bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system
Authors: Strushkevich Natallia , MacKenzie Farrell , Cherkesova Tatyana , Grabovec Irina , Usanov Sergey , Park Hee-Won 
Published: June 2011

In humans, the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1). This complex not only plays a key role in steroidogenesis, but also has long been a model to study electron transfer, multistep catalysis, and C–C bond cleavage performed by monooxygenases. Detailed mechanistic understanding of these processes has been hindered by a lack of structural information. Here we present the crystal structure of the complex of human Adx and CYP11A1—the first of a complex between a eukaryotic CYP and its redox partner. The structures with substrate and a series of reaction intermediates allow us to define the mechanism underlying sequential hydroxylations of the cholesterol and suggest the mechanism of C–C bond cleavage. In the complex the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of CYP11A1. This structure suggests that after an initial protein–protein association driven by electrostatic forces, the complex adopts an optimized geometry between the redox centers. Conservation of the interaction interface suggests that this mechanism is common for all mitochondrial P450s.
A memory-efficient data structure representing exact-match overlap graphs with application for next-generation DNA assembly
Authors: Dinh Hieu , Rajasekaran Sanguthevar 
Published: June 2011

Abstract
Motivation: Exact-match overlap graphs have been broadly used in the context of DNA assembly and the shortest super string problem where the number of strings n ranges from thousands to billions. The length ℓ of the strings is from 25 to 1000, depending on the DNA sequencing technologies. However, many DNA assemblers using overlap graphs suffer from the need for too much time and space in constructing the graphs. It is nearly impossible for these DNA assemblers to handle the huge amount of data produced by the next-generation sequencing technologies where the number n of strings could be several billions. If the overlap graph is explicitly stored, it would require Ω(n 2) memory, which could be prohibitive in practice when n is greater than a hundred million. In this article, we propose a novel data structure using which the overlap graph can be compactly stored. This data structure requires only linear time to construct and and linear memory to store.
Results: For a given set of input strings (also called reads), we can informally define an exact-match overlap graph as follows. Each read is represented as a node in the graph and there is an edge between two nodes if the corresponding reads overlap sufficiently. A formal description follows. The maximal exact-match overlap of two strings x and y, denoted by ov max(x, y), is the longest string which is a suffix of x and a prefix of y. The exact-match overlap graph of n given strings of length ℓ is an edge-weighted graph in which each vertex is associated with a string and there is an edge (x, y) of weight ω=ℓ−|ov max(x, y)| if and only if ω≤λ, where |ov max(x, y)| is the length of ov max(x, y) and λ is a given threshold. In this article, we show that the exact-match overlap graphs can be represented by a compact data structure that can be stored using at most (2λ−1)(2⌈logn⌉+⌈logλ⌉)n bits with a guarantee that the basic operation of accessing an edge takes O(log λ) time. We also propose two algorithms for constructing the data structure for the exact-match overlap graph. The first algorithm runs in O(λℓnlogn) worse-case time and requires O(λ) extra memory. The second one runs in O(λℓn) time and requires O(n) extra memory. Our experimental results on a huge amount of simulated data from sequence assembly show that the data structure can be constructed efficiently in time and memory.
Availability: Our DNA sequence assembler that incorporates the data structure is freely available on the web at http://www.engr.uconn.edu/~htd06001/assembler/leap.zip
Contact: hdinh@engr.uconn.edu; rajasek@engr.uconn.edu
Identification of cavities on protein surface using multiple computational approaches for drug binding site prediction
Authors: Zhang Zengming , Li Yu , Lin Biaoyang , Schroeder Michael , Huang Bingding 
Published: June 2011

Abstract
Motivation: Protein–ligand binding sites are the active sites on protein surface that perform protein functions. Thus, the identification of those binding sites is often the first step to study protein functions and structure-based drug design. There are many computational algorithms and tools developed in recent decades, such as LIGSITEcs/c, PASS, Q-SiteFinder, SURFNET, and so on. In our previous work, MetaPocket, we have proved that it is possible to combine the results of many methods together to improve the prediction result.
Results: Here, we continue our previous work by adding four more methods Fpocket, GHECOM, ConCavity and POCASA to further improve the prediction success rate. The new method MetaPocket 2.0 and the individual approaches are all tested on two datasets of 48 unbound/bound and 210 bound structures as used before. The results show that the average success rate has been raised 5% at the top 1 prediction compared with previous work. Moreover, we construct a non-redundant dataset of drug–target complexes with known structure from DrugBank, DrugPort and PDB database and apply MetaPocket 2.0 to this dataset to predict drug binding sites. As a result, &gt;74% drug binding sites on protein target are correctly identified at the top 3 prediction, and it is 12% better than the best individual approach.
Availability: The web service of MetaPocket 2.0 and all the test datasets are freely available at http://projects.biotec.tu-dresden.de/metapocket/ and http://sysbio.zju.edu.cn/metapocket.
Contact: bhuang@biotec.tu-dresden.de
Supplementary Information: Supplementary data are available at Bioinformatics online.
The FAF-Drugs2 server: a multistep engine to prepare electronic chemical compound collections
Authors: Lagorce David , Maupetit Julien , Baell Jonathan , Sperandio Olivier , Tufféry Pierre , Miteva Maria A. , Galons Hervé , Villoutreix Bruno O. 
Published: June 2011

Abstract
Summary:The FAF-Drugs2 server is a web application that prepares chemical compound libraries prior to virtual screening or that assists hit selection/lead optimization before chemical synthesis or ordering. The FAF-Drugs2 web server is an enhanced version of the FAF-Drugs2 package that now includes Pan Assay Interference Compounds detection. This online toolkit has been designed through a user-centered approach with emphasis on user-friendliness. This is a unique online tool allowing to prepare large compound libraries with in house or user-defined filtering parameters.
Availability: The FAF-Drugs2 server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/FAF-Drugs/.
Contact: david.lagorce@inserm.fr; bruno.villoutreix@inserm.fr
Supplementary information: Supplementary data are available at Bioinformatics online.
Myocarditis as a precipitating factor for heart failure: evaluation and 1‐year follow‐up using cardiovascular magnetic resonance and endomyocardial biopsy
Authors: Mavrogeni Sophie , Spargias Costas , Bratis Costas , Kolovou Genovefa , Markussis Vyron , Papadopoulou Evangelia , Constadoulakis Pantelis , Papadimitropoulos Miltiadis , Douskou Marouso , Pavlides Gregory , Cokkinos Denis 
Published: June 2011

AimsThe aim of this study was to evaluate myocarditis as a precipitating factor for heart failure using cardiovascular magnetic resonance (CMR) and endomyocardial biopsyMethods and resultsEighty‐five patients with suspected myocarditis and 20 controls were evaluated. Seventy‐one patients with positive CMR were referred for endomyocardial biopsy and re‐evaluation after 1 year. Cardiovascular magnetic resonance was performed using STIR T2‐weighted (T2W), early T1‐weighted (EGE), and late gadolinium‐enhanced (LGE) images. Immunohistological and polymerase chain reaction (PCR) analysis of myocardial specimens was employed.In patients with myocarditis, T2 and EGE were increased compared with controls (2.6 ± 0.9 vs. 1.57 ± 0.13, P < 0.001 and 7.9 ± 5.5 vs. 3.59 ± 0.08, P < 0.001, respectively). Late gadolinium enhancement was found in all myocarditis patients. Endomyocardial biopsy performed in 50 of 71 patients with positive CMR showed positive immunohistology in 48% and presence of infectious genomes in 80% (mainly Chlamydia, Herpes, and Parvovirus B19). Left ventricular ejection fraction (LVEF) was significantly decreased compared with controls (47.7 ± 19.2 vs. 64 ± 0.2, P < 0.001). After 1 year, CMR showed normalization of T2 and EGE, and decreased LGE. Left ventricular ejection fraction increased in 36.5% of patients, remained stable in 56.5% and decreased in 7% of patients, in whom biopsy showed persistence of the initial infective agents. A negative correlation was identified between EGE, LGE, and LVEF. Patients with positive biopsies had lower LVEFs.ConclusionIn a Greek population with myocarditis, Chlamydia with viruses was a common finding. Cardiovascular magnetic resonance and PCR proved useful for the detection of myocarditis; EGE and LGE had the best correlation for the development of heart failure. Persistence of the initially detected infective agents was identified in patients who deteriorated further.
Vitamin D Deficiency Is Prevalent in Girls and Women With Rett Syndrome
Authors: Motil Kathleen J. , Barrish Judy O. , Lane Jane , Geerts Suzanne P. , Annese Fran , McNair Lauren , Percy Alan K. , Skinner Steven A. , Neul Jeffrey L. , Glaze Daniel G. 
Published: June 2011

ABSTRACTObjectives:The aim of the study was to determine the prevalence of vitamin D deficiency and identify the relation between 25‐hydroxyvitamin D (25‐(OH)D) levels and the consumption of dietary sources of vitamin D or exposure to anticonvulsants in girls and women with Rett syndrome (RTT).Subjects and Methods:Retrospective review of the medical records of 284 girls and women with RTT to determine serum 25‐(OH)D and parathyroid hormone levels, nutritional status, dietary sources of vitamin D, exposure to anticonvulsants, degree of mobility, and MECP2 status.Results:Twenty percent of girls and women who were tested (n = 157) had 25‐(OH)D levels <50 nmol/L. Multivitamin supplements, vitamin D–fortified milk, and commercial formulas were consumed by 40%, 52%, and 54%, respectively. Anticonvulsants were used by 57%, and 39% ambulated independently. Median 25‐(OH)D levels were lower in individuals who did not receive multivitamin supplements (P < 0.05) or commercial formulas (P < 0.001) than in those who did. Median 25‐(OH)D levels differed (P < 0.01) among racial and ethnic groups, but the number in some groups was small. Nutritional status, use of anticonvulsants, degree of mobility, and MECP2 status did not influence 25‐(OH)D levels.Conclusions:Vitamin D deficiency is prevalent in girls and women with RTT. The use of multivitamin supplements or commercial formulas is associated with improved vitamin D levels. Attention to vitamin D may enhance bone mineral deposition and reduce the frequency of bone fractures in these individuals.
Analysis of the role of the coat protein N‐terminal segment in Potato virus X virion stability and functional activity
Authors: LUKASHINA ELENA , KSENOFONTOV ALEXANDER , FEDOROVA NATALIA , BADUN GENNADY , MUKHAMEDZHANOVA ANNA , KARPOVA OLGA , RODIONOVA NINA , BARATOVA LYUDMILA , DOBROV EVGENY 
Published: June 2011

SUMMARYPreviously, we have reported that intact Potato virus X (PVX) virions cannot be translated in cell‐free systems, but acquire this capacity by the binding of PVX‐specific triple gene block protein 1 (TGBp1) or after phosphorylation of the exposed N‐terminal segment of intravirus coat protein (CP) by protein kinases. With the help of in vitro mutagenesis, a nonphosphorylatable PVX mutant (denoted ST PVX) was prepared in which all 12 S and T residues in the 20‐residue‐long N‐terminal CP segment were substituted by A or G. Contrary to expectations, ST PVX was infectious, produced normal progeny and was translated in vitro in the absence of any additional factors. We suggest that the N‐terminal PVX CP segment somehow participates in virion assembly in vivo and that CP subunits in ST virions may differ in structure from those in the wild‐type (UK3 strain). In the present work, to test this suggestion, we performed a comparative tritium planigraphy study of CP structure in UK3 and ST virions. It was found that the profile of tritium incorporation into ST mutant virions in some CP segments differed from that of normal UK3 virions and from UK3 complexed with the PVX movement protein TGBp1. It is proposed that amino acid substitutions in ST CP and the TGBp1‐driven remodelling of UK3 virions induce structural alterations in intravirus CPs. These alterations affect the predicted RNA recognition motif of PVX CP, but in different ways: for ST PVX, labelling is increased in α‐helices 6 and 7, whereas, in remodelled UK3, labelling is increased in the β‐sheet strands β3, β4 and β5.
CorA, the magnesium/nickel/cobalt transporter, affects virulence and extracellular enzyme production in the soft rot pathogen Pectobacterium carotovorum
Authors: KERSEY CALEB M. , AGYEMANG PAUL A. , DUMENYO C. KORSI 
Published: June 2011

SUMMARYPectobacterium carotovorum (formerly Erwinia carotovora ssp. carotovora) is a phytopathogenic bacterium that causes soft rot disease, characterized by water‐soaked soft decay, resulting from the action of cell wall‐degrading exoenzymes secreted by the pathogen. Virulence in soft rot bacteria is regulated by environmental factors, host and bacterial chemical signals, and a network of global and gene‐specific bacterial regulators. We isolated a mini‐Tn5 mutant of P. carotovorum that is reduced in the production of extracellular pectate lyase, protease, polygalacturonase and cellulase. The mutant is also decreased in virulence as it macerates less host tissues than its parent and is severely impaired in multiplication in planta. The inactivated gene responsible for the reduced virulent phenotype was identified as corA. CorA, a magnesium/nickel/cobalt membrane transporter, is the primary magnesium transporter for many bacteria. Compared with the parent, the CorA‐ mutant is cobalt resistant. The mutant phenotype was confirmed in parental strain P. carotovorum by marker exchange inactivation of corA. A functional corA+ DNA from P. carotovorum restored exoenzyme production and pathogenicity to the mutants. The P. carotovorum corA+ clone also restored motility and cobalt sensitivity to a CorA‐ mutant of Salmonella enterica. These data indicate that CorA is required for exoenzyme production and virulence in P. carotovorum.
Atrium electromechanical interval in left ventricular diastolic dysfunction
Authors: Chao Tze‐Fan , Wang Kang‐Ling , Chuang Chi‐Fang , Chen Shih‐Ann , Yu Wen‐Chung 
Published: June 2011

Eur J Clin Invest 2011AbstractBackground  Left ventricular (LV) diastolic dysfunction has great effects on the left atrium (LA). A recently developed electromechanical interval (PA‐TDI), which was determined as the time interval from the initiation of P wave deflection to the peak of local lateral LA tissue Doppler imaging signal, was reported to be associated with LA electrophysiological properties. The goal of our study was to evaluate the association between the PA‐TDI interval and LV diastolic function.Materials and methods  A total of 224 consecutive patients were enrolled. LV diastolic dysfunction was defined as either (i) impaired relaxation: E/A ratio < 0·75 and E/E′ ratio < 10, (ii) pseudonormal pattern: 0·75 ≤ E/A ratio < 1·5 and E/E′ ratio > 10 or (iii) restrictive pattern: E/A ratio ≥ 1·5 and E/E′ ratio > 10. The PA‐TDI intervals were measured and compared between patients with and without diastolic dysfunction.Results  Fifty‐six per cent of the study population had abnormal diastolic function. The PA‐TDI interval was significantly longer in the diastolic dysfunction group than that in the normal group (147·8 ± 18·2 vs. 130·4 ± 17·0 ms, P < 0·01). In patients with diastolic dysfunction, the PA‐TDI intervals became progressively longer as the diastolic dysfunction progressed from impaired relaxation (141·2 ± 11·4 ms), pseudonormal pattern (147·6 ± 18·0 ms) to restrictive pattern (164·1 ± 20·9 ms).Conclusions  The PA‐TDI interval was significantly longer in patients with LV diastolic dysfunction than those without it. Its prolongation may reflect the severity of atrial remodelling because of the abnormal diastolic function of LV.
Stable extramarital affairs are breaking the heart
Authors: Fisher A. D. , Bandini E. , Corona G. , Monami M. , Cameron Smith M. , Melani C. , Balzi D. , Forti G. , Mannucci E. , Maggi M. 
Published: June 2011

SummaryThe relationship between extramarital affairs and cardiovascular risk is still not completely clarified. The aim of this study was to investigate whether extramarital affairs have a protective effect on cardiovascular risk or, conversely, a deleterious one. Among patients studied, 91.8% of the whole sample reported no or occasional extramarital affairs, while 8.2% declared a stable secondary relationship. During a median follow‐up of 4 [0–8] years, 95 major adverse cardiovascular events (MACE), eight of which were fatal, were observed. Cox analysis, after adjustment for confounding factors, showed that presence of stable extramarital affair was associated with a higher incidence of MACE (HR = 2.13 [1.12; 4.07], p = 0.023). The introduction in the Cox model of patient perceived partner’s hypoactive sexual desire (PPPHSD) attenuates the association (HR 1.86 [0.93; 3.70], p = 0.078). The sample was therefore divided according to PPPHSD. We observed that unadjusted incidence of MACE was significantly associated with presence of extramarital affairs only in men reporting a primal partner without PPPHSD. This association was also confirmed in a Cox regression model, after adjusting for confounders (HR = 2.87 [1.81; 6.98], p = 0.020). We can conclude that to be unfaithful represents an independent risk factor for MACE. Therefore, infidelity induces not only heart trouble in the betrayed partners, but seems to be also able to increase the betrayer’s heart‐related events.
The pharmacokinetics and metabolism of meloxicam in camels after intravenous administration
Authors: WASFI I. A. , AL ALI W. A. , AGHA B. A. , KAMEL A. M. , AL BIRIKI N. A , AL NEAIMI K. M. 
Published: June 2011

Wasfi, I. A., Al Ali, W. A., Agha, B. A., Kamel, A. M., Al Biriki, N. A, Al Neaimi, K. M. The pharmacokinetics and metabolism of meloxicam in camels after intravenous administration.J. vet. Pharmacol. Therap. 35, 155–162.The pharmacokinetics and metabolism of meloxicam was studied in camels (Camelus dromedarus) (n = 6) following intravenous (i.v.) administration of a dose of 0.6 mg·kg/body weight. The results obtained (mean ± SD) were as follows: the terminal elimination half‐life (t1/2β) was 40.2 ± 16.8 h and total body clearance (ClT) was 1.94 ± 0.66 mL·kg/h. The volume of distribution at steady state (VSS) was 92.8 ± 13.7 mL/kg. One metabolite of meloxicam was tentatively identified as methylhydroxy meloxicam. Meloxicam and metabolite were excreted unconjugated in urine. Meloxicam could be detected in plasma 10 days following i.v. administration in camels using a sensitive liquid chromatography tandem mass spectrometry (LC/MS/MS) method.
Heterologous protein transfer within structured myxobacteria biofilms
Authors: Wei Xueming , Pathak Darshankumar T. , Wall Daniel 
Published: June 2011

SummaryMicrobial biofilms represent heterogeneous populations of cells that form intimate contacts. Within these populations cells communicate, cooperate and compete. Myxobacteria are noted for their complex social interactions, including gliding motility and lipoprotein exchange. Here, we investigated cis protein sequence and cellular behaviour requirements for lipoprotein transfer between Myxococcus xanthus cells. Specifically, an outer membrane (OM) type II signal sequence (SS) fused to the heterologous mCherry fluorescent reporter resulted in OM localization. When donor cells harbouring SSOM–mCherry were mixed with GFP‐labelled recipient cells they developed red fluorescence. Our results surprisingly showed that a type II SS for OM localization, but not inner membrane localization, was necessary and sufficient for rapid and efficient heterologous protein transfer. Importantly, transfer did not occur in liquid or on surfaces where cells were poorly aligned. We conclude that cell–cell contact and alignment is a critical step for lipoprotein exchange. We hypothesize that protein transfer facilitates cooperative myxobacteria behaviours.
A mutation within the C‐terminal domain of Sup35p that affects [PSI+] prion propagation
Authors: Kabani Mehdi , Cosnier Bruno , Bousset Luc , Rousset Jean‐Pierre , Melki Ronald , Fabret Céline 
Published: June 2011

SummaryThe epigenetic factor [PSI+] in the yeast Saccharomyces cerevisiae is due to the prion form of Sup35p. The N‐terminal domain of Sup35p (N), alone or together with the middle‐domain (NM), assembles in vitro into fibrils that induce [PSI+] when introduced into yeast cells. The Sup35p C‐terminal domain (C), involved in translation termination, is essential for growth. The involvement of Sup35p C‐terminal domain into [PSI+] propagation is subject to debate. We previously showed that mutation of threonine 341 within Sup35p C‐domain affects translation termination efficiency. Here, we demonstrate that mutating threonine 341 to aspartate or alanine results in synthetic lethality with [PSI+] and weakening of [PSI+] respectively. The corresponding Sup35D and Sup35A proteins assemble into wild‐type like fibrils in vitro, but with a slower elongation rate. Moreover, cross‐seeding between Sup35p and Sup35A is inefficient both in vivo and in vitro, suggesting that the point mutation alters the structural properties of Sup35p within the fibrils. Thus, Sup35p C‐terminal domain modulates [PSI+] prion propagation, possibly through a functional interaction with the N and/or M domains of the protein. Our results clearly demonstrate that Sup35p C‐terminal domain plays a critical role in prion propagation and provide new insights into the mechanism of prion conversion.
Lipoamide dehydrogenase is essential for both bloodstream and procyclic Trypanosoma brucei
Authors: Roldán Angela , Comini Marcelo A. , Crispo Martina , Krauth‐Siegel R. Luise 
Published: June 2011

SummaryLipoamide dehydrogenase (LipDH) is a component of four mitochondrial multienzyme complexes. RNA interference or the deletion of both alleles in bloodstream Trypanosoma brucei resulted in an absolute requirement for exogenous thymidine. In the absence of thymidine, lipdh−/− parasites showed a severely altered morphology and cell cycle distribution. Most probably, in bloodstream cells with their only rudimentary mitochondrion, LipDH is required as component of the glycine cleavage complex which generates methylene‐tetrahydrofolate for dTMP and thus DNA synthesis. The essential role of LipDH in bloodstream parasites was confirmed by an in vivo model. Lipdh−/− cells were unable to infect mice. Our data further revealed that degradation of branched‐chain amino acids takes place but is dispensable. In cultured bloodstream – but not procyclic – African trypanosomes, the total cellular concentration of LipDH increases with increasing cell densities. In procyclic parasites, LipDH mRNA depletion caused an even stronger proliferation defect that was not reversed by thymidine suggesting that in the fully elaborated mitochondrion of these cells the primary effect is not on the glycine cleavage complex. Since the medium used for the cultivation of procyclic cells was not supplemented with glucose, impairment of the 2‐ketoglutarate dehydrogenase complex is probably the main effect of LipDH depletion.