bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner
Authors: Brännström Kristoffer , Öhman Anders , Lindhagen-Persson Malin , Olofsson Anders 
Published: November 2012

Identifying factors that affect the self-assembly of Aβ (amyloid-β peptide) is of utmost importance in the quest to understand the molecular mechanisms causing AD (Alzheimer's disease). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and dysregulated Ca2+ homoeostasis frequently correlates with development of AD. The mechanisms regarding Ca2+ binding, as well as its effect on fibril kinetics, are not fully understood. Using a polymerization assay we show that Ca2+ in a dynamic and reversible manner enhances both the elongation rate and fibrillar stability, where specifically the ‘dock and lock’ phase mechanism is enhanced. Through NMR analysis we found that Ca2+ affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca2+ does not bind the free Aβ monomer. This implies that Ca2+ binding requires an architecture adopted by assembled peptides, and consequently is mediated through intermolecular interactions between adjacent peptides. This gives a mechanistic explanation to the enhancing effect on fibril maturation and indicates structural similarities between prefibrillar structures and mature amyloid. Taken together we show how Ca2+ levels affect the delicate equilibrium between the monomeric and assembled Aβ and how fluctuations in vivo may contribute to development and progression of the disease.
Mineral respiration under extreme acidic conditions: from a supramolecular organization to a molecular adaptation in Acidithiobacillus ferrooxidans
Authors: Roger Magali , Castelle Cindy , Guiral Marianne , Infossi Pascale , Lojou Elisabeth , Giudici-Orticoni Marie-Thérèse , Ilbert Marianne 
Published: November 2012

Acidithiobacillus ferrooxidans is an acidophilic chemolithoautotrophic Gram-negative bacterium that can derive energy from the oxidation of ferrous iron at pH 2 using oxygen as electron acceptor. The study of this bacterium has economic and fundamental biological interest because of its use in the industrial extraction of copper and uranium from ores. For this reason, its respiratory chain has been analysed in detail in recent years. Studies have shown the presence of a functional supercomplex that spans the outer and the inner membranes and allows a direct electron transfer from the extracellular Fe2+ ions to the inner membrane cytochrome c oxidase. Iron induces the expression of two operons encoding proteins implicated in this complex as well as in the regeneration of the reducing power. Most of these are metalloproteins that have been characterized biochemically, structurally and biophysically. For some of them, the molecular basis of their adaptation to the periplasmic acidic environment has been described. Modifications in the metal surroundings have been highlighted for cytochrome c and rusticyanin, whereas, for the cytochrome c oxidase, an additional partner that maintains its stability and activity has been demonstrated recently.
Microcins in action: amazing defence strategies of Enterobacteria
Authors: Rebuffat Sylvie 
Published: November 2012

Probably the oldest and most widespread antimicrobial strategy in living organisms is the use of antimicrobial peptides. Bacteria secrete such defence peptides, termed bacteriocins, that they use for microbial competitions. Microcins are bacteriocins of less than 10 kDa produced by Escherichia coli and related enterobacteria through the ribosomal pathway. They are synthesized as linear precursors, which can further undergo complex post-translational modifications resulting from dedicated maturation enzymes encoded in the microcin gene clusters, and are processed by proteolytic cleavage. Microcins exert potent bactericidal activities that use subtle and clever mechanisms to cross outer and inner membranes of Gram-negative bacteria. To cross the outer membrane, siderophore-microcins hijack receptors involved in iron acquisition. The lasso-peptide microcin J25, which is characterized by a knotted arrangement where the C-terminal tail is threaded through an N-terminal macrolactam ring, uses a hydroxamate siderophore receptor and the inner-membrane protein SbmA for import in sensitive bacteria, where it inhibits bacterial transcription through binding to RNAP (RNA polymerase). Microcin C produced as a heptapeptide adenylate, requires an outer-membrane porin and an inner-membrane ABC (ATP-binding-cassette) transporter to reach the cytoplasm of target bacteria, where it is processed by proteases into a non-hydrolysable aspartyl-adenylate analogue. Therefore, despite showing different killing mechanisms and the absence of any structural homology, microcins have the common characteristic to use Trojan horse strategies to destroy their competitors. They offer new and promising tracks for further design and engineering of novel efficient antibiotics.
Antimicrobial mechanism of lantibiotics
Authors: Islam Mohammad R. , Nagao Jun-ichi , Zendo Takeshi , Sonomoto Kenji 
Published: November 2012

Lantibiotics are ribosomally synthesized antimicrobial peptides that commonly target the cell wall precursor lipid II during their antimicrobial mechanism and exert their inhibitory activity by (i) inhibition of cell wall biosynthesis, and (ii) stable pore formation in the target membrane. Type-A(I) (i.e. nisin) and two-component (i.e. lacticin 3147) lantibiotics initially interact with lipid II to stabilize the complex, which then proceeds to inhibit cell wall biosynthesis and pore formation. Type-A(II) (i.e. nukacin ISK-1) and type-B (i.e. mersacidin) lantibiotics also use lipid II as a docking molecule, but can only inhibit cell wall biosynthesis without forming pores. In the present paper, we review the antimicrobial mechanism of different types of lantibiotics, their current progress and future prospect.
‘Bac’ to the future: bioengineering lantibiotics for designer purposes
Authors: Molloy Evelyn M. , Ross R. Paul , Hill Colin 
Published: November 2012

Bacteriocins are bacterially produced peptides or proteins that inhibit the growth of other bacterial strains. They can have a broad (effective against multiple genera) or narrow (effective against specific species) spectrum of activity. The diversity of bacteriocins found in Nature, in terms of both spectrum of activity and physiochemical properties, offers the possibility of multiple applications in the food and pharmaceutical industries. However, traditional screening strategies may not provide a sufficient range of natural molecules with specifically desired properties. Research suggests that bioengineering of existing inhibitors has the potential to address this issue, extending the application of natural bacteriocins for use in novel settings and against different targets. In the present paper, we discuss the successful implementation of bioengineering strategies to alter and even improve the functional characteristics of a bacteriocin, using the prototypical lantibiotic nisin as an example. Additionally, we describe the recent use of the nisin-modification machinery in vivo to enhance the properties of medically significant peptides.
Pathways of colicin import: utilization of BtuB, OmpF porin and the TolC drug-export protein
Authors: Zakharov Stanislav D. , Sharma Onkar , Zhalnina Mariya , Yamashita Eiki , Cramer William A. 
Published: November 2012

Pathway I. Group A nuclease colicins parasitize and bind tightly (Kd ≤ 10−9 M) to the vitamin B12 receptor on which they diffuse laterally in the OM (outer membrane) and use their long (≥100 Å; 1 Å=0.1 nm) receptor-binding domain as a ‘fishing pole’ to locate the OmpF porin channel for translocation. Crystal structures of OmpF imply that a disordered N-terminal segment of the colicin T-domain initiates insertion. Pathway II. Colicin N does not possess a ‘fishing pole’ receptor-binding domain. Instead, it uses OmpF as the Omp (outer membrane protein) for reception and translocation, processes in which LPS (lipopolysaccharide) may also serve. Keio collection experiments defined the LPS core that is used. Pathway III. Colicin E1 utilizes the drug-export protein TolC for import. CD spectra and thermal-melting analysis predict: (i) N-terminal translocation (T) and central receptor (BtuB) -binding (R) domains are predominantly α-helical; and (ii) helical coiled-coil conformation of the R-domain is similar to that of colicins E3 and Ia. Recombinant colicin peptides spanning the N-terminal translocation domain defined TolC-binding site(s). The N-terminal 40-residue segment lacks the ordered secondary structure. Peptide 41–190 is helical (78%), co-elutes with TolC and occluded TolC channels. Driven by a trans-negative potential, peptides 82–140 and 141–190 occluded TolC channels. The use of TolC for colicin E1 import implies that the interaction of this colicin with the other Tol proteins does not occur in the periplasmic space, but rather through Tol domains in the cytoplasmic membrane, thus explaining colicin E1 cytotoxicity towards a strain in which a 234 residue periplasmic TolA segment is deleted.
Membrane activities of colicin nuclease domains: analogies with antimicrobial peptides
Authors: Vankemmelbeke Mireille , James Richard , Penfold Christopher N. 
Published: November 2012

Nuclease colicins, such as colicin E9, are a class of Escherichia coli bacteriocins that kill E. coli and closely related Gram-negative bacteria through nucleolytic action in the cytoplasm. In order to accomplish this, their cytotoxic domains require transportation across two sets of membranes and the periplasmic space. Currently, little information is available concerning how the membrane translocation processes are achieved, and the present review summarizes our recent results on the in vitro membrane activities of the colicin nuclease domains. Using model membranes, we have analysed the cytotoxic domains of a number of DNase-type colicins and one rRNase colicin for their bilayer insertion depth and for their ability to induce vesicle aggregation, lipid mixing and increased bilayer permeability. We found that, by analogy with AMPs (antimicrobial peptides), the interplay between charge and hydrophobic character of the nuclease domains governs their pleiotropic membrane activities and these results form the basis of ongoing work to unravel the molecular mechanisms underlying their membrane translocation.
Effects of confidence and anxiety on flow state in competition
Authors: Koehn Stefan 
Published: November 2012

AbstractConfidence and anxiety are important variables that underlie the experience of flow in sport. Specifically, research has indicated that confidence displays a positive relationship and anxiety a negative relationship with flow. The aim of this study was to assess potential direct and indirect effects of confidence and anxiety dimensions on flow state in tennis competition. A sample of 59 junior tennis players completed measures of Competitive State Anxiety Inventory‐2d and Flow State Scale‐2. Following predictive analysis, results showed significant positive correlations between confidence (intensity and direction) and anxiety symptoms (only directional perceptions) with flow state. Standard multiple regression analysis indicated confidence as the only significant predictor of flow. The results confirmed a protective function of confidence against debilitating anxiety interpretations, but there were no significant interaction effects between confidence and anxiety on flow state.
A Lasso multi-marker mixed model for association mapping with population structure correction
Authors: Rakitsch Barbara , Lippert Christoph , Stegle Oliver , Borgwardt Karsten 
Published: November 2012

AbstractMotivation: Exploring the genetic basis of heritable traits remains one of the central challenges in biomedical research. In traits with simple Mendelian architectures, single polymorphic loci explain a significant fraction of the phenotypic variability. However, many traits of interest seem to be subject to multifactorial control by groups of genetic loci. Accurate detection of such multivariate associations is non-trivial and often compromised by limited statistical power. At the same time, confounding influences, such as population structure, cause spurious association signals that result in false-positive findings.Results: We propose linear mixed models LMM-Lasso, a mixed model that allows for both multi-locus mapping and correction for confounding effects. Our approach is simple and free of tuning parameters; it effectively controls for population structure and scales to genome-wide datasets. LMM-Lasso simultaneously discovers likely causal variants and allows for multi-marker–based phenotype prediction from genotype. We demonstrate the practical use of LMM-Lasso in genome-wide association studies in Arabidopsis thaliana and linkage mapping in mouse, where our method achieves significantly more accurate phenotype prediction for 91% of the considered phenotypes. At the same time, our model dissects the phenotypic variability into components that result from individual single nucleotide polymorphism effects and population structure. Enrichment of known candidate genes suggests that the individual associations retrieved by LMM-Lasso are likely to be genuine.Availability: Code available under http://webdav.tuebingen.mpg.de/u/karsten/Forschung/research.html.Contact: rakitsch@tuebingen.mpg.de, ippert@microsoft.com or stegle@ebi.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.
An effective framework for reconstructing gene regulatory networks from genetical genomics data
Authors: Flassig R. J. , Heise S. , Sundmacher K. , Klamt S. 
Published: November 2012

AbstractMotivation: Systems Genetics approaches, in particular those relying on genetical genomics data, put forward a new paradigm of large-scale genome and network analysis. These methods use naturally occurring multi-factorial perturbations (e.g. polymorphisms) in properly controlled and screened genetic crosses to elucidate causal relationships in biological networks. However, although genetical genomics data contain rich information, a clear dissection of causes and effects as required for reconstructing gene regulatory networks is not easily possible.Results: We present a framework for reconstructing gene regulatory networks from genetical genomics data where genotype and phenotype correlation measures are used to derive an initial graph which is subsequently reduced by pruning strategies to minimize false positive predictions. Applied to realistic simulated genetic data from a recent DREAM challenge, we demonstrate that our approach is simple yet effective and outperforms more complex methods (including the best performer) with respect to (i) reconstruction quality (especially for small sample sizes) and (ii) applicability to large data sets due to relatively low computational costs. We also present reconstruction results from real genetical genomics data of yeast.Availability: A MATLAB implementation (script) of the reconstruction framework is available at www.mpi-magdeburg.mpg.de/projects/cna/etcdownloads.htmlContact: klamt@mpi-magdeburg.mpg.de
Involvement of Arabidopsis ACYL-COENZYME A DESATURASE-LIKE2 (At2g31360) in the Biosynthesis of the Very-Long-Chain Monounsaturated Fatty Acid Components of Membrane Lipids
Authors: Smith Mark A. , Dauk Melanie , Ramadan Hussein , Yang Hui , Seamons Laura E. , Haslam Richard P. , Beaudoin Frédéric , Ramirez-Erosa Irving , Forseille Li 
Published: November 2012

Abstract
The Arabidopsis (Arabidopsis thaliana) acyl-coenzyme A (CoA) desaturase-like (ADS) gene family contains nine genes encoding fatty acid desaturase-like proteins. The biological function of only one member of the family, fatty acid desaturase5 (AtADS3/FAD5, At3g15850), is known, and this gene encodes the plastidic palmitoyl-monogalactosyldiacylglycerol Ɗ7 desaturase. We cloned seven members of the gene family that are predicted not to have a chloroplast transit peptide and expressed them in the yeast Saccharomyces cerevisiae. All seven have previously undescribed desaturase activity on very-long-chain fatty acid (VLCFA) substrates and exhibit diverse regiospecificity, catalyzing introduction of double bonds relative to the methyl end of the molecule (n-x) at n-6 (AtADS4, At1g06350), n-7 (AtADS1.3, At1g06100 and AtADS4.2, At1g06360), n-9 (AtADS1, At1g06080 and AtADS2, At2g31360) or Ɗ9 (relative to the carboxyl end of the molecule) positions (AtADS1.2, At1g06090 and AtADS1.4, At1g06120). Through forward and reverse genetics it was shown that AtADS2 is involved in the synthesis of the 24:1(n-9) and 26:1(n-9) components (X:Y, where X is chain length and Y is number of double bonds) of seed lipids, sphingolipids, and the membrane phospholipids phosphatidylserine, and phosphatidylethanolamine. Plants deficient in AtADS2 expression showed no obvious phenotype when grown under normal growing conditions, but showed an almost complete loss of phosphatidylethanolamine(42:4), phosphatidylserine(42:4), dihydroxy-monohexosylceramide(42:2)-2, trihydroxy-monohexosylceramide(42:2)-3, and trihydroxy-glycosylinositolphosphoceramide(42:2)-3, lipid species that contain the VLCFA 24:1(n-9), and trihydroxy-glycosylinositolphosphoceramide(44:2)-3, a lipid containing 26:1(n-9). Acyl-CoA profiling of these plants revealed a major reduction in 24:1-CoA and a small reduction in 26:1-CoA. Overexpression of AtADS2 resulted in a substantial increase in the percentage of glycerolipid and sphingolipids species containing 24:1 and a dramatic increase in the percentage of very-long-chain monounsaturated fatty acids in the acyl-CoA pool. Plants deficient in AtADS1 expression had reduced levels of 26:1(n-9) in seed lipids, but no significant changes in leaf phospholipids or sphingolipids were observed. These findings indicate that the 24-carbon and 26-carbon monounsaturated VLCFAs of Arabidopsis result primarily from VLCFA desaturation, rather than by elongation of long chain monounsaturated fatty acids.
Positive ageing – from the political to the personal
Authors: Robertson Guy 
Published: November 2012

PurposeThe aim of this paper is to highlight the corrosive impact of ageism on the health and wellbeing of older people and to propose a practical methodology for addressing the psychological and emotional damage.Design/methodology/approachThe paper examines published research from social gerontology on the impact of negative attitudes on longevity and health and then incorporates research from the realm of positive psychology to produce some practical personal development approaches based on a synthesis of the two.FindingsNegative attitudes, largely fed by societal ageism, can significantly reduce longevity. Altering a person's “explanatory style” can produce significant health and wellbeing benefits. The latter is then proposed as a means of countering the former.Research limitations/implicationsWhilst each element is grounded in robust research evidence, there is as yet no dedicated research to show that the proposed “combined intervention” will have the intended impact.Practical implicationsA methodology is proposed for enabling individuals to examine their negative attitudes towards their own ageing and then use a variety of psychological techniques to ameliorate or replace them with more positive ones, which it is argued, will lead to greater health and wellbeing.Originality/valueThe paper synthesises research from two disparate disciplines (i.e. social gerontology, and psychology) to propose a way of addressing the negative impact of internalised ageist attitudes. The paper offers practical approaches to reverse the psychological and emotional damage caused by prevalent ageism in society. One such transformational programme is outlined.
Making the links: integrating housing, health and care
Authors: Minter Jane 
Published: November 2012

PurposeUsing some case examples from Care & Repair England in the UK, this paper aims to focus on the integration of housing help in a hospital setting.Design/methodology/approachThe paper gives some background on Care & Repair and the development of local housing and hospital linked projects. The broader debate about the role of housing is then considered.FindingsKey recommendations from the case studies are discussed and the wider debate on improving integration is considered in relation to the UK Government's recent Care and Support White Paper.Originality/valueThe paper considers the role that housing plays in health and social care provision and why people engaged in the sector should continue to work towards better integration of housing, health and social care.
Objection, purpose and normality: three ways in which the courts have inhibited safeguarding
Authors: Hewitt David 
Published: November 2012

PurposeThis paper's aim is to consider three ways in which, recently, the English courts have sought to define deprivation of liberty (and, maybe, limit the effect of safeguards against it).Design/methodology/approachTwo significant decisions of the Court of Appeal were considered, together with one each of the House of Lords and the European Court of Human Rights. Consideration was also given to the context of those decisions, as disclosed in official policy documents and at least one piece of academic research.FindingsThe decisions in question have limited the circumstances that will amount to deprivation of liberty and thereby reduced the scope of the Deprivation of Liberty Safeguards (DoLS). The English courts' understanding of false imprisonment is diverging from their understanding of deprivation of liberty. The English courts differ from the European Court of Human Rights in their understanding of the relevance of “purpose” to the question of deprivation of liberty. If the former are correct, the DoLS – and maybe even the Mental Health Act – are redundant.Originality/valueThis is the first time these cases, and this subject, have been analysed in this way; and that these findings have been published together.
The right to take risks
Authors: Faulkner Alison 
Published: November 2012

PurposeCommissioned as part of a Joseph Rowntree Foundation scoping programme, this consultation aims to explore the views of disabled people and service users about risk.Design/methodology/approachThe consultation reached nine individuals and one focus group, reaching a total of 17 disabled people and service users. Their views were supplemented by the literature.FindingsThe landscape of risk and rights is highly complex. Disabled people and service users have quite different concerns about risk to those of the professionals and the regulatory bodies acting on their behalf. Many people talked of the fear of losing their independence, of asserting their rights and the fear of powerlessness in the face of bureaucracy and (sometimes) uncaring staff.Research limitations/implicationsThe profile of rights needs to be raised in an accessible and acceptable way: it is necessary to make the language of rights more commonplace. There is a particular need to reach into mental health and residential care services to find ways of enabling people to have their rights realised. The report has implications for risk assessment and risk management as well as for the regulatory bodies responsible in adult social care. Raising awareness among professionals and policy makers about the risks that service users themselves fear and experience should demonstrate just how important it is that the people whose risk is under consideration are involved in the process.Originality/valueThis paper highlights the views of users of adult social care about risk; their views have rarely been documented.