bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of YidC/Oxa1/Alb3 insertases: three independent gene duplications followed by functional specialization in bacteria, mitochondria and chloroplasts
Authors: Funes Soledad , Kauff Frank , van der Sluis Eli O. , Ott Martin , Herrmann Johannes M. 
Published: January 2011

Abstract
Members of the YidC/Oxa1/Alb3 protein family facilitate the insertion, folding and assembly of proteins of the inner membranes of bacteria and mitochondria and the thylakoid membrane of plastids. All homologs share a conserved hydrophobic core region comprising five transmembrane domains. On the basis of phylogenetic analyses, six subgroups of the family can be distinguished which presumably arose from three independent gene duplications followed by functional specialization. During evolution of bacteria, mitochondria and chloroplasts, subgroup-specific regions were added to the core domain to facilitate the association with ribosomes or other components contributing to the substrate spectrum of YidC/Oxa1/Alb3 proteins.
SLC22 transporter family proteins as targets for cytostatic uptake into tumor cells
Authors: Gupta Shivangi , Burckhardt Gerhard , Hagos Yohannes 
Published: January 2011

AbstractThe response to chemotherapy by tumor cells depends on the concentration of cytostatics accumulated inside the cells. The accumulation of anticancer drugs in tumor cells is mainly dependent on functional expression of efflux and influx transporters and to a minor extent on passive diffusion through the membrane. Efflux transporters of the ABC family are partially responsible for the chemoresistance of cancer cells by secreting these cytostatics. Over the past decades, the role of ABC transporters in the chemoresistance of various malignant tumors has been very well documented. By contrast, very little is known about the impact on tumor therapy of influx transporters belonging to the solute carrier transporters (SLC family). In this review, we focus on the interaction of SLC22 transporters with cytostatics, the expression of these transporters in tumor cells as well as their impact on the chemosensitivity of cancer cells.
Pumping lipids with P4-ATPases
Authors: López-Marqués Rosa L. , Holthuis Joost C.M. , Pomorski Thomas G. 
Published: January 2011

AbstractWhile accumulating evidence indicates that P4-ATPases catalyze phospholipid transport across cellular bilayers, their kinship to cation-pumping ATPases has raised fundamental questions concerning the underlying flippase mechanism. Loss of P4-ATPase function perturbs vesicle formation in late secretory and endocytic compartments. An intriguing concept is that P4-ATPases help drive vesicle budding by generating imbalances in transbilayer lipid numbers. Moreover, activation of P4-ATPases by phosphoinositides and other effectors of coat recruitment provide a potential mechanism to confine flippase activity to sites of vesicle biogenesis. These developments have raised considerable interest in understanding the mechanism, regulation and biological implications of P4-ATPase-catalyzed phospholipid transport.
The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine
Authors: Steinkellner Thomas , Freissmuth Michael , Sitte Harald H. , Montgomery Therese 
Published: January 2011

Abstract
Amphetamine (‘Speed’), methamphetamine (‘Ice’) and its congener 3,4-methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity.
Transporters, Trojan horses and therapeutics: suitability of bile acid and peptide transporters for drug delivery
Authors: Kramer Werner 
Published: January 2011

AbstractMembrane transporters are major determinants for the pharmacokinetic, safety and efficacy behavior of drugs. Available technologies to study function and structure of transport proteins has strongly stimulated research in transporter biology and uncovered their importance for the drug discovery and development process, especially for drug absorption and disposition. Physiological transport systems are investigated as potential ferries to improve drug absorption and membrane permeation and to achieve organ-specific drug action. In particular, the bile acid transport systems in the liver and the small intestine and the oligopeptide transporters are of significant importance for molecular drug delivery.
Pathways of transport protein evolution: recent advances
Authors: Lam Vincent H. , Lee Jong-Hoon , Silverio Abe , Chan Henry , Gomolplitinant Kenny M. , Povolotsky Tatyana L. , Orlova Ekaterina , Sun Eric I. , Welliver Carl H. , Saier Milton H. 
Published: January 2011

AbstractWe herein report recent advances in our understanding of transport protein evolution. Numerous families of complex transmembrane transport proteins are believed to have arisen from short channel-forming amphipathic or hydrophobic peptides by various types of intragenic duplication events. Distinct pathways distinguish families, demonstrating independent origins for some, and allowing assignment of others to superfamilies. Some families have diversified in topology, whereas others have remained uniform. An example of ‘retroevolution’ was discovered where a more complex carrier gave rise to a structurally and functionally simpler channel. The results described in this review article expand our understanding of protein evolution.
Myeloperoxidase-catalyzed oxidative inactivation of human kininogens: the impairment of kinin-precursor and prekallikrein-binding functions
Authors: Kozik Andrzej , Golda Anna , Mak Pawel , Suder Piotr , Silberring Jerzy , Barbasz Anna , Rapala-Kozik Maria 
Published: January 2011

Abstract
Bradykinin-related vasoactive peptides (kinins) are important mediators of local and systemic inflammatory reactions. However, at local inflammatory foci, the production of kinins from proteinaceous precursors (kininogens) can be affected by reactive oxygen species released by phagocyte cells. One of the predominant oxidants at these places is hypochlorous acid which is formed from hydrogen peroxide and chloride ions by neutrophil myeloperoxidase. In this study, inactivation of human kininogens after oxidation with the myeloperoxidase-H2O2-chloride system was observed and analyzed by protein chemistry methods. The kinin release from oxidized kininogens by major kinin-producing enzymes, plasma and tissue kallikreins, proceed with a very low rate. This effect was assigned to apparent inability of kallikreins to process the kinin N-terminus owing to the conversion of the adjacent Met-361 residue to methionine sulfoxide. Additionally, the oxidized high-molecular mass kininogen lost its natural ability to bind plasma prekallikrein. This effect was assigned to the oxidation of Trp-569 residue within the prekallikrein-binding region which is subsequently destructed owing to cleavage of the peptide bond after that residue. One possible pathophysiological consequence of the described effects on kininogens could be the impairment of the normal assembly and triggering of the kinin-forming system on defense cell surfaces.
Identification and characterisation of novel Mss4-binding Rab GTPases
Authors: Wixler Viktor , Wixler Ludmilla , Altenfeld Anika , Ludwig Stephan , Goody Roger S. , Itzen Aymelt 
Published: January 2011

Abstract
The Mss4 (mammalian suppressor of yeast Sec4) is an evolutionarily highly conserved protein and is expressed in all mammalian tissues. Although its precise biological function is still elusive, it has been shown to associate with a subset of secretory Rab proteins (Rab1b, Rab3a, Rab8a, Rab10) and to possess a rather low guanine nucleotide exchange factor (GEF) activity towards them in vitro (Rab1, Rab3a and Rab8a). By screening a human placenta cDNA library with Mss4 as bait, we identified several Rab GTPases (Rab12, Rab13 and Rab18) as novel Mss4-binding Rab proteins. Only exocytic but no endocytic Rab GTPases were found in our search. The binding of Mss4 to Rab proteins was confirmed by direct yeast two-hybrid interaction, by co-immunoprecipitation from lysates of mammalian cells, by immunofluorescence colocalisation as well as by direct in vitro binding studies. Analysis of Mss4 catalytic activity towards different Rab substrates confirmed that it is a somewhat inefficient GEF. These data, together with our mutational analysis of Mss4-Rab binding capacity, support the already proposed idea that Mss4 functions rather as a chaperone for exocytic Rab GTPases than as a GEF.
Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site
Authors: Ahn Jin-Hyung , Lee Ho-Jeong , Lee Eun-Kyoung , Yu Hyun-Kyung , Lee Tae-Ho , Yoon Yeup , Kim Sun-Jin , Kim Jang-Seong 
Published: January 2011

AbstractMany proteins in the fibrinolysis pathway contain antiangiogenic kringle domains. Owing to the high degree of homology between kringle domains, there has been a safety concern that antiangiogenic kringles could interact with common kringle proteins during fibrinolysis leading to adverse effectsin vivo. To address this issue, we investigated the effects of several antiangiogenic kringle proteins including angiostatin, apolipoprotein(a) kringles IV9-IV10-V (LK68), apolipoprotein(a) kringle V (rhLK8) and a derivative of rhLK8 mutated to produce a functional lysine-binding site (Lys-rhLK8) on the entire fibrinolytic processin vitroand analyzed the role of lysine binding. Angiostatin, LK68 and Lys-rhLK8 increased clot lysis time in a dose-dependent manner, inhibited tissue-type plasminogen activator-mediated plasminogen activation on a thrombin-modified fibrinogen (TMF) surface, showed binding to TMF and significantly decreased the amount of plasminogen bound to TMF. The inhibition of fibrinolysis by these proteins appears to be dependent on their functional lysine-binding sites. However, rhLK8 had no effect on these processes owing to an inability to bind lysine. Collectively, these results indicate that antiangiogenic kringles without lysine binding sites might be safer with respect to physiological fibrinolysis than lysine-binding antiangiogenic kringles. However, the clinical signi-ficance of these findings will require further validationin vivo.
PETIR-001, a dual inhibitor of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN), ameliorates experimental autoimmune encephalomyelitis in SJL/J mice
Authors: Reinhold Dirk , Bank Ute , Entz Dominik , Goihl Alexander , Stoye Diana , Wrenger Sabine , Brocke Stefan , Thielitz Anja , Stefin Sofia , Nordhoff Karsten , Heimburg Anke , Täger Michael , Ansorge Siegfried 
Published: January 2011

Abstract
Cellular dipeptidyl peptidase IV (DP IV, CD26) and amino-peptidase N (APN, CD13) play regulatory roles in T cell activation and represent potential targets for treatment of inflammatory disorders. We have developed a novel therapeutic strategy, ‘peptidase-targeted Immunoregulation’ (PETIR™), which simultaneously targets both cellular DP IV and APN via selective binding sites different from the active sites with a single inhibitor. To prove the therapeutic concept of PETIR™ in autoimmunity of the central nervous system (CNS), we evaluated the effect of a single substance, PETIR-001, in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) in SJL/J mice. Administration of PETIR-001 significantly delayed and decreased clinical signs of active EAE, when given in a therapeutic manner intraperitoneally from day 15 to day 24 after induction of EAE. Both the acute phase and the first relapse of EAE were markedly inhibited. Importantly, a similar therapeutic benefit was obtained after oral administration of PETIR-001 from day 12 to day 21 after disease induction. Our results demonstrate that PETIR-001 exhibits a therapeutic effect on EAE in SJL/J mice. Thus, PETIR™ represents a novel and efficient therapeutic approach for immunotherapy of CNS inflammation.
Outside or inside: role of the subcellular localization of DP4-like enzymes for substrate conversion and inhibitor effects
Authors: Bank Ute , Heimburg Anke , Wohlfarth Astrid , Koch Gudrun , Nordhoff Karsten , Julius Heiko , Helmuth Martin , Breyer Doreen , Reinhold Dirk , Täger Michael , Ansorge Siegfried 
Published: January 2011

Abstract
The discovery of the DP4-related enzymes DP8 and DP9 raised controversial discussion regarding the physiological and pathophysiological function of distinct members of the DP4 family. Particularly with regard to their potential relevance in regulating immune functions, it is of interest to know which role the subcellular distribution of the enzymes play. Synthetic substrates as well as low molecular weight inhibitors are widely used as tools, but little is yet known regarding their features in cell experiments, such as their plasma membrane penetration capacity. The fluorogenic substrates Gly-Pro-AMC or (Ala-Pro)2-R110 predominantly detect plasma membrane-bound activities of viable cells (less than 0.1% of fluorochromes R110 or AMC inside viable cells after 1 h incubation). Additionally, the selective and non-selective DP8/9 inhibitors allo-Ile-isoindoline and Lys[Z(NO2)]-pyrrolidide were found to be incapable of passing the plasma membrane easily. This suggests that previously reported cellular effects are not due to inhibition of the cytosolic enzymes DP8 or DP9. Moreover, our enzymatic studies with viable cells provided evidence that DP8 and/or DP9 are also present on the surface of immune cells under certain circumstances and could gain relevance particularly in the absence of DP4 expression. In summary, in cells which do express DP4 on the surface, this archetypical member of the DP4 family is the most relevant peptidase in the regulation of cellular functions.
Revisiting the tubulin folding pathway: new roles in centrosomes and cilia
Authors: Gonçalves João , Tavares Alexandra , Carvalhal Sara , Soares Helena 
Published: January 2011

AbstractCentrosomes and cilia are critical eukaryotic organelles which have been in the spotlight in recent years given their implication in a myriad of cellular and developmental processes. Despite their recognized importance and intense study, there are still many open questions about their biogenesis and function. In the present article, we review the existing data concerning members of the tubulin folding pathway and related proteins, which have been identified at centrosomes and cilia and were shown to have unexpected roles in these structures.
Effect of periodate on lignin for wood adhesive application
Authors: Gosselink Richard J.A. , van Dam Jan E.G. , de Jong Ed , Gellerstedt Göran , Scott Elinor L. , Sanders Johan P.M. 
Published: January 2011

Abstract
Development of eco-friendly binders with no harmful emission during its complete life cycle is of high interest for the wood-based industry. In this paper, a fully renewable binder based on activated lignin and poly-furfuryl alcohol and a partly renewable lignin based phenol-formaldehyde (PF) binder were evaluated. Activation of kraft and soda lignins, isolated respectively from softwood and non-woods, by periodate oxidation was performed to improve lignin reactivity and application in wood adhesives. Periodate oxidation of lignin leads to higher lignin acidity, formation of quinonoid groups under more severe conditions, higher molar mass and higher reactivity towards the curing of furfuryl alcohol within a temperature range currently used in industry. Comparison of a 100% furan-based glue with a furan-based glue substituted by 10% lignin yields comparable product properties. However, periodate-activated lignin leads to lower wood failure, which might be caused by incompletely solubilised lignin particles in the acidic formulation disturbing crosslinking of the furan resin. Unmodified softwood kraft lignin performs well in a PF resin formulation at substitution levels up to 30% (w/w). Periodate oxidation of soda lignins enhances the glue performance because higher wood failure is attained. The higher molar mass after periodate treatment could be an important parameter for development of a stronger wood binder.
Unbiased Relatedness Estimation in Structured Populations
Authors: Wang Jinliang 
Published: January 2011

Abstract
Knowledge of the genetic relatedness between individuals is important in many research areas in quantitative genetics, conservation genetics, forensics, evolution, and ecology. In the absence of pedigree records, relatedness can be estimated from genetic marker data using a number of estimators. These estimators, however, make the critical assumption of a large random mating population without genetic structures. The assumption is frequently violated in the real world where geographic/social structures or nonrandom mating usually lead to genetic structures. In this study, I investigated two approaches to the estimation of relatedness between a pair of individuals from a subpopulation due to recent common ancestors (i.e., relatedness is defined and measured with the current focal subpopulation as reference). The indirect approach uses the allele frequencies of the entire population with and without accounting for the population structure, and the direct approach uses the allele frequencies of the current focal subpopulation. I found by simulations that currently widely applied relatedness estimators are upwardly biased under the indirect approach, but can be modified to become unbiased and more accurate by using Wright's Fst to account for population structures. However, the modified unbiased estimators under the indirect approach are clearly inferior to the unmodified original estimators under the direct approach, even when small samples are used in estimating both allele frequencies and relatedness.
High-Confidence Discovery of Genetic Network Regulators in Expression Quantitative Trait Loci Data
Authors: Duarte Christine W , Zeng Zhao-Bang 
Published: January 2011

Abstract
Expression QTL (eQTL) studies involve the collection of microarray gene expression data and genetic marker data from segregating individuals in a population to search for genetic determinants of differential gene expression. Previous studies have found large numbers of trans-regulated genes (regulated by unlinked genetic loci) that link to a single locus or eQTL “hotspot,” and it would be desirable to find the mechanism of coregulation for these gene groups. However, many difficulties exist with current network reconstruction algorithms such as low power and high computational cost. A common observation for biological networks is that they have a scale-free or power-law architecture. In such an architecture, highly influential nodes exist that have many connections to other nodes. If we assume that this type of architecture applies to genetic networks, then we can simplify the problem of genetic network reconstruction by focusing on discovery of the key regulatory genes at the top of the network. We introduce the concept of “shielding” in which a specific gene expression variable (the shielder) renders a set of other gene expression variables (the shielded genes) independent of the eQTL. We iteratively build networks from the eQTL to the shielder down using tests of conditional independence. We have proposed a novel test for controlling the shielder false-positive rate at a predetermined level by requiring a threshold number of shielded genes per shielder. Using simulation, we have demonstrated that we can control the shielder false-positive rate as well as obtain high shielder and edge specificity. In addition, we have shown our method to be robust to violation of the latent variable assumption, an important feature in the practical application of our method. We have applied our method to a yeast expression QTL data set in which microarray and marker data were collected from the progeny of a backcross of two species of Saccharomyces cerevisiae (Bremet al. 2002). Seven genetic networks have been discovered, and bioinformatic analysis of the discovered regulators and corresponding regulated genes has generated plausible hypotheses for mechanisms of regulation that can be tested in future experiments.
A Hierarchical Bayesian Model for Next-Generation Population Genomics
Authors: Gompert Zachariah , Buerkle C Alex 
Published: January 2011

AbstractThe demography of populations and natural selection shape genetic variation across the genome and understanding the genomic consequences of these evolutionary processes is a fundamental aim of population genetics. We have developed a hierarchical Bayesian model to quantify genome-wide population structure and identify candidate genetic regions affected by selection. This model improves on existing methods by accounting for stochastic sampling of sequences inherent in next-generation sequencing (with pooled or indexed individual samples) and by incorporating genetic distances among haplotypes in measures of genetic differentiation. Using simulations we demonstrate that this model has a low false-positive rate for classifying neutral genetic regions as selected genes (i.e., ϕST outliers), but can detect recent selective sweeps, particularly when genetic regions in multiple populations are affected by selection. Nonetheless, selection affecting just a single population was difficult to detect and resulted in a high false-negative rate under certain conditions. We applied the Bayesian model to two large sets of human population genetic data. We found evidence of widespread positive and balancing selection among worldwide human populations, including many genetic regions previously thought to be under selection. Additionally, we identified novel candidate genes for selection, several of which have been linked to human diseases. This model will facilitate the population genetic analysis of a wide range of organisms on the basis of next-generation sequence data.