ming Min; Zhao, He; Guo, Cheng; Ellis, Michael; Quinn, John F; Kharenko, Olesya A; Norek, Karen; Gesner, Emily M; Young, Peter R; McLure, Kevin G; Wagner, Gregory S; Lakshminarasimhan, Damodharan; White, Andre; Suto, Robert K; Hansen, Henrik C; Kitchen, Douglas B

    2015-07-15

    Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low μM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1). Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Chemical Synthesis and Evaluation of a Disialic Acid-Containing Dextran Polymer as an Inhibitor for the Interaction between Siglec 7 and Its Ligand.

    Science.gov (United States)

    Yamaguchi, Sho; Yoshimura, Atsushi; Yasuda, Yu; Mori, Airi; Tanaka, Hiroshi; Takahashi, Takashi; Kitajima, Ken; Sato, Chihiro

    2017-07-04

    A new sialic acid (Sia)-containing glycopolymer-a fluorescent probe with high-density disialic acid (diSia) on the surface of polysaccharide dextran (diSia-Dex)-was synthesized as a key molecule to regulate the Sia recognition lectins, Siglecs, that are involved in the immune system. According to our original methods, diSia was synthesized by α-selective sialylation, and a dextran template possessing terminal acetylenes and amino groups was prepared. A diSia and a fluorescent molecule were subsequently introduced to surface-modified dextran by Hüisgen reaction and amidation, respectively. The modulatory activity of Siglec7 was evaluated by using synthetic probes. DiSia-Dex showed high binding avidity toward Siglec7, with a K D value of 5.87×10 -10  m, and a high inhibitory activity for the interaction between Siglec7 and a ligand (GD3), with a IC 50 value of 1.0 nm. Notably, diSia-Dex was able to release Siglec7 from the pre-existing Siglec7-GD3 complex, possibly due to its unique properties of a slow dissociation rate and a high association rate. Together, these data show that diSia-Dex can be widely applicable as a modulator of Siglec7 functions. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Selective Inhibitors of Kv11.1 Regulate IL-6 Expression by Macrophages in Response to TLR/IL-1R Ligands

    Directory of Open Access Journals (Sweden)

    Cheryl Hunter

    2010-01-01

    Full Text Available The mechanism by which the platelet-endothelial cell adhesion molecule PECAM-1 regulates leukodiapedesis, vascular endothelial integrity, and proinflammatory cytokine expression in vivo is not known. We recently identified PECAM-1 as a negative regulator of Kv11.1, a specific voltage-gated potassium channel that functioned in human macrophages to reset a resting membrane potential following depolarization. We demonstrate here that dofetilide (DOF, a selective inhibitor of the Kv11.1 current, had a profound inhibitory effect on neutrophil recruitment in mice following TLR/IL-1R–elicited peritonitis or intrascrotal injection of IL-1β, but had no effect on responses seen with TNFα. Furthermore, inhibitors of Kv11.1 (DOF, E4031, and astemizole, but not Kv1.3 (margatoxin, suppressed the expression of IL-6 and MCP-1 cytokines by murine resident peritoneal macrophages, while again having no effect on TNFα. In contrast, IL-6 expression by peritoneal mesothelial cells was unaffected. Using murine P388 cells, which lack endogenous C/EBPβexpression and are unresponsive to LPS for the expression of both IL-6 and MCP-1, we observed that DOF inhibited LPS-induced expression of IL-6 mRNA following ectopic expression of wild-type C/EBPβ, but not a serine-64 point mutant. Finally, DOF inhibited the constitutive activation of cdk2 in murine peritoneal macrophages; cdk2 is known to phosphorylate C/EBPβ at serine-64. Taken together, our results implicate a potential role for Kv11.1 in regulating cdk2 and C/EBPβ activity, where robust transactivation of both IL-6 and MCP-1 transcription is known to be dependent on serine-64 of C/EBPβ. Our data might also explain the altered phenotypes displayed by PECAM-1 knockout mice in several disease models.

  19. How to Rank Journals.

    Science.gov (United States)

    Bradshaw, Corey J A; Brook, Barry W

    2016-01-01

    There are now many methods available to assess the relative citation performance of peer-reviewed journals. Regardless of their individual faults and advantages, citation-based metrics are used by researchers to maximize the citation potential of their articles, and by employers to rank academic track records. The absolute value of any particular index is arguably meaningless unless compared to other journals, and different metrics result in divergent rankings. To provide a simple yet more objective way to rank journals within and among disciplines, we developed a κ-resampled composite journal rank incorporating five popular citation indices: Impact Factor, Immediacy Index, Source-Normalized Impact Per Paper, SCImago Journal Rank and Google 5-year h-index; this approach provides an index of relative rank uncertainty. We applied the approach to six sample sets of scientific journals from Ecology (n = 100 journals), Medicine (n = 100), Multidisciplinary (n = 50); Ecology + Multidisciplinary (n = 25), Obstetrics & Gynaecology (n = 25) and Marine Biology & Fisheries (n = 25). We then cross-compared the κ-resampled ranking for the Ecology + Multidisciplinary journal set to the results of a survey of 188 publishing ecologists who were asked to rank the same journals, and found a 0.68-0.84 Spearman's ρ correlation between the two rankings datasets. Our composite index approach therefore approximates relative journal reputation, at least for that discipline. Agglomerative and divisive clustering and multi-dimensional scaling techniques applied to the Ecology + Multidisciplinary journal set identified specific clusters of similarly ranked journals, with only Nature & Science separating out from the others. When comparing a selection of journals within or among disciplines, we recommend collecting multiple citation-based metrics for a sample of relevant and realistic journals to calculate the composite rankings and their relative uncertainty windows.

  20. On Page Rank

    NARCIS (Netherlands)

    Hoede, C.

    In this paper the concept of page rank for the world wide web is discussed. The possibility of describing the distribution of page rank by an exponential law is considered. It is shown that the concept is essentially equal to that of status score, a centrality measure discussed already in 1953 by

  1. On Rank and Nullity

    Science.gov (United States)

    Dobbs, David E.

    2012-01-01

    This note explains how Emil Artin's proof that row rank equals column rank for a matrix with entries in a field leads naturally to the formula for the nullity of a matrix and also to an algorithm for solving any system of linear equations in any number of variables. This material could be used in any course on matrix theory or linear algebra.

  2. Hitting the Rankings Jackpot

    Science.gov (United States)

    Chapman, David W.

    2008-01-01

    Recently, Samford University was ranked 27th in the nation in a report released by "Forbes" magazine. In this article, the author relates how the people working at Samford University were surprised at its ranking. Although Samford is the largest privately institution in Alabama, its distinguished academic achievements aren't even…

  3. Safety and efficacy of the CD95-ligand inhibitor asunercept in transfusion-dependent patients with low and intermediate risk MDS.

    Science.gov (United States)

    Boch, Tobias; Luft, Thomas; Metzgeroth, Georgia; Mossner, Maximilian; Jann, Johann-Christoph; Nowak, Daniel; Meir, Franziska La; Schumann, Christiane; Klemmer, Jennifer; Brendel, Susanne; Fricke, Harald; Kunz, Claudia; Weiß, Christel; Hofmann, Wolf-Karsten; Nolte, Florian

    2018-05-01

    In low risk MDS, increased apoptosis of erythroid progenitors mediated via CD95 (Fas) activation has been described to result in peripheral cytopenia. Blockade of the CD95 system can improve erythropoiesis in MDS. Asunercept (APG101) is a fusion protein consisting of the extracellular domain of human CD95 and the Fc domain of human IgG1 blocking the interaction between CD95 and its ligand. Here we report on results from a phase I study in 20 transfusion-dependent low and intermediate risk MDS patients treated with intravenous asunercept (EudraCT 2012-003027-37). Primary objectives were safety and tolerability as well as pharmacodynamic effects. Secondary objectives were hematologic improvement, incidence and time to leukemic progression as well as overall survival. Frequency and severity of adverse events were in range of what could be expected in a patient cohort comprising of elderly MDS patients. Two patients experienced a serious adverse event with a suspected relationship to asunercept. The incidence of disease progression was low. In the 20 patients a decrease of the transfusion need from a mean of 10,8 (±5,1) pRBCs during the 12 weeks treatment phase to a mean of 10,0 (±4,2) pRBCs at the end of the study was observed. In conclusion, asunercept was well tolerated and showed efficacy in transfusion-dependent low and intermediate risk MDS patients. Further clinical investigation is warranted, particularly in combination with erythropoiesis stimulating agents (ESAs). Copyright © 2018. Published by Elsevier Ltd.

  4. Safety and Efficacy of Durvalumab (MEDI4736), an Anti–Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer

    Science.gov (United States)

    Massard, Christophe; Gordon, Michael S.; Sharma, Sunil; Rafii, Saeed; Wainberg, Zev A.; Luke, Jason; Curiel, Tyler J.; Colon-Otero, Gerardo; Hamid, Omid; Sanborn, Rachel E.; O’Donnell, Peter H.; Drakaki, Alexandra; Tan, Winston; Kurland, John F.; Rebelatto, Marlon C.; Jin, Xiaoping; Blake-Haskins, John A.; Gupta, Ashok

    2016-01-01

    Purpose To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). Methods A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1–positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. Results A total of 61 patients (40 PD-L1–positive, 21 PD-L1–negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). Conclusion Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1–positive patients with UBC, many of whom were heavily pretreated. PMID:27269937

  5. Rational discovery of dengue type 2 non-competitive inhibitors.

    Science.gov (United States)

    Heh, Choon H; Othman, Rozana; Buckle, Michael J C; Sharifuddin, Yusrizam; Yusof, Rohana; Rahman, Noorsaadah A

    2013-07-01

    Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target, and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13 341 small compounds, with the backbone structures of chalcone, flavanone, and flavone, available in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top-ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared with the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents. © 2013 John Wiley & Sons A/S.

  6. Ligand identification using electron-density map correlations

    International Nuclear Information System (INIS)

    Terwilliger, Thomas C.; Adams, Paul D.; Moriarty, Nigel W.; Cohn, Judith D.

    2007-01-01

    An automated ligand-fitting procedure is applied to (F o − F c )exp(iϕ c ) difference density for 200 commonly found ligands from macromolecular structures in the Protein Data Bank to identify ligands from density maps. A procedure for the identification of ligands bound in crystal structures of macromolecules is described. Two characteristics of the density corresponding to a ligand are used in the identification procedure. One is the correlation of the ligand density with each of a set of test ligands after optimization of the fit of that ligand to the density. The other is the correlation of a fingerprint of the density with the fingerprint of model density for each possible ligand. The fingerprints consist of an ordered list of correlations of each the test ligands with the density. The two characteristics are scored using a Z-score approach in which the correlations are normalized to the mean and standard deviation of correlations found for a variety of mismatched ligand-density pairs, so that the Z scores are related to the probability of observing a particular value of the correlation by chance. The procedure was tested with a set of 200 of the most commonly found ligands in the Protein Data Bank, collectively representing 57% of all ligands in the Protein Data Bank. Using a combination of these two characteristics of ligand density, ranked lists of ligand identifications were made for representative (F o − F c )exp(iϕ c ) difference density from entries in the Protein Data Bank. In 48% of the 200 cases, the correct ligand was at the top of the ranked list of ligands. This approach may be useful in identification of unknown ligands in new macromolecular structures as well as in the identification of which ligands in a mixture have bound to a macromolecule

  7. Re-evolution of the 2-phenylquinolines: ligand-based design, synthesis, and biological evaluation of a potent new class of Staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance.

    Science.gov (United States)

    Sabatini, Stefano; Gosetto, Francesca; Iraci, Nunzio; Barreca, Maria Letizia; Massari, Serena; Sancineto, Luca; Manfroni, Giuseppe; Tabarrini, Oriana; Dimovska, Mirjana; Kaatz, Glenn W; Cecchetti, Violetta

    2013-06-27

    Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.

  8. Parallel screening of drug-like natural compounds using Caco-2 cell permeability QSAR model with applicability domain, lipophilic ligand efficiency index and shape property: A case study of HIV-1 reverse transcriptase inhibitors

    Science.gov (United States)

    Patel, Rikin D.; Kumar, Sivakumar Prasanth; Patel, Chirag N.; Shankar, Shetty Shilpa; Pandya, Himanshu A.; Solanki, Hitesh A.

    2017-10-01

    The traditional drug design strategy centrally focuses on optimizing binding affinity with the receptor target and evaluates pharmacokinetic properties at a later stage which causes high rate of attrition in clinical trials. Alternatively, parallel screening allows evaluation of these properties and affinity simultaneously. In a case study to identify leads from natural compounds with experimental HIV-1 reverse transcriptase (RT) inhibition, we integrated various computational approaches including Caco-2 cell permeability QSAR model with applicability domain (AD) to recognize drug-like natural compounds, molecular docking to study HIV-1 RT interactions and shape similarity analysis with known crystal inhibitors having characteristic butterfly-like model. Further, the lipophilic properties of the compounds refined from the process with best scores were examined using lipophilic ligand efficiency (LLE) index. Seven natural compound hits viz. baicalien, (+)-calanolide A, mniopetal F, fagaronine chloride, 3,5,8-trihydroxy-4-quinolone methyl ether derivative, nitidine chloride and palmatine, were prioritized based on LLE score which demonstrated Caco-2 well absorption labeling, encompassment in AD structural coverage, better receptor affinity, shape adaptation and permissible AlogP value. We showed that this integrative approach is successful in lead exploration of natural compounds targeted against HIV-1 RT enzyme.

  9. Recurrent fuzzy ranking methods

    Science.gov (United States)

    Hajjari, Tayebeh

    2012-11-01

    With the increasing development of fuzzy set theory in various scientific fields and the need to compare fuzzy numbers in different areas. Therefore, Ranking of fuzzy numbers plays a very important role in linguistic decision-making, engineering, business and some other fuzzy application systems. Several strategies have been proposed for ranking of fuzzy numbers. Each of these techniques has been shown to produce non-intuitive results in certain case. In this paper, we reviewed some recent ranking methods, which will be useful for the researchers who are interested in this area.

  10. RANK und RANKL - Vom Knochen zum Mammakarzinom

    Directory of Open Access Journals (Sweden)

    Sigl V

    2012-01-01

    Full Text Available RANK („Receptor Activator of NF-κB“ und sein Ligand RANKL sind Schlüsselmoleküle im Knochenmetabolismus und spielen eine essenzielle Rolle in der Entstehung von pathologischen Knochenveränderungen. Die Deregulation des RANK/RANKL-Systems ist zum Beispiel ein Hauptgrund für das Auftreten von postmenopausaler Osteoporose bei Frauen. Eine weitere wesentliche Funktion von RANK und RANKL liegt in der Entwicklung von milchsekretierenden Drüsen während der Schwangerschaft. Dabei regulieren Sexualhormone, wie zum Beispiel Progesteron, die Expression von RANKL und induzieren dadurch die Proliferation von epithelialen Zellen der Brust. Seit Längerem war schon bekannt, dass RANK und RANKL in der Metastasenbildung von Brustkrebszellen im Knochengewebe beteiligt sind. Wir konnten nun das RANK/RANKLSystem auch als essenziellen Mechanismus in der Entstehung von hormonellem Brustkrebs identifizieren. In diesem Beitrag werden wir daher den neuesten Erkenntnissen besondere Aufmerksamkeit schenken und diese kritisch in Bezug auf Brustkrebsentwicklung betrachten.

  11. Ranking as parameter estimation

    Czech Academy of Sciences Publication Activity Database

    Kárný, Miroslav; Guy, Tatiana Valentine

    2009-01-01

    Roč. 4, č. 2 (2009), s. 142-158 ISSN 1745-7645 R&D Projects: GA MŠk 2C06001; GA AV ČR 1ET100750401; GA MŠk 1M0572 Institutional research plan: CEZ:AV0Z10750506 Keywords : ranking * Bayesian estimation * negotiation * modelling Subject RIV: BB - Applied Statistics, Operational Research http://library.utia.cas.cz/separaty/2009/AS/karny- ranking as parameter estimation.pdf

  12. Hierarchical partial order ranking

    International Nuclear Information System (INIS)

    Carlsen, Lars

    2008-01-01

    Assessing the potential impact on environmental and human health from the production and use of chemicals or from polluted sites involves a multi-criteria evaluation scheme. A priori several parameters are to address, e.g., production tonnage, specific release scenarios, geographical and site-specific factors in addition to various substance dependent parameters. Further socio-economic factors may be taken into consideration. The number of parameters to be included may well appear to be prohibitive for developing a sensible model. The study introduces hierarchical partial order ranking (HPOR) that remedies this problem. By HPOR the original parameters are initially grouped based on their mutual connection and a set of meta-descriptors is derived representing the ranking corresponding to the single groups of descriptors, respectively. A second partial order ranking is carried out based on the meta-descriptors, the final ranking being disclosed though average ranks. An illustrative example on the prioritisation of polluted sites is given. - Hierarchical partial order ranking of polluted sites has been developed for prioritization based on a large number of parameters

  13. Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1: An in Silico Approach

    Directory of Open Access Journals (Sweden)

    Mohamed A. Abdallah Elbadawi

    2015-02-01

    Full Text Available A new Plasmodium falciparum histone deacetylase1 (PfHDAC1 homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1.

  14. Inhibition of osteoclastogenesis by RNA interference targeting RANK

    Directory of Open Access Journals (Sweden)

    Ma Ruofan

    2012-08-01

    Full Text Available Abstract Background Osteoclasts and osteoblasts regulate bone resorption and formation to allow bone remodeling and homeostasis. The balance between bone resorption and formation is disturbed by abnormal recruitment of osteoclasts. Osteoclast differentiation is dependent on the receptor activator of nuclear factor NF-kappa B (RANK ligand (RANKL as well as the macrophage colony-stimulating factor (M-CSF. The RANKL/RANK system and RANK signaling induce osteoclast formation mediated by various cytokines. The RANK/RANKL pathway has been primarily implicated in metabolic, degenerative and neoplastic bone disorders or osteolysis. The central role of RANK/RANKL interaction in osteoclastogenesis makes RANK an attractive target for potential therapies in treatment of osteolysis. The purpose of this study was to assess the effect of inhibition of RANK expression in mouse bone marrow macrophages on osteoclast differentiation and bone resorption. Methods Three pairs of short hairpin RNAs (shRNA targeting RANK were designed and synthesized. The optimal shRNA was selected among three pairs of shRNAs by RANK expression analyzed by Western blot and Real-time PCR. We investigated suppression of osteoclastogenesis of mouse bone marrow macrophages (BMMs using the optimal shRNA by targeting RANK. Results Among the three shRANKs examined, shRANK-3 significantly suppressed [88.3%] the RANK expression (p Conclusions These findings suggest that retrovirus-mediated shRNA targeting RANK inhibits osteoclast differentiation and osteolysis. It may appear an attractive target for preventing osteolysis in humans with a potential clinical application.

  15. Multiplex PageRank.

    Science.gov (United States)

    Halu, Arda; Mondragón, Raúl J; Panzarasa, Pietro; Bianconi, Ginestra

    2013-01-01

    Many complex systems can be described as multiplex networks in which the same nodes can interact with one another in different layers, thus forming a set of interacting and co-evolving networks. Examples of such multiplex systems are social networks where people are involved in different types of relationships and interact through various forms of communication media. The ranking of nodes in multiplex networks is one of the most pressing and challenging tasks that research on complex networks is currently facing. When pairs of nodes can be connected through multiple links and in multiple layers, the ranking of nodes should necessarily reflect the importance of nodes in one layer as well as their importance in other interdependent layers. In this paper, we draw on the idea of biased random walks to define the Multiplex PageRank centrality measure in which the effects of the interplay between networks on the centrality of nodes are directly taken into account. In particular, depending on the intensity of the interaction between layers, we define the Additive, Multiplicative, Combined, and Neutral versions of Multiplex PageRank, and show how each version reflects the extent to which the importance of a node in one layer affects the importance the node can gain in another layer. We discuss these measures and apply them to an online multiplex social network. Findings indicate that taking the multiplex nature of the network into account helps uncover the emergence of rankings of nodes that differ from the rankings obtained from one single layer. Results provide support in favor of the salience of multiplex centrality measures, like Multiplex PageRank, for assessing the prominence of nodes embedded in multiple interacting networks, and for shedding a new light on structural properties that would otherwise remain undetected if each of the interacting networks were analyzed in isolation.

  16. Multiplex PageRank.

    Directory of Open Access Journals (Sweden)

    Arda Halu

    Full Text Available Many complex systems can be described as multiplex networks in which the same nodes can interact with one another in different layers, thus forming a set of interacting and co-evolving networks. Examples of such multiplex systems are social networks where people are involved in different types of relationships and interact through various forms of communication media. The ranking of nodes in multiplex networks is one of the most pressing and challenging tasks that research on complex networks is currently facing. When pairs of nodes can be connected through multiple links and in multiple layers, the ranking of nodes should necessarily reflect the importance of nodes in one layer as well as their importance in other interdependent layers. In this paper, we draw on the idea of biased random walks to define the Multiplex PageRank centrality measure in which the effects of the interplay between networks on the centrality of nodes are directly taken into account. In particular, depending on the intensity of the interaction between layers, we define the Additive, Multiplicative, Combined, and Neutral versions of Multiplex PageRank, and show how each version reflects the extent to which the importance of a node in one layer affects the importance the node can gain in another layer. We discuss these measures and apply them to an online multiplex social network. Findings indicate that taking the multiplex nature of the network into account helps uncover the emergence of rankings of nodes that differ from the rankings obtained from one single layer. Results provide support in favor of the salience of multiplex centrality measures, like Multiplex PageRank, for assessing the prominence of nodes embedded in multiple interacting networks, and for shedding a new light on structural properties that would otherwise remain undetected if each of the interacting networks were analyzed in isolation.

  17. Groundwater contaminant plume ranking

    International Nuclear Information System (INIS)

    1988-08-01

    Containment plumes at Uranium Mill Tailings Remedial Action (UMTRA) Project sites were ranked to assist in Subpart B (i.e., restoration requirements of 40 CFR Part 192) compliance strategies for each site, to prioritize aquifer restoration, and to budget future requests and allocations. The rankings roughly estimate hazards to the environment and human health, and thus assist in determining for which sites cleanup, if appropriate, will provide the greatest benefits for funds available. The rankings are based on the scores that were obtained using the US Department of Energy's (DOE) Modified Hazard Ranking System (MHRS). The MHRS and HRS consider and score three hazard modes for a site: migration, fire and explosion, and direct contact. The migration hazard mode score reflects the potential for harm to humans or the environment from migration of a hazardous substance off a site by groundwater, surface water, and air; it is a composite of separate scores for each of these routes. For ranking the containment plumes at UMTRA Project sites, it was assumed that each site had been remediated in compliance with the EPA standards and that relict contaminant plumes were present. Therefore, only the groundwater route was scored, and the surface water and air routes were not considered. Section 2.0 of this document describes the assumptions and procedures used to score the groundwater route, and Section 3.0 provides the resulting scores for each site. 40 tabs

  18. Ranking economic history journals

    DEFF Research Database (Denmark)

    Di Vaio, Gianfranco; Weisdorf, Jacob Louis

    2010-01-01

    This study ranks-for the first time-12 international academic journals that have economic history as their main topic. The ranking is based on data collected for the year 2007. Journals are ranked using standard citation analysis where we adjust for age, size and self-citation of journals. We also...... compare the leading economic history journals with the leading journals in economics in order to measure the influence on economics of economic history, and vice versa. With a few exceptions, our results confirm the general idea about what economic history journals are the most influential for economic...... history, and that, although economic history is quite independent from economics as a whole, knowledge exchange between the two fields is indeed going on....

  19. Ranking Economic History Journals

    DEFF Research Database (Denmark)

    Di Vaio, Gianfranco; Weisdorf, Jacob Louis

    This study ranks - for the first time - 12 international academic journals that have economic history as their main topic. The ranking is based on data collected for the year 2007. Journals are ranked using standard citation analysis where we adjust for age, size and self-citation of journals. We...... also compare the leading economic history journals with the leading journals in economics in order to measure the influence on economics of economic history, and vice versa. With a few exceptions, our results confirm the general idea about what economic history journals are the most influential...... for economic history, and that, although economic history is quite independent from economics as a whole, knowledge exchange between the two fields is indeed going on....

  20. Dynamic Matrix Rank

    DEFF Research Database (Denmark)

    Frandsen, Gudmund Skovbjerg; Frandsen, Peter Frands

    2009-01-01

    We consider maintaining information about the rank of a matrix under changes of the entries. For n×n matrices, we show an upper bound of O(n1.575) arithmetic operations and a lower bound of Ω(n) arithmetic operations per element change. The upper bound is valid when changing up to O(n0.575) entries...... in a single column of the matrix. We also give an algorithm that maintains the rank using O(n2) arithmetic operations per rank one update. These bounds appear to be the first nontrivial bounds for the problem. The upper bounds are valid for arbitrary fields, whereas the lower bound is valid for algebraically...... closed fields. The upper bound for element updates uses fast rectangular matrix multiplication, and the lower bound involves further development of an earlier technique for proving lower bounds for dynamic computation of rational functions....

  1. Diversifying customer review rankings.

    Science.gov (United States)

    Krestel, Ralf; Dokoohaki, Nima

    2015-06-01

    E-commerce Web sites owe much of their popularity to consumer reviews accompanying product descriptions. On-line customers spend hours and hours going through heaps of textual reviews to decide which products to buy. At the same time, each popular product has thousands of user-generated reviews, making it impossible for a buyer to read everything. Current approaches to display reviews to users or recommend an individual review for a product are based on the recency or helpfulness of each review. In this paper, we present a framework to rank product reviews by optimizing the coverage of the ranking with respect to sentiment or aspects, or by summarizing all reviews with the top-K reviews in the ranking. To accomplish this, we make use of the assigned star rating for a product as an indicator for a review's sentiment polarity and compare bag-of-words (language model) with topic models (latent Dirichlet allocation) as a mean to represent aspects. Our evaluation on manually annotated review data from a commercial review Web site demonstrates the effectiveness of our approach, outperforming plain recency ranking by 30% and obtaining best results by combining language and topic model representations. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. College Rankings. ERIC Digest.

    Science.gov (United States)

    Holub, Tamara

    The popularity of college ranking surveys published by "U.S. News and World Report" and other magazines is indisputable, but the methodologies used to measure the quality of higher education institutions have come under fire by scholars and college officials. Criticisms have focused on methodological flaws, such as failure to consider…

  3. OutRank

    DEFF Research Database (Denmark)

    Müller, Emmanuel; Assent, Ira; Steinhausen, Uwe

    2008-01-01

    Outlier detection is an important data mining task for consistency checks, fraud detection, etc. Binary decision making on whether or not an object is an outlier is not appropriate in many applications and moreover hard to parametrize. Thus, recently, methods for outlier ranking have been proposed...

  4. Improving Ranking Using Quantum Probability

    OpenAIRE

    Melucci, Massimo

    2011-01-01

    The paper shows that ranking information units by quantum probability differs from ranking them by classical probability provided the same data used for parameter estimation. As probability of detection (also known as recall or power) and probability of false alarm (also known as fallout or size) measure the quality of ranking, we point out and show that ranking by quantum probability yields higher probability of detection than ranking by classical probability provided a given probability of ...

  5. 1991 Acceptance priority ranking

    International Nuclear Information System (INIS)

    1991-12-01

    The Standard Contract for Disposal of Spent Nuclear Fuel and/or High- Level Radioactive Waste (10 CFR Part 961) that the Department of Energy (DOE) has executed with the owners and generators of civilian spent nuclear fuel requires annual publication of the Acceptance Priority Ranking (APR). The 1991 APR details the order in which DOE will allocate Federal waste acceptance capacity. As required by the Standard Contract, the ranking is based on the age of permanently discharged spent nuclear fuel (SNF), with the owners of the oldest SNF, on an industry-wide basis, given the highest priority. the 1991 APR will be the basis for the annual allocation of waste acceptance capacity to the Purchasers in the 1991 Annual Capacity Report (ACR), to be issued later this year. This document is based on SNF discharges as of December 31, 1990, and reflects Purchaser comments and corrections, as appropriate, to the draft APR issued on May 15, 1991

  6. Ranking Baltic States Researchers

    Directory of Open Access Journals (Sweden)

    Gyula Mester

    2017-10-01

    Full Text Available In this article, using the h-index and the total number of citations, the best 10 Lithuanian, Latvian and Estonian researchers from several disciplines are ranked. The list may be formed based on the h-index and the total number of citations, given in Web of Science, Scopus, Publish or Perish Program and Google Scholar database. Data for the first 10 researchers are presented. Google Scholar is the most complete. Therefore, to define a single indicator, h-index calculated by Google Scholar may be a good and simple one. The author chooses the Google Scholar database as it is the broadest one.

  7. Fourth-rank cosmology

    International Nuclear Information System (INIS)

    Marrakchi, A.E.L.; Tapia, V.

    1992-05-01

    Some cosmological implications of the recently proposed fourth-rank theory of gravitation are studied. The model exhibits the possibility of being free from the horizon and flatness problems at the price of introducing a negative pressure. The field equations we obtain are compatible with k obs =0 and Ω obs t clas approx. 10 20 t Planck approx. 10 -23 s. When interpreted at the light of General Relativity the treatment is shown to be almost equivalent to that of the standard model of cosmology combined with the inflationary scenario. Hence, an interpretation of the negative pressure hypothesis is provided. (author). 8 refs

  8. University Rankings and Social Science

    OpenAIRE

    Marginson, S.

    2014-01-01

    University rankings widely affect the behaviours of prospective students and their families, university executive leaders, academic faculty, governments and investors in higher education. Yet the social science foundations of global rankings receive little scrutiny. Rankings that simply recycle reputation without any necessary connection to real outputs are of no common value. It is necessary that rankings be soundly based in scientific terms if a virtuous relationship between performance and...

  9. University Rankings and Social Science

    Science.gov (United States)

    Marginson, Simon

    2014-01-01

    University rankings widely affect the behaviours of prospective students and their families, university executive leaders, academic faculty, governments and investors in higher education. Yet the social science foundations of global rankings receive little scrutiny. Rankings that simply recycle reputation without any necessary connection to real…

  10. In silico modification of Zn2+ binding group of suberoylanilide hydroxamic acid (SAHA) by organoselenium compounds as Homo sapiens class II HDAC inhibitor of cervical cancer

    Science.gov (United States)

    Sumo Friend Tambunan, Usman; Bakri, Ridla; Aditya Parikesit, Arli; Ariyani, Titin; Dyah Puspitasari, Ratih; Kerami, Djati

    2016-02-01

    Cervical cancer is the most common cancer in women, and ranks seventh of all cancers worldwide, with 529000 cases in 2008 and more than 85% cases occur in developing countries. One way to treat this cancer is through the inhibition of HDAC enzymes which play a strategic role in the regulation of gene expression. Suberoyl Anilide Hydroxamic Acid (SAHA) or Vorinostat is a drug which commercially available to treat the cancer, but still has some side effects. This research present in silico SAHA modification in Zinc Binding Group (ZBG) by organoselenium compound to get ligands which less side effect. From molecular docking simulation, and interaction analysis, there are five best ligands, namely CC27, HA27, HB28, IB25, and KA7. These five ligands have better binding affinity than the standards, and also have interaction with Zn2+ cofactor of inhibited HDAC enzymes. This research is expected to produce more potent HDAC inhibitor as novel drug for cervical cancer treatment.

  11. DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations.

    Science.gov (United States)

    Chakraborty, Sandeep

    2014-01-01

    The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already 'plastic' binding site. Thus, DOCLASP presents a method for 'soft docking' ligands to proteins with low computational

  12. Programmed Death-Ligand 1 Immunohistochemistry Testing

    DEFF Research Database (Denmark)

    Büttner, Reinhard; Gosney, John R; Skov, Birgit Guldhammer

    2017-01-01

    Purpose Three programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of non-small-cell lung cancer (NSCLC). Treatment with pembrolizumab in NSCLC requires PD-L1 immunohistochemistry (IHC) testing. Nivolumab and atezolizumab are approved without PD-L1...

  13. Structure-based virtual screening of molecular libraries as cdk2 inhibitors

    International Nuclear Information System (INIS)

    Riaz, U.; Khaleeq, M.

    2011-01-01

    CDK2 inhibitor is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate CDK2 inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound with an IC50 value of 89 nM, representing 2-Amino-4,6-di-(4',6'-dibromophenyl)pyrimidine 1, is highly selective for CDK2 inhibitors. The docking structure of compound 1 with CDK2 inhibitor disclosed that the NH moiety and pyrimidine ring appeared to fit tightly into the hydrophobic pocket of CDK2 inhibitor. Additionally, the pyrimidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound can be an effective CDK2 inhibitor candidate for further lead optimization. (author)

  14. Fractional cointegration rank estimation

    DEFF Research Database (Denmark)

    Lasak, Katarzyna; Velasco, Carlos

    the parameters of the model under the null hypothesis of the cointegration rank r = 1, 2, ..., p-1. This step provides consistent estimates of the cointegration degree, the cointegration vectors, the speed of adjustment to the equilibrium parameters and the common trends. In the second step we carry out a sup......-likelihood ratio test of no-cointegration on the estimated p - r common trends that are not cointegrated under the null. The cointegration degree is re-estimated in the second step to allow for new cointegration relationships with different memory. We augment the error correction model in the second step...... to control for stochastic trend estimation effects from the first step. The critical values of the tests proposed depend only on the number of common trends under the null, p - r, and on the interval of the cointegration degrees b allowed, but not on the true cointegration degree b0. Hence, no additional...

  15. Rankings, creatividad y urbanismo

    Directory of Open Access Journals (Sweden)

    JOAQUÍN SABATÉ

    2008-08-01

    Full Text Available La competencia entre ciudades constituye uno de los factores impulsores de procesos de renovación urbana y los rankings han devenido instrumentos de medida de la calidad de las ciudades. Nos detendremos en el caso de un antiguo barrio industrial hoy en vías de transformación en distrito "creativo" por medio de una intervención urbanística de gran escala. Su análisis nos descubre tres claves críticas. En primer lugar, nos obliga a plantearnos la definición de innovación urbana y cómo se integran el pasado, la identidad y la memoria en la construcción del futuro. Nos lleva a comprender que la innovación y el conocimiento no se "dan" casualmente, sino que son el fruto de una larga y compleja red en la que participan saberes, espacios, actores e instituciones diversas en naturaleza, escala y magnitud. Por último nos obliga a reflexionar sobre el valor que se le otorga a lo local en los procesos de renovación urbana.Competition among cities constitutes one ofthe main factors o furban renewal, and rankings have become instruments to indícate cities quality. Studying the transformation of an old industrial quarter into a "creative district" by the means ofa large scale urban project we highlight three main conclusions. First, itasks us to reconsider the notion ofurban innovation and hoto past, identity and memory should intégrate the future development. Second, it shows that innovation and knowledge doesn't yield per chance, but are the result ofa large and complex grid of diverse knowledges, spaces, agents and institutions. Finally itforces us to reflect about the valué attributed to the "local" in urban renewalprocesses.

  16. Ranking nodes in growing networks: When PageRank fails.

    Science.gov (United States)

    Mariani, Manuel Sebastian; Medo, Matúš; Zhang, Yi-Cheng

    2015-11-10

    PageRank is arguably the most popular ranking algorithm which is being applied in real systems ranging from information to biological and infrastructure networks. Despite its outstanding popularity and broad use in different areas of science, the relation between the algorithm's efficacy and properties of the network on which it acts has not yet been fully understood. We study here PageRank's performance on a network model supported by real data, and show that realistic temporal effects make PageRank fail in individuating the most valuable nodes for a broad range of model parameters. Results on real data are in qualitative agreement with our model-based findings. This failure of PageRank reveals that the static approach to information filtering is inappropriate for a broad class of growing systems, and suggest that time-dependent algorithms that are based on the temporal linking patterns of these systems are needed to better rank the nodes.

  17. Neophilia Ranking of Scientific Journals.

    Science.gov (United States)

    Packalen, Mikko; Bhattacharya, Jay

    2017-01-01

    The ranking of scientific journals is important because of the signal it sends to scientists about what is considered most vital for scientific progress. Existing ranking systems focus on measuring the influence of a scientific paper (citations)-these rankings do not reward journals for publishing innovative work that builds on new ideas. We propose an alternative ranking based on the proclivity of journals to publish papers that build on new ideas, and we implement this ranking via a text-based analysis of all published biomedical papers dating back to 1946. In addition, we compare our neophilia ranking to citation-based (impact factor) rankings; this comparison shows that the two ranking approaches are distinct. Prior theoretical work suggests an active role for our neophilia index in science policy. Absent an explicit incentive to pursue novel science, scientists underinvest in innovative work because of a coordination problem: for work on a new idea to flourish, many scientists must decide to adopt it in their work. Rankings that are based purely on influence thus do not provide sufficient incentives for publishing innovative work. By contrast, adoption of the neophilia index as part of journal-ranking procedures by funding agencies and university administrators would provide an explicit incentive for journals to publish innovative work and thus help solve the coordination problem by increasing scientists' incentives to pursue innovative work.

  18. Towards ligand docking including explicit interface water molecules.

    Directory of Open Access Journals (Sweden)

    Gordon Lemmon

    Full Text Available Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta's ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9:1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.

  19. Low-rank coal research

    Energy Technology Data Exchange (ETDEWEB)

    Weber, G. F.; Laudal, D. L.

    1989-01-01

    This work is a compilation of reports on ongoing research at the University of North Dakota. Topics include: Control Technology and Coal Preparation Research (SO{sub x}/NO{sub x} control, waste management), Advanced Research and Technology Development (turbine combustion phenomena, combustion inorganic transformation, coal/char reactivity, liquefaction reactivity of low-rank coals, gasification ash and slag characterization, fine particulate emissions), Combustion Research (fluidized bed combustion, beneficiation of low-rank coals, combustion characterization of low-rank coal fuels, diesel utilization of low-rank coals), Liquefaction Research (low-rank coal direct liquefaction), and Gasification Research (hydrogen production from low-rank coals, advanced wastewater treatment, mild gasification, color and residual COD removal from Synfuel wastewaters, Great Plains Gasification Plant, gasifier optimization).

  20. Ranking Specific Sets of Objects.

    Science.gov (United States)

    Maly, Jan; Woltran, Stefan

    2017-01-01

    Ranking sets of objects based on an order between the single elements has been thoroughly studied in the literature. In particular, it has been shown that it is in general impossible to find a total ranking - jointly satisfying properties as dominance and independence - on the whole power set of objects. However, in many applications certain elements from the entire power set might not be required and can be neglected in the ranking process. For instance, certain sets might be ruled out due to hard constraints or are not satisfying some background theory. In this paper, we treat the computational problem whether an order on a given subset of the power set of elements satisfying different variants of dominance and independence can be found, given a ranking on the elements. We show that this problem is tractable for partial rankings and NP-complete for total rankings.

  1. Wikipedia ranking of world universities

    Science.gov (United States)

    Lages, José; Patt, Antoine; Shepelyansky, Dima L.

    2016-03-01

    We use the directed networks between articles of 24 Wikipedia language editions for producing the wikipedia ranking of world Universities (WRWU) using PageRank, 2DRank and CheiRank algorithms. This approach allows to incorporate various cultural views on world universities using the mathematical statistical analysis independent of cultural preferences. The Wikipedia ranking of top 100 universities provides about 60% overlap with the Shanghai university ranking demonstrating the reliable features of this approach. At the same time WRWU incorporates all knowledge accumulated at 24 Wikipedia editions giving stronger highlights for historically important universities leading to a different estimation of efficiency of world countries in university education. The historical development of university ranking is analyzed during ten centuries of their history.

  2. Statistical methods for ranking data

    CERN Document Server

    Alvo, Mayer

    2014-01-01

    This book introduces advanced undergraduate, graduate students and practitioners to statistical methods for ranking data. An important aspect of nonparametric statistics is oriented towards the use of ranking data. Rank correlation is defined through the notion of distance functions and the notion of compatibility is introduced to deal with incomplete data. Ranking data are also modeled using a variety of modern tools such as CART, MCMC, EM algorithm and factor analysis. This book deals with statistical methods used for analyzing such data and provides a novel and unifying approach for hypotheses testing. The techniques described in the book are illustrated with examples and the statistical software is provided on the authors’ website.

  3. Ranking nodes in growing networks: When PageRank fails

    Science.gov (United States)

    Mariani, Manuel Sebastian; Medo, Matúš; Zhang, Yi-Cheng

    2015-11-01

    PageRank is arguably the most popular ranking algorithm which is being applied in real systems ranging from information to biological and infrastructure networks. Despite its outstanding popularity and broad use in different areas of science, the relation between the algorithm’s efficacy and properties of the network on which it acts has not yet been fully understood. We study here PageRank’s performance on a network model supported by real data, and show that realistic temporal effects make PageRank fail in individuating the most valuable nodes for a broad range of model parameters. Results on real data are in qualitative agreement with our model-based findings. This failure of PageRank reveals that the static approach to information filtering is inappropriate for a broad class of growing systems, and suggest that time-dependent algorithms that are based on the temporal linking patterns of these systems are needed to better rank the nodes.

  4. Reduction of dinitrogen ligands

    International Nuclear Information System (INIS)

    Richards, R.L.

    1983-01-01

    Processes of dinitrogen ligand reduction in complexes of transition metals are considered. The basic character of the dinitrogen ligand is underlined. Data on X-ray photoelectronic spectroscopy and intensities of bands ν (N 2 ) in IR-spectra of nitrogen complexes are given. The mechanism of protonation of an edge dinitrogen ligand is discussed. Model systems and mechanism of nitrogenogenase are compared

  5. PageRank tracker: from ranking to tracking.

    Science.gov (United States)

    Gong, Chen; Fu, Keren; Loza, Artur; Wu, Qiang; Liu, Jia; Yang, Jie

    2014-06-01

    Video object tracking is widely used in many real-world applications, and it has been extensively studied for over two decades. However, tracking robustness is still an issue in most existing methods, due to the difficulties with adaptation to environmental or target changes. In order to improve adaptability, this paper formulates the tracking process as a ranking problem, and the PageRank algorithm, which is a well-known webpage ranking algorithm used by Google, is applied. Labeled and unlabeled samples in tracking application are analogous to query webpages and the webpages to be ranked, respectively. Therefore, determining the target is equivalent to finding the unlabeled sample that is the most associated with existing labeled set. We modify the conventional PageRank algorithm in three aspects for tracking application, including graph construction, PageRank vector acquisition and target filtering. Our simulations with the use of various challenging public-domain video sequences reveal that the proposed PageRank tracker outperforms mean-shift tracker, co-tracker, semiboosting and beyond semiboosting trackers in terms of accuracy, robustness and stability.

  6. Cell adhesion signaling regulates RANK expression in osteoclast precursors.

    Directory of Open Access Journals (Sweden)

    Ayako Mochizuki

    Full Text Available Cells with monocyte/macrophage lineage expressing receptor activator of NF-κB (RANK differentiate into osteoclasts following stimulation with the RANK ligand (RANKL. Cell adhesion signaling is also required for osteoclast differentiation from precursors. However, details of the mechanism by which cell adhesion signals induce osteoclast differentiation have not been fully elucidated. To investigate the participation of cell adhesion signaling in osteoclast differentiation, mouse bone marrow-derived macrophages (BMMs were used as osteoclast precursors, and cultured on either plastic cell culture dishes (adherent condition or the top surface of semisolid methylcellulose gel loaded in culture tubes (non-adherent condition. BMMs cultured under the adherent condition differentiated into osteoclasts in response to RANKL stimulation. However, under the non-adherent condition, the efficiency of osteoclast differentiation was markedly reduced even in the presence of RANKL. These BMMs retained macrophage characteristics including phagocytic function and gene expression profile. Lipopolysaccharide (LPS and tumor necrosis factor -αTNF-α activated the NF-κB-mediated signaling pathways under both the adherent and non-adherent conditions, while RANKL activated the pathways only under the adherent condition. BMMs highly expressed RANK mRNA and protein under the adherent condition as compared to the non-adherent condition. Also, BMMs transferred from the adherent to non-adherent condition showed downregulated RANK expression within 24 hours. In contrast, transferring those from the non-adherent to adherent condition significantly increased the level of RANK expression. Moreover, interruption of cell adhesion signaling by echistatin, an RGD-containing disintegrin, decreased RANK expression in BMMs, while forced expression of either RANK or TNFR-associated factor 6 (TRAF6 in BMMs induced their differentiation into osteoclasts even under the non

  7. Ligands in PSI structures

    International Nuclear Information System (INIS)

    Kumar, Abhinav; Chiu, Hsiu-Ju; Axelrod, Herbert L.; Morse, Andrew; Elsliger, Marc-André; Wilson, Ian A.; Deacon, Ashley

    2010-01-01

    A survey of the types and frequency of ligands that are bound to PSI structures is analyzed as well as their utility in functional annotation of previously uncharacterized proteins. Approximately 65% of PSI structures report some type of ligand(s) that is bound in the crystal structure. Here, a description is given of how such ligands are handled and analyzed at the JCSG and a survey of the types, variety and frequency of ligands that are observed in the PSI structures is also compiled and analyzed, including illustrations of how these bound ligands have provided functional clues for annotation of proteins with little or no previous experimental characterization. Furthermore, a web server was developed as a tool to mine and analyze the PSI structures for bound ligands and other identifying features

  8. Discovery and SAR of hydantoin TACE inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Wensheng; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Chen, Lei; Dai, Chaoyang; Feltz, Robert J.; Girijavallabhan, Vinay M.; Kim, Seong Heon; Kozlowski, Joseph A.; Lavey, Brian J.; Li, Dansu; Lundell, Daniel; Niu, Xiaoda; Piwinski, John J.; Popovici-Muller, Janeta; Rizvi, Razia; Rosner, Kristin E.; Shankar, Bandarpalle B.; Shih, Neng-Yang; Siddiqui, M.A.; Sun, J.; Tong, L.; Umland, S.; Wong, M.K.; Yang, D.Y.; Zhou, G. (Merck)

    2010-09-03

    We disclose inhibitors of TNF-{alpha} converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.

  9. Universal scaling in sports ranking

    International Nuclear Information System (INIS)

    Deng Weibing; Li Wei; Cai Xu; Bulou, Alain; Wang Qiuping A

    2012-01-01

    Ranking is a ubiquitous phenomenon in human society. On the web pages of Forbes, one may find all kinds of rankings, such as the world's most powerful people, the world's richest people, the highest-earning tennis players, and so on and so forth. Herewith, we study a specific kind—sports ranking systems in which players' scores and/or prize money are accrued based on their performances in different matches. By investigating 40 data samples which span 12 different sports, we find that the distributions of scores and/or prize money follow universal power laws, with exponents nearly identical for most sports. In order to understand the origin of this universal scaling we focus on the tennis ranking systems. By checking the data we find that, for any pair of players, the probability that the higher-ranked player tops the lower-ranked opponent is proportional to the rank difference between the pair. Such a dependence can be well fitted to a sigmoidal function. By using this feature, we propose a simple toy model which can simulate the competition of players in different matches. The simulations yield results consistent with the empirical findings. Extensive simulation studies indicate that the model is quite robust with respect to the modifications of some parameters. (paper)

  10. LIBRA: LIgand Binding site Recognition Application.

    Science.gov (United States)

    Hung, Le Viet; Caprari, Silvia; Bizai, Massimiliano; Toti, Daniele; Polticelli, Fabio

    2015-12-15

    In recent years, structural genomics and ab initio molecular modeling activities are leading to the availability of a large number of structural models of proteins whose biochemical function is not known. The aim of this study was the development of a novel software tool that, given a protein's structural model, predicts the presence and identity of active sites and/or ligand binding sites. The algorithm implemented by ligand binding site recognition application (LIBRA) is based on a graph theory approach to find the largest subset of similar residues between an input protein and a collection of known functional sites. The algorithm makes use of two predefined databases for active sites and ligand binding sites, respectively, derived from the Catalytic Site Atlas and the Protein Data Bank. Tests indicate that LIBRA is able to identify the correct binding/active site in 90% of the cases analyzed, 90% of which feature the identified site as ranking first. As far as ligand binding site recognition is concerned, LIBRA outperforms other structure-based ligand binding sites detection tools with which it has been compared. The application, developed in Java SE 7 with a Swing GUI embedding a JMol applet, can be run on any OS equipped with a suitable Java Virtual Machine (JVM), and is available at the following URL: http://www.computationalbiology.it/software/LIBRAv1.zip. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Automated identification of crystallographic ligands using sparse-density representations

    International Nuclear Information System (INIS)

    Carolan, C. G.; Lamzin, V. S.

    2014-01-01

    A novel procedure for identifying ligands in macromolecular crystallographic electron-density maps is introduced. Density clusters in such maps can be rapidly attributed to one of 82 different ligands in an automated manner. A novel procedure for the automatic identification of ligands in macromolecular crystallographic electron-density maps is introduced. It is based on the sparse parameterization of density clusters and the matching of the pseudo-atomic grids thus created to conformationally variant ligands using mathematical descriptors of molecular shape, size and topology. In large-scale tests on experimental data derived from the Protein Data Bank, the procedure could quickly identify the deposited ligand within the top-ranked compounds from a database of candidates. This indicates the suitability of the method for the identification of binding entities in fragment-based drug screening and in model completion in macromolecular structure determination

  12. PageRank of integers

    International Nuclear Information System (INIS)

    Frahm, K M; Shepelyansky, D L; Chepelianskii, A D

    2012-01-01

    We up a directed network tracing links from a given integer to its divisors and analyze the properties of the Google matrix of this network. The PageRank vector of this matrix is computed numerically and it is shown that its probability is approximately inversely proportional to the PageRank index thus being similar to the Zipf law and the dependence established for the World Wide Web. The spectrum of the Google matrix of integers is characterized by a large gap and a relatively small number of nonzero eigenvalues. A simple semi-analytical expression for the PageRank of integers is derived that allows us to find this vector for matrices of billion size. This network provides a new PageRank order of integers. (paper)

  13. Freudenthal ranks: GHZ versus W

    International Nuclear Information System (INIS)

    Borsten, L

    2013-01-01

    The Hilbert space of three-qubit pure states may be identified with a Freudenthal triple system. Every state has an unique Freudenthal rank ranging from 1 to 4, which is determined by a set of automorphism group covariants. It is shown here that the optimal success rates for winning a three-player non-local game, varying over all local strategies, are strictly ordered by the Freudenthal rank of the shared three-qubit resource. (paper)

  14. Ranking Queries on Uncertain Data

    CERN Document Server

    Hua, Ming

    2011-01-01

    Uncertain data is inherent in many important applications, such as environmental surveillance, market analysis, and quantitative economics research. Due to the importance of those applications and rapidly increasing amounts of uncertain data collected and accumulated, analyzing large collections of uncertain data has become an important task. Ranking queries (also known as top-k queries) are often natural and useful in analyzing uncertain data. Ranking Queries on Uncertain Data discusses the motivations/applications, challenging problems, the fundamental principles, and the evaluation algorith

  15. Ranking in evolving complex networks

    Science.gov (United States)

    Liao, Hao; Mariani, Manuel Sebastian; Medo, Matúš; Zhang, Yi-Cheng; Zhou, Ming-Yang

    2017-05-01

    Complex networks have emerged as a simple yet powerful framework to represent and analyze a wide range of complex systems. The problem of ranking the nodes and the edges in complex networks is critical for a broad range of real-world problems because it affects how we access online information and products, how success and talent are evaluated in human activities, and how scarce resources are allocated by companies and policymakers, among others. This calls for a deep understanding of how existing ranking algorithms perform, and which are their possible biases that may impair their effectiveness. Many popular ranking algorithms (such as Google's PageRank) are static in nature and, as a consequence, they exhibit important shortcomings when applied to real networks that rapidly evolve in time. At the same time, recent advances in the understanding and modeling of evolving networks have enabled the development of a wide and diverse range of ranking algorithms that take the temporal dimension into account. The aim of this review is to survey the existing ranking algorithms, both static and time-aware, and their applications to evolving networks. We emphasize both the impact of network evolution on well-established static algorithms and the benefits from including the temporal dimension for tasks such as prediction of network traffic, prediction of future links, and identification of significant nodes.

  16. Ranking structures and rank-rank correlations of countries: The FIFA and UEFA cases

    Science.gov (United States)

    Ausloos, Marcel; Cloots, Rudi; Gadomski, Adam; Vitanov, Nikolay K.

    2014-04-01

    Ranking of agents competing with each other in complex systems may lead to paradoxes according to the pre-chosen different measures. A discussion is presented on such rank-rank, similar or not, correlations based on the case of European countries ranked by UEFA and FIFA from different soccer competitions. The first question to be answered is whether an empirical and simple law is obtained for such (self-) organizations of complex sociological systems with such different measuring schemes. It is found that the power law form is not the best description contrary to many modern expectations. The stretched exponential is much more adequate. Moreover, it is found that the measuring rules lead to some inner structures in both cases.

  17. Identification of significant features by the Global Mean Rank test.

    Science.gov (United States)

    Klammer, Martin; Dybowski, J Nikolaj; Hoffmann, Daniel; Schaab, Christoph

    2014-01-01

    With the introduction of omics-technologies such as transcriptomics and proteomics, numerous methods for the reliable identification of significantly regulated features (genes, proteins, etc.) have been developed. Experimental practice requires these tests to successfully deal with conditions such as small numbers of replicates, missing values, non-normally distributed expression levels, and non-identical distributions of features. With the MeanRank test we aimed at developing a test that performs robustly under these conditions, while favorably scaling with the number of replicates. The test proposed here is a global one-sample location test, which is based on the mean ranks across replicates, and internally estimates and controls the false discovery rate. Furthermore, missing data is accounted for without the need of imputation. In extensive simulations comparing MeanRank to other frequently used methods, we found that it performs well with small and large numbers of replicates, feature dependent variance between replicates, and variable regulation across features on simulation data and a recent two-color microarray spike-in dataset. The tests were then used to identify significant changes in the phosphoproteomes of cancer cells induced by the kinase inhibitors erlotinib and 3-MB-PP1 in two independently published mass spectrometry-based studies. MeanRank outperformed the other global rank-based methods applied in this study. Compared to the popular Significance Analysis of Microarrays and Linear Models for Microarray methods, MeanRank performed similar or better. Furthermore, MeanRank exhibits more consistent behavior regarding the degree of regulation and is robust against the choice of preprocessing methods. MeanRank does not require any imputation of missing values, is easy to understand, and yields results that are easy to interpret. The software implementing the algorithm is freely available for academic and commercial use.

  18. Applying ligands profiling using multiple extended electron distribution based field templates and feature trees similarity searching in the discovery of new generation of urea-based antineoplastic kinase inhibitors.

    Directory of Open Access Journals (Sweden)

    Eman M Dokla

    Full Text Available This study provides a comprehensive computational procedure for the discovery of novel urea-based antineoplastic kinase inhibitors while focusing on diversification of both chemotype and selectivity pattern. It presents a systematic structural analysis of the different binding motifs of urea-based kinase inhibitors and the corresponding configurations of the kinase enzymes. The computational model depends on simultaneous application of two protocols. The first protocol applies multiple consecutive validated virtual screening filters including SMARTS, support vector-machine model (ROC = 0.98, Bayesian model (ROC = 0.86 and structure-based pharmacophore filters based on urea-based kinase inhibitors complexes retrieved from literature. This is followed by hits profiling against different extended electron distribution (XED based field templates representing different kinase targets. The second protocol enables cancericidal activity verification by using the algorithm of feature trees (Ftrees similarity searching against NCI database. Being a proof-of-concept study, this combined procedure was experimentally validated by its utilization in developing a novel series of urea-based derivatives of strong anticancer activity. This new series is based on 3-benzylbenzo[d]thiazol-2(3H-one scaffold which has interesting chemical feasibility and wide diversification capability. Antineoplastic activity of this series was assayed in vitro against NCI 60 tumor-cell lines showing very strong inhibition of GI(50 as low as 0.9 uM. Additionally, its mechanism was unleashed using KINEX™ protein kinase microarray-based small molecule inhibitor profiling platform and cell cycle analysis showing a peculiar selectivity pattern against Zap70, c-src, Mink1, csk and MeKK2 kinases. Interestingly, it showed activity on syk kinase confirming the recent studies finding of the high activity of diphenyl urea containing compounds against this kinase. Allover, the new series

  19. Schiff base ligand

    Indian Academy of Sciences (India)

    Unknown

    Low-temperature stoichiometric Schiff base reaction in air in 3 : 1 mole ratio between benz- aldehyde and triethylenetetramine (trien) in methanol yields a novel tetraaza µ-bis(bidentate) acyclic ligand L. It was .... electrochemical work was performed as reported in ..... change in ligand shape through change in oxidation.

  20. Ranking species in mutualistic networks

    Science.gov (United States)

    Domínguez-García, Virginia; Muñoz, Miguel A.

    2015-02-01

    Understanding the architectural subtleties of ecological networks, believed to confer them enhanced stability and robustness, is a subject of outmost relevance. Mutualistic interactions have been profusely studied and their corresponding bipartite networks, such as plant-pollinator networks, have been reported to exhibit a characteristic ``nested'' structure. Assessing the importance of any given species in mutualistic networks is a key task when evaluating extinction risks and possible cascade effects. Inspired in a recently introduced algorithm -similar in spirit to Google's PageRank but with a built-in non-linearity- here we propose a method which -by exploiting their nested architecture- allows us to derive a sound ranking of species importance in mutualistic networks. This method clearly outperforms other existing ranking schemes and can become very useful for ecosystem management and biodiversity preservation, where decisions on what aspects of ecosystems to explicitly protect need to be made.

  1. Ranking Theory and Conditional Reasoning.

    Science.gov (United States)

    Skovgaard-Olsen, Niels

    2016-05-01

    Ranking theory is a formal epistemology that has been developed in over 600 pages in Spohn's recent book The Laws of Belief, which aims to provide a normative account of the dynamics of beliefs that presents an alternative to current probabilistic approaches. It has long been received in the AI community, but it has not yet found application in experimental psychology. The purpose of this paper is to derive clear, quantitative predictions by exploiting a parallel between ranking theory and a statistical model called logistic regression. This approach is illustrated by the development of a model for the conditional inference task using Spohn's (2013) ranking theoretic approach to conditionals. Copyright © 2015 Cognitive Science Society, Inc.

  2. University rankings in computer science

    DEFF Research Database (Denmark)

    Ehret, Philip; Zuccala, Alesia Ann; Gipp, Bela

    2017-01-01

    This is a research-in-progress paper concerning two types of institutional rankings, the Leiden and QS World ranking, and their relationship to a list of universities’ ‘geo-based’ impact scores, and Computing Research and Education Conference (CORE) participation scores in the field of computer...... science. A ‘geo-based’ impact measure examines the geographical distribution of incoming citations to a particular university’s journal articles for a specific period of time. It takes into account both the number of citations and the geographical variability in these citations. The CORE participation...... score is calculated on the basis of the number of weighted proceedings papers that a university has contributed to either an A*, A, B, or C conference as ranked by the Computing Research and Education Association of Australasia. In addition to calculating the correlations between the distinct university...

  3. Expression of nociceptive ligands in canine osteosarcoma.

    Science.gov (United States)

    Shor, S; Fadl-Alla, B A; Pondenis, H C; Zhang, X; Wycislo, K L; Lezmi, S; Fan, T M

    2015-01-01

    Canine osteosarcoma (OS) is associated with localized pain as a result of tissue injury from tumor infiltration and peritumoral inflammation. Malignant bone pain is caused by stimulation of peripheral pain receptors, termed nociceptors, which reside in the localized tumor microenvironment, including the periosteal and intramedullary bone cavities. Several nociceptive ligands have been determined to participate directly or indirectly in generating bone pain associated with diverse skeletal abnormalities. Canine OS cells actively produce nociceptive ligands with the capacity to directly or indirectly activate peripheral pain receptors residing in the bone tumor microenvironment. Ten dogs with appendicular OS. Expression of nerve growth factor, endothelin-1, and microsomal prostaglandin E synthase-1 was characterized in OS cell lines and naturally occurring OS samples. In 10 dogs with OS, circulating concentrations of nociceptive ligands were quantified and correlated with subjective pain scores and tumor volume in patients treated with standardized palliative therapies. Canine OS cells express and secrete nerve growth factor, endothelin-1, and prostaglandin E2. Naturally occurring OS samples uniformly express nociceptive ligands. In a subset of OS-bearing dogs, circulating nociceptive ligand concentrations were detectable but failed to correlate with pain status. Localized foci of nerve terminal proliferation were identified in a minority of primary bone tumor samples. Canine OS cells express nociceptive ligands, potentially permitting active participation of OS cells in the generation of malignant bone pain. Specific inhibitors of nociceptive ligand signaling pathways might improve pain control in dogs with OS. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

  4. Subtracting a best rank-1 approximation may increase tensor rank

    NARCIS (Netherlands)

    Stegeman, Alwin; Comon, Pierre

    2010-01-01

    It has been shown that a best rank-R approximation of an order-k tensor may not exist when R >= 2 and k >= 3. This poses a serious problem to data analysts using tensor decompositions it has been observed numerically that, generally, this issue cannot be solved by consecutively computing and

  5. Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma) Independent Novel Function of IFNgammaR2 as a Bax Inhibitor

    Science.gov (United States)

    2016-10-01

    Cisplatin (2uM, 30 hrs) PN (5uM, 55hrs) + Cisplatin (2uM, 30 hrs) •  Thorough studies are needed to examine the unknown mechanism of IFNgR2 and Bax as well as...mouse xenograft model. Task3: To determine the mechanism of increased IFNγR2 expression in PCa. We found that NFkB inhibitor suppressed IFNγR2 expression...suggesting that hyper-activation of NFkB may be one of the mechanisms of IFNγR2 overexpression in PCa. These results support our hypothesis that

  6. Consistent ranking of volatility models

    DEFF Research Database (Denmark)

    Hansen, Peter Reinhard; Lunde, Asger

    2006-01-01

    We show that the empirical ranking of volatility models can be inconsistent for the true ranking if the evaluation is based on a proxy for the population measure of volatility. For example, the substitution of a squared return for the conditional variance in the evaluation of ARCH-type models can...... variance in out-of-sample evaluations rather than the squared return. We derive the theoretical results in a general framework that is not specific to the comparison of volatility models. Similar problems can arise in comparisons of forecasting models whenever the predicted variable is a latent variable....

  7. Ligand modeling and design

    Energy Technology Data Exchange (ETDEWEB)

    Hay, B.P. [Pacific Northwest National Lab., Richland, WA (United States)

    1997-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used in the cost-effective removal of specific radionuclides from nuclear waste streams. Organic ligands with metal ion specificity are critical components in the development of solvent extraction and ion exchange processes that are highly selective for targeted radionuclides. The traditional approach to the development of such ligands involves lengthy programs of organic synthesis and testing, which in the absence of reliable methods for screening compounds before synthesis, results in wasted research effort. The author`s approach breaks down and simplifies this costly process with the aid of computer-based molecular modeling techniques. Commercial software for organic molecular modeling is being configured to examine the interactions between organic ligands and metal ions, yielding an inexpensive, commercially or readily available computational tool that can be used to predict the structures and energies of ligand-metal complexes. Users will be able to correlate the large body of existing experimental data on structure, solution binding affinity, and metal ion selectivity to develop structural design criteria. These criteria will provide a basis for selecting ligands that can be implemented in separations technologies through collaboration with other DOE national laboratories and private industry. The initial focus will be to select ether-based ligands that can be applied to the recovery and concentration of the alkali and alkaline earth metal ions including cesium, strontium, and radium.

  8. Let Us Rank Journalism Programs

    Science.gov (United States)

    Weber, Joseph

    2014-01-01

    Unlike law, business, and medical schools, as well as universities in general, journalism schools and journalism programs have rarely been ranked. Publishers such as "U.S. News & World Report," "Forbes," "Bloomberg Businessweek," and "Washington Monthly" do not pay them much mind. What is the best…

  9. On Rank Driven Dynamical Systems

    Science.gov (United States)

    Veerman, J. J. P.; Prieto, F. J.

    2014-08-01

    We investigate a class of models related to the Bak-Sneppen (BS) model, initially proposed to study evolution. The BS model is extremely simple and yet captures some forms of "complex behavior" such as self-organized criticality that is often observed in physical and biological systems. In this model, random fitnesses in are associated to agents located at the vertices of a graph . Their fitnesses are ranked from worst (0) to best (1). At every time-step the agent with the worst fitness and some others with a priori given rank probabilities are replaced by new agents with random fitnesses. We consider two cases: The exogenous case where the new fitnesses are taken from an a priori fixed distribution, and the endogenous case where the new fitnesses are taken from the current distribution as it evolves. We approximate the dynamics by making a simplifying independence assumption. We use Order Statistics and Dynamical Systems to define a rank-driven dynamical system that approximates the evolution of the distribution of the fitnesses in these rank-driven models, as well as in the BS model. For this simplified model we can find the limiting marginal distribution as a function of the initial conditions. Agreement with experimental results of the BS model is excellent.

  10. PageRank (II): Mathematics

    African Journals Online (AJOL)

    maths/stats

    ... GAUSS SEIDEL'S. NUMERICAL ALGORITHMS IN PAGE RANK ANALYSIS. ... The convergence is guaranteed, if the absolute value of the largest eigen ... improved Gauss-Seidel iteration algorithm, based on the decomposition. U. L. D. M. +. +. = ..... This corresponds to determine the eigen vector of T with eigen value 1.

  11. Multiple graph regularized protein domain ranking

    KAUST Repository

    Wang, Jim Jing-Yan

    2012-11-19

    Background: Protein domain ranking is a fundamental task in structural biology. Most protein domain ranking methods rely on the pairwise comparison of protein domains while neglecting the global manifold structure of the protein domain database. Recently, graph regularized ranking that exploits the global structure of the graph defined by the pairwise similarities has been proposed. However, the existing graph regularized ranking methods are very sensitive to the choice of the graph model and parameters, and this remains a difficult problem for most of the protein domain ranking methods.Results: To tackle this problem, we have developed the Multiple Graph regularized Ranking algorithm, MultiG-Rank. Instead of using a single graph to regularize the ranking scores, MultiG-Rank approximates the intrinsic manifold of protein domain distribution by combining multiple initial graphs for the regularization. Graph weights are learned with ranking scores jointly and automatically, by alternately minimizing an objective function in an iterative algorithm. Experimental results on a subset of the ASTRAL SCOP protein domain database demonstrate that MultiG-Rank achieves a better ranking performance than single graph regularized ranking methods and pairwise similarity based ranking methods.Conclusion: The problem of graph model and parameter selection in graph regularized protein domain ranking can be solved effectively by combining multiple graphs. This aspect of generalization introduces a new frontier in applying multiple graphs to solving protein domain ranking applications. 2012 Wang et al; licensee BioMed Central Ltd.

  12. Multiple graph regularized protein domain ranking

    KAUST Repository

    Wang, Jim Jing-Yan; Bensmail, Halima; Gao, Xin

    2012-01-01

    Background: Protein domain ranking is a fundamental task in structural biology. Most protein domain ranking methods rely on the pairwise comparison of protein domains while neglecting the global manifold structure of the protein domain database. Recently, graph regularized ranking that exploits the global structure of the graph defined by the pairwise similarities has been proposed. However, the existing graph regularized ranking methods are very sensitive to the choice of the graph model and parameters, and this remains a difficult problem for most of the protein domain ranking methods.Results: To tackle this problem, we have developed the Multiple Graph regularized Ranking algorithm, MultiG-Rank. Instead of using a single graph to regularize the ranking scores, MultiG-Rank approximates the intrinsic manifold of protein domain distribution by combining multiple initial graphs for the regularization. Graph weights are learned with ranking scores jointly and automatically, by alternately minimizing an objective function in an iterative algorithm. Experimental results on a subset of the ASTRAL SCOP protein domain database demonstrate that MultiG-Rank achieves a better ranking performance than single graph regularized ranking methods and pairwise similarity based ranking methods.Conclusion: The problem of graph model and parameter selection in graph regularized protein domain ranking can be solved effectively by combining multiple graphs. This aspect of generalization introduces a new frontier in applying multiple graphs to solving protein domain ranking applications. 2012 Wang et al; licensee BioMed Central Ltd.

  13. 14 CFR 1214.1105 - Final ranking.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Final ranking. 1214.1105 Section 1214.1105... Recruitment and Selection Program § 1214.1105 Final ranking. Final rankings will be based on a combination of... preference will be included in this final ranking in accordance with applicable regulations. ...

  14. Multiple graph regularized protein domain ranking.

    Science.gov (United States)

    Wang, Jim Jing-Yan; Bensmail, Halima; Gao, Xin

    2012-11-19

    Protein domain ranking is a fundamental task in structural biology. Most protein domain ranking methods rely on the pairwise comparison of protein domains while neglecting the global manifold structure of the protein domain database. Recently, graph regularized ranking that exploits the global structure of the graph defined by the pairwise similarities has been proposed. However, the existing graph regularized ranking methods are very sensitive to the choice of the graph model and parameters, and this remains a difficult problem for most of the protein domain ranking methods. To tackle this problem, we have developed the Multiple Graph regularized Ranking algorithm, MultiG-Rank. Instead of using a single graph to regularize the ranking scores, MultiG-Rank approximates the intrinsic manifold of protein domain distribution by combining multiple initial graphs for the regularization. Graph weights are learned with ranking scores jointly and automatically, by alternately minimizing an objective function in an iterative algorithm. Experimental results on a subset of the ASTRAL SCOP protein domain database demonstrate that MultiG-Rank achieves a better ranking performance than single graph regularized ranking methods and pairwise similarity based ranking methods. The problem of graph model and parameter selection in graph regularized protein domain ranking can be solved effectively by combining multiple graphs. This aspect of generalization introduces a new frontier in applying multiple graphs to solving protein domain ranking applications.

  15. Multiple graph regularized protein domain ranking

    Directory of Open Access Journals (Sweden)

    Wang Jim

    2012-11-01

    Full Text Available Abstract Background Protein domain ranking is a fundamental task in structural biology. Most protein domain ranking methods rely on the pairwise comparison of protein domains while neglecting the global manifold structure of the protein domain database. Recently, graph regularized ranking that exploits the global structure of the graph defined by the pairwise similarities has been proposed. However, the existing graph regularized ranking methods are very sensitive to the choice of the graph model and parameters, and this remains a difficult problem for most of the protein domain ranking methods. Results To tackle this problem, we have developed the Multiple Graph regularized Ranking algorithm, MultiG-Rank. Instead of using a single graph to regularize the ranking scores, MultiG-Rank approximates the intrinsic manifold of protein domain distribution by combining multiple initial graphs for the regularization. Graph weights are learned with ranking scores jointly and automatically, by alternately minimizing an objective function in an iterative algorithm. Experimental results on a subset of the ASTRAL SCOP protein domain database demonstrate that MultiG-Rank achieves a better ranking performance than single graph regularized ranking methods and pairwise similarity based ranking methods. Conclusion The problem of graph model and parameter selection in graph regularized protein domain ranking can be solved effectively by combining multiple graphs. This aspect of generalization introduces a new frontier in applying multiple graphs to solving protein domain ranking applications.

  16. A Survey on PageRank Computing

    OpenAIRE

    Berkhin, Pavel

    2005-01-01

    This survey reviews the research related to PageRank computing. Components of a PageRank vector serve as authority weights for web pages independent of their textual content, solely based on the hyperlink structure of the web. PageRank is typically used as a web search ranking component. This defines the importance of the model and the data structures that underly PageRank processing. Computing even a single PageRank is a difficult computational task. Computing many PageRanks is a much mor...

  17. Combination of 2D/3D ligand-based similarity search in rapid virtual screening from multimillion compound repositories. Selection and biological evaluation of potential PDE4 and PDE5 inhibitors.

    Science.gov (United States)

    Dobi, Krisztina; Hajdú, István; Flachner, Beáta; Fabó, Gabriella; Szaszkó, Mária; Bognár, Melinda; Magyar, Csaba; Simon, István; Szisz, Dániel; Lőrincz, Zsolt; Cseh, Sándor; Dormán, György

    2014-05-28

    Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities.

  18. Time evolution of Wikipedia network ranking

    Science.gov (United States)

    Eom, Young-Ho; Frahm, Klaus M.; Benczúr, András; Shepelyansky, Dima L.

    2013-12-01

    We study the time evolution of ranking and spectral properties of the Google matrix of English Wikipedia hyperlink network during years 2003-2011. The statistical properties of ranking of Wikipedia articles via PageRank and CheiRank probabilities, as well as the matrix spectrum, are shown to be stabilized for 2007-2011. A special emphasis is done on ranking of Wikipedia personalities and universities. We show that PageRank selection is dominated by politicians while 2DRank, which combines PageRank and CheiRank, gives more accent on personalities of arts. The Wikipedia PageRank of universities recovers 80% of top universities of Shanghai ranking during the considered time period.

  19. Validating rankings in soccer championships

    Directory of Open Access Journals (Sweden)

    Annibal Parracho Sant'Anna

    2012-08-01

    Full Text Available The final ranking of a championship is determined by quality attributes combined with other factors which should be filtered out of any decision on relegation or draft for upper level tournaments. Factors like referees' mistakes and difficulty of certain matches due to its accidental importance to the opponents should have their influence reduced. This work tests approaches to combine classification rules considering the imprecision of the number of points as a measure of quality and of the variables that provide reliable explanation for it. Two home-advantage variables are tested and shown to be apt to enter as explanatory variables. Independence between the criteria is checked against the hypothesis of maximal correlation. The importance of factors and of composition rules is evaluated on the basis of correlation between rank vectors, number of classes and number of clubs in tail classes. Data from five years of the Brazilian Soccer Championship are analyzed.

  20. Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series.

    Science.gov (United States)

    Güssregen, Stefan; Matter, Hans; Hessler, Gerhard; Lionta, Evanthia; Heil, Jochen; Kast, Stefan M

    2017-07-24

    Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design. Unlike molecular dynamics-based approaches, 3D RISM theory allows for fast and noise-free calculations using the same detailed level of solute-solvent interaction description. Here we correlate molecular water entities instead of mere site density maxima with local contributions to the solvation free energy using novel algorithms. Distinct water molecules and hydration sites are investigated in multiple protein-ligand X-ray structures, namely streptavidin, factor Xa, and factor VIIa, based on 3D RISM-derived free energy density fields. Our approach allows the semiquantitative assessment of whether a given structural water molecule can potentially be targeted for replacement in structure-based design. Finally, PLS-based regression models from free energy density fields used within a 3D-QSAR approach (CARMa - comparative analysis of 3D RISM Maps) are shown to be able to extract relevant information for the interpretation of structure-activity relationship (SAR) trends, as demonstrated for a series of serine protease inhibitors.

  1. Minkowski metrics in creating universal ranking algorithms

    Directory of Open Access Journals (Sweden)

    Andrzej Ameljańczyk

    2014-06-01

    Full Text Available The paper presents a general procedure for creating the rankings of a set of objects, while the relation of preference based on any ranking function. The analysis was possible to use the ranking functions began by showing the fundamental drawbacks of commonly used functions in the form of a weighted sum. As a special case of the ranking procedure in the space of a relation, the procedure based on the notion of an ideal element and generalized Minkowski distance from the element was proposed. This procedure, presented as universal ranking algorithm, eliminates most of the disadvantages of ranking functions in the form of a weighted sum.[b]Keywords[/b]: ranking functions, preference relation, ranking clusters, categories, ideal point, universal ranking algorithm

  2. Functional Multiplex PageRank

    Science.gov (United States)

    Iacovacci, Jacopo; Rahmede, Christoph; Arenas, Alex; Bianconi, Ginestra

    2016-10-01

    Recently it has been recognized that many complex social, technological and biological networks have a multilayer nature and can be described by multiplex networks. Multiplex networks are formed by a set of nodes connected by links having different connotations forming the different layers of the multiplex. Characterizing the centrality of the nodes in a multiplex network is a challenging task since the centrality of the node naturally depends on the importance associated to links of a certain type. Here we propose to assign to each node of a multiplex network a centrality called Functional Multiplex PageRank that is a function of the weights given to every different pattern of connections (multilinks) existent in the multiplex network between any two nodes. Since multilinks distinguish all the possible ways in which the links in different layers can overlap, the Functional Multiplex PageRank can describe important non-linear effects when large relevance or small relevance is assigned to multilinks with overlap. Here we apply the Functional Page Rank to the multiplex airport networks, to the neuronal network of the nematode C. elegans, and to social collaboration and citation networks between scientists. This analysis reveals important differences existing between the most central nodes of these networks, and the correlations between their so-called pattern to success.

  3. Low rank magnetic resonance fingerprinting.

    Science.gov (United States)

    Mazor, Gal; Weizman, Lior; Tal, Assaf; Eldar, Yonina C

    2016-08-01

    Magnetic Resonance Fingerprinting (MRF) is a relatively new approach that provides quantitative MRI using randomized acquisition. Extraction of physical quantitative tissue values is preformed off-line, based on acquisition with varying parameters and a dictionary generated according to the Bloch equations. MRF uses hundreds of radio frequency (RF) excitation pulses for acquisition, and therefore high under-sampling ratio in the sampling domain (k-space) is required. This under-sampling causes spatial artifacts that hamper the ability to accurately estimate the quantitative tissue values. In this work, we introduce a new approach for quantitative MRI using MRF, called Low Rank MRF. We exploit the low rank property of the temporal domain, on top of the well-known sparsity of the MRF signal in the generated dictionary domain. We present an iterative scheme that consists of a gradient step followed by a low rank projection using the singular value decomposition. Experiments on real MRI data demonstrate superior results compared to conventional implementation of compressed sensing for MRF at 15% sampling ratio.

  4. Ranking Support Vector Machine with Kernel Approximation

    Directory of Open Access Journals (Sweden)

    Kai Chen

    2017-01-01

    Full Text Available Learning to rank algorithm has become important in recent years due to its successful application in information retrieval, recommender system, and computational biology, and so forth. Ranking support vector machine (RankSVM is one of the state-of-art ranking models and has been favorably used. Nonlinear RankSVM (RankSVM with nonlinear kernels can give higher accuracy than linear RankSVM (RankSVM with a linear kernel for complex nonlinear ranking problem. However, the learning methods for nonlinear RankSVM are still time-consuming because of the calculation of kernel matrix. In this paper, we propose a fast ranking algorithm based on kernel approximation to avoid computing the kernel matrix. We explore two types of kernel approximation methods, namely, the Nyström method and random Fourier features. Primal truncated Newton method is used to optimize the pairwise L2-loss (squared Hinge-loss objective function of the ranking model after the nonlinear kernel approximation. Experimental results demonstrate that our proposed method gets a much faster training speed than kernel RankSVM and achieves comparable or better performance over state-of-the-art ranking algorithms.

  5. Ranking Support Vector Machine with Kernel Approximation.

    Science.gov (United States)

    Chen, Kai; Li, Rongchun; Dou, Yong; Liang, Zhengfa; Lv, Qi

    2017-01-01

    Learning to rank algorithm has become important in recent years due to its successful application in information retrieval, recommender system, and computational biology, and so forth. Ranking support vector machine (RankSVM) is one of the state-of-art ranking models and has been favorably used. Nonlinear RankSVM (RankSVM with nonlinear kernels) can give higher accuracy than linear RankSVM (RankSVM with a linear kernel) for complex nonlinear ranking problem. However, the learning methods for nonlinear RankSVM are still time-consuming because of the calculation of kernel matrix. In this paper, we propose a fast ranking algorithm based on kernel approximation to avoid computing the kernel matrix. We explore two types of kernel approximation methods, namely, the Nyström method and random Fourier features. Primal truncated Newton method is used to optimize the pairwise L2-loss (squared Hinge-loss) objective function of the ranking model after the nonlinear kernel approximation. Experimental results demonstrate that our proposed method gets a much faster training speed than kernel RankSVM and achieves comparable or better performance over state-of-the-art ranking algorithms.

  6. 2D MI-DRAGON: a new predictor for protein-ligands interactions and theoretic-experimental studies of US FDA drug-target network, oxoisoaporphine inhibitors for MAO-A and human parasite proteins.

    Science.gov (United States)

    Prado-Prado, Francisco; García-Mera, Xerardo; Escobar, Manuel; Sobarzo-Sánchez, Eduardo; Yañez, Matilde; Riera-Fernandez, Pablo; González-Díaz, Humberto

    2011-12-01

    There are many pairs of possible Drug-Proteins Interactions that may take place or not (DPIs/nDPIs) between drugs with high affinity/non-affinity for different proteins. This fact makes expensive in terms of time and resources, for instance, the determination of all possible ligands-protein interactions for a single drug. In this sense, we can use Quantitative Structure-Activity Relationships (QSAR) models to carry out rational DPIs prediction. Unfortunately, almost all QSAR models predict activity against only one target. To solve this problem we can develop multi-target QSAR (mt-QSAR) models. In this work, we introduce the technique 2D MI-DRAGON a new predictor for DPIs based on two different well-known software. We use the software MARCH-INSIDE (MI) to calculate 3D structural parameters for targets and the software DRAGON was used to calculated 2D molecular descriptors all drugs showing known DPIs present in the Drug Bank (US FDA benchmark dataset). Both classes of parameters were used as input of different Artificial Neural Network (ANN) algorithms to seek an accurate non-linear mt-QSAR predictor. The best ANN model found is a Multi-Layer Perceptron (MLP) with profile MLP 21:21-31-1:1. This MLP classifies correctly 303 out of 339 DPIs (Sensitivity = 89.38%) and 480 out of 510 nDPIs (Specificity = 94.12%), corresponding to training Accuracy = 92.23%. The validation of the model was carried out by means of external predicting series with Sensitivity = 92.18% (625/678 DPIs; Specificity = 90.12% (730/780 nDPIs) and Accuracy = 91.06%. 2D MI-DRAGON offers a good opportunity for fast-track calculation of all possible DPIs of one drug enabling us to re-construct large drug-target or DPIs Complex Networks (CNs). For instance, we reconstructed the CN of the US FDA benchmark dataset with 855 nodes 519 drugs+336 targets). We predicted CN with similar topology (observed and predicted values of average distance are equal to 6.7 vs. 6.6). These CNs can be used to explore

  7. LIGAND-BINDING SITES ON THE MYCOBACTERIUM TUBERCULOSIS UREASE

    Directory of Open Access Journals (Sweden)

    Lisnyak Yu. V.

    2017-10-01

    Full Text Available Introduction. Mycobacterium tuberculosis is the causative agent of tuberculosis that remains a serious medical and social health problem. Despite intensive efforts have been made in the past decade, there are no new efficient anti-tuberculosis drugs today, and that need is growing due to the spread of drug-resistant strains of M.tuberculosis. M. tuberculosis urease (MTU, being an important factor of the bacterium viability and virulence, is an attractive target for anti-tuberculosis drugs acting by inhibition of urease activity. However, the commercially available urease inhibitors are toxic and unstable, that prevent their clinical use. Therefore, new more potent anti-tuberculosis drugs inhibiting new targets are urgently needed. A useful tool for the search of novel inhibitors is a computational drug design. The inhibitor design is significantly easier if binding sites on the enzyme are identified in advance. This paper aimed to determine the probable ligand binding sites on the surface of M. tuberculosis urease. Methods. To identify ligand binding sites on MTU surface, сomputational solvent mapping method FTSite was applied by the use of MTU homology model we have built earlier. The method places molecular probes (small organic molecules containing various functional groups on a dense grid defined around the enzyme, and for each probe finds favorable positions. The selected poses are refined by free energy minimization, the low energy conformations are clustered, and the clusters are ranked on the basis of the average free energy. FTSite server outputs the protein residues delineating a binding sites and the probe molecules representing each cluster. To predict allosteric pockets on MTU, AlloPred and AlloSite servers were applied. AlloPred uses the normal mode analysis (NMA and models how the dynamics of a protein would be altered in the presence of a modulator at a specific pocket. Pockets on the enzyme are predicted using the Fpocket

  8. SibRank: Signed bipartite network analysis for neighbor-based collaborative ranking

    Science.gov (United States)

    Shams, Bita; Haratizadeh, Saman

    2016-09-01

    Collaborative ranking is an emerging field of recommender systems that utilizes users' preference data rather than rating values. Unfortunately, neighbor-based collaborative ranking has gained little attention despite its more flexibility and justifiability. This paper proposes a novel framework, called SibRank that seeks to improve the state of the art neighbor-based collaborative ranking methods. SibRank represents users' preferences as a signed bipartite network, and finds similar users, through a novel personalized ranking algorithm in signed networks.

  9. Targeting Selectins and Their Ligands in Cancer

    Directory of Open Access Journals (Sweden)

    Alessandro eNatoni

    2016-04-01

    Full Text Available Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids have been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases. Humans differentially express twenty different sialyltransferases in a tissue-specific manner, each of which catalyze the attachment of sialic acids via different glycosidic linkages (2-3; 2-6 or 2-8 to the underlying glycan chain. One important mechanism whereby overexpression of sialyltransferases contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural-isomer sialyl-Lewis A, which are synthesized by the combined action of alpha 1-3-fucosyltransferases, 2-3-sialyltransferases, 1-4-galactosyltranferases, and N-acetyl--glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these sialyltransferases have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular sialyltransferases, could be beneficial to many cancer patients. Potential strategies include sialyltransferase inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of sialyltransferase inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical

  10. Rank Two Affine Manifolds in Genus 3

    OpenAIRE

    Aulicino, David; Nguyen, Duc-Manh

    2016-01-01

    We complete the classification of rank two affine manifolds in the moduli space of translation surfaces in genus three. Combined with a recent result of Mirzakhani and Wright, this completes the classification of higher rank affine manifolds in genus three.

  11. Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

    Science.gov (United States)

    Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

    2015-01-01

    Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.

  12. The Privilege of Ranking: Google Plays Ball.

    Science.gov (United States)

    Wiggins, Richard

    2003-01-01

    Discussion of ranking systems used in various settings, including college football and academic admissions, focuses on the Google search engine. Explains the PageRank mathematical formula that scores Web pages by connecting the number of links; limitations, including authenticity and accuracy of ranked Web pages; relevancy; adjusting algorithms;…

  13. A Comprehensive Analysis of Marketing Journal Rankings

    Science.gov (United States)

    Steward, Michelle D.; Lewis, Bruce R.

    2010-01-01

    The purpose of this study is to offer a comprehensive assessment of journal standings in Marketing from two perspectives. The discipline perspective of rankings is obtained from a collection of published journal ranking studies during the past 15 years. The studies in the published ranking stream are assessed for reliability by examining internal…

  14. Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads.

    Science.gov (United States)

    Manoharan, Prabu; Ghoshal, Nanda

    2018-05-01

    Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer's disease therapeutics.

  15. Glutamate receptor ligands

    DEFF Research Database (Denmark)

    Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea

    2002-01-01

    Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...

  16. Modelling of potentially promising SARS protease inhibitors

    International Nuclear Information System (INIS)

    Plewczynski, Dariusz; Hoffmann, Marcin; Grotthuss, Marcin von; Knizewski, Lukasz; Rychewski, Leszek; Eitner, Krystian; Ginalski, Krzysztof

    2007-01-01

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation

  17. Modelling of potentially promising SARS protease inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Plewczynski, Dariusz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Hoffmann, Marcin [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Grotthuss, Marcin von [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Knizewski, Lukasz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Rychewski, Leszek [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Eitner, Krystian [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Ginalski, Krzysztof [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland)

    2007-07-18

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation.

  18. Ligand recognition by RAR and RXR receptors: binding and selectivity.

    Science.gov (United States)

    Sussman, Fredy; de Lera, Angel R

    2005-10-06

    Fundamental biological functions, most notably embriogenesis, cell growth, cell differentiation, and cell apoptosis, are in part regulated by a complex genomic network that starts with the binding (and activation) of retinoids to their cognate receptors, members of the superfamily of nuclear receptors. We have studied ligand recognition of retinoic receptors (RXRalpha and RARgamma) using a molecular-mechanics-based docking method. The protocol used in this work is able to rank the affinity of pairs of ligands for a single retinoid receptor, the highest values corresponding to those that adapt better to the shape of the binding site and generate the optimal set of electrostatic and apolar interactions with the receptor. Moreover, our studies shed light onto some of the energetic contributions to retinoid receptor ligand selectivity. In this regard we show that there is a difference in polarity between the binding site regions that anchor the carboxylate in RAR and RXR, which translates itself into large differences in the energy of interaction of both receptors with the same ligand. We observe that the latter energy change is canceled off by the solvation energy penalty upon binding. This energy compensation is borne out as well by experiments that address the effect of site-directed mutagenesis on ligand binding to RARgamma. The hypothesis that the difference in binding site polarity might be exploited to build RXR-selective ligands is tested with some compounds having a thiazolidinedione anchoring group.

  19. Two-dimensional ranking of Wikipedia articles

    Science.gov (United States)

    Zhirov, A. O.; Zhirov, O. V.; Shepelyansky, D. L.

    2010-10-01

    The Library of Babel, described by Jorge Luis Borges, stores an enormous amount of information. The Library exists ab aeterno. Wikipedia, a free online encyclopaedia, becomes a modern analogue of such a Library. Information retrieval and ranking of Wikipedia articles become the challenge of modern society. While PageRank highlights very well known nodes with many ingoing links, CheiRank highlights very communicative nodes with many outgoing links. In this way the ranking becomes two-dimensional. Using CheiRank and PageRank we analyze the properties of two-dimensional ranking of all Wikipedia English articles and show that it gives their reliable classification with rich and nontrivial features. Detailed studies are done for countries, universities, personalities, physicists, chess players, Dow-Jones companies and other categories.

  20. 24 CFR 599.401 - Ranking of applications.

    Science.gov (United States)

    2010-04-01

    ... 24 Housing and Urban Development 3 2010-04-01 2010-04-01 false Ranking of applications. 599.401... Communities § 599.401 Ranking of applications. (a) Ranking order. Rural and urban applications will be ranked... applications ranked first. (b) Separate ranking categories. After initial ranking, both rural and urban...

  1. Agro-tourism and ranking

    Science.gov (United States)

    Cioca, L. I.; Giurea, R.; Precazzini, I.; Ragazzi, M.; Achim, M. I.; Schiavon, M.; Rada, E. C.

    2018-05-01

    Nowadays the global tourism growth has caused a significant interest in research focused on the impact of the tourism on environment and community. The purpose of this study is to introduce a new ranking for the classification of tourist accommodation establishments with the functions of agro-tourism boarding house type by examining the sector of agro-tourism based on a research aimed to improve the economic, socio-cultural and environmental performance of agrotourism structures. This paper links the criteria for the classification of agro-tourism boarding houses (ABHs) to the impact of agro-tourism activities on the environment, enhancing an eco-friendly approach on agro-tourism activities by increasing the quality reputation of the agro-tourism products and services. Taking into account the impact on the environment, agrotourism can play an important role by protecting and conserving it.

  2. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T. [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India); Wani, Mohan R., E-mail: mohanwani@nccs.res.in [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India)

    2010-09-03

    Research highlights: {yields} IL-3 inhibits receptor activator of NF-{kappa}B ligand (RANKL)-induced osteoclastogenesis. {yields} IL-3 inhibits RANKL-induced JNK activation. {yields} IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. {yields} IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. {yields} IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-{kappa}B (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  3. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    International Nuclear Information System (INIS)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T.; Wani, Mohan R.

    2010-01-01

    Research highlights: → IL-3 inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. → IL-3 inhibits RANKL-induced JNK activation. → IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. → IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. → IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-κB (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  4. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the f......Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

  5. Radiobiology with DNA ligands

    International Nuclear Information System (INIS)

    Weinreich, R.; Argentini, M.; Guenther, I.; Koziorowski, J.; Larsson, B.; Nievergelt-Egido, M.C.; Salt, C.; Wyer, L.; Dos Santos, D.F.; Hansen, H.J.

    1997-01-01

    The paper deals with the following topics: labelling of DNA ligands and other tumour-affinic compounds with 4.15-d 124 I, radiotoxicity of Hoechst 33258 and 33342 and of iodinated Hoechst 33258 in cell cultures, preparation of 76 Br-, 123 I-, and 221 At-labelled 5-halo-2'-deoxyuridine, chemical syntheses of boron derivatives of Hoechst 33258.III., Gadolinium neutron capture therapy

  6. Error analysis of stochastic gradient descent ranking.

    Science.gov (United States)

    Chen, Hong; Tang, Yi; Li, Luoqing; Yuan, Yuan; Li, Xuelong; Tang, Yuanyan

    2013-06-01

    Ranking is always an important task in machine learning and information retrieval, e.g., collaborative filtering, recommender systems, drug discovery, etc. A kernel-based stochastic gradient descent algorithm with the least squares loss is proposed for ranking in this paper. The implementation of this algorithm is simple, and an expression of the solution is derived via a sampling operator and an integral operator. An explicit convergence rate for leaning a ranking function is given in terms of the suitable choices of the step size and the regularization parameter. The analysis technique used here is capacity independent and is novel in error analysis of ranking learning. Experimental results on real-world data have shown the effectiveness of the proposed algorithm in ranking tasks, which verifies the theoretical analysis in ranking error.

  7. Methodology for ranking restoration options

    International Nuclear Information System (INIS)

    Hedemann Jensen, Per

    1999-04-01

    The work described in this report has been performed as a part of the RESTRAT Project FI4P-CT95-0021a (PL 950128) co-funded by the Nuclear Fission Safety Programme of the European Commission. The RESTRAT project has the overall objective of developing generic methodologies for ranking restoration techniques as a function of contamination and site characteristics. The project includes analyses of existing remediation methodologies and contaminated sites, and is structured in the following steps: characterisation of relevant contaminated sites; identification and characterisation of relevant restoration techniques; assessment of the radiological impact; development and application of a selection methodology for restoration options; formulation of generic conclusions and development of a manual. The project is intended to apply to situations in which sites with nuclear installations have been contaminated with radioactive materials as a result of the operation of these installations. The areas considered for remedial measures include contaminated land areas, rivers and sediments in rivers, lakes, and sea areas. Five contaminated European sites have been studied. Various remedial measures have been envisaged with respect to the optimisation of the protection of the populations being exposed to the radionuclides at the sites. Cost-benefit analysis and multi-attribute utility analysis have been applied for optimisation. Health, economic and social attributes have been included and weighting factors for the different attributes have been determined by the use of scaling constants. (au)

  8. Citation graph based ranking in Invenio

    CERN Document Server

    Marian, Ludmila; Rajman, Martin; Vesely, Martin

    2010-01-01

    Invenio is the web-based integrated digital library system developed at CERN. Within this framework, we present four types of ranking models based on the citation graph that complement the simple approach based on citation counts: time-dependent citation counts, a relevancy ranking which extends the PageRank model, a time-dependent ranking which combines the freshness of citations with PageRank and a ranking that takes into consideration the external citations. We present our analysis and results obtained on two main data sets: Inspire and CERN Document Server. Our main contributions are: (i) a study of the currently available ranking methods based on the citation graph; (ii) the development of new ranking methods that correct some of the identified limitations of the current methods such as treating all citations of equal importance, not taking time into account or considering the citation graph complete; (iii) a detailed study of the key parameters for these ranking methods. (The original publication is ava...

  9. Communities in Large Networks: Identification and Ranking

    DEFF Research Database (Denmark)

    Olsen, Martin

    2008-01-01

    We study the problem of identifying and ranking the members of a community in a very large network with link analysis only, given a set of representatives of the community. We define the concept of a community justified by a formal analysis of a simple model of the evolution of a directed graph. ...... and its immediate surroundings. The members are ranked with a “local” variant of the PageRank algorithm. Results are reported from successful experiments on identifying and ranking Danish Computer Science sites and Danish Chess pages using only a few representatives....

  10. Ranking Entities in Networks via Lefschetz Duality

    DEFF Research Database (Denmark)

    Aabrandt, Andreas; Hansen, Vagn Lundsgaard; Poulsen, Bjarne

    2014-01-01

    then be ranked according to how essential their positions are in the network by considering the effect of their respective absences. Defining a ranking of a network which takes the individual position of each entity into account has the purpose of assigning different roles to the entities, e.g. agents......, in the network. In this paper it is shown that the topology of a given network induces a ranking of the entities in the network. Further, it is demonstrated how to calculate this ranking and thus how to identify weak sub-networks in any given network....

  11. Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors

    DEFF Research Database (Denmark)

    Nguyen, E.D.; Meiler, J.; Norn, C.

    2013-01-01

    screening and to design and optimize drug candidates. However, low sequence identity between receptors, conformational flexibility, and chemical diversity of ligands present an enormous challenge to molecular modeling approaches. It is our hypothesis that rapid Monte-Carlo sampling of protein backbone...... extracellular loop. Furthermore, these models are consistently correlated with low Rosetta energy score. To predict their binding modes, ligand conformers of the 14 ligands co-crystalized with the GPCRs were docked against the top ranked comparative models. In contrast to the comparative models themselves...

  12. LigSearch: a knowledge-based web server to identify likely ligands for a protein target

    Energy Technology Data Exchange (ETDEWEB)

    Beer, Tjaart A. P. de; Laskowski, Roman A. [European Bioinformatics Institute (EMBL–EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD (United Kingdom); Duban, Mark-Eugene [Northwestern University Feinberg School of Medicine, Chicago, Illinois (United States); Chan, A. W. Edith [University College London, London WC1E 6BT (United Kingdom); Anderson, Wayne F. [Northwestern University Feinberg School of Medicine, Chicago, Illinois (United States); Thornton, Janet M., E-mail: thornton@ebi.ac.uk [European Bioinformatics Institute (EMBL–EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD (United Kingdom)

    2013-12-01

    LigSearch is a web server for identifying ligands likely to bind to a given protein. Identifying which ligands might bind to a protein before crystallization trials could provide a significant saving in time and resources. LigSearch, a web server aimed at predicting ligands that might bind to and stabilize a given protein, has been developed. Using a protein sequence and/or structure, the system searches against a variety of databases, combining available knowledge, and provides a clustered and ranked output of possible ligands. LigSearch can be accessed at http://www.ebi.ac.uk/thornton-srv/databases/LigSearch.

  13. RANKL/RANK: from bone loss to the prevention of breast cancer.

    Science.gov (United States)

    Sigl, Verena; Jones, Laundette P; Penninger, Josef M

    2016-11-01

    RANK and RANKL, a receptor ligand pair belonging to the tumour necrosis factor family, are the critical regulators of osteoclast development and bone metabolism. Besides their essential function in bone, RANK and RANKL have also been identified as the key factors for the formation of a lactating mammary gland in pregnancy. Mechanistically, RANK and RANKL link the sex hormone progesterone with stem cell expansion and proliferation of mammary epithelial cells. Based on their normal physiology, RANKL/RANK control the onset of hormone-induced breast cancer through the expansion of mammary progenitor cells. Recently, we and others were able to show that RANK and RANKL are also critical regulators of BRCA1-mutation-driven breast cancer. Currently, the preventive strategy for BRCA1-mutation carriers includes preventive mastectomy, associated with wide-ranging risks and psychosocial effects. The search for an alternative non-invasive prevention strategy is therefore of paramount importance. As our work strongly implicates RANK and RANKL as key molecules involved in the initiation of BRCA1-associated breast cancer, we propose that anti-RANKL therapy could be a feasible preventive strategy for women carrying BRCA1 mutations, and by extension to other women with high risk of breast cancer. © 2016 The Authors.

  14. Singular Value Decomposition and Ligand Binding Analysis

    Directory of Open Access Journals (Sweden)

    André Luiz Galo

    2013-01-01

    Full Text Available Singular values decomposition (SVD is one of the most important computations in linear algebra because of its vast application for data analysis. It is particularly useful for resolving problems involving least-squares minimization, the determination of matrix rank, and the solution of certain problems involving Euclidean norms. Such problems arise in the spectral analysis of ligand binding to macromolecule. Here, we present a spectral data analysis method using SVD (SVD analysis and nonlinear fitting to determine the binding characteristics of intercalating drugs to DNA. This methodology reduces noise and identifies distinct spectral species similar to traditional principal component analysis as well as fitting nonlinear binding parameters. We applied SVD analysis to investigate the interaction of actinomycin D and daunomycin with native DNA. This methodology does not require prior knowledge of ligand molar extinction coefficients (free and bound, which potentially limits binding analysis. Data are acquired simply by reconstructing the experimental data and by adjusting the product of deconvoluted matrices and the matrix of model coefficients determined by the Scatchard and McGee and von Hippel equation.

  15. Bexarotene ligand pharmaceuticals.

    Science.gov (United States)

    Hurst, R E

    2000-12-01

    Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the treatment of cutaneous T-cell lymphoma (CTCL), as Targretin capsules, in the US in January 2000 [359023]. The company filed an NDA for Targretin capsules in June 1999, and for topical gel in December 1999 [329011], [349982] specifically for once-daily oral administration for the treatment of patients with early-stage CTCL who have not tolerated other therapies, patients with refractory or persistent early stage CTCL and patients with refractory advanced stage CTCL. The FDA approved Targretin capsules at the end of December 1999 for once-daily oral treatment of all stages of CTCL in patients refractory to at least one prior systemic therapy, at an initial dose of 300 mg/m2/day. After an NDA was submitted in December 1999 for Targretin gel, the drug received Priority Review status for use as a treatment of cutaneous lesions in patients with stage IA, IB or IIA CTCL [354836]. The FDA issued an approvable letter in June 2000, and granted marketing clearance for CTCL in the same month [370687], [372768], [372769], [373279]. Ligand had received Orphan Drug designation for this indication [329011]. At the request of the FDA, Ligand agreed to carry out certain post-approval phase IV and pharmacokinetic studies [351604]. The company filed an MAA with the EMEA for Targretin Capsules to treat lymphoma in November 1999 [348944]. The NDA for Targretin gel is based on a multicenter phase III trial that was conducted in the US, Canada, Europe and Australia involving 50 patients and a multicenter phase I/II clinical program involving 67 patients. Targretin gel was evaluated for the treatment of patients with early stage CTCL (IA-IIA) who were refractory to, intolerant to, or reached a response plateau for at least 6 months on at least two prior therapies. Efficacy results exceeded the protocol-defined response

  16. Ranking scientific publications: the effect of nonlinearity

    Science.gov (United States)

    Yao, Liyang; Wei, Tian; Zeng, An; Fan, Ying; di, Zengru

    2014-10-01

    Ranking the significance of scientific publications is a long-standing challenge. The network-based analysis is a natural and common approach for evaluating the scientific credit of papers. Although the number of citations has been widely used as a metric to rank papers, recently some iterative processes such as the well-known PageRank algorithm have been applied to the citation networks to address this problem. In this paper, we introduce nonlinearity to the PageRank algorithm when aggregating resources from different nodes to further enhance the effect of important papers. The validation of our method is performed on the data of American Physical Society (APS) journals. The results indicate that the nonlinearity improves the performance of the PageRank algorithm in terms of ranking effectiveness, as well as robustness against malicious manipulations. Although the nonlinearity analysis is based on the PageRank algorithm, it can be easily extended to other iterative ranking algorithms and similar improvements are expected.

  17. Ranking scientific publications: the effect of nonlinearity.

    Science.gov (United States)

    Yao, Liyang; Wei, Tian; Zeng, An; Fan, Ying; Di, Zengru

    2014-10-17

    Ranking the significance of scientific publications is a long-standing challenge. The network-based analysis is a natural and common approach for evaluating the scientific credit of papers. Although the number of citations has been widely used as a metric to rank papers, recently some iterative processes such as the well-known PageRank algorithm have been applied to the citation networks to address this problem. In this paper, we introduce nonlinearity to the PageRank algorithm when aggregating resources from different nodes to further enhance the effect of important papers. The validation of our method is performed on the data of American Physical Society (APS) journals. The results indicate that the nonlinearity improves the performance of the PageRank algorithm in terms of ranking effectiveness, as well as robustness against malicious manipulations. Although the nonlinearity analysis is based on the PageRank algorithm, it can be easily extended to other iterative ranking algorithms and similar improvements are expected.

  18. Neural Ranking Models with Weak Supervision

    NARCIS (Netherlands)

    Dehghani, M.; Zamani, H.; Severyn, A.; Kamps, J.; Croft, W.B.

    2017-01-01

    Despite the impressive improvements achieved by unsupervised deep neural networks in computer vision and NLP tasks, such improvements have not yet been observed in ranking for information retrieval. The reason may be the complexity of the ranking problem, as it is not obvious how to learn from

  19. A Rational Method for Ranking Engineering Programs.

    Science.gov (United States)

    Glower, Donald D.

    1980-01-01

    Compares two methods for ranking academic programs, the opinion poll v examination of career successes of the program's alumni. For the latter, "Who's Who in Engineering" and levels of research funding provided data. Tables display resulting data and compare rankings by the two methods for chemical engineering and civil engineering. (CS)

  20. Lerot: An Online Learning to Rank Framework

    NARCIS (Netherlands)

    Schuth, A.; Hofmann, K.; Whiteson, S.; de Rijke, M.

    2013-01-01

    Online learning to rank methods for IR allow retrieval systems to optimize their own performance directly from interactions with users via click feedback. In the software package Lerot, presented in this paper, we have bundled all ingredients needed for experimenting with online learning to rank for

  1. Adaptive distributional extensions to DFR ranking

    DEFF Research Database (Denmark)

    Petersen, Casper; Simonsen, Jakob Grue; Järvelin, Kalervo

    2016-01-01

    -fitting distribution. We call this model Adaptive Distributional Ranking (ADR) because it adapts the ranking to the statistics of the specific dataset being processed each time. Experiments on TREC data show ADR to outperform DFR models (and their extensions) and be comparable in performance to a query likelihood...

  2. Contests with rank-order spillovers

    NARCIS (Netherlands)

    M.R. Baye (Michael); D. Kovenock (Dan); C.G. de Vries (Casper)

    2012-01-01

    textabstractThis paper presents a unified framework for characterizing symmetric equilibrium in simultaneous move, two-player, rank-order contests with complete information, in which each player's strategy generates direct or indirect affine "spillover" effects that depend on the rank-order of her

  3. Classification of rank 2 cluster varieties

    DEFF Research Database (Denmark)

    Mandel, Travis

    We classify rank 2 cluster varieties (those whose corresponding skew-form has rank 2) according to the deformation type of a generic fiber U of their X-spaces, as defined by Fock and Goncharov. Our approach is based on the work of Gross, Hacking, and Keel for cluster varieties and log Calabi...

  4. Using centrality to rank web snippets

    NARCIS (Netherlands)

    Jijkoun, V.; de Rijke, M.; Peters, C.; Jijkoun, V.; Mandl, T.; Müller, H.; Oard, D.W.; Peñas, A.; Petras, V.; Santos, D.

    2008-01-01

    We describe our participation in the WebCLEF 2007 task, targeted at snippet retrieval from web data. Our system ranks snippets based on a simple similarity-based centrality, inspired by the web page ranking algorithms. We experimented with retrieval units (sentences and paragraphs) and with the

  5. Mining Feedback in Ranking and Recommendation Systems

    Science.gov (United States)

    Zhuang, Ziming

    2009-01-01

    The amount of online information has grown exponentially over the past few decades, and users become more and more dependent on ranking and recommendation systems to address their information seeking needs. The advance in information technologies has enabled users to provide feedback on the utilities of the underlying ranking and recommendation…

  6. Entity Ranking using Wikipedia as a Pivot

    NARCIS (Netherlands)

    R. Kaptein; P. Serdyukov; A.P. de Vries (Arjen); J. Kamps

    2010-01-01

    htmlabstractIn this paper we investigate the task of Entity Ranking on the Web. Searchers looking for entities are arguably better served by presenting a ranked list of entities directly, rather than a list of web pages with relevant but also potentially redundant information about

  7. Entity ranking using Wikipedia as a pivot

    NARCIS (Netherlands)

    Kaptein, R.; Serdyukov, P.; de Vries, A.; Kamps, J.; Huang, X.J.; Jones, G.; Koudas, N.; Wu, X.; Collins-Thompson, K.

    2010-01-01

    In this paper we investigate the task of Entity Ranking on the Web. Searchers looking for entities are arguably better served by presenting a ranked list of entities directly, rather than a list of web pages with relevant but also potentially redundant information about these entities. Since

  8. Rank 2 fusion rings are complete intersections

    DEFF Research Database (Denmark)

    Andersen, Troels Bak

    We give a non-constructive proof that fusion rings attached to a simple complex Lie algebra of rank 2 are complete intersections.......We give a non-constructive proof that fusion rings attached to a simple complex Lie algebra of rank 2 are complete intersections....

  9. A Ranking Method for Evaluating Constructed Responses

    Science.gov (United States)

    Attali, Yigal

    2014-01-01

    This article presents a comparative judgment approach for holistically scored constructed response tasks. In this approach, the grader rank orders (rather than rate) the quality of a small set of responses. A prior automated evaluation of responses guides both set formation and scaling of rankings. Sets are formed to have similar prior scores and…

  10. Ranking Music Data by Relevance and Importance

    DEFF Research Database (Denmark)

    Ruxanda, Maria Magdalena; Nanopoulos, Alexandros; Jensen, Christian Søndergaard

    2008-01-01

    Due to the rapidly increasing availability of audio files on the Web, it is relevant to augment search engines with advanced audio search functionality. In this context, the ranking of the retrieved music is an important issue. This paper proposes a music ranking method capable of flexibly fusing...

  11. Ranking of Unwarranted Variations in Healthcare Treatments

    NARCIS (Netherlands)

    Moes, Herry; Brekelmans, Ruud; Hamers, Herbert; Hasaart, F.

    2017-01-01

    In this paper, we introduce a framework designed to identify and rank possible unwarranted variation of treatments in healthcare. The innovative aspect of this framework is a ranking procedure that aims to identify healthcare institutions where unwarranted variation is most severe, and diagnosis

  12. The Rankings Game: Who's Playing Whom?

    Science.gov (United States)

    Burness, John F.

    2008-01-01

    This summer, Forbes magazine published its new rankings of "America's Best Colleges," implying that it had developed a methodology that would give the public the information that it needed to choose a college wisely. "U.S. News & World Report," which in 1983 published the first annual ranking, just announced its latest ratings last week--including…

  13. Dynamic collective entity representations for entity ranking

    NARCIS (Netherlands)

    Graus, D.; Tsagkias, M.; Weerkamp, W.; Meij, E.; de Rijke, M.

    2016-01-01

    Entity ranking, i.e., successfully positioning a relevant entity at the top of the ranking for a given query, is inherently difficult due to the potential mismatch between the entity's description in a knowledge base, and the way people refer to the entity when searching for it. To counter this

  14. Ligand deconstruction: Why some fragment binding positions are conserved and others are not

    Science.gov (United States)

    Kozakov, Dima; Hall, David R.; Jehle, Stefan; Luo, Lingqi; Ochiana, Stefan O.; Jones, Elizabeth V.; Pollastri, Michael; Allen, Karen N.; Whitty, Adrian; Vajda, Sandor

    2015-01-01

    Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand. PMID:25918377

  15. Ligand deconstruction: Why some fragment binding positions are conserved and others are not.

    Science.gov (United States)

    Kozakov, Dima; Hall, David R; Jehle, Stefan; Jehle, Sefan; Luo, Lingqi; Ochiana, Stefan O; Jones, Elizabeth V; Pollastri, Michael; Allen, Karen N; Whitty, Adrian; Vajda, Sandor

    2015-05-19

    Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots--regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

  16. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).

    Science.gov (United States)

    Kung, Pei-Pei; Bingham, Patrick; Brooun, Alexei; Collins, Michael; Deng, Ya-Li; Dinh, Dac; Fan, Connie; Gajiwala, Ketan S; Grantner, Rita; Gukasyan, Hovhannes J; Hu, Wenyue; Huang, Buwen; Kania, Robert; Kephart, Susan E; Krivacic, Cody; Kumpf, Robert A; Khamphavong, Penney; Kraus, Manfred; Liu, Wei; Maegley, Karen A; Nguyen, Lisa; Ren, Shijian; Richter, Dan; Rollins, Robert A; Sach, Neal; Sharma, Shikhar; Sherrill, John; Spangler, Jillian; Stewart, Albert E; Sutton, Scott; Uryu, Sean; Verhelle, Dominique; Wang, Hui; Wang, Shuiwang; Wythes, Martin; Xin, Shuibo; Yamazaki, Shinji; Zhu, Huichun; Zhu, JinJiang; Zehnder, Luke; Edwards, Martin

    2018-02-08

    A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp 3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

  17. Comparing classical and quantum PageRanks

    Science.gov (United States)

    Loke, T.; Tang, J. W.; Rodriguez, J.; Small, M.; Wang, J. B.

    2017-01-01

    Following recent developments in quantum PageRanking, we present a comparative analysis of discrete-time and continuous-time quantum-walk-based PageRank algorithms. Relative to classical PageRank and to different extents, the quantum measures better highlight secondary hubs and resolve ranking degeneracy among peripheral nodes for all networks we studied in this paper. For the discrete-time case, we investigated the periodic nature of the walker's probability distribution for a wide range of networks and found that the dominant period does not grow with the size of these networks. Based on this observation, we introduce a new quantum measure using the maximum probabilities of the associated walker during the first couple of periods. This is particularly important, since it leads to a quantum PageRanking scheme that is scalable with respect to network size.

  18. Universal emergence of PageRank

    Energy Technology Data Exchange (ETDEWEB)

    Frahm, K M; Georgeot, B; Shepelyansky, D L, E-mail: frahm@irsamc.ups-tlse.fr, E-mail: georgeot@irsamc.ups-tlse.fr, E-mail: dima@irsamc.ups-tlse.fr [Laboratoire de Physique Theorique du CNRS, IRSAMC, Universite de Toulouse, UPS, 31062 Toulouse (France)

    2011-11-18

    The PageRank algorithm enables us to rank the nodes of a network through a specific eigenvector of the Google matrix, using a damping parameter {alpha} Element-Of ]0, 1[. Using extensive numerical simulations of large web networks, with a special accent on British University networks, we determine numerically and analytically the universal features of the PageRank vector at its emergence when {alpha} {yields} 1. The whole network can be divided into a core part and a group of invariant subspaces. For {alpha} {yields} 1, PageRank converges to a universal power-law distribution on the invariant subspaces whose size distribution also follows a universal power law. The convergence of PageRank at {alpha} {yields} 1 is controlled by eigenvalues of the core part of the Google matrix, which are extremely close to unity, leading to large relaxation times as, for example, in spin glasses. (paper)

  19. Universal emergence of PageRank

    International Nuclear Information System (INIS)

    Frahm, K M; Georgeot, B; Shepelyansky, D L

    2011-01-01

    The PageRank algorithm enables us to rank the nodes of a network through a specific eigenvector of the Google matrix, using a damping parameter α ∈ ]0, 1[. Using extensive numerical simulations of large web networks, with a special accent on British University networks, we determine numerically and analytically the universal features of the PageRank vector at its emergence when α → 1. The whole network can be divided into a core part and a group of invariant subspaces. For α → 1, PageRank converges to a universal power-law distribution on the invariant subspaces whose size distribution also follows a universal power law. The convergence of PageRank at α → 1 is controlled by eigenvalues of the core part of the Google matrix, which are extremely close to unity, leading to large relaxation times as, for example, in spin glasses. (paper)

  20. PageRank and rank-reversal dependence on the damping factor

    Science.gov (United States)

    Son, S.-W.; Christensen, C.; Grassberger, P.; Paczuski, M.

    2012-12-01

    PageRank (PR) is an algorithm originally developed by Google to evaluate the importance of web pages. Considering how deeply rooted Google's PR algorithm is to gathering relevant information or to the success of modern businesses, the question of rank stability and choice of the damping factor (a parameter in the algorithm) is clearly important. We investigate PR as a function of the damping factor d on a network obtained from a domain of the World Wide Web, finding that rank reversal happens frequently over a broad range of PR (and of d). We use three different correlation measures, Pearson, Spearman, and Kendall, to study rank reversal as d changes, and we show that the correlation of PR vectors drops rapidly as d changes from its frequently cited value, d0=0.85. Rank reversal is also observed by measuring the Spearman and Kendall rank correlation, which evaluate relative ranks rather than absolute PR. Rank reversal happens not only in directed networks containing rank sinks but also in a single strongly connected component, which by definition does not contain any sinks. We relate rank reversals to rank pockets and bottlenecks in the directed network structure. For the network studied, the relative rank is more stable by our measures around d=0.65 than at d=d0.

  1. PageRank and rank-reversal dependence on the damping factor.

    Science.gov (United States)

    Son, S-W; Christensen, C; Grassberger, P; Paczuski, M

    2012-12-01

    PageRank (PR) is an algorithm originally developed by Google to evaluate the importance of web pages. Considering how deeply rooted Google's PR algorithm is to gathering relevant information or to the success of modern businesses, the question of rank stability and choice of the damping factor (a parameter in the algorithm) is clearly important. We investigate PR as a function of the damping factor d on a network obtained from a domain of the World Wide Web, finding that rank reversal happens frequently over a broad range of PR (and of d). We use three different correlation measures, Pearson, Spearman, and Kendall, to study rank reversal as d changes, and we show that the correlation of PR vectors drops rapidly as d changes from its frequently cited value, d_{0}=0.85. Rank reversal is also observed by measuring the Spearman and Kendall rank correlation, which evaluate relative ranks rather than absolute PR. Rank reversal happens not only in directed networks containing rank sinks but also in a single strongly connected component, which by definition does not contain any sinks. We relate rank reversals to rank pockets and bottlenecks in the directed network structure. For the network studied, the relative rank is more stable by our measures around d=0.65 than at d=d_{0}.

  2. A tilting approach to ranking influence

    KAUST Repository

    Genton, Marc G.

    2014-12-01

    We suggest a new approach, which is applicable for general statistics computed from random samples of univariate or vector-valued or functional data, to assessing the influence that individual data have on the value of a statistic, and to ranking the data in terms of that influence. Our method is based on, first, perturbing the value of the statistic by ‘tilting’, or reweighting, each data value, where the total amount of tilt is constrained to be the least possible, subject to achieving a given small perturbation of the statistic, and, then, taking the ranking of the influence of data values to be that which corresponds to ranking the changes in data weights. It is shown, both theoretically and numerically, that this ranking does not depend on the size of the perturbation, provided that the perturbation is sufficiently small. That simple result leads directly to an elegant geometric interpretation of the ranks; they are the ranks of the lengths of projections of the weights onto a ‘line’ determined by the first empirical principal component function in a generalized measure of covariance. To illustrate the generality of the method we introduce and explore it in the case of functional data, where (for example) it leads to generalized boxplots. The method has the advantage of providing an interpretable ranking that depends on the statistic under consideration. For example, the ranking of data, in terms of their influence on the value of a statistic, is different for a measure of location and for a measure of scale. This is as it should be; a ranking of data in terms of their influence should depend on the manner in which the data are used. Additionally, the ranking recognizes, rather than ignores, sign, and in particular can identify left- and right-hand ‘tails’ of the distribution of a random function or vector.

  3. A Ranking Approach to Genomic Selection.

    Science.gov (United States)

    Blondel, Mathieu; Onogi, Akio; Iwata, Hiroyoshi; Ueda, Naonori

    2015-01-01

    Genomic selection (GS) is a recent selective breeding method which uses predictive models based on whole-genome molecular markers. Until now, existing studies formulated GS as the problem of modeling an individual's breeding value for a particular trait of interest, i.e., as a regression problem. To assess predictive accuracy of the model, the Pearson correlation between observed and predicted trait values was used. In this paper, we propose to formulate GS as the problem of ranking individuals according to their breeding value. Our proposed framework allows us to employ machine learning methods for ranking which had previously not been considered in the GS literature. To assess ranking accuracy of a model, we introduce a new measure originating from the information retrieval literature called normalized discounted cumulative gain (NDCG). NDCG rewards more strongly models which assign a high rank to individuals with high breeding value. Therefore, NDCG reflects a prerequisite objective in selective breeding: accurate selection of individuals with high breeding value. We conducted a comparison of 10 existing regression methods and 3 new ranking methods on 6 datasets, consisting of 4 plant species and 25 traits. Our experimental results suggest that tree-based ensemble methods including McRank, Random Forests and Gradient Boosting Regression Trees achieve excellent ranking accuracy. RKHS regression and RankSVM also achieve good accuracy when used with an RBF kernel. Traditional regression methods such as Bayesian lasso, wBSR and BayesC were found less suitable for ranking. Pearson correlation was found to correlate poorly with NDCG. Our study suggests two important messages. First, ranking methods are a promising research direction in GS. Second, NDCG can be a useful evaluation measure for GS.

  4. First rank symptoms for schizophrenia.

    Science.gov (United States)

    Soares-Weiser, Karla; Maayan, Nicola; Bergman, Hanna; Davenport, Clare; Kirkham, Amanda J; Grabowski, Sarah; Adams, Clive E

    2015-01-25

    Early and accurate diagnosis and treatment of schizophrenia may have long-term advantages for the patient; the longer psychosis goes untreated the more severe the repercussions for relapse and recovery. If the correct diagnosis is not schizophrenia, but another psychotic disorder with some symptoms similar to schizophrenia, appropriate treatment might be delayed, with possible severe repercussions for the person involved and their family. There is widespread uncertainty about the diagnostic accuracy of First Rank Symptoms (FRS); we examined whether they are a useful diagnostic tool to differentiate schizophrenia from other psychotic disorders. To determine the diagnostic accuracy of one or multiple FRS for diagnosing schizophrenia, verified by clinical history and examination by a qualified professional (e.g. psychiatrists, nurses, social workers), with or without the use of operational criteria and checklists, in people thought to have non-organic psychotic symptoms. We conducted searches in MEDLINE, EMBASE, and PsycInfo using OvidSP in April, June, July 2011 and December 2012. We also searched MEDION in December 2013. We selected studies that consecutively enrolled or randomly selected adults and adolescents with symptoms of psychosis, and assessed the diagnostic accuracy of FRS for schizophrenia compared to history and clinical examination performed by a qualified professional, which may or may not involve the use of symptom checklists or based on operational criteria such as ICD and DSM. Two review authors independently screened all references for inclusion. Risk of bias in included studies were assessed using the QUADAS-2 instrument. We recorded the number of true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN) for constructing a 2 x 2 table for each study or derived 2 x 2 data from reported summary statistics such as sensitivity, specificity, and/or likelihood ratios. We included 21 studies with a total of 6253 participants

  5. Improved efficacy of soluble human receptor activator of nuclear factor kappa B (RANK) fusion protein by site-directed mutagenesis.

    Science.gov (United States)

    Son, Young Jun; Han, Jihye; Lee, Jae Yeon; Kim, HaHyung; Chun, Taehoon

    2015-06-01

    Soluble human receptor activator of nuclear factor kappa B fusion immunoglobulin (hRANK-Ig) has been considered as one of the therapeutic agents to treat osteoporosis or diseases associated with bone destruction by blocking the interaction between RANK and the receptor activator of nuclear factor kappa B ligand (RANKL). However, no scientific record showing critical amino acid residues within the structural interface between the human RANKL and RANK complex is yet available. In this study, we produced several mutants of hRANK-Ig by replacement of amino acid residue(s) and tested whether the mutants had increased binding affinity to human RANKL. Based on the results from flow cytometry and surface plasmon resonance analyses, the replacement of E(125) with D(125), or E(125) and C(127) with D(125) and F(127) within loop 3 of cysteine-rich domain 3 of hRANK-Ig increases binding affinity to human RANKL over the wild-type hRANK-Ig. This result may provide the first example of improvement in the efficacy of hRANK-Ig by protein engineering and may give additional information to understand a more defined structural interface between hRANK and RANKL.

  6. [Syk inhibitors].

    Science.gov (United States)

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  7. Adiabatic quantum algorithm for search engine ranking.

    Science.gov (United States)

    Garnerone, Silvano; Zanardi, Paolo; Lidar, Daniel A

    2012-06-08

    We propose an adiabatic quantum algorithm for generating a quantum pure state encoding of the PageRank vector, the most widely used tool in ranking the relative importance of internet pages. We present extensive numerical simulations which provide evidence that this algorithm can prepare the quantum PageRank state in a time which, on average, scales polylogarithmically in the number of web pages. We argue that the main topological feature of the underlying web graph allowing for such a scaling is the out-degree distribution. The top-ranked log(n) entries of the quantum PageRank state can then be estimated with a polynomial quantum speed-up. Moreover, the quantum PageRank state can be used in "q-sampling" protocols for testing properties of distributions, which require exponentially fewer measurements than all classical schemes designed for the same task. This can be used to decide whether to run a classical update of the PageRank.

  8. Ranking Adverse Drug Reactions With Crowdsourcing

    KAUST Repository

    Gottlieb, Assaf

    2015-03-23

    Background: There is no publicly available resource that provides the relative severity of adverse drug reactions (ADRs). Such a resource would be useful for several applications, including assessment of the risks and benefits of drugs and improvement of patient-centered care. It could also be used to triage predictions of drug adverse events. Objective: The intent of the study was to rank ADRs according to severity. Methods: We used Internet-based crowdsourcing to rank ADRs according to severity. We assigned 126,512 pairwise comparisons of ADRs to 2589 Amazon Mechanical Turk workers and used these comparisons to rank order 2929 ADRs. Results: There is good correlation (rho=.53) between the mortality rates associated with ADRs and their rank. Our ranking highlights severe drug-ADR predictions, such as cardiovascular ADRs for raloxifene and celecoxib. It also triages genes associated with severe ADRs such as epidermal growth-factor receptor (EGFR), associated with glioblastoma multiforme, and SCN1A, associated with epilepsy. Conclusions: ADR ranking lays a first stepping stone in personalized drug risk assessment. Ranking of ADRs using crowdsourcing may have useful clinical and financial implications, and should be further investigated in the context of health care decision making.

  9. Ranking adverse drug reactions with crowdsourcing.

    Science.gov (United States)

    Gottlieb, Assaf; Hoehndorf, Robert; Dumontier, Michel; Altman, Russ B

    2015-03-23

    There is no publicly available resource that provides the relative severity of adverse drug reactions (ADRs). Such a resource would be useful for several applications, including assessment of the risks and benefits of drugs and improvement of patient-centered care. It could also be used to triage predictions of drug adverse events. The intent of the study was to rank ADRs according to severity. We used Internet-based crowdsourcing to rank ADRs according to severity. We assigned 126,512 pairwise comparisons of ADRs to 2589 Amazon Mechanical Turk workers and used these comparisons to rank order 2929 ADRs. There is good correlation (rho=.53) between the mortality rates associated with ADRs and their rank. Our ranking highlights severe drug-ADR predictions, such as cardiovascular ADRs for raloxifene and celecoxib. It also triages genes associated with severe ADRs such as epidermal growth-factor receptor (EGFR), associated with glioblastoma multiforme, and SCN1A, associated with epilepsy. ADR ranking lays a first stepping stone in personalized drug risk assessment. Ranking of ADRs using crowdsourcing may have useful clinical and financial implications, and should be further investigated in the context of health care decision making.

  10. Syk inhibitors.

    Science.gov (United States)

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  11. Discovery of DNA repair inhibitors by combinatorial library profiling

    Science.gov (United States)

    Moeller, Benjamin J.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

    2011-01-01

    Small molecule inhibitors of DNA repair are emerging as potent and selective anti-cancer therapies, but the sheer magnitude of the protein networks involved in DNA repair processes poses obstacles to discovery of effective candidate drugs. To address this challenge, we used a subtractive combinatorial selection approach to identify a panel of peptide ligands that bind DNA repair complexes. Supporting the concept that these ligands have therapeutic potential, we show that one selected peptide specifically binds and non-competitively inactivates DNA-PKcs, a protein kinase critical in double-strand DNA break repair. In doing so, this ligand sensitizes BRCA-deficient tumor cells to genotoxic therapy. Our findings establish a platform for large-scale parallel screening for ligand-directed DNA repair inhibitors, with immediate applicability to cancer therapy. PMID:21343400

  12. Ligand Depot: a data warehouse for ligands bound to macromolecules.

    Science.gov (United States)

    Feng, Zukang; Chen, Li; Maddula, Himabindu; Akcan, Ozgur; Oughtred, Rose; Berman, Helen M; Westbrook, John

    2004-09-01

    Ligand Depot is an integrated data resource for finding information about small molecules bound to proteins and nucleic acids. The initial release (version 1.0, November, 2003) focuses on providing chemical and structural information for small molecules found as part of the structures deposited in the Protein Data Bank. Ligand Depot accepts keyword-based queries and also provides a graphical interface for performing chemical substructure searches. A wide variety of web resources that contain information on small molecules may also be accessed through Ligand Depot. Ligand Depot is available at http://ligand-depot.rutgers.edu/. Version 1.0 supports multiple operating systems including Windows, Unix, Linux and the Macintosh operating system. The current drawing tool works in Internet Explorer, Netscape and Mozilla on Windows, Unix and Linux.

  13. RankExplorer: Visualization of Ranking Changes in Large Time Series Data.

    Science.gov (United States)

    Shi, Conglei; Cui, Weiwei; Liu, Shixia; Xu, Panpan; Chen, Wei; Qu, Huamin

    2012-12-01

    For many applications involving time series data, people are often interested in the changes of item values over time as well as their ranking changes. For example, people search many words via search engines like Google and Bing every day. Analysts are interested in both the absolute searching number for each word as well as their relative rankings. Both sets of statistics may change over time. For very large time series data with thousands of items, how to visually present ranking changes is an interesting challenge. In this paper, we propose RankExplorer, a novel visualization method based on ThemeRiver to reveal the ranking changes. Our method consists of four major components: 1) a segmentation method which partitions a large set of time series curves into a manageable number of ranking categories; 2) an extended ThemeRiver view with embedded color bars and changing glyphs to show the evolution of aggregation values related to each ranking category over time as well as the content changes in each ranking category; 3) a trend curve to show the degree of ranking changes over time; 4) rich user interactions to support interactive exploration of ranking changes. We have applied our method to some real time series data and the case studies demonstrate that our method can reveal the underlying patterns related to ranking changes which might otherwise be obscured in traditional visualizations.

  14. Augmenting the Deliberative Method for Ranking Risks.

    Science.gov (United States)

    Susel, Irving; Lasley, Trace; Montezemolo, Mark; Piper, Joel

    2016-01-01

    The Department of Homeland Security (DHS) characterized and prioritized the physical cross-border threats and hazards to the nation stemming from terrorism, market-driven illicit flows of people and goods (illegal immigration, narcotics, funds, counterfeits, and weaponry), and other nonmarket concerns (movement of diseases, pests, and invasive species). These threats and hazards pose a wide diversity of consequences with very different combinations of magnitudes and likelihoods, making it very challenging to prioritize them. This article presents the approach that was used at DHS to arrive at a consensus regarding the threats and hazards that stand out from the rest based on the overall risk they pose. Due to time constraints for the decision analysis, it was not feasible to apply multiattribute methodologies like multiattribute utility theory or the analytic hierarchy process. Using a holistic approach was considered, such as the deliberative method for ranking risks first published in this journal. However, an ordinal ranking alone does not indicate relative or absolute magnitude differences among the risks. Therefore, the use of the deliberative method for ranking risks is not sufficient for deciding whether there is a material difference between the top-ranked and bottom-ranked risks, let alone deciding what the stand-out risks are. To address this limitation of ordinal rankings, the deliberative method for ranking risks was augmented by adding an additional step to transform the ordinal ranking into a ratio scale ranking. This additional step enabled the selection of stand-out risks to help prioritize further analysis. © 2015 Society for Risk Analysis.

  15. Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response.

    Science.gov (United States)

    Davra, Viralkumar; Kimani, Stanley G; Calianese, David; Birge, Raymond B

    2016-11-29

    The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology. As a result, several classes of TAM inhibitors that include small molecule tyrosine kinase inhibitors, monoclonal antibodies, decoy receptors, as well as novel strategies to target TAM ligands are being developed. This paper will review the biology of TAM receptors and their ligands with a focus on cancer, as well as evidence-based data for the continued pursuit of TAM/Gas6 inhibitors in clinical practice.

  16. Communities in Large Networks: Identification and Ranking

    DEFF Research Database (Denmark)

    Olsen, Martin

    2008-01-01

    show that the problem of deciding whether a non trivial community exists is NP complete. Nevertheless, experiments show that a very simple greedy approach can identify members of a community in the Danish part of the web graph with time complexity only dependent on the size of the found community...... and its immediate surroundings. The members are ranked with a “local” variant of the PageRank algorithm. Results are reported from successful experiments on identifying and ranking Danish Computer Science sites and Danish Chess pages using only a few representatives....

  17. A Universal Rank-Size Law

    Science.gov (United States)

    2016-01-01

    A mere hyperbolic law, like the Zipf’s law power function, is often inadequate to describe rank-size relationships. An alternative theoretical distribution is proposed based on theoretical physics arguments starting from the Yule-Simon distribution. A modeling is proposed leading to a universal form. A theoretical suggestion for the “best (or optimal) distribution”, is provided through an entropy argument. The ranking of areas through the number of cities in various countries and some sport competition ranking serves for the present illustrations. PMID:27812192

  18. Metal-ligand interactions

    Science.gov (United States)

    Ervin, Kent M.

    Experimental studies of the interactions of small transition-metal cluster anions with carbonyl ligands are reviewed and compared with neutral and cationic clusters. Under thermal conditions, the reaction rates of transition-metal clusters with carbon monoxide are measured as a function of cluster size. Saturation limits for carbon monoxide addition can be related to the geometric structures of the clusters. Both energy-resolved threshold collision-induced dissociation experiments and time-resolved photodissociation experiments are used to measure metal-carbonyl binding energies. For platinum and palladium trimer anions, the carbonyl binding energies are assigned to different geometric binding sites. Platinum and palladium cluster anions catalyse the oxidation of carbon monoxide to carbon dioxide in a full catalytic cycle at thermal energies.

  19. Melatonin: functions and ligands.

    Science.gov (United States)

    Singh, Mahaveer; Jadhav, Hemant R

    2014-09-01

    Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the 'hormone of darkness'. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Azidoblebbistatin, a photoreactive myosin inhibitor

    Science.gov (United States)

    Képiró, Miklós; Várkuti, Boglárka H.; Bodor, Andrea; Hegyi, György; Drahos, László; Kovács, Mihály; Málnási-Csizmadia, András

    2012-01-01

    Photoreactive compounds are important tools in life sciences that allow precisely timed covalent crosslinking of ligands and targets. Using a unique technique we have synthesized azidoblebbistatin, which is a derivative of blebbistatin, the most widely used myosin inhibitor. Without UV irradiation azidoblebbistatin exhibits identical inhibitory properties to those of blebbistatin. Using UV irradiation, azidoblebbistatin can be covalently crosslinked to myosin, which greatly enhances its in vitro and in vivo effectiveness. Photo-crosslinking also eliminates limitations associated with the relatively low myosin affinity and water solubility of blebbistatin. The wavelength used for photo-crosslinking is not toxic for cells and tissues, which confers a great advantage in in vivo tests. Because the crosslink results in an irreversible association of the inhibitor to myosin and the irradiation eliminates the residual activity of unbound inhibitor molecules, azidoblebbistatin has a great potential to become a highly effective tool in both structural studies of actomyosin contractility and the investigation of cellular and physiological functions of myosin II. We used azidoblebbistatin to identify previously unknown low-affinity targets of the inhibitor (EC50 ≥ 50 μM) in Dictyostelium discoideum, while the strongest interactant was found to be myosin II (EC50 = 5 μM). Our results demonstrate that azidoblebbistatin, and potentially other azidated drugs, can become highly useful tools for the identification of strong- and weak-binding cellular targets and the determination of the apparent binding affinities in in vivo conditions. PMID:22647605

  1. Macrocyclic G-quadruplex ligands

    DEFF Research Database (Denmark)

    Nielsen, M C; Ulven, Trond

    2010-01-01

    are macrocyclic structures which have been modeled after the natural product telomestatin or from porphyrin-based ligands discovered in the late 1990s. These two structural classes of G-quadruplex ligands are reviewed here with special attention to selectivity and structure-activity relationships, and with focus...

  2. Scalable Faceted Ranking in Tagging Systems

    Science.gov (United States)

    Orlicki, José I.; Alvarez-Hamelin, J. Ignacio; Fierens, Pablo I.

    Nowadays, web collaborative tagging systems which allow users to upload, comment on and recommend contents, are growing. Such systems can be represented as graphs where nodes correspond to users and tagged-links to recommendations. In this paper we analyze the problem of computing a ranking of users with respect to a facet described as a set of tags. A straightforward solution is to compute a PageRank-like algorithm on a facet-related graph, but it is not feasible for online computation. We propose an alternative: (i) a ranking for each tag is computed offline on the basis of tag-related subgraphs; (ii) a faceted order is generated online by merging rankings corresponding to all the tags in the facet. Based on the graph analysis of YouTube and Flickr, we show that step (i) is scalable. We also present efficient algorithms for step (ii), which are evaluated by comparing their results with two gold standards.

  3. Evaluation of treatment effects by ranking

    DEFF Research Database (Denmark)

    Halekoh, U; Kristensen, K

    2008-01-01

    In crop experiments measurements are often made by a judge evaluating the crops' conditions after treatment. In the present paper an analysis is proposed for experiments where plots of crops treated differently are mutually ranked. In the experimental layout the crops are treated on consecutive...... plots usually placed side by side in one or more rows. In the proposed method a judge ranks several neighbouring plots, say three, by ranking them from best to worst. For the next observation the judge moves on by no more than two plots, such that up to two plots will be re-evaluated again...... in a comparison with the new plot(s). Data from studies using this set-up were analysed by a Thurstonian random utility model, which assumed that the judge's rankings were obtained by comparing latent continuous utilities or treatment effects. For the latent utilities a variance component model was considered...

  4. Superfund Hazard Ranking System Training Course

    Science.gov (United States)

    The Hazard Ranking System (HRS) training course is a four and ½ day, intermediate-level course designed for personnel who are required to compile, draft, and review preliminary assessments (PAs), site inspections (SIs), and HRS documentation records/packag

  5. Who's bigger? where historical figures really rank

    CERN Document Server

    Skiena, Steven

    2014-01-01

    Is Hitler bigger than Napoleon? Washington bigger than Lincoln? Picasso bigger than Einstein? Quantitative analysts are rapidly finding homes in social and cultural domains, from finance to politics. What about history? In this fascinating book, Steve Skiena and Charles Ward bring quantitative analysis to bear on ranking and comparing historical reputations. They evaluate each person by aggregating the traces of millions of opinions, just as Google ranks webpages. The book includes a technical discussion for readers interested in the details of the methods, but no mathematical or computational background is necessary to understand the rankings or conclusions. Along the way, the authors present the rankings of more than one thousand of history's most significant people in science, politics, entertainment, and all areas of human endeavor. Anyone interested in history or biography can see where their favorite figures place in the grand scheme of things.

  6. Ranking Forestry Investments With Parametric Linear Programming

    Science.gov (United States)

    Paul A. Murphy

    1976-01-01

    Parametric linear programming is introduced as a technique for ranking forestry investments under multiple constraints; it combines the advantages of simple tanking and linear programming as capital budgeting tools.

  7. Block models and personalized PageRank.

    Science.gov (United States)

    Kloumann, Isabel M; Ugander, Johan; Kleinberg, Jon

    2017-01-03

    Methods for ranking the importance of nodes in a network have a rich history in machine learning and across domains that analyze structured data. Recent work has evaluated these methods through the "seed set expansion problem": given a subset [Formula: see text] of nodes from a community of interest in an underlying graph, can we reliably identify the rest of the community? We start from the observation that the most widely used techniques for this problem, personalized PageRank and heat kernel methods, operate in the space of "landing probabilities" of a random walk rooted at the seed set, ranking nodes according to weighted sums of landing probabilities of different length walks. Both schemes, however, lack an a priori relationship to the seed set objective. In this work, we develop a principled framework for evaluating ranking methods by studying seed set expansion applied to the stochastic block model. We derive the optimal gradient for separating the landing probabilities of two classes in a stochastic block model and find, surprisingly, that under reasonable assumptions the gradient is asymptotically equivalent to personalized PageRank for a specific choice of the PageRank parameter [Formula: see text] that depends on the block model parameters. This connection provides a formal motivation for the success of personalized PageRank in seed set expansion and node ranking generally. We use this connection to propose more advanced techniques incorporating higher moments of landing probabilities; our advanced methods exhibit greatly improved performance, despite being simple linear classification rules, and are even competitive with belief propagation.

  8. Block models and personalized PageRank

    OpenAIRE

    Kloumann, Isabel M.; Ugander, Johan; Kleinberg, Jon

    2016-01-01

    Methods for ranking the importance of nodes in a network have a rich history in machine learning and across domains that analyze structured data. Recent work has evaluated these methods though the seed set expansion problem: given a subset $S$ of nodes from a community of interest in an underlying graph, can we reliably identify the rest of the community? We start from the observation that the most widely used techniques for this problem, personalized PageRank and heat kernel methods, operate...

  9. How Many Alternatives Can Be Ranked? A Comparison of the Paired Comparison and Ranking Methods.

    Science.gov (United States)

    Ock, Minsu; Yi, Nari; Ahn, Jeonghoon; Jo, Min-Woo

    2016-01-01

    To determine the feasibility of converting ranking data into paired comparison (PC) data and suggest the number of alternatives that can be ranked by comparing a PC and a ranking method. Using a total of 222 health states, a household survey was conducted in a sample of 300 individuals from the general population. Each respondent performed a PC 15 times and a ranking method 6 times (two attempts of ranking three, four, and five health states, respectively). The health states of the PC and the ranking method were constructed to overlap each other. We converted the ranked data into PC data and examined the consistency of the response rate. Applying probit regression, we obtained the predicted probability of each method. Pearson correlation coefficients were determined between the predicted probabilities of those methods. The mean absolute error was also assessed between the observed and the predicted values. The overall consistency of the response rate was 82.8%. The Pearson correlation coefficients were 0.789, 0.852, and 0.893 for ranking three, four, and five health states, respectively. The lowest mean absolute error was 0.082 (95% confidence interval [CI] 0.074-0.090) in ranking five health states, followed by 0.123 (95% CI 0.111-0.135) in ranking four health states and 0.126 (95% CI 0.113-0.138) in ranking three health states. After empirically examining the consistency of the response rate between a PC and a ranking method, we suggest that using five alternatives in the ranking method may be superior to using three or four alternatives. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  10. PPARγ ligand production is tightly linked to clonal expansion during initiation of adipocyte differentiation

    DEFF Research Database (Denmark)

    Hallenborg, Philip; Petersen, Rasmus Koefoed; Feddersen, Søren

    2014-01-01

    of differentiation. Concomitant with agonist production, murine fibroblasts undergo two rounds of mitosis referred to as mitotic clonal expansion. Here we show that mouse embryonic fibroblasts deficient in either of two cell cycle inhibitors, the transcription factor p53 or its target gene encoding the cyclin...... cycle inhibitory compounds decreased PPAR ligand production in differentiating 3T3-L1 preadipocytes. Furthermore, these inhibitors abolished the release of arachidonic acid induced by the hormonal cocktail initiating adipogenesis. Collectively, our results suggest that murine fibroblasts require clonal...... expansion for PPAR ligand production at the onset of adipocyte differentiation....

  11. Rank distributions: A panoramic macroscopic outlook

    Science.gov (United States)

    Eliazar, Iddo I.; Cohen, Morrel H.

    2014-01-01

    This paper presents a panoramic macroscopic outlook of rank distributions. We establish a general framework for the analysis of rank distributions, which classifies them into five macroscopic "socioeconomic" states: monarchy, oligarchy-feudalism, criticality, socialism-capitalism, and communism. Oligarchy-feudalism is shown to be characterized by discrete macroscopic rank distributions, and socialism-capitalism is shown to be characterized by continuous macroscopic size distributions. Criticality is a transition state between oligarchy-feudalism and socialism-capitalism, which can manifest allometric scaling with multifractal spectra. Monarchy and communism are extreme forms of oligarchy-feudalism and socialism-capitalism, respectively, in which the intrinsic randomness vanishes. The general framework is applied to three different models of rank distributions—top-down, bottom-up, and global—and unveils each model's macroscopic universality and versatility. The global model yields a macroscopic classification of the generalized Zipf law, an omnipresent form of rank distributions observed across the sciences. An amalgamation of the three models establishes a universal rank-distribution explanation for the macroscopic emergence of a prevalent class of continuous size distributions, ones governed by unimodal densities with both Pareto and inverse-Pareto power-law tails.

  12. Fair ranking of researchers and research teams.

    Science.gov (United States)

    Vavryčuk, Václav

    2018-01-01

    The main drawback of ranking of researchers by the number of papers, citations or by the Hirsch index is ignoring the problem of distributing authorship among authors in multi-author publications. So far, the single-author or multi-author publications contribute to the publication record of a researcher equally. This full counting scheme is apparently unfair and causes unjust disproportions, in particular, if ranked researchers have distinctly different collaboration profiles. These disproportions are removed by less common fractional or authorship-weighted counting schemes, which can distribute the authorship credit more properly and suppress a tendency to unjustified inflation of co-authors. The urgent need of widely adopting a fair ranking scheme in practise is exemplified by analysing citation profiles of several highly-cited astronomers and astrophysicists. While the full counting scheme often leads to completely incorrect and misleading ranking, the fractional or authorship-weighted schemes are more accurate and applicable to ranking of researchers as well as research teams. In addition, they suppress differences in ranking among scientific disciplines. These more appropriate schemes should urgently be adopted by scientific publication databases as the Web of Science (Thomson Reuters) or the Scopus (Elsevier).

  13. Class A scavenger receptor promotes osteoclast differentiation via the enhanced expression of receptor activator of NF-{kappa}B (RANK)

    Energy Technology Data Exchange (ETDEWEB)

    Takemura, Kenichi [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan); Department of Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (Japan); Sakashita, Naomi; Fujiwara, Yukio; Komohara, Yoshihiro; Lei, XiaoFeng; Ohnishi, Koji [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan); Suzuki, Hiroshi [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido (Japan); Kodama, Tatsuhiko [Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo (Japan); Mizuta, Hiroshi [Department of Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (Japan); Takeya, Motohiro, E-mail: takeya@kumamoto-u.ac.jp [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan)

    2010-01-22

    Osteoclasts originate from bone marrow monocyte/macrophage lineage cells, and their differentiation depends on macrophage colony-stimulating factor (M-CSF) and receptor activator nuclear factor kappa B (RANK) ligand. Class A scavenger receptor (SR-A) is one of the principal functional molecules of macrophages, and its level of expression declines during osteoclast differentiation. To investigate the role of SR-A in osteoclastogenesis, we examined pathological changes in femoral bone and the expression levels of osteoclastogenesis-related molecules in SR-A{sup -/-} mice. The femoral osseous density of SR-A{sup -/-} mice was higher than that of SR-A{sup +/+} mice, and the number of multinucleated osteoclasts was significantly decreased. An in vitro differentiation assay revealed that the differentiation of multinucleated osteoclasts from bone marrow-derived progenitor cells is impaired in SR-A{sup -/-} mice. Elimination of SR-A did not alter the expression level of the M-CSF receptor, c-fms; however, the expression levels of RANK and RANK-related osteoclast-differentiation molecules such as nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) and microphthalmia-associated transcription factor (MITF) significantly decreased. Furthermore, acetylated low-density lipoprotein (AcLDL), an SR-A ligand, significantly increased the expression level of RANK and MITF during osteoclast differentiation. These data indicate that SR-A promotes osteoclastogenesis via augmentation of the expression level of RANK and its related molecules.

  14. Expression profile of osteoprotegerin, RANK and RANKL genes in the femoral head of patients with avascular necrosis.

    Science.gov (United States)

    Samara, Stavroula; Dailiana, Zoe; Chassanidis, Christos; Koromila, Theodora; Papatheodorou, Loukia; Malizos, Konstantinos N; Kollia, Panagoula

    2014-02-01

    Femoral head avascular necrosis (AVN) is a recalcitrant disease of the hip that leads to joint destruction. Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor kappa-B (RANK) and RANK ligand (RANKL) regulate the balance between osteoclasts-osteoblasts. The expression of these genes affects the maturation and function of osteoblasts-osteoclasts and bone remodeling. In this study, we investigated the molecular pathways leading to AVN by studying the expression profile of OPG, RANK and RANKL genes. Quantitative Real Time-PCR was performed for evaluation of OPG, RANK and RANKL expression. Analysis was based on parallel evaluation of mRNA and protein levels in normal/necrotic sites of 42 osteonecrotic femoral heads (FHs). OPG and RANKL protein levels were estimated by western blotting. The OPG mRNA levels were higher (insignificantly) in the necrotic than the normal site (p > 0.05). Although the expression of RANK and RANKL was significantly lower than OPG in both sites, RANK and RANKL mRNA levels were higher in the necrotic part than the normal (p < 0.05). Protein levels of OPG and RANKL showed no remarkable divergence. Our results indicate that differential expression mechanisms for OPG, RANK and RANKL that could play an important role in the progress of bone remodeling in the necrotic area, disturbing bone homeostasis. This finding may have an effect on the resulting bone destruction and the subsequent collapse of the hip joint. Copyright © 2013. Published by Elsevier Inc.

  15. PageRank as a method to rank biomedical literature by importance.

    Science.gov (United States)

    Yates, Elliot J; Dixon, Louise C

    2015-01-01

    Optimal ranking of literature importance is vital in overcoming article overload. Existing ranking methods are typically based on raw citation counts, giving a sum of 'inbound' links with no consideration of citation importance. PageRank, an algorithm originally developed for ranking webpages at the search engine, Google, could potentially be adapted to bibliometrics to quantify the relative importance weightings of a citation network. This article seeks to validate such an approach on the freely available, PubMed Central open access subset (PMC-OAS) of biomedical literature. On-demand cloud computing infrastructure was used to extract a citation network from over 600,000 full-text PMC-OAS articles. PageRanks and citation counts were calculated for each node in this network. PageRank is highly correlated with citation count (R = 0.905, P PageRank can be trivially computed on commodity cluster hardware and is linearly correlated with citation count. Given its putative benefits in quantifying relative importance, we suggest it may enrich the citation network, thereby overcoming the existing inadequacy of citation counts alone. We thus suggest PageRank as a feasible supplement to, or replacement of, existing bibliometric ranking methods.

  16. Two novel mixed-ligand complexes containing organosulfonate ligands.

    Science.gov (United States)

    Li, Mingtian; Huang, Jun; Zhou, Xuan; Fang, Hua; Ding, Liyun

    2008-07-01

    The structures reported herein, viz. bis(4-aminonaphthalene-1-sulfonato-kappaO)bis(4,5-diazafluoren-9-one-kappa(2)N,N')copper(II), [Cu(C(10)H(8)NO(3)S)(2)(C(11)H(6)N(2)O)(2)], (I), and poly[[[diaquacadmium(II)]-bis(mu-4-aminonaphthalene-1-sulfonato)-kappa(2)O:N;kappa(2)N:O] dihydrate], {[Cd(C(10)H(8)NO(3)S)(2)(H(2)O)(2)].2H(2)O}(n), (II), are rare examples of sulfonate-containing complexes where the anion does not fulfill a passive charge-balancing role, but takes an active part in coordination as a monodentate and/or bridging ligand. Monomeric complex (I) possesses a crystallographic inversion center at the Cu(II) atom, and the asymmetric unit contains one-half of a Cu atom, one complete 4-aminonaphthalene-1-sulfonate (ans) ligand and one 4,5-diazafluoren-9-one (DAFO) ligand. The Cu(II) atom has an elongated distorted octahedral coordination geometry formed by two O atoms from two monodentate ans ligands and by four N atoms from two DAFO molecules. Complex (II) is polymeric and its crystal structure is built up by one-dimensional chains and solvent water molecules. Here also the cation (a Cd(II) atom) lies on a crystallographic inversion center and adopts a slightly distorted octahedral geometry. Each ans anion serves as a bridging ligand linking two Cd(II) atoms into one-dimensional infinite chains along the [010] direction, with each Cd(II) center coordinated by four ans ligands via O and N atoms and by two aqua ligands. In both structures, there are significant pi-pi stacking interactions between adjacent ligands and hydrogen bonds contribute to the formation of two- and three-dimensional networks.

  17. Country-specific determinants of world university rankings

    OpenAIRE

    Pietrucha, Jacek

    2017-01-01

    This paper examines country-specific factors that affect the three most influential world university rankings (the Academic Ranking of World Universities, the QS World University Ranking, and the Times Higher Education World University Ranking). We run a cross sectional regression that covers 42–71 countries (depending on the ranking and data availability). We show that the position of universities from a country in the ranking is determined by the following country-specific variables: econom...

  18. Global network centrality of university rankings

    Science.gov (United States)

    Guo, Weisi; Del Vecchio, Marco; Pogrebna, Ganna

    2017-10-01

    Universities and higher education institutions form an integral part of the national infrastructure and prestige. As academic research benefits increasingly from international exchange and cooperation, many universities have increased investment in improving and enabling their global connectivity. Yet, the relationship of university performance and its global physical connectedness has not been explored in detail. We conduct, to our knowledge, the first large-scale data-driven analysis into whether there is a correlation between university relative ranking performance and its global connectivity via the air transport network. The results show that local access to global hubs (as measured by air transport network betweenness) strongly and positively correlates with the ranking growth (statistical significance in different models ranges between 5% and 1% level). We also found that the local airport's aggregate flight paths (degree) and capacity (weighted degree) has no effect on university ranking, further showing that global connectivity distance is more important than the capacity of flight connections. We also examined the effect of local city economic development as a confounding variable and no effect was observed suggesting that access to global transportation hubs outweighs economic performance as a determinant of university ranking. The impact of this research is that we have determined the importance of the centrality of global connectivity and, hence, established initial evidence for further exploring potential connections between university ranking and regional investment policies on improving global connectivity.

  19. Diversity rankings among bacterial lineages in soil.

    Science.gov (United States)

    Youssef, Noha H; Elshahed, Mostafa S

    2009-03-01

    We used rarefaction curve analysis and diversity ordering-based approaches to rank the 11 most frequently encountered bacterial lineages in soil according to diversity in 5 previously reported 16S rRNA gene clone libraries derived from agricultural, undisturbed tall grass prairie and forest soils (n=26,140, 28 328, 31 818, 13 001 and 53 533). The Planctomycetes, Firmicutes and the delta-Proteobacteria were consistently ranked among the most diverse lineages in all data sets, whereas the Verrucomicrobia, Gemmatimonadetes and beta-Proteobacteria were consistently ranked among the least diverse. On the other hand, the rankings of alpha-Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes and Chloroflexi varied widely in different soil clone libraries. In general, lineages exhibiting largest differences in diversity rankings also exhibited the largest difference in relative abundance in the data sets examined. Within these lineages, a positive correlation between relative abundance and diversity was observed within the Acidobacteria, Actinobacteria and Chloroflexi, and a negative diversity-abundance correlation was observed within the Bacteroidetes. The ecological and evolutionary implications of these results are discussed.

  20. Social class rank, essentialism, and punitive judgment.

    Science.gov (United States)

    Kraus, Michael W; Keltner, Dacher

    2013-08-01

    Recent evidence suggests that perceptions of social class rank influence a variety of social cognitive tendencies, from patterns of causal attribution to moral judgment. In the present studies we tested the hypotheses that upper-class rank individuals would be more likely to endorse essentialist lay theories of social class categories (i.e., that social class is founded in genetically based, biological differences) than would lower-class rank individuals and that these beliefs would decrease support for restorative justice--which seeks to rehabilitate offenders, rather than punish unlawful action. Across studies, higher social class rank was associated with increased essentialism of social class categories (Studies 1, 2, and 4) and decreased support for restorative justice (Study 4). Moreover, manipulated essentialist beliefs decreased preferences for restorative justice (Study 3), and the association between social class rank and class-based essentialist theories was explained by the tendency to endorse beliefs in a just world (Study 2). Implications for how class-based essentialist beliefs potentially constrain social opportunity and mobility are discussed.

  1. Correcting ligands, metabolites, and pathways

    NARCIS (Netherlands)

    Ott, M.A.; Vriend, G.

    2006-01-01

    BACKGROUND: A wide range of research areas in bioinformatics, molecular biology and medicinal chemistry require precise chemical structure information about molecules and reactions, e.g. drug design, ligand docking, metabolic network reconstruction, and systems biology. Most available databases,

  2. Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells.

    Science.gov (United States)

    Tanimoto, Azusa; Yamada, Tadaaki; Nanjo, Shigeki; Takeuchi, Shinji; Ebi, Hiromichi; Kita, Kenji; Matsumoto, Kunio; Yano, Seiji

    2014-07-15

    Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4)--anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.

  3. Low Rank Approximation Algorithms, Implementation, Applications

    CERN Document Server

    Markovsky, Ivan

    2012-01-01

    Matrix low-rank approximation is intimately related to data modelling; a problem that arises frequently in many different fields. Low Rank Approximation: Algorithms, Implementation, Applications is a comprehensive exposition of the theory, algorithms, and applications of structured low-rank approximation. Local optimization methods and effective suboptimal convex relaxations for Toeplitz, Hankel, and Sylvester structured problems are presented. A major part of the text is devoted to application of the theory. Applications described include: system and control theory: approximate realization, model reduction, output error, and errors-in-variables identification; signal processing: harmonic retrieval, sum-of-damped exponentials, finite impulse response modeling, and array processing; machine learning: multidimensional scaling and recommender system; computer vision: algebraic curve fitting and fundamental matrix estimation; bioinformatics for microarray data analysis; chemometrics for multivariate calibration; ...

  4. Resolution of ranking hierarchies in directed networks

    Science.gov (United States)

    Barucca, Paolo; Lillo, Fabrizio

    2018-01-01

    Identifying hierarchies and rankings of nodes in directed graphs is fundamental in many applications such as social network analysis, biology, economics, and finance. A recently proposed method identifies the hierarchy by finding the ordered partition of nodes which minimises a score function, termed agony. This function penalises the links violating the hierarchy in a way depending on the strength of the violation. To investigate the resolution of ranking hierarchies we introduce an ensemble of random graphs, the Ranked Stochastic Block Model. We find that agony may fail to identify hierarchies when the structure is not strong enough and the size of the classes is small with respect to the whole network. We analytically characterise the resolution threshold and we show that an iterated version of agony can partly overcome this resolution limit. PMID:29394278

  5. Ranking beta sheet topologies of proteins

    DEFF Research Database (Denmark)

    Fonseca, Rasmus; Helles, Glennie; Winter, Pawel

    2010-01-01

    One of the challenges of protein structure prediction is to identify long-range interactions between amino acids. To reliably predict such interactions, we enumerate, score and rank all beta-topologies (partitions of beta-strands into sheets, orderings of strands within sheets and orientations...... of paired strands) of a given protein. We show that the beta-topology corresponding to the native structure is, with high probability, among the top-ranked. Since full enumeration is very time-consuming, we also suggest a method to deal with proteins with many beta-strands. The results reported...... in this paper are highly relevant for ab initio protein structure prediction methods based on decoy generation. The top-ranked beta-topologies can be used to find initial conformations from which conformational searches can be started. They can also be used to filter decoys by removing those with poorly...

  6. Data envelopment analysis of randomized ranks

    Directory of Open Access Journals (Sweden)

    Sant'Anna Annibal P.

    2002-01-01

    Full Text Available Probabilities and odds, derived from vectors of ranks, are here compared as measures of efficiency of decision-making units (DMUs. These measures are computed with the goal of providing preliminary information before starting a Data Envelopment Analysis (DEA or the application of any other evaluation or composition of preferences methodology. Preferences, quality and productivity evaluations are usually measured with errors or subject to influence of other random disturbances. Reducing evaluations to ranks and treating the ranks as estimates of location parameters of random variables, we are able to compute the probability of each DMU being classified as the best according to the consumption of each input and the production of each output. Employing the probabilities of being the best as efficiency measures, we stretch distances between the most efficient units. We combine these partial probabilities in a global efficiency score determined in terms of proximity to the efficiency frontier.

  7. Ranking spreaders by decomposing complex networks

    International Nuclear Information System (INIS)

    Zeng, An; Zhang, Cheng-Jun

    2013-01-01

    Ranking the nodes' ability of spreading in networks is crucial for designing efficient strategies to hinder spreading in the case of diseases or accelerate spreading in the case of information dissemination. In the well-known k-shell method, nodes are ranked only according to the links between the remaining nodes (residual links) while the links connecting to the removed nodes (exhausted links) are entirely ignored. In this Letter, we propose a mixed degree decomposition (MDD) procedure in which both the residual degree and the exhausted degree are considered. By simulating the epidemic spreading process on real networks, we show that the MDD method can outperform the k-shell and degree methods in ranking spreaders.

  8. Sign rank versus Vapnik-Chervonenkis dimension

    Science.gov (United States)

    Alon, N.; Moran, Sh; Yehudayoff, A.

    2017-12-01

    This work studies the maximum possible sign rank of sign (N × N)-matrices with a given Vapnik-Chervonenkis dimension d. For d=1, this maximum is three. For d=2, this maximum is \\widetilde{\\Theta}(N1/2). For d >2, similar but slightly less accurate statements hold. The lower bounds improve on previous ones by Ben-David et al., and the upper bounds are novel. The lower bounds are obtained by probabilistic constructions, using a theorem of Warren in real algebraic topology. The upper bounds are obtained using a result of Welzl about spanning trees with low stabbing number, and using the moment curve. The upper bound technique is also used to: (i) provide estimates on the number of classes of a given Vapnik-Chervonenkis dimension, and the number of maximum classes of a given Vapnik-Chervonenkis dimension--answering a question of Frankl from 1989, and (ii) design an efficient algorithm that provides an O(N/log(N)) multiplicative approximation for the sign rank. We also observe a general connection between sign rank and spectral gaps which is based on Forster's argument. Consider the adjacency (N × N)-matrix of a Δ-regular graph with a second eigenvalue of absolute value λ and Δ ≤ N/2. We show that the sign rank of the signed version of this matrix is at least Δ/λ. We use this connection to prove the existence of a maximum class C\\subseteq\\{+/- 1\\}^N with Vapnik-Chervonenkis dimension 2 and sign rank \\widetilde{\\Theta}(N1/2). This answers a question of Ben-David et al. regarding the sign rank of large Vapnik-Chervonenkis classes. We also describe limitations of this approach, in the spirit of the Alon-Boppana theorem. We further describe connections to communication complexity, geometry, learning theory, and combinatorics. Bibliography: 69 titles.

  9. RankProdIt: A web-interactive Rank Products analysis tool

    Directory of Open Access Journals (Sweden)

    Laing Emma

    2010-08-01

    Full Text Available Abstract Background The first objective of a DNA microarray experiment is typically to generate a list of genes or probes that are found to be differentially expressed or represented (in the case of comparative genomic hybridizations and/or copy number variation between two conditions or strains. Rank Products analysis comprises a robust algorithm for deriving such lists from microarray experiments that comprise small numbers of replicates, for example, less than the number required for the commonly used t-test. Currently, users wishing to apply Rank Products analysis to their own microarray data sets have been restricted to the use of command line-based software which can limit its usage within the biological community. Findings Here we have developed a web interface to existing Rank Products analysis tools allowing users to quickly process their data in an intuitive and step-wise manner to obtain the respective Rank Product or Rank Sum, probability of false prediction and p-values in a downloadable file. Conclusions The online interactive Rank Products analysis tool RankProdIt, for analysis of any data set containing measurements for multiple replicated conditions, is available at: http://strep-microarray.sbs.surrey.ac.uk/RankProducts

  10. Rank-based Tests of the Cointegrating Rank in Semiparametric Error Correction Models

    NARCIS (Netherlands)

    Hallin, M.; van den Akker, R.; Werker, B.J.M.

    2012-01-01

    Abstract: This paper introduces rank-based tests for the cointegrating rank in an Error Correction Model with i.i.d. elliptical innovations. The tests are asymptotically distribution-free, and their validity does not depend on the actual distribution of the innovations. This result holds despite the

  11. When sparse coding meets ranking: a joint framework for learning sparse codes and ranking scores

    KAUST Repository

    Wang, Jim Jing-Yan

    2017-06-28

    Sparse coding, which represents a data point as a sparse reconstruction code with regard to a dictionary, has been a popular data representation method. Meanwhile, in database retrieval problems, learning the ranking scores from data points plays an important role. Up to now, these two problems have always been considered separately, assuming that data coding and ranking are two independent and irrelevant problems. However, is there any internal relationship between sparse coding and ranking score learning? If yes, how to explore and make use of this internal relationship? In this paper, we try to answer these questions by developing the first joint sparse coding and ranking score learning algorithm. To explore the local distribution in the sparse code space, and also to bridge coding and ranking problems, we assume that in the neighborhood of each data point, the ranking scores can be approximated from the corresponding sparse codes by a local linear function. By considering the local approximation error of ranking scores, the reconstruction error and sparsity of sparse coding, and the query information provided by the user, we construct a unified objective function for learning of sparse codes, the dictionary and ranking scores. We further develop an iterative algorithm to solve this optimization problem.

  12. Learning to rank for information retrieval

    CERN Document Server

    Liu, Tie-Yan

    2011-01-01

    Due to the fast growth of the Web and the difficulties in finding desired information, efficient and effective information retrieval systems have become more important than ever, and the search engine has become an essential tool for many people. The ranker, a central component in every search engine, is responsible for the matching between processed queries and indexed documents. Because of its central role, great attention has been paid to the research and development of ranking technologies. In addition, ranking is also pivotal for many other information retrieval applications, such as coll

  13. Cointegration rank testing under conditional heteroskedasticity

    DEFF Research Database (Denmark)

    Cavaliere, Giuseppe; Rahbek, Anders Christian; Taylor, Robert M.

    2010-01-01

    We analyze the properties of the conventional Gaussian-based cointegrating rank tests of Johansen (1996, Likelihood-Based Inference in Cointegrated Vector Autoregressive Models) in the case where the vector of series under test is driven by globally stationary, conditionally heteroskedastic......, relative to tests based on the asymptotic critical values or the i.i.d. bootstrap, the wild bootstrap rank tests perform very well in small samples under a variety of conditionally heteroskedastic innovation processes. An empirical application to the term structure of interest rates is given....

  14. Ranking health between countries in international comparisons

    DEFF Research Database (Denmark)

    Brønnum-Hansen, Henrik

    2014-01-01

    Cross-national comparisons and ranking of summary measures of population health sometimes give rise to inconsistent and diverging conclusions. In order to minimise confusion, international comparative studies ought to be based on well-harmonised data with common standards of definitions and docum......Cross-national comparisons and ranking of summary measures of population health sometimes give rise to inconsistent and diverging conclusions. In order to minimise confusion, international comparative studies ought to be based on well-harmonised data with common standards of definitions...

  15. Preference Learning and Ranking by Pairwise Comparison

    Science.gov (United States)

    Fürnkranz, Johannes; Hüllermeier, Eyke

    This chapter provides an overview of recent work on preference learning and ranking via pairwise classification. The learning by pairwise comparison (LPC) paradigm is the natural machine learning counterpart to the relational approach to preference modeling and decision making. From a machine learning point of view, LPC is especially appealing as it decomposes a possibly complex prediction problem into a certain number of learning problems of the simplest type, namely binary classification. We explain how to approach different preference learning problems, such as label and instance ranking, within the framework of LPC. We primarily focus on methodological aspects, but also address theoretical questions as well as algorithmic and complexity issues.

  16. Compressed Sensing with Rank Deficient Dictionaries

    DEFF Research Database (Denmark)

    Hansen, Thomas Lundgaard; Johansen, Daniel Højrup; Jørgensen, Peter Bjørn

    2012-01-01

    In compressed sensing it is generally assumed that the dictionary matrix constitutes a (possibly overcomplete) basis of the signal space. In this paper we consider dictionaries that do not span the signal space, i.e. rank deficient dictionaries. We show that in this case the signal-to-noise ratio...... (SNR) in the compressed samples can be increased by selecting the rows of the measurement matrix from the column space of the dictionary. As an example application of compressed sensing with a rank deficient dictionary, we present a case study of compressed sensing applied to the Coarse Acquisition (C...

  17. Ranking mutual funds using Sortino method

    Directory of Open Access Journals (Sweden)

    Khosro Faghani Makrani

    2014-04-01

    Full Text Available One of the primary concerns on most business activities is to determine an efficient method for ranking mutual funds. This paper performs an empirical investigation to rank 42 mutual funds listed on Tehran Stock Exchange using Sortino method over the period 2011-2012. The results of survey have been compared with market return and the results have confirmed that there were some positive and meaningful relationships between Sortino return and market return. In addition, there were some positive and meaningful relationship between two Sortino methods.

  18. Research of Subgraph Estimation Page Rank Algorithm for Web Page Rank

    Directory of Open Access Journals (Sweden)

    LI Lan-yin

    2017-04-01

    Full Text Available The traditional PageRank algorithm can not efficiently perform large data Webpage scheduling problem. This paper proposes an accelerated algorithm named topK-Rank,which is based on PageRank on the MapReduce platform. It can find top k nodes efficiently for a given graph without sacrificing accuracy. In order to identify top k nodes,topK-Rank algorithm prunes unnecessary nodes and edges in each iteration to dynamically construct subgraphs,and iteratively estimates lower/upper bounds of PageRank scores through subgraphs. Theoretical analysis shows that this method guarantees result exactness. Experiments show that topK-Rank algorithm can find k nodes much faster than the existing approaches.

  19. In-silico screening and validation of high-affinity tetra-peptide inhibitor of Leishmania donovani O-acetyl serine sulfhydrylase (OASS).

    Science.gov (United States)

    Kant, Vishnu; Vijayakumar, Saravanan; Sahoo, Ganesh Chandra; Chaudhery, Shailendra S; Das, Pradeep

    2018-02-07

    OASS is a specific enzyme that helps Leishmania parasite to survive the oxidative stress condition in human macrophages. SAT C-terminal peptides in several organisms, including Leishmania, were reported to inhibit or reduce the activity of OASS. Small peptide and small molecules mimicking the SAT C-terminal residues are designed and tested for the inhibition of OASS in different organisms. Hence, in this study, all the possible tetra-peptide combinations were designed and screened based on the docking ability with Leishmania donovani OASS (Ld-OASS). The top ranked peptides were further validated for the stability using 50 ns molecular dynamic simulation. In order to identify the better binding capability of the peptides, the top peptides complexed with Ld-OASS were also subjected to molecular dynamic simulation. The docking and simulation results favored the peptide EWSI to possess greater advantage than previously reported peptide (DWSI) in binding with Ld-OASS active site. Also, screening of non-peptide inhibitor of Asinex Biodesign library based on the shape similarity of EWSI and DWSI was performed. The top similar molecules of each peptides were docked on to Ld-OASS active site and subsequently simulated for 20 ns. The results suggested that the ligand that shares high shape similarity with EWSI possess better binding capability than the ligand that shares high shape similarity with DWSI. This study revealed that the tetra-peptide EWSI had marginal advantage over DWSI in binding with Ld-OASS, thereby providing basis for defining a pharmacophoric scaffold for the design of peptidomimetic inhibitors as well as non-peptide inhibitors of Ld-OASS.

  20. AMMOS2: a web server for protein-ligand-water complexes refinement via molecular mechanics.

    Science.gov (United States)

    Labbé, Céline M; Pencheva, Tania; Jereva, Dessislava; Desvillechabrol, Dimitri; Becot, Jérôme; Villoutreix, Bruno O; Pajeva, Ilza; Miteva, Maria A

    2017-07-03

    AMMOS2 is an interactive web server for efficient computational refinement of protein-small organic molecule complexes. The AMMOS2 protocol employs atomic-level energy minimization of a large number of experimental or modeled protein-ligand complexes. The web server is based on the previously developed standalone software AMMOS (Automatic Molecular Mechanics Optimization for in silico Screening). AMMOS utilizes the physics-based force field AMMP sp4 and performs optimization of protein-ligand interactions at five levels of flexibility of the protein receptor. The new version 2 of AMMOS implemented in the AMMOS2 web server allows the users to include explicit water molecules and individual metal ions in the protein-ligand complexes during minimization. The web server provides comprehensive analysis of computed energies and interactive visualization of refined protein-ligand complexes. The ligands are ranked by the minimized binding energies allowing the users to perform additional analysis for drug discovery or chemical biology projects. The web server has been extensively tested on 21 diverse protein-ligand complexes. AMMOS2 minimization shows consistent improvement over the initial complex structures in terms of minimized protein-ligand binding energies and water positions optimization. The AMMOS2 web server is freely available without any registration requirement at the URL: http://drugmod.rpbs.univ-paris-diderot.fr/ammosHome.php. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. RANK, RANKL and osteoprotegerin in arthritic bone loss

    Directory of Open Access Journals (Sweden)

    M.C. Bezerra

    2005-02-01

    Full Text Available Rheumatoid arthritis is characterized by the presence of inflammatory synovitis and destruction of joint cartilage and bone. Tissue proteinases released by synovia, chondrocytes and pannus can cause cartilage destruction and cytokine-activated osteoclasts have been implicated in bone erosions. Rheumatoid arthritis synovial tissues produce a variety of cytokines and growth factors that induce monocyte differentiation to osteoclasts and their proliferation, activation and longer survival in tissues. More recently, a major role in bone erosion has been attributed to the receptor activator of nuclear factor kappa B ligand (RANKL released by activated lymphocytes and osteoblasts. In fact, osteoclasts are markedly activated after RANKL binding to the cognate RANK expressed on the surface of these cells. RANKL expression can be upregulated by bone-resorbing factors such as glucocorticoids, vitamin D3, interleukin 1 (IL-1, IL-6, IL-11, IL-17, tumor necrosis factor-alpha, prostaglandin E2, or parathyroid hormone-related peptide. Supporting this idea, inhibition of RANKL by osteoprotegerin, a natural soluble RANKL receptor, prevents bone loss in experimental models. Tumor growth factor-ß released from bone during active bone resorption has been suggested as one feedback mechanism for upregulating osteoprotegerin and estrogen can increase its production on osteoblasts. Modulation of these systems provides the opportunity to inhibit bone loss and deformity in chronic arthritis.

  2. A ranking method for the concurrent learning of compounds with various activity profiles.

    Science.gov (United States)

    Dörr, Alexander; Rosenbaum, Lars; Zell, Andreas

    2015-01-01

    In this study, we present a SVM-based ranking algorithm for the concurrent learning of compounds with different activity profiles and their varying prioritization. To this end, a specific labeling of each compound was elaborated in order to infer virtual screening models against multiple targets. We compared the method with several state-of-the-art SVM classification techniques that are capable of inferring multi-target screening models on three chemical data sets (cytochrome P450s, dehydrogenases, and a trypsin-like protease data set) containing three different biological targets each. The experiments show that ranking-based algorithms show an increased performance for single- and multi-target virtual screening. Moreover, compounds that do not completely fulfill the desired activity profile are still ranked higher than decoys or compounds with an entirely undesired profile, compared to other multi-target SVM methods. SVM-based ranking methods constitute a valuable approach for virtual screening in multi-target drug design. The utilization of such methods is most helpful when dealing with compounds with various activity profiles and the finding of many ligands with an already perfectly matching activity profile is not to be expected.

  3. Subject Gateway Sites and Search Engine Ranking.

    Science.gov (United States)

    Thelwall, Mike

    2002-01-01

    Discusses subject gateway sites and commercial search engines for the Web and presents an explanation of Google's PageRank algorithm. The principle question addressed is the conditions under which a gateway site will increase the likelihood that a target page is found in search engines. (LRW)

  4. Rank reduction of correlation matrices by majorization

    NARCIS (Netherlands)

    R. Pietersz (Raoul); P.J.F. Groenen (Patrick)

    2004-01-01

    textabstractIn this paper a novel method is developed for the problem of finding a low-rank correlation matrix nearest to a given correlation matrix. The method is based on majorization and therefore it is globally convergent. The method is computationally efficient, is straightforward to implement,

  5. Ranking related entities: components and analyses

    NARCIS (Netherlands)

    Bron, M.; Balog, K.; de Rijke, M.

    2010-01-01

    Related entity finding is the task of returning a ranked list of homepages of relevant entities of a specified type that need to engage in a given relationship with a given source entity. We propose a framework for addressing this task and perform a detailed analysis of four core components;

  6. Ranking Very Many Typed Entities on Wikipedia

    NARCIS (Netherlands)

    Zaragoza, Hugo; Rode, H.; Mika, Peter; Atserias, Jordi; Ciaramita, Massimiliano; Attardi, Guiseppe

    2007-01-01

    We discuss the problem of ranking very many entities of different types. In particular we deal with a heterogeneous set of types, some being very generic and some very specific. We discuss two approaches for this problem: i) exploiting the entity containment graph and ii) using a Web search engine

  7. On the Dirac groups of rank n

    International Nuclear Information System (INIS)

    Ferreira, P.L.; Alcaras, J.A.C.

    1980-01-01

    The group theoretical properties of the Dirac groups of rank n are discussed together with the properties and construction of their IR's. The cases n even and n odd show distinct features. Furthermore, for n odd, the cases n=4K+1 and n=4K+3 exhibit some different properties too. (Author) [pt

  8. On rank 2 Seiberg-Witten equations

    International Nuclear Information System (INIS)

    Massamba, F.; Thompson, G.

    2004-02-01

    We introduce and study a set of rank 2 Seiberg-Witten equations. We show that the moduli space of solutions is a compact, orientational and smooth manifold. For minimal surfaces of general type we are able to determine the basic classes. (author)

  9. A tilting approach to ranking influence

    KAUST Repository

    Genton, Marc G.; Hall, Peter

    2014-01-01

    We suggest a new approach, which is applicable for general statistics computed from random samples of univariate or vector-valued or functional data, to assessing the influence that individual data have on the value of a statistic, and to ranking

  10. Texture Repairing by Unified Low Rank Optimization

    Institute of Scientific and Technical Information of China (English)

    Xiao Liang; Xiang Ren; Zhengdong Zhang; Yi Ma

    2016-01-01

    In this paper, we show how to harness both low-rank and sparse structures in regular or near-regular textures for image completion. Our method is based on a unified formulation for both random and contiguous corruption. In addition to the low rank property of texture, the algorithm also uses the sparse assumption of the natural image: because the natural image is piecewise smooth, it is sparse in certain transformed domain (such as Fourier or wavelet transform). We combine low-rank and sparsity properties of the texture image together in the proposed algorithm. Our algorithm based on convex optimization can automatically and correctly repair the global structure of a corrupted texture, even without precise information about the regions to be completed. This algorithm integrates texture rectification and repairing into one optimization problem. Through extensive simulations, we show our method can complete and repair textures corrupted by errors with both random and contiguous supports better than existing low-rank matrix recovery methods. Our method demonstrates significant advantage over local patch based texture synthesis techniques in dealing with large corruption, non-uniform texture, and large perspective deformation.

  11. Semantic association ranking schemes for information retrieval ...

    Indian Academy of Sciences (India)

    retrieval applications using term association graph representation ... Department of Computer Science and Engineering, Government College of ... Introduction ... leads to poor precision, e.g., model, python, and chip. ...... The approaches proposed in this paper focuses on the query-centric re-ranking of search results.

  12. Efficient Rank Reduction of Correlation Matrices

    NARCIS (Netherlands)

    I. Grubisic (Igor); R. Pietersz (Raoul)

    2005-01-01

    textabstractGeometric optimisation algorithms are developed that efficiently find the nearest low-rank correlation matrix. We show, in numerical tests, that our methods compare favourably to the existing methods in the literature. The connection with the Lagrange multiplier method is established,

  13. Zero forcing parameters and minimum rank problems

    NARCIS (Netherlands)

    Barioli, F.; Barrett, W.; Fallat, S.M.; Hall, H.T.; Hogben, L.; Shader, B.L.; Driessche, van den P.; Holst, van der H.

    2010-01-01

    The zero forcing number Z(G), which is the minimum number of vertices in a zero forcing set of a graph G, is used to study the maximum nullity/minimum rank of the family of symmetric matrices described by G. It is shown that for a connected graph of order at least two, no vertex is in every zero

  14. A note on ranking assignments using reoptimization

    DEFF Research Database (Denmark)

    Pedersen, Christian Roed; Nielsen, L.R.; Andersen, K.A.

    2005-01-01

    We consider the problem of ranking assignments according to cost in the classical linear assignment problem. An algorithm partitioning the set of possible assignments, as suggested by Murty, is presented where, for each partition, the optimal assignment is calculated using a new reoptimization...

  15. Language Games: University Responses to Ranking Metrics

    Science.gov (United States)

    Heffernan, Troy A.; Heffernan, Amanda

    2018-01-01

    League tables of universities that measure performance in various ways are now commonplace, with numerous bodies providing their own rankings of how institutions throughout the world are seen to be performing on a range of metrics. This paper uses Lyotard's notion of language games to theorise that universities are regaining some power over being…

  16. Ranking Thinning Potential of Lodgepole Pine Stands

    OpenAIRE

    United States Department of Agriculture, Forest Service

    1987-01-01

    This paper presents models for predicting edge-response of dominant and codominant trees to clearing. Procedures are given for converting predictions to a thinning response index, for ranking stands for thinning priority. Data requirements, sampling suggestions, examples of application, and suggestions for management use are included to facilitate use as a field guide.

  17. Primate Innovation: Sex, Age and Social Rank

    NARCIS (Netherlands)

    Reader, S.M.; Laland, K.N.

    2001-01-01

    Analysis of an exhaustive survey of primate behavior collated from the published literature revealed significant variation in rates of innovation among individuals of different sex, age and social rank. We searched approximately 1,000 articles in four primatology journals, together with other

  18. Biomechanics Scholar Citations across Academic Ranks

    Directory of Open Access Journals (Sweden)

    Knudson Duane

    2015-11-01

    Full Text Available Study aim: citations to the publications of a scholar have been used as a measure of the quality or influence of their research record. A world-wide descriptive study of the citations to the publications of biomechanics scholars of various academic ranks was conducted.

  19. An algorithm for ranking assignments using reoptimization

    DEFF Research Database (Denmark)

    Pedersen, Christian Roed; Nielsen, Lars Relund; Andersen, Kim Allan

    2008-01-01

    We consider the problem of ranking assignments according to cost in the classical linear assignment problem. An algorithm partitioning the set of possible assignments, as suggested by Murty, is presented where, for each partition, the optimal assignment is calculated using a new reoptimization...... technique. Computational results for the new algorithm are presented...

  20. Ranking Workplace Competencies: Student and Graduate Perceptions.

    Science.gov (United States)

    Rainsbury, Elizabeth; Hodges, Dave; Burchell, Noel; Lay, Mark

    2002-01-01

    New Zealand business students and graduates made similar rankings of the five most important workplace competencies: computer literacy, customer service orientation, teamwork and cooperation, self-confidence, and willingness to learn. Graduates placed greater importance on most of the 24 competencies, resulting in a statistically significant…

  1. Comparing survival curves using rank tests

    NARCIS (Netherlands)

    Albers, Willem/Wim

    1990-01-01

    Survival times of patients can be compared using rank tests in various experimental setups, including the two-sample case and the case of paired data. Attention is focussed on two frequently occurring complications in medical applications: censoring and tail alternatives. A review is given of the

  2. A generalization of Friedman's rank statistic

    NARCIS (Netherlands)

    Kroon, de J.; Laan, van der P.

    1983-01-01

    In this paper a very natural generalization of the two·way analysis of variance rank statistic of FRIEDMAN is given. The general distribution-free test procedure based on this statistic for the effect of J treatments in a random block design can be applied in general two-way layouts without

  3. Probabilistic relation between In-Degree and PageRank

    NARCIS (Netherlands)

    Litvak, Nelli; Scheinhardt, Willem R.W.; Volkovich, Y.

    2008-01-01

    This paper presents a novel stochastic model that explains the relation between power laws of In-Degree and PageRank. PageRank is a popularity measure designed by Google to rank Web pages. We model the relation between PageRank and In-Degree through a stochastic equation, which is inspired by the

  4. Generalized reduced rank tests using the singular value decomposition

    NARCIS (Netherlands)

    Kleibergen, F.R.; Paap, R.

    2002-01-01

    We propose a novel statistic to test the rank of a matrix. The rank statistic overcomes deficiencies of existing rank statistics, like: necessity of a Kronecker covariance matrix for the canonical correlation rank statistic of Anderson (1951), sensitivity to the ordering of the variables for the LDU

  5. Nominal versus Attained Weights in Universitas 21 Ranking

    Science.gov (United States)

    Soh, Kaycheng

    2014-01-01

    Universitas 21 Ranking of National Higher Education Systems (U21 Ranking) is one of the three new ranking systems appearing in 2012. In contrast with the other systems, U21 Ranking uses countries as the unit of analysis. It has several features which lend it with greater trustworthiness, but it also shared some methodological issues with the other…

  6. The effect of new links on Google PageRank

    NARCIS (Netherlands)

    Avrachenkov, Konstatin; Litvak, Nelli

    2004-01-01

    PageRank is one of the principle criteria according to which Google ranks Web pages. PageRank can be interpreted as a frequency of visiting a Web page by a random surfer and thus it reflects the popularity of a Web page. We study the effect of newly created links on Google PageRank. We discuss to

  7. Generalized Reduced Rank Tests using the Singular Value Decomposition

    NARCIS (Netherlands)

    F.R. Kleibergen (Frank); R. Paap (Richard)

    2003-01-01

    textabstractWe propose a novel statistic to test the rank of a matrix. The rank statistic overcomes deficiencies of existing rank statistics, like: necessity of a Kronecker covariance matrix for the canonical correlation rank statistic of Anderson (1951), sensitivity to the ordering of the variables

  8. Determination of activities of human carbonic anhydrase II inhibitors ...

    African Journals Online (AJOL)

    Purpose: To evaluate the activities of new curcumin analogs as carbonic anhydrase II (CA-II) inhibitor. Methods: Carbonic anhydrase II (CA-II) inhibition was determined by each ligand capability to inhibit the esterase activity of CA-II using 4-NPA as a substrate in 96-well plates. Dimethyl sulfoxide was used to dissolve each ...

  9. VaRank: a simple and powerful tool for ranking genetic variants

    Directory of Open Access Journals (Sweden)

    Véronique Geoffroy

    2015-03-01

    Full Text Available Background. Most genetic disorders are caused by single nucleotide variations (SNVs or small insertion/deletions (indels. High throughput sequencing has broadened the catalogue of human variation, including common polymorphisms, rare variations or disease causing mutations. However, identifying one variation among hundreds or thousands of others is still a complex task for biologists, geneticists and clinicians.Results. We have developed VaRank, a command-line tool for the ranking of genetic variants detected by high-throughput sequencing. VaRank scores and prioritizes variants annotated either by Alamut Batch or SnpEff. A barcode allows users to quickly view the presence/absence of variants (with homozygote/heterozygote status in analyzed samples. VaRank supports the commonly used VCF input format for variants analysis thus allowing it to be easily integrated into NGS bioinformatics analysis pipelines. VaRank has been successfully applied to disease-gene identification as well as to molecular diagnostics setup for several hundred patients.Conclusions. VaRank is implemented in Tcl/Tk, a scripting language which is platform-independent but has been tested only on Unix environment. The source code is available under the GNU GPL, and together with sample data and detailed documentation can be downloaded from http://www.lbgi.fr/VaRank/.

  10. Model of Decision Making through Consensus in Ranking Case

    Science.gov (United States)

    Tarigan, Gim; Darnius, Open

    2018-01-01

    The basic problem to determine ranking consensus is a problem to combine some rankings those are decided by two or more Decision Maker (DM) into ranking consensus. DM is frequently asked to present their preferences over a group of objects in terms of ranks, for example to determine a new project, new product, a candidate in a election, and so on. The problem in ranking can be classified into two major categories; namely, cardinal and ordinal rankings. The objective of the study is to obtin the ranking consensus by appying some algorithms and methods. The algorithms and methods used in this study were partial algorithm, optimal ranking consensus, BAK (Borde-Kendal)Model. A method proposed as an alternative in ranking conssensus is a Weighted Distance Forward-Backward (WDFB) method, which gave a little difference i ranking consensus result compare to the result oethe example solved by Cook, et.al (2005).

  11. Statistical Optimality in Multipartite Ranking and Ordinal Regression.

    Science.gov (United States)

    Uematsu, Kazuki; Lee, Yoonkyung

    2015-05-01

    Statistical optimality in multipartite ranking is investigated as an extension of bipartite ranking. We consider the optimality of ranking algorithms through minimization of the theoretical risk which combines pairwise ranking errors of ordinal categories with differential ranking costs. The extension shows that for a certain class of convex loss functions including exponential loss, the optimal ranking function can be represented as a ratio of weighted conditional probability of upper categories to lower categories, where the weights are given by the misranking costs. This result also bridges traditional ranking methods such as proportional odds model in statistics with various ranking algorithms in machine learning. Further, the analysis of multipartite ranking with different costs provides a new perspective on non-smooth list-wise ranking measures such as the discounted cumulative gain and preference learning. We illustrate our findings with simulation study and real data analysis.

  12. HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

    DEFF Research Database (Denmark)

    Vanangamudi, Murugesan; Poongavanam, Vasanthanathan; Namasivayam, Vigneshwaran

    2017-01-01

    BACKGROUND: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising......: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine...

  13. Differential invariants for higher-rank tensors. A progress report

    International Nuclear Information System (INIS)

    Tapial, V.

    2004-07-01

    We outline the construction of differential invariants for higher-rank tensors. In section 2 we outline the general method for the construction of differential invariants. A first result is that the simplest tensor differential invariant contains derivatives of the same order as the rank of the tensor. In section 3 we review the construction for the first-rank tensors (vectors) and second-rank tensors (metrics). In section 4 we outline the same construction for higher-rank tensors. (author)

  14. Beyond Low Rank: A Data-Adaptive Tensor Completion Method

    OpenAIRE

    Zhang, Lei; Wei, Wei; Shi, Qinfeng; Shen, Chunhua; Hengel, Anton van den; Zhang, Yanning

    2017-01-01

    Low rank tensor representation underpins much of recent progress in tensor completion. In real applications, however, this approach is confronted with two challenging problems, namely (1) tensor rank determination; (2) handling real tensor data which only approximately fulfils the low-rank requirement. To address these two issues, we develop a data-adaptive tensor completion model which explicitly represents both the low-rank and non-low-rank structures in a latent tensor. Representing the no...

  15. LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

    KAUST Repository

    Chen, Peng; Huang, Jianhua Z; Gao, Xin

    2014-01-01

    Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction

  16. Phosphatidylinositol 3-kinase is essential for kit ligand-mediated survival, whereas interleukin-3 and flt3 ligand induce expression of antiapoptotic Bcl-2 family genes

    DEFF Research Database (Denmark)

    Karlsson, Richard; Engström, Maria; Jönsson, Maria

    2003-01-01

    Cytokines such as interleukin 3 (IL-3), kit ligand (KL), and flt3 ligand (FL) promote survival of hematopoietic stem cells and myeloid progenitor cells. In many cell types, members of the Bcl-2 gene family are major regulators of survival, but the mediating mechanisms are not fully understood....... Using two myeloid progenitor cell lines, FDCP-mix and FDC-P1, as well as primary mouse bone marrow progenitors, we demonstrate that KL-mediated survival is dependent on the activation of phosphatidylinositol-3 (PI-3) kinase. The inhibitor LY294002 was able to completely abolish survival mediated by KL...

  17. When sparse coding meets ranking: a joint framework for learning sparse codes and ranking scores

    KAUST Repository

    Wang, Jim Jing-Yan; Cui, Xuefeng; Yu, Ge; Guo, Lili; Gao, Xin

    2017-01-01

    Sparse coding, which represents a data point as a sparse reconstruction code with regard to a dictionary, has been a popular data representation method. Meanwhile, in database retrieval problems, learning the ranking scores from data points plays

  18. Fourth-rank gravity. A progress report

    International Nuclear Information System (INIS)

    Tapia, V.

    1992-04-01

    We consider the consequences of describing the metric properties of space-time through a quartic line element. The associated ''metric'' is a fourth-rank tensor. After developing some fundamentals for such geometry, we construct a field theory for the gravitational field. This theory coincides with General Relativity in the vacuum case. Departures from General Relativity are obtained only in the presence of matter. We develop a simple cosmological model which is not in contradiction with the observed value Ω approx. 0.2-0.3 for the energy density parameter. A further application concerns conformal field theory. We are able to prove that a conformal field theory possesses an infinite-dimensional symmetry group only if the dimension of space-time is equal to the rank of the metric. In this case we are able to construct an integrable conformal field theory in four dimensions. The model is renormalisable by power counting. (author). 9 refs

  19. Low-rank quadratic semidefinite programming

    KAUST Repository

    Yuan, Ganzhao

    2013-04-01

    Low rank matrix approximation is an attractive model in large scale machine learning problems, because it can not only reduce the memory and runtime complexity, but also provide a natural way to regularize parameters while preserving learning accuracy. In this paper, we address a special class of nonconvex quadratic matrix optimization problems, which require a low rank positive semidefinite solution. Despite their non-convexity, we exploit the structure of these problems to derive an efficient solver that converges to their local optima. Furthermore, we show that the proposed solution is capable of dramatically enhancing the efficiency and scalability of a variety of concrete problems, which are of significant interest to the machine learning community. These problems include the Top-k Eigenvalue problem, Distance learning and Kernel learning. Extensive experiments on UCI benchmarks have shown the effectiveness and efficiency of our proposed method. © 2012.

  20. Ranking oil sands bitumen recovery techniques

    Energy Technology Data Exchange (ETDEWEB)

    Lam, A.; Nobes, D.S.; Lipsett, M.G. [Alberta Univ., Edmonton, AB (Canada). Dept. of Mechanical Engineering

    2009-07-01

    The preference ranking organization method (PROMETHEE) was used to assess and rank 3 techniques for in situ bitumen recovery: (1) steam assisted gravity drainage; (2) vapour extraction (VAPEX); and (3) toe-to-heel air injection (THAI). The study used a business scenario where management-type indicators included potential production rates; estimated overall operating costs; energy consumption; facilities requirement; recovery efficiency; and energy loss. Amounts of carbon dioxide (CO{sub 2}) emissions were also considered, as well as the production depth, formation thickness, and API gravity of the produced bitumen. The study showed that THAI recovery methods had the most beneficial criteria weighting of the 3 processes, while SAGD was the least favourable choice. However, SAGD processes are the most widely used of the 3 processes, while THAI has only been demonstrated on a limited scale. It was concluded that the maturity of a technology should be weighted more heavily when using the PROMETHEE method. 8 refs., 2 tabs.

  1. Low-rank quadratic semidefinite programming

    KAUST Repository

    Yuan, Ganzhao; Zhang, Zhenjie; Ghanem, Bernard; Hao, Zhifeng

    2013-01-01

    Low rank matrix approximation is an attractive model in large scale machine learning problems, because it can not only reduce the memory and runtime complexity, but also provide a natural way to regularize parameters while preserving learning accuracy. In this paper, we address a special class of nonconvex quadratic matrix optimization problems, which require a low rank positive semidefinite solution. Despite their non-convexity, we exploit the structure of these problems to derive an efficient solver that converges to their local optima. Furthermore, we show that the proposed solution is capable of dramatically enhancing the efficiency and scalability of a variety of concrete problems, which are of significant interest to the machine learning community. These problems include the Top-k Eigenvalue problem, Distance learning and Kernel learning. Extensive experiments on UCI benchmarks have shown the effectiveness and efficiency of our proposed method. © 2012.

  2. Social Media Impact on Website Ranking

    OpenAIRE

    Vaghela, Dushyant

    2014-01-01

    Internet is fast becoming critically important to commerce, industry and individuals. Search Engine (SE) is the most vital component for communication network and also used for discover information for users or people. Search engine optimization (SEO) is the process that is mostly used to increasing traffic from free, organic or natural listings on search engines and also helps to increase website ranking. It includes techniques like link building, directory submission, classified submission ...

  3. On Locally Most Powerful Sequential Rank Tests

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2017-01-01

    Roč. 36, č. 1 (2017), s. 111-125 ISSN 0747-4946 R&D Projects: GA ČR GA17-07384S Grant - others:Nadační fond na podporu vědy(CZ) Neuron Institutional support: RVO:67985807 Keywords : nonparametric test s * sequential ranks * stopping variable Subject RIV: BA - General Mathematics OBOR OECD: Pure mathematics Impact factor: 0.339, year: 2016

  4. Probabilistic real-time contingency ranking method

    International Nuclear Information System (INIS)

    Mijuskovic, N.A.; Stojnic, D.

    2000-01-01

    This paper describes a real-time contingency method based on a probabilistic index-expected energy not supplied. This way it is possible to take into account the stochastic nature of the electric power system equipment outages. This approach enables more comprehensive ranking of contingencies and it is possible to form reliability cost values that can form the basis for hourly spot price calculations. The electric power system of Serbia is used as an example for the method proposed. (author)

  5. Returns to Tenure: Time or Rank?

    DEFF Research Database (Denmark)

    Buhai, Ioan Sebastian

    -specific investment, efficiency-wages or adverse-selection models. However, rent extracting arguments as suggested by the theory of internal labor markets, indicate that the relative position of the worker in the seniority hierarchy of the firm, her 'seniority rank', may also explain part of the observed returns...... relative to their peer workers), as predicted by theories on unionized and insider-outsider markets....

  6. Efficient Low Rank Tensor Ring Completion

    OpenAIRE

    Wang, Wenqi; Aggarwal, Vaneet; Aeron, Shuchin

    2017-01-01

    Using the matrix product state (MPS) representation of the recently proposed tensor ring decompositions, in this paper we propose a tensor completion algorithm, which is an alternating minimization algorithm that alternates over the factors in the MPS representation. This development is motivated in part by the success of matrix completion algorithms that alternate over the (low-rank) factors. In this paper, we propose a spectral initialization for the tensor ring completion algorithm and ana...

  7. Rosetta Ligand docking with flexible XML protocols.

    Science.gov (United States)

    Lemmon, Gordon; Meiler, Jens

    2012-01-01

    RosettaLigand is premiere software for predicting how a protein and a small molecule interact. Benchmark studies demonstrate that 70% of the top scoring RosettaLigand predicted interfaces are within 2Å RMSD from the crystal structure [1]. The latest release of Rosetta ligand software includes many new features, such as (1) docking of multiple ligands simultaneously, (2) representing ligands as fragments for greater flexibility, (3) redesign of the interface during docking, and (4) an XML script based interface that gives the user full control of the ligand docking protocol.

  8. Citation ranking versus peer evaluation of senior faculty research performance

    DEFF Research Database (Denmark)

    Meho, Lokman I.; Sonnenwald, Diane H.

    2000-01-01

    The purpose of this study is to analyze the relationship between citation ranking and peer evaluation in assessing senior faculty research performance. Other studies typically derive their peer evaluation data directly from referees, often in the form of ranking. This study uses two additional...... indicator of research performance of senior faculty members? Citation data, book reviews, and peer ranking were compiled and examined for faculty members specializing in Kurdish studies. Analysis shows that normalized citation ranking and citation content analysis data yield identical ranking results....... Analysis also shows that normalized citation ranking and citation content analysis, book reviews, and peer ranking perform similarly (i.e., are highly correlated) for high-ranked and low-ranked senior scholars. Additional evaluation methods and measures that take into account the context and content...

  9. Association between Metabolic Syndrome and Job Rank.

    Science.gov (United States)

    Mehrdad, Ramin; Pouryaghoub, Gholamreza; Moradi, Mahboubeh

    2018-01-01

    The occupation of the people can influence the development of metabolic syndrome. To determine the association between metabolic syndrome and its determinants with the job rank in workers of a large car factory in Iran. 3989 male workers at a large car manufacturing company were invited to participate in this cross-sectional study. Demographic and anthropometric data of the participants, including age, height, weight, and abdominal circumference were measured. Blood samples were taken to measure lipid profile and blood glucose level. Metabolic syndrome was diagnosed in each participant based on ATPIII 2001 criteria. The workers were categorized based on their job rank into 3 groups of (1) office workers, (2) workers with physical exertion, and (3) workers with chemical exposure. The study characteristics, particularly the frequency of metabolic syndrome and its determinants were compared among the study groups. The prevalence of metabolic syndrome in our study was 7.7% (95% CI 6.9 to 8.5). HDL levels were significantly lower in those who had chemical exposure (p=0.045). Diastolic blood pressure was significantly higher in those who had mechanical exertion (p=0.026). The frequency of metabolic syndrome in the office workers, workers with physical exertion, and workers with chemical exposure was 7.3%, 7.9%, and 7.8%, respectively (p=0.836). Seemingly, there is no association between metabolic syndrome and job rank.

  10. Rank-dependant factorization of entanglement evolution

    International Nuclear Information System (INIS)

    Siomau, Michael

    2016-01-01

    Highlights: • In some cases the complex entanglement evolution can be factorized on simple terms. • We suggest factorization equations for multiqubit entanglement evolution. • The factorization is solely defined by the rank of the final state density matrices. • The factorization is independent on the local noisy channels and initial pure states. - Abstract: The description of the entanglement evolution of a complex quantum system can be significantly simplified due to the symmetries of the initial state and the quantum channels, which simultaneously affect parts of the system. Using concurrence as the entanglement measure, we study the entanglement evolution of few qubit systems, when each of the qubits is affected by a local unital channel independently on the others. We found that for low-rank density matrices of the final quantum state, such complex entanglement dynamics can be completely described by a combination of independent factors representing the evolution of entanglement of the initial state, when just one of the qubits is affected by a local channel. We suggest necessary conditions for the rank of the density matrices to represent the entanglement evolution through the factors. Our finding is supported with analytical examples and numerical simulations.

  11. Fourth-rank gravity and cosmology

    International Nuclear Information System (INIS)

    Marrakchi, A.L.; Tapia, V.

    1992-07-01

    We consider the consequences of describing the metric properties of space-time through a quartic line element. The associated ''metric'' is a fourth-rank tensor G μυλπ . In order to recover a Riemannian behaviour of the geometry it is necessary to have G μυλπ = g (μυ g λπ) . We construct a theory for the gravitational field based on the fourth-rank metric G μυλπ . In the absence of matter the fourth-rank metric becomes separable and the theory coincides with General Relativity. In the presence of matter we can maintain Riemmanianicity, but now gravitation couples, as compared to General Relativity, in a different way to matter. We develop a simple cosmological model based on a FRW metric with matter described by a perfect fluid. For the present time the field equations are compatible with k OBS = O and Ω OBS t CLAS approx. 10 20 t PLANCK approx. 10 -23 s. Our final and most important result is the fact that the entropy is an increasing function of time. When interpreted at the light of General Relativity the treatment is shown to be almost equivalent to that of the standard model of cosmology combined with the inflationary scenario. (author). 16 refs, 1 fig

  12. Ranking agility factors affecting hospitals in Iran

    Directory of Open Access Journals (Sweden)

    M. Abdi Talarposht

    2017-04-01

    Full Text Available Background: Agility is an effective response to the changing and unpredictable environment and using these changes as opportunities for organizational improvement. Objective: The aim of the present study was to rank the factors affecting agile supply chain of hospitals of Iran. Methods: This applied study was conducted by cross sectional-descriptive method at some point of 2015 for one year. The research population included managers, administrators, faculty members and experts were selected hospitals. A total of 260 people were selected as sample from the health centers. The construct validity of the questionnaire was approved by confirmatory factor analysis test and its reliability was approved by Cronbach's alpha (α=0.97. All data were analyzed by Kolmogorov-Smirnov, Chi-square and Friedman tests. Findings: The development of staff skills, the use of information technology, the integration of processes, appropriate planning, and customer satisfaction and product quality had a significant impact on the agility of public hospitals of Iran (P<0.001. New product introductions had earned the highest ranking and the development of staff skills earned the lowest ranking. Conclusion: The new product introduction, market responsiveness and sensitivity, reduce costs, and the integration of organizational processes, ratings better to have acquired agility hospitals in Iran. Therefore, planners and officials of hospitals have to, through the promotion quality and variety of services customer-oriented, providing a basis for investing in the hospital and etc to apply for agility supply chain public hospitals of Iran.

  13. Estimation of rank correlation for clustered data.

    Science.gov (United States)

    Rosner, Bernard; Glynn, Robert J

    2017-06-30

    It is well known that the sample correlation coefficient (R xy ) is the maximum likelihood estimator of the Pearson correlation (ρ xy ) for independent and identically distributed (i.i.d.) bivariate normal data. However, this is not true for ophthalmologic data where X (e.g., visual acuity) and Y (e.g., visual field) are available for each eye and there is positive intraclass correlation for both X and Y in fellow eyes. In this paper, we provide a regression-based approach for obtaining the maximum likelihood estimator of ρ xy for clustered data, which can be implemented using standard mixed effects model software. This method is also extended to allow for estimation of partial correlation by controlling both X and Y for a vector U_ of other covariates. In addition, these methods can be extended to allow for estimation of rank correlation for clustered data by (i) converting ranks of both X and Y to the probit scale, (ii) estimating the Pearson correlation between probit scores for X and Y, and (iii) using the relationship between Pearson and rank correlation for bivariate normally distributed data. The validity of the methods in finite-sized samples is supported by simulation studies. Finally, two examples from ophthalmology and analgesic abuse are used to illustrate the methods. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  14. Ranking environmental liabilities at a petroleum refinery

    International Nuclear Information System (INIS)

    Lupo, M.

    1995-01-01

    A new computer model is available to allow the management of a petroleum refinery to prioritize environmental action and construct a holistic approach to remediation. A large refinery may have numerous solid waste management units regulated by the Resource Conservation and Recovery Act (RCRA), as well as process units that emit hazardous chemicals into the environment. These sources can impact several environmental media, potentially including the air, the soil, the groundwater, the unsaturated zone water, and surface water. The number of chemicals of concern may be large. The new model is able to rank the sources by considering the impact of each chemical in each medium from each source in terms of concentration, release rate, and a weighted index based on toxicity. In addition to environmental impact, the sources can be ranked in three other ways: (1) by cost to remediate, (2) by environmental risk reduction caused by the remediation in terms of the decreases in release rate, concentration, and weighted index, and (3) by cost-benefit, which is the environmental risk reduction for each source divided by the cost of the remedy. Ranking each unit in the refinery allows management to use its limited environmental resources in a pro-active strategic manner that produces long-term results, rather than in reactive, narrowly focused, costly, regulatory-driven campaigns that produce only short-term results

  15. Iris Template Protection Based on Local Ranking

    Directory of Open Access Journals (Sweden)

    Dongdong Zhao

    2018-01-01

    Full Text Available Biometrics have been widely studied in recent years, and they are increasingly employed in real-world applications. Meanwhile, a number of potential threats to the privacy of biometric data arise. Iris template protection demands that the privacy of iris data should be protected when performing iris recognition. According to the international standard ISO/IEC 24745, iris template protection should satisfy the irreversibility, revocability, and unlinkability. However, existing works about iris template protection demonstrate that it is difficult to satisfy the three privacy requirements simultaneously while supporting effective iris recognition. In this paper, we propose an iris template protection method based on local ranking. Specifically, the iris data are first XORed (Exclusive OR operation with an application-specific string; next, we divide the results into blocks and then partition the blocks into groups. The blocks in each group are ranked according to their decimal values, and original blocks are transformed to their rank values for storage. We also extend the basic method to support the shifting strategy and masking strategy, which are two important strategies for iris recognition. We demonstrate that the proposed method satisfies the irreversibility, revocability, and unlinkability. Experimental results on typical iris datasets (i.e., CASIA-IrisV3-Interval, CASIA-IrisV4-Lamp, UBIRIS-V1-S1, and MMU-V1 show that the proposed method could maintain the recognition performance while protecting the privacy of iris data.

  16. Multiple pathways of sigma(1) receptor ligand uptakes into primary cultured neuronal cells.

    Science.gov (United States)

    Yamamoto, H; Karasawa, J; Sagi, N; Takahashi, S; Horikomi, K; Okuyama, S; Nukada, T; Sora, I; Yamamoto, T

    2001-08-03

    addition, pretreatment of cells with a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), a myosin light chain kinase inhibitor, 1-(5-chloronaphthalene-1-sulfonyl)homopiperazine (ML-9), or microsomal Ca(2+)-ATPase inhibitors resulted in a reduction of the amount of sigma receptor ligand uptake. These findings suggest that the Ca(2+) pump on the endoplasmic reticulum and/or calmodulin-related events might be involved in the regulation of the uptake of sigma receptor ligands into primary neuronal cells.

  17. Immune Checkpoint Inhibitor-Associated Type 1 Diabetes Mellitus: Case Series, Review of the Literature, and Optimal Management

    OpenAIRE

    Kapke, Jonathan; Shaheen, Zachary; Kilari, Deepak; Knudson, Paul; Wong, Stuart

    2017-01-01

    With the introduction of immune checkpoint inhibitors into clinical practice, various autoimmune toxicities have been described. Antibodies targeting the receptor:ligand pairing of programmed death receptor-1 (PD-1) and its cognate ligand programmed death-ligand 1 (PD-L1) in rare reports have been associated with autoimmune diabetes mellitus. We report 2 cases of rapid-onset, insulin-dependent, type 1 diabetes mellitus in the setting of administration of nivolumab, a fully human monoclonal an...

  18. Country-specific determinants of world university rankings.

    Science.gov (United States)

    Pietrucha, Jacek

    2018-01-01

    This paper examines country-specific factors that affect the three most influential world university rankings (the Academic Ranking of World Universities, the QS World University Ranking, and the Times Higher Education World University Ranking). We run a cross sectional regression that covers 42-71 countries (depending on the ranking and data availability). We show that the position of universities from a country in the ranking is determined by the following country-specific variables: economic potential of the country, research and development expenditure, long-term political stability (freedom from war, occupation, coups and major changes in the political system), and institutional variables, including government effectiveness.

  19. Vanadium Compounds as PTP Inhibitors

    Directory of Open Access Journals (Sweden)

    Elsa Irving

    2017-12-01

    Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

  20. Crystallization of protein–ligand complexes

    International Nuclear Information System (INIS)

    Hassell, Anne M.; An, Gang; Bledsoe, Randy K.; Bynum, Jane M.; Carter, H. Luke III; Deng, Su-Jun J.; Gampe, Robert T.; Grisard, Tamara E.; Madauss, Kevin P.; Nolte, Robert T.; Rocque, Warren J.; Wang, Liping; Weaver, Kurt L.; Williams, Shawn P.; Wisely, G. Bruce; Xu, Robert; Shewchuk, Lisa M.

    2007-01-01

    Methods presented for growing protein–ligand complexes fall into the categories of co-expression of the protein with the ligands of interest, use of the ligands during protein purification, cocrystallization and soaking the ligands into existing crystals. Obtaining diffraction-quality crystals has long been a bottleneck in solving the three-dimensional structures of proteins. Often proteins may be stabilized when they are complexed with a substrate, nucleic acid, cofactor or small molecule. These ligands, on the other hand, have the potential to induce significant conformational changes to the protein and ab initio screening may be required to find a new crystal form. This paper presents an overview of strategies in the following areas for obtaining crystals of protein–ligand complexes: (i) co-expression of the protein with the ligands of interest, (ii) use of the ligands during protein purification, (iii) cocrystallization and (iv) soaks

  1. Ranking U-Sapiens 2010-2

    Directory of Open Access Journals (Sweden)

    Carlos-Roberto Peña-Barrera

    2011-08-01

    Full Text Available Los principales objetivos de esta investigación son los siguientes: (1 que la comunidad científica nacional e internacional y la sociedad en general co-nozcan los resultados del Ranking U-Sapiens Colombia 2010_2, el cual clasifica a cada institución de educación superior colombiana según puntaje, posición y cuartil; (2 destacar los movimientos más importantes al comparar los resultados del ranking 2010_1 con los del 2010_2; (3 publicar las respuestas de algunos actores de la academia nacional con respecto a la dinámica de la investigación en el país; (4 reconocer algunas instituciones, medios de comunicación e investigadores que se han interesado a modo de reflexión, referenciación o citación por esta investigación; y (5 dar a conocer el «Sello Ranking U-Sapiens Colombia» para las IES clasificadas. El alcance de este estudio en cuanto a actores abordó todas y cada una de las IES nacionales (aunque solo algunas lograran entrar al ranking y en cuanto a tiempo, un periodo referido al primer semestre de 2010 con respecto a: (1 los resultados 2010-1 de revistas indexadas en Publindex, (2 los programas de maestrías y doctorados activos durante 2010-1 según el Ministerio de Educación Nacional, y (3 los resultados de grupos de investigación clasificados para 2010 según Colciencias. El método empleado para esta investigación es el mismo que para el ranking 2010_1, salvo por una especificación aún más detallada en uno de los pasos del modelo (las variables α, β, γ; es completamente cuantitativo y los datos de las variables que fundamentan sus resultados provienen de Colciencias y el Ministerio de Educación Nacional; y en esta ocasión se darán a conocer los resultados por variable para 2010_1 y 2010_2. Los resultados más relevantes son estos: (1 entraron 8 IES al ranking y salieron 3; (2 las 3 primeras IES son públicas; (3 en total hay 6 instituciones universitarias en el ranking; (4 7 de las 10 primeras IES son

  2. Architecture effects on multivalent interactions by polypeptide-based multivalent ligands

    Science.gov (United States)

    Liu, Shuang

    Multivalent interactions are characterized by the simultaneous binding between multiple ligands and multiple binding sites, either in solutions or at interfaces. In biological systems, most multivalent interactions occur between protein receptors and carbohydrate ligands through hydrogen-bonding and hydrophobic interactions. Compared with weak affinity binding between one ligand and one binding site, i.e. monovalent interaction, multivalent interactioins provide greater avidity and specificity, and therefore play unique roles in a broad range of biological activities. Moreover, the studies of multivalent interactions are also essential for producing effective inhibitors and effectors of biological processes that could have important therapeutic applications. Synthetic multivalent ligands have been designed to mimic the biological functions of natural multivalent interactions, and various types of scaffolds have been used to display multiple ligands, including small molecules, linear polymers, dendrimers, nanoparticle surfaces, monolayer surfaces and liposomes. Studies have shown that multivalent interactions can be highly affected by various architectural parameters of these multivalent ligands, including ligand identities, valencies, spacing, ligand densities, nature of linker arms, scaffold length and scaffold conformation. Most of these multivalent ligands are chemically synthesized and have limitations of controlling over sequence and conformation, which is a barrier for mimicking ordered and controlled natural biological systems. Therefore, multivalent ligands with precisely controlled architecture are required for improved structure-function relationship studies. Protein engineering methods with subsequent chemical coupling of ligands provide significant advantages of controlling over backbone conformation and functional group placement, and therefore have been used to synthesize recombinant protein-based materials with desired properties similar to natural

  3. -Pincer Ligand Family through Ligand Post-Modification

    KAUST Repository

    Huang, Mei-Hui; Hu, Jinsong; Huang, Kuo-Wei

    2017-01-01

    A series of air-stable nickel complexes containing triazine-based PN3P-pincer ligands were synthesized and fully characterized. Complex 3 contains a de-aromatized central triazine ring from the deprotonation of one of the N–H arms. With a post-modification strategy, the Me-PN3P*NiCl complex (3) could be converted into a new class of diimine–traizine PN3P-pincer nickel complexes.

  4. -Pincer Ligand Family through Ligand Post-Modification

    KAUST Repository

    Huang, Mei-Hui

    2017-10-02

    A series of air-stable nickel complexes containing triazine-based PN3P-pincer ligands were synthesized and fully characterized. Complex 3 contains a de-aromatized central triazine ring from the deprotonation of one of the N–H arms. With a post-modification strategy, the Me-PN3P*NiCl complex (3) could be converted into a new class of diimine–traizine PN3P-pincer nickel complexes.

  5. Reactivity of halide and pseudohalide ligands

    International Nuclear Information System (INIS)

    Kukushkin, Yu.N.

    1987-01-01

    Reactivity of halide and pseudohalide (cyanide, azide, thiocyanate, cyanate) ligands tending to form bridge bonds in transition metal (Re, Mo, W) complexes is considered. Complexes where transition metal salts are ligands of other, complex-forming ion, are described. Transformation of innerspheric pseudohalide ligands is an important way of directed synthesis of these metal coordination compounds

  6. Ranking the Online Documents Based on Relative Credibility Measures

    Directory of Open Access Journals (Sweden)

    Ahmad Dahlan

    2013-09-01

    Full Text Available Information searching is the most popular activity in Internet. Usually the search engine provides the search results ranked by the relevance. However, for a certain purpose that concerns with information credibility, particularly citing information for scientific works, another approach of ranking the search engine results is required. This paper presents a study on developing a new ranking method based on the credibility of information. The method is built up upon two well-known algorithms, PageRank and Citation Analysis. The result of the experiment that used Spearman Rank Correlation Coefficient to compare the proposed rank (generated by the method with the standard rank (generated manually by a group of experts showed that the average Spearman 0 < rS < critical value. It means that the correlation was proven but it was not significant. Hence the proposed rank does not satisfy the standard but the performance could be improved.

  7. Ranking the Online Documents Based on Relative Credibility Measures

    Directory of Open Access Journals (Sweden)

    Ahmad Dahlan

    2009-05-01

    Full Text Available Information searching is the most popular activity in Internet. Usually the search engine provides the search results ranked by the relevance. However, for a certain purpose that concerns with information credibility, particularly citing information for scientific works, another approach of ranking the search engine results is required. This paper presents a study on developing a new ranking method based on the credibility of information. The method is built up upon two well-known algorithms, PageRank and Citation Analysis. The result of the experiment that used Spearman Rank Correlation Coefficient to compare the proposed rank (generated by the method with the standard rank (generated manually by a group of experts showed that the average Spearman 0 < rS < critical value. It means that the correlation was proven but it was not significant. Hence the proposed rank does not satisfy the standard but the performance could be improved.

  8. Algebraic and computational aspects of real tensor ranks

    CERN Document Server

    Sakata, Toshio; Miyazaki, Mitsuhiro

    2016-01-01

    This book provides comprehensive summaries of theoretical (algebraic) and computational aspects of tensor ranks, maximal ranks, and typical ranks, over the real number field. Although tensor ranks have been often argued in the complex number field, it should be emphasized that this book treats real tensor ranks, which have direct applications in statistics. The book provides several interesting ideas, including determinant polynomials, determinantal ideals, absolutely nonsingular tensors, absolutely full column rank tensors, and their connection to bilinear maps and Hurwitz-Radon numbers. In addition to reviews of methods to determine real tensor ranks in details, global theories such as the Jacobian method are also reviewed in details. The book includes as well an accessible and comprehensive introduction of mathematical backgrounds, with basics of positive polynomials and calculations by using the Groebner basis. Furthermore, this book provides insights into numerical methods of finding tensor ranks through...

  9. Effect of urea on protein-ligand association.

    Science.gov (United States)

    Stepanian, Lora; Son, Ikbae; Chalikian, Tigran V

    2017-12-01

    We combine experimental and theoretical approaches to investigate the influence of a cosolvent on a ligand-protein association event. We apply fluorescence measurements to determining the affinity of the inhibitor tri-N-acetylglucosamine [(GlcNAc) 3 ] for lysozyme at urea concentrations ranging from 0 to 8M. Notwithstanding that, at room temperature and neutral pH, lysozyme retains its native conformation up to the solubility limit of urea, the affinity of (GlcNAc) 3 for the protein steadily decreases as the concentration of urea increases. We analyze the urea dependence of the binding free energy within the framework of a simplified statistical thermodynamics-based model that accounts for the excluded volume effect and direct solute-solvent interactions. The analysis reveals that the detrimental action of urea on the inhibitor-lysozyme binding originates from competition between the free energy contributions of the excluded volume effect and direct solute-solvent interactions. The free energy contribution of direct urea-solute interactions narrowly overcomes the excluded volume contribution thereby resulting in urea weakening the protein-ligand association. More broadly, the successful application of the simple model employed in this work points to the possibility of its use in quantifying the stabilizing/destabilizing action of individual cosolvents on biochemical folding and binding reactions. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Computational multiscale modeling in protein--ligand docking.

    Science.gov (United States)

    Taufer, Michela; Armen, Roger; Chen, Jianhan; Teller, Patricia; Brooks, Charles

    2009-01-01

    In biological systems, the binding of small molecule ligands to proteins is a crucial process for almost every aspect of biochemistry and molecular biology. Enzymes are proteins that function by catalyzing specific biochemical reactions that convert reactants into products. Complex organisms are typically composed of cells in which thousands of enzymes participate in complex and interconnected biochemical pathways. Some enzymes serve as sequential steps in specific pathways (such as energy metabolism), while others function to regulate entire pathways and cellular functions [1]. Small molecule ligands can be designed to bind to a specific enzyme and inhibit the biochemical reaction. Inhibiting the activity of key enzymes may result in the entire biochemical pathways being turned on or off [2], [3]. Many small molecule drugs marketed today function in this generic way as enzyme inhibitors. If research identifies a specific enzyme as being crucial to the progress of disease, then this enzyme may be targeted with an inhibitor, which may slow down or reverse the progress of disease. In this way, enzymes are targeted from specific pathogens (e.g., virus, bacteria, fungi) for infectious diseases [4], [5], and human enzymes are targeted for noninfectious diseases such as cardiovascular disease, cancer, diabetes, and neurodegenerative diseases [6].

  11. On Locally Most Powerful Sequential Rank Tests

    Czech Academy of Sciences Publication Activity Database

    Kalina, Jan

    2017-01-01

    Roč. 36, č. 1 (2017), s. 111-125 ISSN 0747-4946 R&D Projects: GA ČR GA17-07384S Grant - others:Nadační fond na podporu vědy(CZ) Neuron Institutional support: RVO:67985556 Keywords : nonparametric test s * sequential ranks * stopping variable Subject RIV: BA - General Mathematics OBOR OECD: Pure mathematics Impact factor: 0.339, year: 2016 http://library.utia.cas.cz/separaty/2017/SI/kalina-0474065.pdf

  12. Motion in fourth-rank gravity

    International Nuclear Information System (INIS)

    Tapia, V.

    1992-04-01

    Recently we have explored the consequences of describing the metric properties of our universe through a quartic line element. In this geometry the natural object is a fourth-rank metric, i.e., a tensor with four indices. Based on this geometry we constructed a simple field theory for the gravitational field. The field equations coincide with the Einstein field equations in the vacuum case. This fact, however, does not guarantee the observational equivalence of both theories since one must still verify that, as a consequence of the field equations, test particles move along geodesics. This letter is aimed at establishing this result. (author). 7 refs

  13. Classical impurities associated to high rank algebras

    Energy Technology Data Exchange (ETDEWEB)

    Doikou, Anastasia, E-mail: A.Doikou@hw.ac.uk [Department of Mathematics, Heriot–Watt University, EH14 4AS, Edinburgh (United Kingdom); Department of Computer Engineering and Informatics, University of Patras, Patras GR-26500 (Greece)

    2014-07-15

    Classical integrable impurities associated with high rank (gl{sub N}) algebras are investigated. A particular prototype, i.e. the vector non-linear Schrödinger (NLS) model, is chosen as an example. A systematic construction of local integrals of motion as well as the time components of the corresponding Lax pairs is presented based on the underlying classical algebra. Suitable gluing conditions compatible with integrability are also extracted. The defect contribution is also examined in the case where non-trivial integrable conditions are implemented. It turns out that the integrable boundaries may drastically alter the bulk behavior, and in particular the defect contribution.

  14. Low-rank driving in quantum systems

    International Nuclear Information System (INIS)

    Burkey, R.S.

    1989-01-01

    A new property of quantum systems called low-rank driving is introduced. Numerous simplifications in the solution of the time-dependent Schroedinger equation are pointed out for systems having this property. These simplifications are in the areas of finding eigenvalues, taking the Laplace transform, converting Schroedinger's equation to an integral form, discretizing the continuum, generalizing the Weisskopf-Wigner approximation, band-diagonalizing the Hamiltonian, finding new exact solutions to Schroedinger's equation, and so forth. The principal physical application considered is the phenomenon of coherent populations-trapping in continuum-continuum interactions

  15. Classical impurities associated to high rank algebras

    International Nuclear Information System (INIS)

    Doikou, Anastasia

    2014-01-01

    Classical integrable impurities associated with high rank (gl N ) algebras are investigated. A particular prototype, i.e. the vector non-linear Schrödinger (NLS) model, is chosen as an example. A systematic construction of local integrals of motion as well as the time components of the corresponding Lax pairs is presented based on the underlying classical algebra. Suitable gluing conditions compatible with integrability are also extracted. The defect contribution is also examined in the case where non-trivial integrable conditions are implemented. It turns out that the integrable boundaries may drastically alter the bulk behavior, and in particular the defect contribution

  16. Sampling protein motion and solvent effect during ligand binding

    Science.gov (United States)

    Limongelli, Vittorio; Marinelli, Luciana; Cosconati, Sandro; La Motta, Concettina; Sartini, Stefania; Mugnaini, Laura; Da Settimo, Federico; Novellino, Ettore; Parrinello, Michele

    2012-01-01

    An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one. PMID:22238423

  17. Two Ranking Methods of Single Valued Triangular Neutrosophic Numbers to Rank and Evaluate Information Systems Quality

    Directory of Open Access Journals (Sweden)

    Samah Ibrahim Abdel Aal

    2018-03-01

    Full Text Available The concept of neutrosophic can provide a generalization of fuzzy set and intuitionistic fuzzy set that make it is the best fit in representing indeterminacy and uncertainty. Single Valued Triangular Numbers (SVTrN-numbers is a special case of neutrosophic set that can handle ill-known quantity very difficult problems. This work intended to introduce a framework with two types of ranking methods. The results indicated that each ranking method has its own advantage. In this perspective, the weighted value and ambiguity based method gives more attention to uncertainty in ranking and evaluating ISQ as well as it takes into account cut sets of SVTrN numbers that can reflect the information on Truth-membership-membership degree, false membership-membership degree and Indeterminacy-membership degree. The value index and ambiguity index method can reflect the decision maker's subjectivity attitude to the SVTrN- numbers.

  18. Isotope-edited proton NMR study on the structure of a pepsin/inhibitor complex

    International Nuclear Information System (INIS)

    Fesik, S.W.; Luly, J.R.; Erickson, J.W.; Abad-Zapatero, C.

    1988-01-01

    A general approach is illustrated for providing detailed structural information on large enzyme/inhibitor complexes using NMR spectroscopy. The method involves the use of isotopically labeled ligands to simplify two-dimensional NOE spectra of large molecular complexes by isotope-editing techniques. With this approach, the backbone and side-chain conformations (at the P 2 and P 3 sites) of a tightly bound inhibitor of porcine pepsin have bene determined. In addition, structural information on the active site of pepsin has been obtained. Due to the sequence homology between porcine pepsin and human renin, this structural information may prove useful for modeling renin/inhibitor complexes with the ultimate goal of designing more effective renin inhibitors. Moreover, this general approach can be applied to study other biological systems of interest such as other enzyme/inhibitor complexes, ligands bound to soluble receptors, and enzyme/substrate interactions

  19. Classification of Beta-lactamases and penicillin binding proteins using ligand-centric network models.

    Directory of Open Access Journals (Sweden)

    Hakime Öztürk

    Full Text Available β-lactamase mediated antibiotic resistance is an important health issue and the discovery of new β-lactam type antibiotics or β-lactamase inhibitors is an area of intense research. Today, there are about a thousand β-lactamases due to the evolutionary pressure exerted by these ligands. While β-lactamases hydrolyse the β-lactam ring of antibiotics, rendering them ineffective, Penicillin-Binding Proteins (PBPs, which share high structural similarity with β-lactamases, also confer antibiotic resistance to their host organism by acquiring mutations that allow them to continue their participation in cell wall biosynthesis. In this paper, we propose a novel approach to include ligand sharing information for classifying and clustering β-lactamases and PBPs in an effort to elucidate the ligand induced evolution of these β-lactam binding proteins. We first present a detailed summary of the β-lactamase and PBP families in the Protein Data Bank, as well as the compounds they bind to. Then, we build two different types of networks in which the proteins are represented as nodes, and two proteins are connected by an edge with a weight that depends on the number of shared identical or similar ligands. These models are analyzed under three different edge weight settings, namely unweighted, weighted, and normalized weighted. A detailed comparison of these six networks showed that the use of ligand sharing information to cluster proteins resulted in modules comprising proteins with not only sequence similarity but also functional similarity. Consideration of ligand similarity highlighted some interactions that were not detected in the identical ligand network. Analysing the β-lactamases and PBPs using ligand-centric network models enabled the identification of novel relationships, suggesting that these models can be used to examine other protein families to obtain information on their ligand induced evolutionary paths.

  20. Effect of the Flexible Regions of the Oncoprotein Mouse Double Minute X on Inhibitor Binding Affinity.

    Science.gov (United States)

    Qin, Lingyun; Liu, Huili; Chen, Rong; Zhou, Jingjing; Cheng, Xiyao; Chen, Yao; Huang, Yongqi; Su, Zhengding

    2017-11-07

    The oncoprotein MdmX (mouse double minute X) is highly homologous to Mdm2 (mouse double minute 2) in terms of their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and alters inhibitor binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables us to understand protein-ligand interactions, the mechanism underlying how a flexible binding pocket adapts an inhibitor has been less explored experimentally. In this work, we have investigated how the intrinsic flexible regions of the N-terminal domain of MdmX (N-MdmX) affect the affinity of the Mdm2 inhibitor nutlin-3a using protein engineering. Guided by heteronuclear nuclear Overhauser effect measurements, we identified the flexible regions that affect inhibitor binding affinity around the ligand-binding pocket on N-MdmX. A disulfide engineering mutant, N-MdmX C25-C110/C76-C88 , which incorporated two staples to rigidify the ligand-binding pocket, allowed an affinity for nutlin-3a higher than that of wild-type N-MdmX (K d ∼ 0.48 vs K d ∼ 20.3 μM). Therefore, this mutant provides not only an effective protein model for screening and designing of MdmX inhibitors but also a valuable clue for enhancing the intermolecular interactions of the pharmacophores of a ligand with pronounced flexible regions. In addition, our results revealed an allosteric ligand-binding mechanism of N-MdmX in which the ligand initially interacts with a compact core, followed by augmenting intermolecular interactions with intrinsic flexible regions. This strategy should also be applicable to many other protein targets to accelerate drug discovery.

  1. The BiPublishers ranking: Main results and methodological problems when constructing rankings of academic publishers

    Directory of Open Access Journals (Sweden)

    Torres-Salinas, Daniel

    2015-12-01

    Full Text Available We present the results of the Bibliometric Indicators for Publishers project (also known as BiPublishers. This project represents the first attempt to systematically develop bibliometric publisher rankings. The data for this project was derived from the Book Citation Index and the study time period was 2009-2013. We have developed 42 rankings: 4 by fields and 38 by disciplines. We display six indicators for publishers divided into three types: output, impact and publisher’s profile. The aim is to capture different characteristics of the research performance of publishers. 254 publishers were processed and classified according to publisher type: commercial publishers and university presses. We present the main publishers by field and then discuss the principal challenges presented when developing this type of tool. The BiPublishers ranking is an on-going project which aims to develop and explore new data sources and indicators to better capture and define the research impact of publishers.Presentamos los resultados del proyecto Bibliometric Indicators for Publishers (BiPublishers. Es el primer proyecto que desarrolla de manera sistemática rankings bibliométricos de editoriales. La fuente de datos empleada es el Book Citation Index y el periodo de análisis 2009-2013. Se presentan 42 rankings: 4 por áreas y 38 por disciplinas. Mostramos seis indicadores por editorial divididos según su tipología: producción, impacto y características editoriales. Se procesaron 254 editoriales y se clasificaron según el tipo: comerciales y universitarias. Se presentan las principales editoriales por áreas. Después, se discuten los principales retos a superar en el desarrollo de este tipo de herramientas. El ranking Bipublishers es un proyecto en desarrollo que persigue analizar y explorar nuevas fuentes de datos e indicadores para captar y definir el impacto de las editoriales académicas.

  2. Generalized PageRank on Directed Configuration Networks

    NARCIS (Netherlands)

    Chen, Ningyuan; Litvak, Nelli; Olvera-Cravioto, Mariana

    2017-01-01

    Note: formula is not displayed correctly. This paper studies the distribution of a family of rankings, which includes Google’s PageRank, on a directed configuration model. In particular, it is shown that the distribution of the rank of a randomly chosen node in the graph converges in distribution to

  3. PageRank in scale-free random graphs

    NARCIS (Netherlands)

    Chen, Ningyuan; Litvak, Nelli; Olvera-Cravioto, Mariana; Bonata, Anthony; Chung, Fan; Pralat, Paweł

    2014-01-01

    We analyze the distribution of PageRank on a directed configuration model and show that as the size of the graph grows to infinity, the PageRank of a randomly chosen node can be closely approximated by the PageRank of the root node of an appropriately constructed tree. This tree approximation is in

  4. Ranking Quality in Higher Education: Guiding or Misleading?

    Science.gov (United States)

    Bergseth, Brita; Petocz, Peter; Abrandt Dahlgren, Madeleine

    2014-01-01

    The study examines two different models of measuring, assessing and ranking quality in higher education. Do different systems of quality assessment lead to equivalent conclusions about the quality of education? This comparative study is based on the rankings of 24 Swedish higher education institutions. Two ranking actors have independently…

  5. Revisiting the Relationship between Institutional Rank and Student Engagement

    Science.gov (United States)

    Zilvinskis, John; Louis Rocconi

    2018-01-01

    College rankings dominate the conversation regarding quality in postsecondary education. However, the criteria used to rank institutions often have nothing to do with the quality of education students receive. A decade ago, Pike (2004) demonstrated that institutional rank had little association with student involvement in educational activities.…

  6. Academic Ranking--From Its Genesis to Its International Expansion

    Science.gov (United States)

    Vieira, Rosilene C.; Lima, Manolita C.

    2015-01-01

    Given the visibility and popularity of rankings that encompass the measurement of quality of post-graduate courses, for instance, the MBA (Master of Business Administration) or graduate studies program (MSc and PhD) as do global academic rankings--Academic Ranking of World Universities-ARWU, Times Higher/Thomson Reuters World University Ranking…

  7. 7 CFR 1491.6 - Ranking considerations and proposal selection.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Ranking considerations and proposal selection. 1491.6... PROGRAM General Provisions § 1491.6 Ranking considerations and proposal selection. (a) Before the State.... The national ranking criteria will be established by the Chief and the State criteria will be...

  8. 46 CFR 282.11 - Ranking of flags.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Ranking of flags. 282.11 Section 282.11 Shipping... COMMERCE OF THE UNITED STATES Foreign-Flag Competition § 282.11 Ranking of flags. The operators under each... priority of costs which are representative of the flag. For liner cargo vessels, the ranking of operators...

  9. 10 CFR 455.131 - State ranking of grant applications.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false State ranking of grant applications. 455.131 Section 455... State ranking of grant applications. (a) Except as provided by § 455.92 of this part, all eligible... audit or energy use evaluation pursuant to § 455.20(k). Each State shall develop separate rankings for...

  10. Control by Numbers: New Managerialism and Ranking in Higher Education

    Science.gov (United States)

    Lynch, Kathleen

    2015-01-01

    This paper analyses the role of rankings as an instrument of new managerialism. It shows how rankings are reconstituting the purpose of universities, the role of academics and the definition of what it is to be a student. The paper opens by examining the forces that have facilitated the emergence of the ranking industry and the ideologies…

  11. Paired comparisons analysis: an axiomatic approach to ranking methods

    NARCIS (Netherlands)

    Gonzalez-Diaz, J.; Hendrickx, Ruud; Lohmann, E.R.M.A.

    2014-01-01

    In this paper we present an axiomatic analysis of several ranking methods for general tournaments. We find that the ranking method obtained by applying maximum likelihood to the (Zermelo-)Bradley-Terry model, the most common method in statistics and psychology, is one of the ranking methods that

  12. Extracting Rankings for Spatial Keyword Queries from GPS Data

    DEFF Research Database (Denmark)

    Keles, Ilkcan; Jensen, Christian Søndergaard; Saltenis, Simonas

    2018-01-01

    Studies suggest that many search engine queries have local intent. We consider the evaluation of ranking functions important for such queries. The key challenge is to be able to determine the “best” ranking for a query, as this enables evaluation of the results of ranking functions. We propose...

  13. Tutorial: Calculating Percentile Rank and Percentile Norms Using SPSS

    Science.gov (United States)

    Baumgartner, Ted A.

    2009-01-01

    Practitioners can benefit from using norms, but they often have to develop their own percentile rank and percentile norms. This article is a tutorial on how to quickly and easily calculate percentile rank and percentile norms using SPSS, and this information is presented for a data set. Some issues in calculating percentile rank and percentile…

  14. Variation in rank abundance replicate samples and impact of clustering

    NARCIS (Netherlands)

    Neuteboom, J.H.; Struik, P.C.

    2005-01-01

    Calculating a single-sample rank abundance curve by using the negative-binomial distribution provides a way to investigate the variability within rank abundance replicate samples and yields a measure of the degree of heterogeneity of the sampled community. The calculation of the single-sample rank

  15. A Fast Algorithm for Generating Permutation Distribution of Ranks in ...

    African Journals Online (AJOL)

    ... function of the distribution of the ranks. This further gives insight into the permutation distribution of a rank statistics. The algorithm is implemented with the aid of the computer algebra system Mathematica. Key words: Combinatorics, generating function, permutation distribution, rank statistics, partitions, computer algebra.

  16. Ligand-regulated peptide aptamers.

    Science.gov (United States)

    Miller, Russell A

    2009-01-01

    The peptide aptamer approach employs high-throughput selection to identify members of a randomized peptide library displayed from a scaffold protein by virtue of their interaction with a target molecule. Extending this approach, we have developed a peptide aptamer scaffold protein that can impart small-molecule control over the aptamer-target interaction. This ligand-regulated peptide (LiRP) scaffold, consisting of the protein domains FKBP12, FRB, and GST, binds to the cell-permeable small-molecule rapamycin and the binding of this molecule can prevent the interaction of the randomizable linker region connecting FKBP12 with FRB. Here we present a detailed protocol for the creation of a peptide aptamer plasmid library, selection of peptide aptamers using the LiRP scaffold in a yeast two-hybrid system, and the screening of those peptide aptamers for a ligand-regulated interaction.

  17. Ligand binding by PDZ domains

    DEFF Research Database (Denmark)

    Chi, Celestine N.; Bach, Anders; Strømgaard, Kristian

    2012-01-01

    , for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well...... as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context....

  18. CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects.

    Science.gov (United States)

    Dalvin, Lauren A; Shields, Carol L; Orloff, Marlana; Sato, Takami; Shields, Jerry A

    2018-06-01

    To review immune checkpoint inhibitor indications and ophthalmic side effects. A literature review was performed using a PubMed search for publications between 1990 and 2017. Immune checkpoint inhibitors are designed to treat system malignancies by targeting one of three ligands, leading to T-cell activation for attack against malignant cells. These ligands (and targeted drug) include cytotoxic T-lymphocyte antigen-4 (CTLA-4, ipilimumab), programmed death protein 1 (PD-1, pembrolizumab, nivolumab), and programmed death ligand-1 (PD-L1, atezolizumab, avelumab, durvalumab). These medications upregulate the immune system and cause autoimmune-like side effects. Ophthalmic side effects most frequently manifest as uveitis (1%) and dry eye (1-24%). Other side effects include myasthenia gravis (n = 19 reports), inflammatory orbitopathy (n = 11), keratitis (n = 3), cranial nerve palsy (n = 3), optic neuropathy (n = 2), serous retinal detachment (n = 2), extraocular muscle myopathy (n = 1), atypical chorioretinal lesions (n = 1), immune retinopathy (n = 1), and neuroretinitis (n = 1). Most inflammatory side effects are managed with topical or periocular corticosteroids, but advanced cases require systemic corticosteroids and cessation of checkpoint inhibitor therapy. Checkpoint inhibitors enhance the immune system by releasing inhibition on T cells, with risk of autoimmune-like side effects. Ophthalmologists should include immune-related adverse events in their differential when examining cancer patients with new ocular symptoms.

  19. Bitopic Ligands and Metastable Binding Sites

    DEFF Research Database (Denmark)

    Fronik, Philipp; Gaiser, Birgit I; Sejer Pedersen, Daniel

    2017-01-01

    of orthosteric binding sites. Bitopic ligands have been employed to address the selectivity problem by combining (linking) an orthosteric ligand with an allosteric modulator, theoretically leading to high-affinity subtype selective ligands. However, it remains a challenge to identify suitable allosteric binding...... that have been reported to date, this type of bitopic ligands would be composed of two identical pharmacophores. Herein, we outline the concept of bitopic ligands, review metastable binding sites, and discuss their potential as a new source of allosteric binding sites....

  20. Rank hypocrisies the insult of the REF

    CERN Document Server

    Sayer, Derek

    2015-01-01

    "The REF is right out of Havel's and Kundera's Eastern Europe: a state-administered exercise to rank academic research like hotel chains dependent on the active collaboration of the UK professoriate. In crystalline text steeped in cold rage, Sayer takes aim at the REF's central claim, that it is a legitimate process of expert peer review. He critiques university and national-level REF processes against actual practices of scholarly review as found in academic journals, university presses, and North American tenure procedures. His analysis is damning. If the REF fails as scholarly review, how can academics and universities continue to participate? And how can government use its rankings as a basis for public policy?" - Tarak Barkawi, Reader in the Department of International Relations, London School of Economics "Many academics across the world have come to see the REF as an arrogant attempt to raise national research standards that has resulted in a variety of self-inflicted wounds to UK higher education. Der...

  1. Demographic Ranking of the Baltic Sea States

    Directory of Open Access Journals (Sweden)

    Sluka N.

    2014-06-01

    Full Text Available The relevance of the study lies in the acute need to modernise the tools for a more accurate and comparable reflection of the demographic reality of spatial objects of different scales. This article aims to test the methods of “demographic rankings” developed by Yermakov and Shmakov. The method is based on the principles of indirect standardisation of the major demographic coefficients relative to the age structure.The article describes the first attempt to apply the method to the analysis of birth and mortality rates in 1995 and 2010 for 140 countries against the global average, and for the Baltic Sea states against the European average. The grouping of countries and the analysis of changes over the given period confirmed a number of demographic development trends and the persistence of wide territorial disparities in major indicators. The authors identify opposite trends in ranking based on the standardised birth (country consolidation at the level of averaged values and mortality (polarisation rates. The features of demographic process development in the Baltic regions states are described against the global and European background. The study confirmed the validity of the demographic ranking method, which can be instrumental in solving not only scientific but also practical tasks, including those in the field of demographic and social policy.

  2. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    Kung, H.F.

    1994-01-01

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  3. Secreted and Transmembrane Wnt Inhibitors and Activators

    Science.gov (United States)

    Cruciat, Cristina-Maria; Niehrs, Christof

    2013-01-01

    Signaling by the Wnt family of secreted glycoproteins plays important roles in embryonic development and adult homeostasis. Wnt signaling is modulated by a number of evolutionarily conserved inhibitors and activators. Wnt inhibitors belong to small protein families, including sFRP, Dkk, WIF, Wise/SOST, Cerberus, IGFBP, Shisa, Waif1, APCDD1, and Tiki1. Their common feature is to antagonize Wnt signaling by preventing ligand–receptor interactions or Wnt receptor maturation. Conversely, the Wnt activators, R-spondin and Norrin, promote Wnt signaling by binding to Wnt receptors or releasing a Wnt-inhibitory step. With few exceptions, these antagonists and agonists are not pure Wnt modulators, but also affect additional signaling pathways, such as TGF-β and FGF signaling. Here we discuss their interactions with Wnt ligands and Wnt receptors, their role in developmental processes, as well as their implication in disease. PMID:23085770

  4. Workflows and performances in the ranking prediction of 2016 D3R Grand Challenge 2: lessons learned from a collaborative effort.

    Science.gov (United States)

    Gao, Ying-Duo; Hu, Yuan; Crespo, Alejandro; Wang, Deping; Armacost, Kira A; Fells, James I; Fradera, Xavier; Wang, Hongwu; Wang, Huijun; Sherborne, Brad; Verras, Andreas; Peng, Zhengwei

    2018-01-01

    The 2016 D3R Grand Challenge 2 includes both pose and affinity or ranking predictions. This article is focused exclusively on affinity predictions submitted to the D3R challenge from a collaborative effort of the modeling and informatics group. Our submissions include ranking of 102 ligands covering 4 different chemotypes against the FXR ligand binding domain structure, and the relative binding affinity predictions of the two designated free energy subsets of 15 and 18 compounds. Using all the complex structures prepared in the same way allowed us to cover many types of workflows and compare their performances effectively. We evaluated typical workflows used in our daily structure-based design modeling support, which include docking scores, force field-based scores, QM/MM, MMGBSA, MD-MMGBSA, and MacroModel interaction energy estimations. The best performing methods for the two free energy subsets are discussed. Our results suggest that affinity ranking still remains very challenging; that the knowledge of more structural information does not necessarily yield more accurate predictions; and that visual inspection and human intervention are considerably important for ranking. Knowledge of the mode of action and protein flexibility along with visualization tools that depict polar and hydrophobic maps are very useful for visual inspection. QM/MM-based workflows were found to be powerful in affinity ranking and are encouraged to be applied more often. The standardized input and output enable systematic analysis and support methodology development and improvement for high level blinded predictions.

  5. Workflows and performances in the ranking prediction of 2016 D3R Grand Challenge 2: lessons learned from a collaborative effort

    Science.gov (United States)

    Gao, Ying-Duo; Hu, Yuan; Crespo, Alejandro; Wang, Deping; Armacost, Kira A.; Fells, James I.; Fradera, Xavier; Wang, Hongwu; Wang, Huijun; Sherborne, Brad; Verras, Andreas; Peng, Zhengwei

    2018-01-01

    The 2016 D3R Grand Challenge 2 includes both pose and affinity or ranking predictions. This article is focused exclusively on affinity predictions submitted to the D3R challenge from a collaborative effort of the modeling and informatics group. Our submissions include ranking of 102 ligands covering 4 different chemotypes against the FXR ligand binding domain structure, and the relative binding affinity predictions of the two designated free energy subsets of 15 and 18 compounds. Using all the complex structures prepared in the same way allowed us to cover many types of workflows and compare their performances effectively. We evaluated typical workflows used in our daily structure-based design modeling support, which include docking scores, force field-based scores, QM/MM, MMGBSA, MD-MMGBSA, and MacroModel interaction energy estimations. The best performing methods for the two free energy subsets are discussed. Our results suggest that affinity ranking still remains very challenging; that the knowledge of more structural information does not necessarily yield more accurate predictions; and that visual inspection and human intervention are considerably important for ranking. Knowledge of the mode of action and protein flexibility along with visualization tools that depict polar and hydrophobic maps are very useful for visual inspection. QM/MM-based workflows were found to be powerful in affinity ranking and are encouraged to be applied more often. The standardized input and output enable systematic analysis and support methodology development and improvement for high level blinded predictions.

  6. Generalization Performance of Regularized Ranking With Multiscale Kernels.

    Science.gov (United States)

    Zhou, Yicong; Chen, Hong; Lan, Rushi; Pan, Zhibin

    2016-05-01

    The regularized kernel method for the ranking problem has attracted increasing attentions in machine learning. The previous regularized ranking algorithms are usually based on reproducing kernel Hilbert spaces with a single kernel. In this paper, we go beyond this framework by investigating the generalization performance of the regularized ranking with multiscale kernels. A novel ranking algorithm with multiscale kernels is proposed and its representer theorem is proved. We establish the upper bound of the generalization error in terms of the complexity of hypothesis spaces. It shows that the multiscale ranking algorithm can achieve satisfactory learning rates under mild conditions. Experiments demonstrate the effectiveness of the proposed method for drug discovery and recommendation tasks.

  7. Exact distributions of two-sample rank statistics and block rank statistics using computer algebra

    NARCIS (Netherlands)

    Wiel, van de M.A.

    1998-01-01

    We derive generating functions for various rank statistics and we use computer algebra to compute the exact null distribution of these statistics. We present various techniques for reducing time and memory space used by the computations. We use the results to write Mathematica notebooks for

  8. Low ranks make the difference : How achievement goals and ranking information affect cooperation intentions

    NARCIS (Netherlands)

    Poortvliet, P. Marijn; Janssen, Onne; Van Yperen, N.W.; Van de Vliert, E.

    This investigation tested the joint effect of achievement goals and ranking information on information exchange intentions with a commensurate exchange partner. Results showed that individuals with performance goals were less inclined to cooperate with an exchange partner when they had low or high

  9. Thermodynamics of ligand binding to histone deacetylase like amidohydrolase from Bordetella/Alcaligenes.

    Science.gov (United States)

    Meyners, Christian; Baud, Matthias G J; Fuchter, Matthew J; Meyer-Almes, Franz-Josef

    2014-03-01

    Thermodynamic studies on ligand-protein binding have become increasingly important in the process of drug design. In combination with structural data and molecular dynamics simulations, thermodynamic studies provide relevant information about the mode of interaction between compounds and their target proteins and therefore build a sound basis for further drug optimization. Using the example of histone deacetylases (HDACs), particularly the histone deacetylase like amidohydrolase (HDAH) from Bordetella/Alcaligenes, a novel sensitive competitive fluorescence resonance energy transfer-based binding assay was developed and the thermodynamics of interaction of both fluorescent ligands and inhibitors to histone deacetylase like amidohydrolase were investigated. The assay consumes only small amounts of valuable target proteins and is suitable for fast kinetic and mechanistic studies as well as high throughput screening applications. Binding affinity increased with increasing length of aliphatic spacers (n = 4-7) between the hydroxamate moiety and the dansyl head group of ligand probes. Van't Hoff plots revealed an optimum in enthalpy contribution to the free energy of binding for the dansyl-ligand with hexyl spacer. The selectivity in the series of dansyl-ligands against human class I HDAC1 but not class II HDACs 4 and 6 increased with the ratio of ΔH(0)/ΔG(0). The data clearly emphasize the importance of thermodynamic signatures as useful general guidance for the optimization of ligands or rational drug design. Copyright © 2014 John Wiley & Sons, Ltd.

  10. SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [3H]dextromethorphan and σligands to guinea pig brain

    International Nuclear Information System (INIS)

    Klein, M.; Canoll, P.D.; Musacchio, J.M.

    1991-01-01

    The DM 1 /σ 1 site binds dextromethorphan (DM) and σ receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [ 3 H]dextromethorphan, [ 3 H]3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine and (+)-[ 3 H]1,3-Di-o-tolyl-guanidine ([ 3 H]DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM K i values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM 1 σ 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed K i values of 9-13 and 3-4 μM respectively against the three labeled ligands. These results, the broad specificity of the DM 1 /σ 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor

  11. Are university rankings useful to improve research? A systematic review.

    Science.gov (United States)

    Vernon, Marlo M; Balas, E Andrew; Momani, Shaher

    2018-01-01

    Concerns about reproducibility and impact of research urge improvement initiatives. Current university ranking systems evaluate and compare universities on measures of academic and research performance. Although often useful for marketing purposes, the value of ranking systems when examining quality and outcomes is unclear. The purpose of this study was to evaluate usefulness of ranking systems and identify opportunities to support research quality and performance improvement. A systematic review of university ranking systems was conducted to investigate research performance and academic quality measures. Eligibility requirements included: inclusion of at least 100 doctoral granting institutions, be currently produced on an ongoing basis and include both global and US universities, publish rank calculation methodology in English and independently calculate ranks. Ranking systems must also include some measures of research outcomes. Indicators were abstracted and contrasted with basic quality improvement requirements. Exploration of aggregation methods, validity of research and academic quality indicators, and suitability for quality improvement within ranking systems were also conducted. A total of 24 ranking systems were identified and 13 eligible ranking systems were evaluated. Six of the 13 rankings are 100% focused on research performance. For those reporting weighting, 76% of the total ranks are attributed to research indicators, with 24% attributed to academic or teaching quality. Seven systems rely on reputation surveys and/or faculty and alumni awards. Rankings influence academic choice yet research performance measures are the most weighted indicators. There are no generally accepted academic quality indicators in ranking systems. No single ranking system provides a comprehensive evaluation of research and academic quality. Utilizing a combined approach of the Leiden, Thomson Reuters Most Innovative Universities, and the SCImago ranking systems may provide

  12. Asynchronous Gossip for Averaging and Spectral Ranking

    Science.gov (United States)

    Borkar, Vivek S.; Makhijani, Rahul; Sundaresan, Rajesh

    2014-08-01

    We consider two variants of the classical gossip algorithm. The first variant is a version of asynchronous stochastic approximation. We highlight a fundamental difficulty associated with the classical asynchronous gossip scheme, viz., that it may not converge to a desired average, and suggest an alternative scheme based on reinforcement learning that has guaranteed convergence to the desired average. We then discuss a potential application to a wireless network setting with simultaneous link activation constraints. The second variant is a gossip algorithm for distributed computation of the Perron-Frobenius eigenvector of a nonnegative matrix. While the first variant draws upon a reinforcement learning algorithm for an average cost controlled Markov decision problem, the second variant draws upon a reinforcement learning algorithm for risk-sensitive control. We then discuss potential applications of the second variant to ranking schemes, reputation networks, and principal component analysis.

  13. Fuzzy-set based contingency ranking

    International Nuclear Information System (INIS)

    Hsu, Y.Y.; Kuo, H.C.

    1992-01-01

    In this paper, a new approach based on fuzzy set theory is developed for contingency ranking of Taiwan power system. To examine whether a power system can remain in a secure and reliable operating state under contingency conditions, those contingency cases that will result in loss-of-load, loss-of generation, or islanding are first identified. Then 1P-1Q iteration of fast decoupled load flow is preformed to estimate post-contingent quantities (line flows, bus voltages) for other contingency cases. Based on system operators' past experience, each post-contingent quantity is assigned a degree of severity according to the potential damage that could be imposed on the power system by the quantity, should the contingency occurs. An approach based on fuzzy set theory is developed to deal with the imprecision of linguistic terms

  14. Motif discovery in ranked lists of sequences

    DEFF Research Database (Denmark)

    Nielsen, Morten Muhlig; Tataru, Paula; Madsen, Tobias

    2016-01-01

    Motif analysis has long been an important method to characterize biological functionality and the current growth of sequencing-based genomics experiments further extends its potential. These diverse experiments often generate sequence lists ranked by some functional property. There is therefore...... advantage of the regular expression feature, including enrichments for combinations of different microRNA seed sites. The method is implemented and made publicly available as an R package and supports high parallelization on multi-core machinery....... a growing need for motif analysis methods that can exploit this coupled data structure and be tailored for specific biological questions. Here, we present an exploratory motif analysis tool, Regmex (REGular expression Motif EXplorer), which offers several methods to evaluate the correlation of motifs...

  15. Immune checkpoint inhibitors for metastatic bladder cancer.

    Science.gov (United States)

    Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

    2018-03-01

    Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Ranked retrieval of Computational Biology models.

    Science.gov (United States)

    Henkel, Ron; Endler, Lukas; Peters, Andre; Le Novère, Nicolas; Waltemath, Dagmar

    2010-08-11

    The study of biological systems demands computational support. If targeting a biological problem, the reuse of existing computational models can save time and effort. Deciding for potentially suitable models, however, becomes more challenging with the increasing number of computational models available, and even more when considering the models' growing complexity. Firstly, among a set of potential model candidates it is difficult to decide for the model that best suits ones needs. Secondly, it is hard to grasp the nature of an unknown model listed in a search result set, and to judge how well it fits for the particular problem one has in mind. Here we present an improved search approach for computational models of biological processes. It is based on existing retrieval and ranking methods from Information Retrieval. The approach incorporates annotations suggested by MIRIAM, and additional meta-information. It is now part of the search engine of BioModels Database, a standard repository for computational models. The introduced concept and implementation are, to our knowledge, the first application of Information Retrieval techniques on model search in Computational Systems Biology. Using the example of BioModels Database, it was shown that the approach is feasible and extends the current possibilities to search for relevant models. The advantages of our system over existing solutions are that we incorporate a rich set of meta-information, and that we provide the user with a relevance ranking of the models found for a query. Better search capabilities in model databases are expected to have a positive effect on the reuse of existing models.

  17. Potent inhibition of tau fibrillization with a multivalent ligand

    International Nuclear Information System (INIS)

    Honson, Nicolette S.; Jensen, Jordan R.; Darby, Michael V.; Kuret, Jeff

    2007-01-01

    Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at ∼80 nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors

  18. Regulation by Phloroglucinol of Nrf2/Maf-Mediated Expression of Antioxidant Enzymes and Inhibition of Osteoclastogenesis via the RANKL/RANK Signaling Pathway: In Silico study

    Science.gov (United States)

    Rahim, Agus Hadian; Setiawan, Bambang; Dewi, Firli Rahmah Primula; Noor, Zairin

    2015-01-01

    Introduction: Phloroglucinol is an antioxidant compound with many positive effects on health. The purpose of this study was to determine the role of phloroglucinol in osteoclastogenesis via the RANKL/RANK signaling pathway and the activity of the transcription factor Nrf2. Material and methods: Analysis was performed in silico using the primary method of docking by the use of Hex 8.0 software and Haddock web server. Analysis of interactions was then performed to determine interactions between the ligand and its receptors by using the software LigPlus and LigandScout 3.1. Results: Results indicated that phloroglucinol compound was thought to inhibit osteoclastogenesis via three mechanisms: inhibiting RANKL−RANK interaction, sustaining the RANKL−OPG bond, and increasing the activity of the transcription factor Nrf2. PMID:26483597

  19. HPPD: ligand- and target-based virtual screening on a herbicide target.

    Science.gov (United States)

    López-Ramos, Miriam; Perruccio, Francesca

    2010-05-24

    Hydroxyphenylpyruvate dioxygenase (HPPD) has proven to be a very successful target for the development of herbicides with bleaching properties, and today HPPD inhibitors are well established in the agrochemical market. Syngenta has a long history of HPPD-inhibitor research, and HPPD was chosen as a case study for the validation of diverse ligand- and target-based virtual screening approaches to identify compounds with inhibitory properties. Two-dimensional extended connectivity fingerprints, three-dimensional shape-based tools (ROCS, EON, and Phase-shape) and a pharmacophore approach (Phase) were used as ligand-based methods; Glide and Gold were used as target-based. Both the virtual screening utility and the scaffold-hopping ability of the screening tools were assessed. Particular emphasis was put on the specific pitfalls to take into account for the design of a virtual screening campaign in an agrochemical context, as compared to a pharmaceutical environment.

  20. Structural studies of P-type ATPase–ligand complexes using an X-ray free-electron laser

    Directory of Open Access Journals (Sweden)

    Maike Bublitz

    2015-07-01

    Full Text Available Membrane proteins are key players in biological systems, mediating signalling events and the specific transport of e.g. ions and metabolites. Consequently, membrane proteins are targeted by a large number of currently approved drugs. Understanding their functions and molecular mechanisms is greatly dependent on structural information, not least on complexes with functionally or medically important ligands. Structure determination, however, is hampered by the difficulty of obtaining well diffracting, macroscopic crystals. Here, the feasibility of X-ray free-electron-laser-based serial femtosecond crystallography (SFX for the structure determination of membrane protein–ligand complexes using microcrystals of various native-source and recombinant P-type ATPase complexes is demonstrated. The data reveal the binding sites of a variety of ligands, including lipids and inhibitors such as the hallmark P-type ATPase inhibitor orthovanadate. By analyzing the resolution dependence of ligand densities and overall model qualities, SFX data quality metrics as well as suitable refinement procedures are discussed. Even at relatively low resolution and multiplicity, the identification of ligands can be demonstrated. This makes SFX a useful tool for ligand screening and thus for unravelling the molecular mechanisms of biologically active proteins.

  1. Structural studies of P-type ATPase–ligand complexes using an X-ray free-electron laser

    Energy Technology Data Exchange (ETDEWEB)

    Bublitz, Maike; Nass, Karol; Drachmann, Nikolaj D.; Markvardsen, Anders J.; Gutmann, Matthias J.; Barends, Thomas R. M.; Mattle, Daniel; Shoeman, Robert L.; Doak, R. Bruce; Boutet, Sébastien; Messerschmidt, Marc; Seibert, Marvin M.; Williams, Garth J.; Foucar, Lutz; Reinhard, Linda; Sitsel, Oleg; Gregersen, Jonas L.; Clausen, Johannes D.; Boesen, Thomas; Gotfryd, Kamil; Wang, Kai-Tuo; Olesen, Claus; Møller, Jesper V.; Nissen, Poul; Schlichting, Ilme

    2015-06-11

    Membrane proteins are key players in biological systems, mediating signalling events and the specific transport ofe.g.ions and metabolites. Consequently, membrane proteins are targeted by a large number of currently approved drugs. Understanding their functions and molecular mechanisms is greatly dependent on structural information, not least on complexes with functionally or medically important ligands. Structure determination, however, is hampered by the difficulty of obtaining well diffracting, macroscopic crystals. Here, the feasibility of X-ray free-electron-laser-based serial femtosecond crystallography (SFX) for the structure determination of membrane protein–ligand complexes using microcrystals of various native-source and recombinant P-type ATPase complexes is demonstrated. The data reveal the binding sites of a variety of ligands, including lipids and inhibitors such as the hallmark P-type ATPase inhibitor orthovanadate. By analyzing the resolution dependence of ligand densities and overall model qualities, SFX data quality metrics as well as suitable refinement procedures are discussed. Even at relatively low resolution and multiplicity, the identification of ligands can be demonstrated. This makes SFX a useful tool for ligand screening and thus for unravelling the molecular mechanisms of biologically active proteins.

  2. An R package for analyzing and modeling ranking data.

    Science.gov (United States)

    Lee, Paul H; Yu, Philip L H

    2013-05-14

    In medical informatics, psychology, market research and many other fields, researchers often need to analyze and model ranking data. However, there is no statistical software that provides tools for the comprehensive analysis of ranking data. Here, we present pmr, an R package for analyzing and modeling ranking data with a bundle of tools. The pmr package enables descriptive statistics (mean rank, pairwise frequencies, and marginal matrix), Analytic Hierarchy Process models (with Saaty's and Koczkodaj's inconsistencies), probability models (Luce model, distance-based model, and rank-ordered logit model), and the visualization of ranking data with multidimensional preference analysis. Examples of the use of package pmr are given using a real ranking dataset from medical informatics, in which 566 Hong Kong physicians ranked the top five incentives (1: competitive pressures; 2: increased savings; 3: government regulation; 4: improved efficiency; 5: improved quality care; 6: patient demand; 7: financial incentives) to the computerization of clinical practice. The mean rank showed that item 4 is the most preferred item and item 3 is the least preferred item, and significance difference was found between physicians' preferences with respect to their monthly income. A multidimensional preference analysis identified two dimensions that explain 42% of the total variance. The first can be interpreted as the overall preference of the seven items (labeled as "internal/external"), and the second dimension can be interpreted as their overall variance of (labeled as "push/pull factors"). Various statistical models were fitted, and the best were found to be weighted distance-based models with Spearman's footrule distance. In this paper, we presented the R package pmr, the first package for analyzing and modeling ranking data. The package provides insight to users through descriptive statistics of ranking data. Users can also visualize ranking data by applying a thought

  3. Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models.

    Directory of Open Access Journals (Sweden)

    Iveta Novakova

    Full Text Available The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line for proper data comparison.

  4. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    Directory of Open Access Journals (Sweden)

    Stéphanie Pérot

    Full Text Available Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely

  5. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    Science.gov (United States)

    Pérot, Stéphanie; Regad, Leslie; Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A; Villoutreix, Bruno O; Camproux, Anne-Claude

    2013-01-01

    Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket

  6. Ligand photo-isomerization triggers conformational changes in iGluR2 ligand binding domain.

    Directory of Open Access Journals (Sweden)

    Tino Wolter

    Full Text Available Neurological glutamate receptors bind a variety of artificial ligands, both agonistic and antagonistic, in addition to glutamate. Studying their small molecule binding properties increases our understanding of the central nervous system and a variety of associated pathologies. The large, oligomeric multidomain membrane protein contains a large and flexible ligand binding domains which undergoes large conformational changes upon binding different ligands. A recent application of glutamate receptors is their activation or inhibition via photo-switchable ligands, making them key systems in the emerging field of optochemical genetics. In this work, we present a theoretical study on the binding mode and complex stability of a novel photo-switchable ligand, ATA-3, which reversibly binds to glutamate receptors ligand binding domains (LBDs. We propose two possible binding modes for this ligand based on flexible ligand docking calculations and show one of them to be analogues to the binding mode of a similar ligand, 2-BnTetAMPA. In long MD simulations, it was observed that transitions between both binding poses involve breaking and reforming the T686-E402 protein hydrogen bond. Simulating the ligand photo-isomerization process shows that the two possible configurations of the ligand azo-group have markedly different complex stabilities and equilibrium binding modes. A strong but slow protein response is observed after ligand configuration changes. This provides a microscopic foundation for the observed difference in ligand activity upon light-switching.

  7. Generation of pharmacophores and classification of drugs using protein-ligand complexes

    Directory of Open Access Journals (Sweden)

    Eliana Velasquez

    2014-04-01

    Full Text Available Pharmacophore identification is a veryimportant step in de novo design, leadoptimization, chemogenomics, and virtualscreening of drugs. Unfortunately,the high cost of comercial software forpharmacophore detection is a commonlimiting factor for researchers with limitedfunding. This paper presents a set offreely available perl routines that weredesigned to help in the process of 3Dpharmacophore identification and QSARstudies. These routines also allowed theclassification of ligands based on theirtridimensional similarity and bindingmechanism. The family of phosphodiesterasesand their inhibitors were used astest model.

  8. Effect of iodination site on binding of radiolabeled ligand by insulin antibodies and insulin autoantibodies

    International Nuclear Information System (INIS)

    Diaz, J.L.; Wilkin, T.J.

    1988-01-01

    Four human insulins and four porcine insulins, each monoiodinated to the same specific activity at one of the four tyrosine residues (A14, A19, B16, B26) and purified by reversed-phase liquid chromatography, were tested in a radiobinding assay against a panel of insulin-antibody (IA)-positive sera from 10 insulin-treated diabetics and insulin-autoantibody-positive (IAA) sera from 10 nondiabetics. Of the 10 IAA-positive sera, five were fully cross reactive with both insulin species, and five were specific for human insulin. The rank order of binding of sera with the four ligands from each species was random for IA (mean rank values of 1.9 for A14, 2.0 for A19, 2.5 for B16, and 3.6 for B26 from a possible ranking range of 1 to 4), but more consistent for non-human-insulin-specific IAA (mean rank values 1.3 for A14, 3.8 for A19, 1.7 for B16, and 3.2 for B26 for labeled human insulins; 1.2 for A14, 4.0 for A19, 1.8 for B16, and 3.0 for B26 for labeled porcine insulins). The rank order of binding was virtually uniform for human-insulin-specific IAA (mean values 1.2 for A14, 3.0 for A19, 1.8 for B16, and 4.0 for B26). The influence of iodination site on the binding of labeled insulin appears to be dependent on the proximity of the labeled tyrosine to the antibody binding site and the clonal diversity, or restriction, of insulin-binding antibodies in the test serum. When IA and IAA are measured, the implications of this study regarding the choice of assay ligand may be important

  9. Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3

    DEFF Research Database (Denmark)

    Hudson, Brian D; Tikhonova, Irina G; Pandey, Sunil K

    2012-01-01

    Free fatty acid receptors 2 and 3 (FFA2 and FFA3) are G protein-coupled receptors for short chain free fatty acids (SCFAs). They respond to the same set of endogenous ligands but with distinct rank-order of potency such that acetate (C2) has been described as FFA2-selective, whereas propionate (C...

  10. Feature ranking and rank aggregation for automatic sleep stage classification: a comparative study.

    Science.gov (United States)

    Najdi, Shirin; Gharbali, Ali Abdollahi; Fonseca, José Manuel

    2017-08-18

    Nowadays, sleep quality is one of the most important measures of healthy life, especially considering the huge number of sleep-related disorders. Identifying sleep stages using polysomnographic (PSG) signals is the traditional way of assessing sleep quality. However, the manual process of sleep stage classification is time-consuming, subjective and costly. Therefore, in order to improve the accuracy and efficiency of the sleep stage classification, researchers have been trying to develop automatic classification algorithms. Automatic sleep stage classification mainly consists of three steps: pre-processing, feature extraction and classification. Since classification accuracy is deeply affected by the extracted features, a poor feature vector will adversely affect the classifier and eventually lead to low classification accuracy. Therefore, special attention should be given to the feature extraction and selection process. In this paper the performance of seven feature selection methods, as well as two feature rank aggregation methods, were compared. Pz-Oz EEG, horizontal EOG and submental chin EMG recordings of 22 healthy males and females were used. A comprehensive feature set including 49 features was extracted from these recordings. The extracted features are among the most common and effective features used in sleep stage classification from temporal, spectral, entropy-based and nonlinear categories. The feature selection methods were evaluated and compared using three criteria: classification accuracy, stability, and similarity. Simulation results show that MRMR-MID achieves the highest classification performance while Fisher method provides the most stable ranking. In our simulations, the performance of the aggregation methods was in the average level, although they are known to generate more stable results and better accuracy. The Borda and RRA rank aggregation methods could not outperform significantly the conventional feature ranking methods. Among

  11. Blind Pose Prediction, Scoring, and Affinity Ranking of the CSAR 2014 Dataset.

    Science.gov (United States)

    Martiny, Virginie Y; Martz, François; Selwa, Edithe; Iorga, Bogdan I

    2016-06-27

    The 2014 CSAR Benchmark Exercise was focused on three protein targets: coagulation factor Xa, spleen tyrosine kinase, and bacterial tRNA methyltransferase. Our protocol involved a preliminary analysis of the structural information available in the Protein Data Bank for the protein targets, which allowed the identification of the most appropriate docking software and scoring functions to be used for the rescoring of several docking conformations datasets, as well as for pose prediction and affinity ranking. The two key points of this study were (i) the prior evaluation of molecular modeling tools that are most adapted for each target and (ii) the increased search efficiency during the docking process to better explore the conformational space of big and flexible ligands.

  12. Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2.

    Directory of Open Access Journals (Sweden)

    Juan A Bueren-Calabuig

    2015-06-01

    Full Text Available Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29 peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2.

  13. Using incomplete citation data for MEDLINE results ranking.

    Science.gov (United States)

    Herskovic, Jorge R; Bernstam, Elmer V

    2005-01-01

    Information overload is a significant problem for modern medicine. Searching MEDLINE for common topics often retrieves more relevant documents than users can review. Therefore, we must identify documents that are not only relevant, but also important. Our system ranks articles using citation counts and the PageRank algorithm, incorporating data from the Science Citation Index. However, citation data is usually incomplete. Therefore, we explore the relationship between the quantity of citation information available to the system and the quality of the result ranking. Specifically, we test the ability of citation count and PageRank to identify "important articles" as defined by experts from large result sets with decreasing citation information. We found that PageRank performs better than simple citation counts, but both algorithms are surprisingly robust to information loss. We conclude that even an incomplete citation database is likely to be effective for importance ranking.

  14. Co-integration Rank Testing under Conditional Heteroskedasticity

    DEFF Research Database (Denmark)

    Cavaliere, Guiseppe; Rahbæk, Anders; Taylor, A.M. Robert

    null distributions of the rank statistics coincide with those derived by previous authors who assume either i.i.d. or (strict and covariance) stationary martingale difference innovations. We then propose wild bootstrap implementations of the co-integrating rank tests and demonstrate that the associated...... bootstrap rank statistics replicate the first-order asymptotic null distributions of the rank statistics. We show the same is also true of the corresponding rank tests based on the i.i.d. bootstrap of Swensen (2006). The wild bootstrap, however, has the important property that, unlike the i.i.d. bootstrap......, it preserves in the re-sampled data the pattern of heteroskedasticity present in the original shocks. Consistent with this, numerical evidence sug- gests that, relative to tests based on the asymptotic critical values or the i.i.d. bootstrap, the wild bootstrap rank tests perform very well in small samples un...

  15. Social Rank, Stress, Fitness, and Life Expectancy in Wild Rabbits

    Science.gov (United States)

    von Holst, Dietrich; Hutzelmeyer, Hans; Kaetzke, Paul; Khaschei, Martin; Schönheiter, Ronald

    Wild rabbits of the two sexes have separate linear rank orders, which are established and maintained by intensive fights. The social rank of individuals strongly influence their fitness: males and females that gain a high social rank, at least at the outset of their second breeding season, have a much higher lifetime fitness than subordinate individuals. This is because of two separate factors: a much higher fecundity and annual reproductive success and a 50% longer reproductive life span. These results are in contrast to the view in evolutionary biology that current reproduction can be increased only at the expense of future survival and/or fecundity. These concepts entail higher physiological costs in high-ranking mammals, which is not supported by our data: In wild rabbits the physiological costs of social positions are caused predominantly by differential psychosocial stress responses that are much lower in high-ranking than in low-ranking individuals.

  16. Development of immobilized ligands for actinide separations

    International Nuclear Information System (INIS)

    Paine, R.T.

    1994-01-01

    Primary goals during this grant period were to (1) synthesize new bifunctional chelating ligands, (2) characterize the structural features of the Ln and An coordination complexes formed by these ligands, (3) use structural data to iteratively design new classes of multifunctional ligands, and (4) explore additional routes for attachment of key ligands to solid supports that could be useful for chromatographic separations. Some highlights of recently published work as well as a summary of submitted, unpublished and/or still in progress research are outlined

  17. RANK/RANKL/OPG Signalization Implication in Periodontitis: New Evidence from a RANK Transgenic Mouse Model

    Directory of Open Access Journals (Sweden)

    Bouchra Sojod

    2017-05-01

    Full Text Available Periodontitis is based on a complex inflammatory over-response combined with possible genetic predisposition factors. The RANKL/RANK/OPG signaling pathway is implicated in bone resorption through its key function in osteoclast differentiation and activation, as well as in the inflammatory response. This central element of osteo-immunology has been suggested to be perturbed in several diseases, including periodontitis, as it is a predisposing factor for this disease. The aim of the present study was to validate this hypothesis using a transgenic mouse line, which over-expresses RANK (RTg and develops a periodontitis-like phenotype at 5 months of age. RTg mice exhibited severe alveolar bone loss, an increased number of TRAP positive cells, and disorganization of periodontal ligaments. This phenotype was more pronounced in females. We also observed dental root resorption lacunas. Hyperplasia of the gingival epithelium, including Malassez epithelial rests, was visible as early as 25 days, preceding any other symptoms. These results demonstrate that perturbations of the RANKL/RANK/OPG system constitute a core element of periodontitis, and more globally, osteo-immune diseases.

  18. RANK/RANKL/OPG Signalization Implication in Periodontitis: New Evidence from a RANK Transgenic Mouse Model

    Science.gov (United States)

    Sojod, Bouchra; Chateau, Danielle; Mueller, Christopher G.; Babajko, Sylvie; Berdal, Ariane; Lézot, Frédéric; Castaneda, Beatriz

    2017-01-01

    Periodontitis is based on a complex inflammatory over-response combined with possible genetic predisposition factors. The RANKL/RANK/OPG signaling pathway is implicated in bone resorption through its key function in osteoclast differentiation and activation, as well as in the inflammatory response. This central element of osteo-immunology has been suggested to be perturbed in several diseases, including periodontitis, as it is a predisposing factor for this disease. The aim of the present study was to validate this hypothesis using a transgenic mouse line, which over-expresses RANK (RTg) and develops a periodontitis-like phenotype at 5 months of age. RTg mice exhibited severe alveolar bone loss, an increased number of TRAP positive cells, and disorganization of periodontal ligaments. This phenotype was more pronounced in females. We also observed dental root resorption lacunas. Hyperplasia of the gingival epithelium, including Malassez epithelial rests, was visible as early as 25 days, preceding any other symptoms. These results demonstrate that perturbations of the RANKL/RANK/OPG system constitute a core element of periodontitis, and more globally, osteo-immune diseases. PMID:28596739

  19. RANKL/RANK/OPG cytokine receptor system: mRNA expression pattern in BPH, primary and metastatic prostate cancer disease.

    Science.gov (United States)

    Christoph, Frank; König, Frank; Lebentrau, Steffen; Jandrig, Burkhard; Krause, Hans; Strenziok, Romy; Schostak, Martin

    2018-02-01

    The cytokine system RANKL (receptor activator of NF-κB ligand), its receptor RANK and the antagonist OPG (osteoprotegerin) play a critical role in bone turnover. Our investigation was conducted to describe the gene expression at primary tumour site in prostate cancer patients and correlate the results with Gleason Score and PSA level. Seventy-one samples were obtained from prostate cancer patients at the time of radical prostatectomy and palliative prostate resection (n = 71). Patients with benign prostate hyperplasia served as controls (n = 60). We performed real-time RT-PCR after microdissection of the samples. The mRNA expression of RANK was highest in tumour tissue from patients with bone metastases (p BPH or locally confined tumours, also shown in clinical subgroups distinguished by Gleason Score (BPH tissue but did not exceed as much as in the tumour tissue. We demonstrated that RANK, RANKL and OPG are directly expressed by prostate cancer cells at the primary tumour site and showed a clear correlation with Gleason Score, serum PSA level and advanced disease. In BPH, mRNA expression is also detectable, but RANK expression does not exceed as much as compared to tumour tissue.

  20. Molecular Docking Simulation of Neuraminidase Influenza A Subtype H1N1 with Potential Inhibitor of Disulfide Cyclic Peptide (DNY, NNY, LRL)

    Science.gov (United States)

    Putra, R. P.; Imaniastuti, R.; Nasution, M. A. F.; Kerami, Djati; Tambunan, U. S. F.

    2018-04-01

    Oseltamivir resistance as an inhibitor of neuraminidase influenza A virus subtype H1N1 has been reported lately. Therefore, to solve this problem, several kinds of research has been conducted to design and discover disulfide cyclic peptide ligands through molecular docking method, to find the potential inhibitors for neuraminidase H1N1 which then can disturb the virus replication. This research was studied and evaluated the interaction of ligands toward enzyme using molecular docking simulation, which was performed on three disulfide cyclic peptide inhibitors (DNY, LRL, and NNT), along with oseltamivir and zanamivir as the standard ligands using MOE 2008.10 software. The docking simulation shows that all disulfide cyclic peptide ligands have lower Gibbs free binding energies (ΔGbinding) than the standard ligands, with DNY ligand has the lowest ΔGbinding at -7.8544 kcal/mol. Furthermore, these ligands were also had better molecular interactions with neuraminidase than the standards, owing by the hydrogen bonds that were formed during the docking simulation. In the end, we concluded that DNY, LRL and NNT ligands have the potential to be developed as the inhibitor of neuraminidase H1N1.

  1. Discovering author impact: A PageRank perspective

    OpenAIRE

    Yan, Erjia; Ding, Ying

    2010-01-01

    This article provides an alternative perspective for measuring author impact by applying PageRank algorithm to a coauthorship network. A weighted PageRank algorithm considering citation and coauthorship network topology is proposed. We test this algorithm under different damping factors by evaluating author impact in the informetrics research community. In addition, we also compare this weighted PageRank with the h-index, citation, and program committee (PC) membership of the International So...

  2. Convolutional Codes with Maximum Column Sum Rank for Network Streaming

    OpenAIRE

    Mahmood, Rafid; Badr, Ahmed; Khisti, Ashish

    2015-01-01

    The column Hamming distance of a convolutional code determines the error correction capability when streaming over a class of packet erasure channels. We introduce a metric known as the column sum rank, that parallels column Hamming distance when streaming over a network with link failures. We prove rank analogues of several known column Hamming distance properties and introduce a new family of convolutional codes that maximize the column sum rank up to the code memory. Our construction invol...

  3. Ranking agricultural, environmental and natural resource economics journals: A note

    OpenAIRE

    Halkos, George; Tzeremes, Nickolaos

    2012-01-01

    This paper by applying Data Envelopment Analysis (DEA) ranks for the first time Economics journals in the field of Agricultural, Environmental and Natural Resource. Specifically, by using one composite input and one composite output the paper ranks 32 journals. In addition for the first time three different quality ranking reports have been incorporated to the DEA modelling problem in order to classify the journals into four categories (‘A’ to ‘D’). The results reveal that the journals with t...

  4. Is there a 'Mid-Rank Trap' for Universities'

    OpenAIRE

    Chang Da Wan

    2015-01-01

    The middle-income trap is an economic phenomenon to describe economies that have stagnated at the middle-income level and failed to progress into the high-income level. Inspired by this economic concept, this paper explores a hypothesis: is there a 'mid-rank trap' for universities in the exercise to rank universities globally' Using the rankings between 2004 and 2014 that were jointly and separately developed by Times Higher Education and Quacquarelli Symonds Company, this paper argues that t...

  5. Asympotic efficiency of signed - rank symmetry tests under skew alternatives.

    OpenAIRE

    Alessandra Durio; Yakov Nikitin

    2002-01-01

    The efficiency of some known tests for symmetry such as the sign test, the Wilcoxon signed-rank test or more general linear signed rank tests was studied mainly under the classical alternatives of location. However it is interesting to compare the efficiencies of these tests under asymmetric alternatives like the so-called skew alternative proposed in Azzalini (1985). We find and compare local Bahadur efficiencies of linear signed-rank statistics for skew alternatives and discuss also the con...

  6. Reduced Rank Adaptive Filtering in Impulsive Noise Environments

    KAUST Repository

    Soury, Hamza

    2014-01-06

    An impulsive noise environment is used in this paper. A new aspect of signal truncation is deployed to reduce the harmful effect of the impulsive noise to the signal. A full rank direct solution is derived followed by an iterative solution. The reduced rank adaptive filter is presented in this environment by using two methods for rank reduction. The minimized objective function is defined using the Lp norm. The results are presented and the efficiency of each algorithm is discussed.

  7. Reduced Rank Adaptive Filtering in Impulsive Noise Environments

    KAUST Repository

    Soury, Hamza; Abed-Meraim, Karim; Alouini, Mohamed-Slim

    2014-01-01

    An impulsive noise environment is used in this paper. A new aspect of signal truncation is deployed to reduce the harmful effect of the impulsive noise to the signal. A full rank direct solution is derived followed by an iterative solution. The reduced rank adaptive filter is presented in this environment by using two methods for rank reduction. The minimized objective function is defined using the Lp norm. The results are presented and the efficiency of each algorithm is discussed.

  8. A Citation-Based Ranking of Strategic Management Journals

    OpenAIRE

    Azar, Ofer H.; Brock, David M.

    2007-01-01

    Rankings of strategy journals are important for authors, readers, and promotion and tenure committees. We present several rankings, based either on the number of articles that cited the journal or the per-article impact. Our analyses cover various periods between 1991 and 2006, for most of which the Strategic Management Journal was in first place and Journal of Economics & Management Strategy (JEMS) second, although JEMS ranked first in certain instances. Long Range Planning and Technology An...

  9. Ligand-induced changes in the structure and dynamics of Escherichia coli peptide deformylase.

    Science.gov (United States)

    Amero, Carlos D; Byerly, Douglas W; McElroy, Craig A; Simmons, Amber; Foster, Mark P

    2009-08-18

    Peptide deformylase (PDF) is an enzyme that is responsible for removing the formyl group from nascently synthesized polypeptides in bacteria, attracting much attention as a potential target for novel antibacterial agents. Efforts to develop potent inhibitors of the enzyme have progressed on the basis of classical medicinal chemistry, combinatorial chemistry, and structural approaches, yet the validity of PDF as an antibacterial target hangs, in part, on the ability of inhibitors to selectively target this enzyme in favor of structurally related metallohydrolases. We have used (15)N NMR spectroscopy and isothermal titration calorimetry to investigate the high-affinity interaction of EcPDF with actinonin, a naturally occurring potent EcPDF inhibitor. Backbone amide chemical shifts, residual dipolar couplings, hydrogen-deuterium exchange, and (15)N relaxation reveal structural and dynamic effects of ligand binding in the immediate vicinity of the ligand-binding site as well as at remote sites. A comparison of the crystal structures of free and actinonin-bound EcPDF with the solution data suggests that most of the consequences of the ligand binding to the protein are lost or obscured during crystallization. The results of these studies improve our understanding of the thermodynamic global minimum and have important implications for structure-based drug design.

  10. Connectivity ranking of heterogeneous random conductivity models

    Science.gov (United States)

    Rizzo, C. B.; de Barros, F.

    2017-12-01

    To overcome the challenges associated with hydrogeological data scarcity, the hydraulic conductivity (K) field is often represented by a spatial random process. The state-of-the-art provides several methods to generate 2D or 3D random K-fields, such as the classic multi-Gaussian fields or non-Gaussian fields, training image-based fields and object-based fields. We provide a systematic comparison of these models based on their connectivity. We use the minimum hydraulic resistance as a connectivity measure, which it has been found to be strictly correlated with early time arrival of dissolved contaminants. A computationally efficient graph-based algorithm is employed, allowing a stochastic treatment of the minimum hydraulic resistance through a Monte-Carlo approach and therefore enabling the computation of its uncertainty. The results show the impact of geostatistical parameters on the connectivity for each group of random fields, being able to rank the fields according to their minimum hydraulic resistance.

  11. Multirelational Social Recommendations via Multigraph Ranking.

    Science.gov (United States)

    Mao, Mingsong; Lu, Jie; Zhang, Guangquan; Zhang, Jinlong

    2017-12-01

    Recommender systems aim to identify relevant items for particular users in large-scale online applications. The historical rating data of users is a valuable input resource for many recommendation models such as collaborative filtering (CF), but these models are known to suffer from the rating sparsity problem when the users or items under consideration have insufficient rating records. With the continued growth of online social networks, the increased user-to-user relationships are reported to be helpful and can alleviate the CF rating sparsity problem. Although researchers have developed a range of social network-based recommender systems, there is no unified model to handle multirelational social networks. To address this challenge, this paper represents different user relationships in a multigraph and develops a multigraph ranking model to identify and recommend the nearest neighbors of particular users in high-order environments. We conduct empirical experiments on two real-world datasets: 1) Epinions and 2) Last.fm, and the comprehensive comparison with other approaches demonstrates that our model improves recommendation performance in terms of both recommendation coverage and accuracy, especially when the rating data are sparse.

  12. Improving CBIR Systems Using Automated Ranking

    Directory of Open Access Journals (Sweden)

    B. D. Reljin

    2012-11-01

    Full Text Available The most common way of searching images on the Internet and in private collections is based on a similarity measuring of a series of text words that are assigned to each image with users query series. This method imposes strong constraints (the number of words to describe the image, the time necessary to thoroughly describe the subjective experience of images, the level of details in the picture, language barrier, etc., and is therefore very inefficient. Modern researches in this area are focused on the contentbased searching images (CBIR. In this way, all described disadvantages are overcome and the quality of searching results is improved. This paper presents a solution for CBIR systems where the search procedure is enhanced using sophisticated extraction and ranking of extracted images. The searching procedure is based on extraction and preprocessing of a large number of low level image features. Thus, when the user defines a query image, the proposed algorithm based on artificial intelligence, shows to the user a group of images which are most similar to a query image by content. The proposed algorithm is iterative, so the user can direct the searching procedure to an expected outcome and get a set of images that are more similar to the query one.

  13. Method ranks competing projects by priorities, risk

    International Nuclear Information System (INIS)

    Moeckel, D.R.

    1993-01-01

    A practical, objective guide for ranking projects based on risk-based priorities has been developed by Sun Pipe Line Co. The deliberately simple system guides decisions on how to allocate scarce company resources because all managers employ the same criteria in weighing potential risks to the company versus benefits. Managers at all levels are continuously having to comply with an ever growing amount of legislative and regulatory requirements while at the same time trying to run their businesses effectively. The system primarily is designed for use as a compliance oversight and tracking process to document, categorize, and follow-up on work concerning various issues or projects. That is, the system consists of an electronic database which is updated periodically, and is used by various levels of management to monitor progress of health, safety, environmental and compliance-related projects. Criteria used in determining a risk factor and assigning a priority also have been adapted and found useful for evaluating other types of projects. The process enables management to better define potential risks and/or loss of benefits that are being accepted when a project is rejected from an immediate work plan or budget. In times of financial austerity, it is extremely important that the right decisions are made at the right time

  14. A Note on the PageRank of Undirected Graphs

    OpenAIRE

    Grolmusz, Vince

    2012-01-01

    The PageRank is a widely used scoring function of networks in general and of the World Wide Web graph in particular. The PageRank is defined for directed graphs, but in some special cases applications for undirected graphs occur. In the literature it is widely noted that the PageRank for undirected graphs are proportional to the degrees of the vertices of the graph. We prove that statement for a particular personalization vector in the definition of the PageRank, and we also show that in gene...

  15. Multidimensional ranking the design and development of U-Multirank

    CERN Document Server

    Ziegele, Frank

    2012-01-01

    During the last decades ranking has become one of the most controversial issues in higher education and research. It is widely recognized now that, although some of the current rankings can be severely criticized, they seem to be here to stay. In addition, rankings appear to have a great impact on decision-makers at all levels of higher education and research systems worldwide, including in universities. Rankings reflect a growing international competition among universities for talent and resources; at the same time they reinforce competition by their very results. Yet major concerns remain a

  16. Rank diversity of languages: generic behavior in computational linguistics.

    Science.gov (United States)

    Cocho, Germinal; Flores, Jorge; Gershenson, Carlos; Pineda, Carlos; Sánchez, Sergio

    2015-01-01

    Statistical studies of languages have focused on the rank-frequency distribution of words. Instead, we introduce here a measure of how word ranks change in time and call this distribution rank diversity. We calculate this diversity for books published in six European languages since 1800, and find that it follows a universal lognormal distribution. Based on the mean and standard deviation associated with the lognormal distribution, we define three different word regimes of languages: "heads" consist of words which almost do not change their rank in time, "bodies" are words of general use, while "tails" are comprised by context-specific words and vary their rank considerably in time. The heads and bodies reflect the size of language cores identified by linguists for basic communication. We propose a Gaussian random walk model which reproduces the rank variation of words in time and thus the diversity. Rank diversity of words can be understood as the result of random variations in rank, where the size of the variation depends on the rank itself. We find that the core size is similar for all languages studied.

  17. Rank Diversity of Languages: Generic Behavior in Computational Linguistics

    Science.gov (United States)

    Cocho, Germinal; Flores, Jorge; Gershenson, Carlos; Pineda, Carlos; Sánchez, Sergio

    2015-01-01

    Statistical studies of languages have focused on the rank-frequency distribution of words. Instead, we introduce here a measure of how word ranks change in time and call this distribution rank diversity. We calculate this diversity for books published in six European languages since 1800, and find that it follows a universal lognormal distribution. Based on the mean and standard deviation associated with the lognormal distribution, we define three different word regimes of languages: “heads” consist of words which almost do not change their rank in time, “bodies” are words of general use, while “tails” are comprised by context-specific words and vary their rank considerably in time. The heads and bodies reflect the size of language cores identified by linguists for basic communication. We propose a Gaussian random walk model which reproduces the rank variation of words in time and thus the diversity. Rank diversity of words can be understood as the result of random variations in rank, where the size of the variation depends on the rank itself. We find that the core size is similar for all languages studied. PMID:25849150

  18. Tensor rank of the tripartite state |W>xn

    International Nuclear Information System (INIS)

    Yu Nengkun; Guo Cheng; Duan Runyao; Chitambar, Eric

    2010-01-01

    Tensor rank refers to the number of product states needed to express a given multipartite quantum state. Its nonadditivity as an entanglement measure has recently been observed. In this Brief Report, we estimate the tensor rank of multiple copies of the tripartite state |W>=(1/√(3))(|100>+|010>+|001>). Both an upper bound and a lower bound of this rank are derived. In particular, it is proven that the rank of |W> x 2 is 7, thus resolving a previously open problem. Some implications of this result are discussed in terms of transformation rates between |W> xn and multiple copies of the state |GHZ>=(1/√(2))(|000>+|111>).

  19. Proceedings of the sixteenth biennial low-rank fuels symposium

    International Nuclear Information System (INIS)

    1991-01-01

    Low-rank coals represent a major energy resource for the world. The Low-Rank Fuels Symposium, building on the traditions established by the Lignite Symposium, focuses on the key opportunities for this resource. This conference offers a forum for leaders from industry, government, and academia to gather to share current information on the opportunities represented by low-rank coals. In the United States and throughout the world, the utility industry is the primary user of low-rank coals. As such, current experiences and future opportunities for new technologies in this industry were the primary focuses of the symposium

  20. Learning to rank for information retrieval and natural language processing

    CERN Document Server

    Li, Hang

    2014-01-01

    Learning to rank refers to machine learning techniques for training a model in a ranking task. Learning to rank is useful for many applications in information retrieval, natural language processing, and data mining. Intensive studies have been conducted on its problems recently, and significant progress has been made. This lecture gives an introduction to the area including the fundamental problems, major approaches, theories, applications, and future work.The author begins by showing that various ranking problems in information retrieval and natural language processing can be formalized as tw

  1. Rank of quantized universal enveloping algebras and modular functions

    International Nuclear Information System (INIS)

    Majid, S.; Soibelman, Ya.S.

    1991-01-01

    We compute an intrinsic rank invariant for quasitriangular Hopf algebras in the case of general quantum groups U q (g). As a function of q the rank has remarkable number theoretic properties connected with modular covariance and Galois theory. A number of examples are treated in detail, including rank (U q (su(3)) and rank (U q (e 8 )). We briefly indicate a physical interpretation as relating Chern-Simons theory with the theory of a quantum particle confined to an alcove of g. (orig.)

  2. Extreme learning machine for ranking: generalization analysis and applications.

    Science.gov (United States)

    Chen, Hong; Peng, Jiangtao; Zhou, Yicong; Li, Luoqing; Pan, Zhibin

    2014-05-01

    The extreme learning machine (ELM) has attracted increasing attention recently with its successful applications in classification and regression. In this paper, we investigate the generalization performance of ELM-based ranking. A new regularized ranking algorithm is proposed based on the combinations of activation functions in ELM. The generalization analysis is established for the ELM-based ranking (ELMRank) in terms of the covering numbers of hypothesis space. Empirical results on the benchmark datasets show the competitive performance of the ELMRank over the state-of-the-art ranking methods. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Treatment plan ranking using physical and biological indices

    International Nuclear Information System (INIS)

    Ebert, M. A.; University of Western Asutralia, WA

    2001-01-01

    Full text: The ranking of dose distributions is of importance in several areas such as i) comparing rival treatment plans, ii) comparing iterations in an optimisation routine, and iii) dose-assessment of clinical trial data. This study aimed to investigate the influence of choice of objective function in ranking tumour dose distributions. A series of physical (mean, maximum, minimum, standard deviation of dose) dose-volume histogram (DVH) reduction indices and biologically-based (tumour-control probability - TCP; equivalent uniform dose -EUD) indices were used to rank a series of hypothetical DVHs, as well as DVHs obtained from a series of 18 prostate patients. The distribution in ranking and change in distribution with change in indice parameters were investigated. It is found that not only is the ranking of DVHs dependent on the actual model used to perform the DVH reduction, it is also found to depend on the inherent characteristics of each model (i.e., selected parameters). The adjacent figure shows an example where the 18 prostate patients are ranked (grey-scale from black to white) by EUD when an α value of 0.8 Gy -1 is used in the model. The change of ranking as α varies is evident. Conclusion: This study has shown that the characteristics of the model selected in plan optimisation or DVH ranking will have an impact on the ranking obtained. Copyright (2001) Australasian College of Physical Scientists and Engineers in Medicine

  4. Ranking accounting, banking and finance journals: A note

    OpenAIRE

    Halkos, George; Tzeremes, Nickolaos

    2012-01-01

    This paper by applying Data Envelopment Analysis (DEA) ranks Economics journals in the field of Accounting, Banking and Finance. By using one composite input and one composite output the paper ranks 57 journals. In addition for the first time three different quality ranking reports have been incorporated to the DEA modelling problem in order to classify the journals into four categories (‘A’ to ‘D’). The results reveal that the journals with the highest rankings in the field are Journal of Fi...

  5. Proceedings of the sixteenth biennial low-rank fuels symposium

    Energy Technology Data Exchange (ETDEWEB)

    1991-01-01

    Low-rank coals represent a major energy resource for the world. The Low-Rank Fuels Symposium, building on the traditions established by the Lignite Symposium, focuses on the key opportunities for this resource. This conference offers a forum for leaders from industry, government, and academia to gather to share current information on the opportunities represented by low-rank coals. In the United States and throughout the world, the utility industry is the primary user of low-rank coals. As such, current experiences and future opportunities for new technologies in this industry were the primary focuses of the symposium.

  6. Econophysics of a ranked demand and supply resource allocation problem

    Science.gov (United States)

    Priel, Avner; Tamir, Boaz

    2018-01-01

    We present a two sided resource allocation problem, between demands and supplies, where both parties are ranked. For example, in Big Data problems where a set of different computational tasks is divided between a set of computers each with its own resources, or between employees and employers where both parties are ranked, the employees by their fitness and the employers by their package benefits. The allocation process can be viewed as a repeated game where in each iteration the strategy is decided by a meta-rule, based on the ranks of both parties and the results of the previous games. We show the existence of a phase transition between an absorbing state, where all demands are satisfied, and an active one where part of the demands are always left unsatisfied. The phase transition is governed by the ratio between supplies and demand. In a job allocation problem we find positive correlation between the rank of the workers and the rank of the factories; higher rank workers are usually allocated to higher ranked factories. These all suggest global emergent properties stemming from local variables. To demonstrate the global versus local relations, we introduce a local inertial force that increases the rank of employees in proportion to their persistence time in the same factory. We show that such a local force induces non trivial global effects, mostly to benefit the lower ranked employees.

  7. Low-Rank Matrix Factorization With Adaptive Graph Regularizer.

    Science.gov (United States)

    Lu, Gui-Fu; Wang, Yong; Zou, Jian

    2016-05-01

    In this paper, we present a novel low-rank matrix factorization algorithm with adaptive graph regularizer (LMFAGR). We extend the recently proposed low-rank matrix with manifold regularization (MMF) method with an adaptive regularizer. Different from MMF, which constructs an affinity graph in advance, LMFAGR can simultaneously seek graph weight matrix and low-dimensional representations of data. That is, graph construction and low-rank matrix factorization are incorporated into a unified framework, which results in an automatically updated graph rather than a predefined one. The experimental results on some data sets demonstrate that the proposed algorithm outperforms the state-of-the-art low-rank matrix factorization methods.

  8. Molecular regulation of MICA expression after HDAC inhibitor treatment of cancer cells

    DEFF Research Database (Denmark)

    Jensen, Helle

    and NKG2D-ligands are upregulated on the surface of abnormal cells. We have previously shown that cancer cells can be stimulated to express the NKG2D-ligands MICA/B after exposure to HDAC-inhibitors (HDAC-i), an occurrence that is not observed in healthy cells. Here we characterize the molecular signal...... pathways that lead to MICA expression after HDAC-inhibitor treatment of cancer cells. Chelating Calcium with Bapta-AM or EGTA potently inhibited HDAC-inhibitor and CMV mediated MICA/B expression. It was further observed that ER Calcium stores were depleted after HDAC-inhibitor treatment. NF-kB activity can...

  9. Molecular Dynamics simulations of Inhibitor of Apoptosis Proteins and identification of potential small molecule inhibitors.

    Science.gov (United States)

    Jayakumar, Jayanthi; Anishetty, Sharmila

    2014-05-01

    Chemotherapeutic resistance due to over expression of Inhibitor of Apoptosis Proteins (IAPs) XIAP, survivin and livin has been observed in various cancers. In the current study, Molecular Dynamics (MD) simulations were carried out for all three IAPs and a common ligand binding scaffold was identified. Further, a novel sequence based motif specific to these IAPs was designed. SMAC is an endogenous inhibitor of IAPs. Screening of ChemBank for compounds similar to lead SMAC-non-peptidomimetics yielded a cemadotin related compound NCIMech_000654. Cemadotin is a derivative of natural anti-tumor peptide dolastatin-15; hence these compounds were docked against all three IAPs. Based on our analysis, we propose that NCIMech_000654/dolastatin-15/cemadotin derivatives may be investigated for their potential in inhibiting XIAP, survivin and livin. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Macrocyclic ligands for uranium complexation

    International Nuclear Information System (INIS)

    Potts, K.T.

    1991-04-01

    A highly preorganized 24-macrocycle containing biuret, thiobiuret and pyridine subunits has been prepared by high dilution ring-closure procedures. Intermediate products to this macrocycle have been utilized to extend this synthetic route to include further representatives where solubility and stability will be influenced by substituent variation. A 1:1 complex has been formed from uranyl acetate and a quinquepyridine derivative, this representing a new type of ligand for the uranyl ion. A very convenient synthetic procedure that will allow the incorporation of these macrocycles into polymeric systems has been developed for the introduction of a vinyl substituent into the 4-position of the pyridine ring. Using triflate, vinyltributyltin and Pd 0 chemistry, this procedure should make a variety of substituted 4-vinylpyridines available for the first time. 3 refs

  11. A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery

    Science.gov (United States)

    Cholko, Timothy; Chen, Wei; Tang, Zhiye; Chang, Chia-en A.

    2018-05-01

    Abnormal activity of cyclin-dependent kinase 8 (CDK8) along with its partner protein cyclin C (CycC) is a common feature of many diseases including colorectal cancer. Using molecular dynamics (MD) simulations, this study determined the dynamics of the CDK8-CycC system and we obtained detailed breakdowns of binding energy contributions for four type-I and five type-II CDK8 inhibitors. We revealed system motions and conformational changes that will affect ligand binding, confirmed the essentialness of CycC for inclusion in future computational studies, and provide guidance in development of CDK8 binders. We employed unbiased all-atom MD simulations for 500 ns on twelve CDK8-CycC systems, including apoproteins and protein-ligand complexes, then performed principal component analysis (PCA) and measured the RMSF of key regions to identify protein dynamics. Binding pocket volume analysis identified conformational changes that accompany ligand binding. Next, H-bond analysis, residue-wise interaction calculations, and MM/PBSA were performed to characterize protein-ligand interactions and find the binding energy. We discovered that CycC is vital for maintaining a proper conformation of CDK8 to facilitate ligand binding and that the system exhibits motion that should be carefully considered in future computational work. Surprisingly, we found that motion of the activation loop did not affect ligand binding. Type-I and type-II ligand binding is driven by van der Waals interactions, but electrostatic energy and entropic penalties affect type-II binding as well. Binding of both ligand types affects protein flexibility. Based on this we provide suggestions for development of tighter-binding CDK8 inhibitors and offer insight that can aid future computational studies.

  12. Discovery of potent and selective CDK8 inhibitors through FBDD approach.

    Science.gov (United States)

    Han, Xingchun; Jiang, Min; Zhou, Chengang; Zhou, Zheng; Xu, Zhiheng; Wang, Lisha; Mayweg, Alexander V; Niu, Rui; Jin, Tai-Guang; Yang, Song

    2017-09-15

    A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Ligand- and cell-dependent determinants of internalization and cAMP modulation by delta opioid receptor (DOR) agonists

    Science.gov (United States)

    Charfi, Iness; Nagi, Karim; Mnie-Filali, Ouissame; Thibault, Dominic; Balboni, Gianfranco; Schiller, Peter W.; Trudeau, Louis-Eric

    2014-01-01

    Signaling bias refers to G protein-coupled receptor ligand ability to preferentially activate one type of signal over another. Bias to evoke signaling as opposed to sequestration has been proposed as a predictor of opioid ligand potential for generating tolerance. Here we measured whether delta opioid receptor agonists preferentially inhibited cyclase activity over internalization in HEK cells. Efficacy (τ) and affinity (KA) values were estimated from functional data and bias was calculated from efficiency coefficients (log τ/KA). This approach better represented the data as compared to alternative methods that estimate bias exclusively from τ values. Log (τ/KA) coefficients indicated that SNC-80 and UFP-512 promoted cyclase inhibition more efficiently than DOR internalization as compared to DPDPE (bias factor for SNC-80: 50 and for UFP-512: 132). Molecular determinants of internalization were different in HEK293 cells and neurons with βarrs contributing to internalization in both cell types, while PKC and GRK2 activities were only involved in neurons. Rank orders of ligand ability to engage different internalization mechanisms in neurons were compared to rank order of Emax values for cyclase assays in HEK cells. Comparison revealed a significant reversal in rank order for cyclase Emax values and βarr-dependent internalization in neurons, indicating that these responses were ligand-specific. Despite this evidence, and because kinases involved in internalization were not the same across cellular backgrounds, it is not possible to assert if the magnitude and nature of bias revealed by rank orders of maximal responses is the same as the one measured in HEK cells. PMID:24022593

  14. Forward projections of energy market competitiveness rankings

    International Nuclear Information System (INIS)

    2008-01-01

    By July 2007, the provisions of the second Internal Market Directives for Electricity and Gas had been implemented in the majority of EU Member States. These fundamental changes in market opening, ownership structures and network access conditions, together with the increasing maturity of liberalised trading and retail markets, can be expected to affect the behaviour of existing and potential market participants, consequently affecting the energy market competitiveness of alternative countries. While the UK was the most competitive of the EU and G7 energy markets in 2006, the dynamic effect of the liberalisation programme across Continental Europe may challenge that position in the future. This report assesses how competitiveness rankings may evolve in the future, identifying changes that could take place in the UK and the rest of the EU from 2007 to 201 1. It goes on to explore the potential risk that the competitiveness of the UK's energy markets will decline relative to those of other countries in the EU and G7, to the extent that the PSA target will not be met. A detailed analysis of the potential changes in the UK markets is undertaken, including the development of upside and downside scenarios showing the positive and negative effects of changes in market structure and behaviour on the UK's competitiveness score. Changes in market structures required for energy markets in both the 2006 comparator group and the rest of the EU to become as competitive as the UK are then assessed, along with the plausibility of these changes given the current and future market, legislative and regulatory environments

  15. CXCR4 Ligands : The Next Big Hit?

    NARCIS (Netherlands)

    Walenkamp, Annemiek M. E.; Lapa, Constantin; Herrmann, Ken; Wester, Hans-Juergen

    2017-01-01

    The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic cancers. Binding of its ligand, C-X-C chemokine ligand 12 (CXCL12), results in receptor internalization and

  16. Ligand-receptor Interactions by NMR Spectroscopy

    Directory of Open Access Journals (Sweden)

    Novak. P.

    2008-04-01

    Full Text Available Today NMR spectroscopy is a method of choice for elucidation of interactions between biomolecules and the potential ligands. Knowledge on these interactions is an essential prerequisite for the rational drug design. The most important contribution of NMR to drug design a few years ago was the 3D structure determination of proteins. Besides delivering the 3D structures of the free proteins as a raw material for the modeling studies on ligand binding, NMR can directly yield valuable experimental data on the biologically important protein-ligand complexes. In addition to X-ray diffraction, NMR spectroscopy can provide information on the internal protein dynamics ordynamics of intermolecular interactions. Changes in NMR parameters allow us to detect ("SAR by NMR" and quantitatively determine binding affinities (titration, diffusion NMR experiments, etc. of potential ligands. Also, it is possible to determine the binding site and conformations of ligands, receptors and receptor-ligand complexes with the help of NMR methods such as tr-NOESY. Epitopes or functional groups responsible for binding of ligands to the receptor can be identified by employing STD or WaterLOGSY experiments. In this review are described some of the most frequent NMR methods for the characterization of the interactions between biomolecules and ligands, together with their advantages and disadvantages.

  17. Autocrine signal transmission with extracellular ligand degradation

    Science.gov (United States)

    Muratov, C B; Posta, F; Shvartsman, S Y

    2009-03-01

    Traveling waves of cell signaling in epithelial layers orchestrate a number of important processes in developing and adult tissues. These waves can be mediated by positive feedback autocrine loops, a mode of cell signaling where binding of a diffusible extracellular ligand to a cell surface receptor can lead to further ligand release. We formulate and analyze a biophysical model that accounts for ligand-induced ligand release, extracellular ligand diffusion and ligand-receptor interaction. We focus on the case when the main mode for ligand degradation is extracellular and analyze the problem with the sharp threshold positive feedback nonlinearity. We derive expressions that link the speed of propagation and other characteristics of traveling waves to the parameters of the biophysical processes, such as diffusion rates, receptor expression level, etc. Analyzing the derived expressions we found that traveling waves in such systems can exhibit a number of unusual properties, e.g. non-monotonic dependence of the speed of propagation on ligand diffusivity. Our results for the fully developed traveling fronts can be used to analyze wave initiation from localized perturbations, a scenario that frequently arises in the in vitro models of epithelial wound healing, and guide future modeling studies of cell communication in epithelial layers.

  18. Organotellurium ligands – designing and complexation reactions

    Indian Academy of Sciences (India)

    Unknown

    membered rings it is negative and ~30 ppm only. Keywords. Organotellurium ligands; hybrid telluroether; platinum metal complexes; tellurium-125 NMR. 1. Introduction. Tellurium is the noblest metalloid which may act as a Lewis acid as well as Lewis base. The ligand chemistry of tellurium, which acts as a 'soft' donor, was ...

  19. Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?

    Directory of Open Access Journals (Sweden)

    Roger von Moos

    2013-08-01

    Full Text Available Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer.

  20. Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators

    Science.gov (United States)

    Lazennec, Gwendal; Canaple, Laurence; Saugy, Damien; Wahli, Walter

    2000-01-01

    The nuclear peroxisome proliferator-activated receptors (PPARs) α, β and γ activate the transcription of multiple genes involved in lipid metabolism. Several natural and synthetic ligands have been identified for each PPAR isotype but little is known about the phosphorylation state of these receptors. We show here that activators of protein kinase A (PKA) can enhance mouse PPAR activity in the absence and the presence of exogenous ligands in transient transfection experiments. The activation function 1 (AF-1) of PPARs was dispensable for transcriptional enhancement, whereas the activation function 2 (AF-2) was required for this effect. We also show that several domains of PPAR can be phosphorylated by PKA in vitro. Moreover, gel experiments suggest that PKA stabilizes binding of the liganded PPAR to DNA. PKA inhibitors decreased not only the kinase dependent induction of PPARs but also their ligand-dependent induction, suggesting that the ligands may also mobilize the PKA pathway to lead to maximal transcriptional induction by PPARs. Moreover, comparing PPARα KO with PPARα wild-type mice, we show that the expression of the ACO gene can be regulated by PKA-activated PPARα in liver. These data demonstrate that the PKA pathway is an important modulator of PPAR activity and we propose a model associating this pathway in the control of fatty acid β-oxidation under conditions of fasting, stress and exercise. PMID:11117527

  1. Quantifying high-affinity binding of hydrophobic ligands by isothermal titration calorimetry.

    Science.gov (United States)

    Krainer, Georg; Broecker, Jana; Vargas, Carolyn; Fanghänel, Jörg; Keller, Sandro

    2012-12-18

    A fast and reliable quantification of the binding thermodynamics of hydrophobic high-affinity ligands employing a new calorimetric competition experiment is described. Although isothermal titration calorimetry is the method of choice for a quantitative characterization of intermolecular interactions in solution, a reliable determination of a dissociation constant (K(D)) is typically limited to the range 100 μM > K(D) > 1 nM. Interactions displaying higher or lower K(D) values can be assessed indirectly, provided that a suitable competing ligand is available whose K(D) falls within the directly accessible affinity window. This established displacement assay, however, requires the high-affinity ligand to be soluble at high concentrations in aqueous buffer and, consequently, poses serious problems in the study of protein binding involving small-molecule ligands dissolved in organic solvents--a familiar case in many drug-discovery projects relying on compound libraries. The calorimetric competition assay introduced here overcomes this limitation, thus allowing for a detailed thermodynamic description of high-affinity receptor-ligand interactions involving poorly water-soluble compounds. Based on a single titration of receptor into a dilute mixture of the two competing ligands, this competition assay provides accurate and precise values for the dissociation constants and binding enthalpies of both high- and moderate-affinity ligands. We discuss the theoretical background underlying the approach, demonstrate its practical application to metal ion chelation and high-affinity protein-inhibitor interactions, and explore its potential and limitations with the aid of simulations and statistical analyses.

  2. Development and first application of an operating events ranking tool

    International Nuclear Information System (INIS)

    Šimić, Zdenko; Zerger, Benoit; Banov, Reni

    2015-01-01

    Highlights: • A method using analitycal hierarchy process for ranking operating events is developed and tested. • The method is applied for 5 years of U.S. NRC Licensee Event Reports (1453 events). • Uncertainty and sensitivity of the ranking results are evaluated. • Real events assessment shows potential of the method for operating experience feedback. - Abstract: The operating experience feedback is important for maintaining and improving safety and availability in nuclear power plants. Detailed investigation of all events is challenging since it requires excessive resources, especially in case of large event databases. This paper presents an event groups ranking method to complement the analysis of individual operating events. The basis for the method is the use of an internationally accepted events characterization scheme that allows different ways of events grouping and ranking. The ranking method itself consists of implementing the analytical hierarchy process (AHP) by means of a custom developed tool which allows events ranking based on ranking indexes pre-determined by expert judgment. Following the development phase, the tool was applied to analyze a complete set of 5 years of real nuclear power plants operating events (1453 events). The paper presents the potential of this ranking method to identify possible patterns throughout the event database and therefore to give additional insights into the events as well as to give quantitative input for the prioritization of further more detailed investigation of selected event groups

  3. University Rankings: How Well Do They Measure Library Service Quality?

    Science.gov (United States)

    Jackson, Brian

    2015-01-01

    University rankings play an increasingly large role in shaping the goals of academic institutions and departments, while removing universities themselves from the evaluation process. This study compares the library-related results of two university ranking publications with scores on the LibQUAL+™ survey to identify if library service quality--as…

  4. Jackknife Variance Estimator for Two Sample Linear Rank Statistics

    Science.gov (United States)

    1988-11-01

    Accesion For - - ,NTIS GPA&I "TIC TAB Unann c, nc .. [d Keywords: strong consistency; linear rank test’ influence function . i , at L By S- )Distribut...reverse if necessary and identify by block number) FIELD IGROUP SUB-GROUP Strong consistency; linear rank test; influence function . 19. ABSTRACT

  5. Monte Carlo methods of PageRank computation

    NARCIS (Netherlands)

    Litvak, Nelli

    2004-01-01

    We describe and analyze an on-line Monte Carlo method of PageRank computation. The PageRank is being estimated basing on results of a large number of short independent simulation runs initiated from each page that contains outgoing hyperlinks. The method does not require any storage of the hyperlink

  6. Positioning Open Access Journals in a LIS Journal Ranking

    Science.gov (United States)

    Xia, Jingfeng

    2012-01-01

    This research uses the h-index to rank the quality of library and information science journals between 2004 and 2008. Selected open access (OA) journals are included in the ranking to assess current OA development in support of scholarly communication. It is found that OA journals have gained momentum supporting high-quality research and…

  7. Feeding rank in the Derby eland: lessons for management ...

    African Journals Online (AJOL)

    High-ranking individuals in good condition limited access to supplementary feeding to their lower-ranking herdmates. Effective supplementary feeding should therefore be provided in excess amounts to enable younger and weaker individuals in need to benefit from it, despite their lower positions in the hierarchy. Keywords: ...

  8. Balancing exploration and exploitation in learning to rank online

    NARCIS (Netherlands)

    Hofmann, K.; Whiteson, S.; de Rijke, M.

    2011-01-01

    As retrieval systems become more complex, learning to rank approaches are being developed to automatically tune their parameters. Using online learning to rank approaches, retrieval systems can learn directly from implicit feedback, while they are running. In such an online setting, algorithms need

  9. Ranking production units according to marginal efficiency contribution

    DEFF Research Database (Denmark)

    Ghiyasi, Mojtaba; Hougaard, Jens Leth

    League tables associated with various forms of service activities from schools to hospitals illustrate the public need for ranking institutions by their productive performance. We present a new method for ranking production units which is based on each units marginal contribution to the technical...

  10. Trachomatous Scar Ranking: A Novel Outcome for Trachoma Studies.

    Science.gov (United States)

    Baldwin, Angela; Ryner, Alexander M; Tadesse, Zerihun; Shiferaw, Ayalew; Callahan, Kelly; Fry, Dionna M; Zhou, Zhaoxia; Lietman, Thomas M; Keenan, Jeremy D

    2017-06-01

    AbstractWe evaluated a new trachoma scarring ranking system with potential use in clinical research. The upper right tarsal conjunctivas of 427 individuals from Ethiopian villages with hyperendemic trachoma were photographed. An expert grader first assigned a scar grade to each photograph using the 1981 World Health Organization (WHO) grading system. Then, all photographs were ranked from least (rank = 1) to most scarring (rank = 427). Photographic grading found 79 (18.5%) conjunctivae without scarring (C0), 191 (44.7%) with minimal scarring (C1), 105 (24.6%) with moderate scarring (C2), and 52 (12.2%) with severe scarring (C3). The ranking method demonstrated good internal validity, exhibiting a monotonic increase in the median rank across the levels of the 1981 WHO grading system. Intrarater repeatability was better for the ranking method (intraclass correlation coefficient = 0.84, 95% CI = 0.74-0.94). Exhibiting better internal and external validity, this ranking method may be useful for evaluating the difference in scarring between groups of individuals.

  11. Optimal ranking regime analysis of TreeFlow dendrohydrological reconstructions

    Science.gov (United States)

    The Optimal Ranking Regime (ORR) method was used to identify 6-100 year time windows containing significant ranking sequences in 55 western U.S. streamflow reconstructions, and reconstructions of the level of the Great Salt Lake and San Francisco Bay salinity during 1500-2007. The method’s ability t...

  12. The Ranking Phenomenon and the Experience of Academics in Taiwan

    Science.gov (United States)

    Lo, William Yat Wai

    2014-01-01

    The primary aim of the paper is to examine how global university rankings have influenced the higher education sector in Taiwan from the perspective of academics. A qualitative case study method was used to examine how university ranking influenced the Taiwanese higher education at institutional and individual levels, respectively, thereby…

  13. Ranking Regime and the Future of Vernacular Scholarship

    Science.gov (United States)

    Ishikawa, Mayumi

    2014-01-01

    World university rankings and their global popularity present a number of far-reaching impacts for vernacular scholarship. This article employs a multidimensional approach to analyze the ranking regime's threat to local scholarship and knowledge construction through a study of Japanese research universities. First, local conditions that have led…

  14. The Distribution of the Sum of Signed Ranks

    Science.gov (United States)

    Albright, Brian

    2012-01-01

    We describe the calculation of the distribution of the sum of signed ranks and develop an exact recursive algorithm for the distribution as well as an approximation of the distribution using the normal. The results have applications to the non-parametric Wilcoxon signed-rank test.

  15. Ranking Exponential Trapezoidal Fuzzy Numbers by Median Value

    Directory of Open Access Journals (Sweden)

    S. Rezvani

    2013-12-01

    Full Text Available In this paper, we want represented a method for ranking of two exponential trapezoidal fuzzy numbers. A median value is proposed for the ranking of exponential trapezoidal fuzzy numbers. For the validation the results of the proposed approach are compared with different existing approaches.

  16. Rank dependent expected utility models of tax evasion.

    OpenAIRE

    Erling Eide

    2001-01-01

    In this paper the rank-dependent expected utility theory is substituted for the expected utility theory in models of tax evasion. It is demonstrated that the comparative statics results of the expected utility, portfolio choice model of tax evasion carry over to the more general rank dependent expected utility model.

  17. Prototyping a Distributed Information Retrieval System That Uses Statistical Ranking.

    Science.gov (United States)

    Harman, Donna; And Others

    1991-01-01

    Built using a distributed architecture, this prototype distributed information retrieval system uses statistical ranking techniques to provide better service to the end user. Distributed architecture was shown to be a feasible alternative to centralized or CD-ROM information retrieval, and user testing of the ranking methodology showed both…

  18. RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?

    Science.gov (United States)

    Van den Wyngaert, Tim; Wouters, Kristien; Huizing, Manon T; Vermorken, Jan B

    2011-12-01

    The purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162). The ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation. A total of 89 ONJ cases (1.57%; 95% CI, 1.26-1.92) were reported with 52 (1.83%; 95% CI, 1.37-2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92-1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92-2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99-2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66-2.45; p = 0.5). Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.

  19. Oxovanadium (iv) complexes with n/o- and o-donor ligands: their synthesis, characterization, semiempirical study and alkaline phosphatase activity (abstract)

    International Nuclear Information System (INIS)

    Munawar, K.S.; Ali, S.; Khan, A.N.

    2011-01-01

    Various N/O- and O-donor ligands and their oxovanadium complexes have been synthesized and characterized by different techniques such as FTIR, elemental analysis, thermogravimetery and conductometry. The IR data show the bidentate nature of the ligands and reveals hexa-coordinated geometry in the solid state which is also confirmed by semi-empirical study. Conductance measurements reveal the non-electrolytic nature of the complexes. These complexes have been checked for their alkaline phosphatase activity in the presence and absence of inhibitor which shows that by the addition of inhibitor the activity of enzyme decreases and at higher concentration it is completely inhibited. (author)

  20. UTV Expansion Pack: Special-Purpose Rank-Revealing Algorithms

    DEFF Research Database (Denmark)

    Fierro, Ricardo D.; Hansen, Per Christian

    2005-01-01

    This collection of Matlab 7.0 software supplements and complements the package UTV Tools from 1999, and includes implementations of special-purpose rank-revealing algorithms developed since the publication of the original package. We provide algorithms for computing and modifying symmetric rank-r...... values of a sparse or structured matrix. These new algorithms have applications in signal processing, optimization and LSI information retrieval.......This collection of Matlab 7.0 software supplements and complements the package UTV Tools from 1999, and includes implementations of special-purpose rank-revealing algorithms developed since the publication of the original package. We provide algorithms for computing and modifying symmetric rank......-revealing VSV decompositions, we expand the algorithms for the ULLV decomposition of a matrix pair to handle interference-type problems with a rank-deficient covariance matrix, and we provide a robust and reliable Lanczos algorithm which - despite its simplicity - is able to capture all the dominant singular...