bluuebunny/crossref_metadata_2025_split huggingface dataset:
Employee Shareholder ‘Status’: Dismantling the Contract of Employment
Authors: Prassl Jeremias 
Published: November 2013

Abstract
On 1 September 2013, a new Employee Shareholder status came into force in the UK. Under its provisions, employees can be denied access to key employment rights such as unfair dismissal protection and redundancy pay in return for a shareholding in their employer valued at a minimum of £2,000. This article sets out the details of the new status, and evaluates its impact from several angles. The notion of the employee shareholder is difficult to square with the existing frameworks of UK Employment and Company Law; it is also unnecessary and exceedingly complex and thus fails to live up to the Coalition Government’s proclaimed goals. Whilst extensive uptake is unlikely in consequence, the Employee Shareholder status nonetheless represents an unprecedented attack on the very core relationship of employment law, the contract of employment: divorced from employment protective norms, it loses its key public-regulatory function, the distribution of risk between workers and their employing entities. As a result, employment rights become subject to market forces in negotiation between workers and their employers.
DNA binding properties of human Cdc45 suggest a function as molecular wedge for DNA unwinding
Authors: Szambowska Anna , Tessmer Ingrid , Kursula Petri , Usskilat Christian , Prus Piotr , Pospiech Helmut , Grosse Frank 
Published: November 2013

AbstractThe cell division cycle protein 45 (Cdc45) represents an essential replication factor that, together with the Mcm2-7 complex and the four subunits of GINS, forms the replicative DNA helicase in eukaryotes. Recombinant human Cdc45 (hCdc45) was structurally characterized and its DNA-binding properties were determined. Synchrotron radiation circular dichroism spectroscopy, dynamic light scattering, small-angle X-ray scattering and atomic force microscopy revealed that hCdc45 exists as an alpha-helical monomer and possesses a structure similar to its bacterial homolog RecJ. hCdc45 bound long (113-mer or 80-mer) single-stranded DNA fragments with a higher affinity than shorter ones (34-mer). hCdc45 displayed a preference for 3′ protruding strands and bound tightly to single-strand/double-strand DNA junctions, such as those presented by Y-shaped DNA, bubbles and displacement loops, all of which appear transiently during the initiation of DNA replication. Collectively, our findings suggest that hCdc45 not only binds to but also slides on DNA with a 3′–5′ polarity and, thereby acts as a molecular ‘wedge’ to initiate DNA strand displacement.
Differential contribution of basic residues to HIV-1 nucleocapsid protein’s nucleic acid chaperone function and retroviral replication
Authors: Wu Hao , Mitra Mithun , Naufer M. Nabuan , McCauley Micah J. , Gorelick Robert J. , Rouzina Ioulia , Musier-Forsyth Karin , Williams Mark C. 
Published: November 2013

AbstractThe human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein contains 15 basic residues located throughout its 55-amino acid sequence, as well as one aromatic residue in each of its two CCHC-type zinc finger motifs. NC facilitates nucleic acid (NA) rearrangements via its chaperone activity, but the structural basis for this activity and its consequences in vivo are not completely understood. Here, we investigate the role played by basic residues in the N-terminal domain, the N-terminal zinc finger and the linker region between the two zinc fingers. We use in vitro ensemble and single-molecule DNA stretching experiments to measure the characteristics of wild-type and mutant HIV-1 NC proteins, and correlate these results with cell-based HIV-1 replication assays. All of the cationic residue mutations lead to NA interaction defects, as well as reduced HIV-1 infectivity, and these effects are most pronounced on neutralizing all five N-terminal cationic residues. HIV-1 infectivity in cells is correlated most strongly with NC’s NA annealing capabilities as well as its ability to intercalate the DNA duplex. Although NC’s aromatic residues participate directly in DNA intercalation, our findings suggest that specific basic residues enhance these interactions, resulting in optimal NA chaperone activity.
A Scalable Formulation for Engineering Combination Therapies for Evolutionary Dynamics of Disease
Authors: Jonsson Vanessa , Rantzer Anders , Murray Richard M. 
Published: November 2013

AbstractIt has been shown that optimal controller synthesis for positive systems can be formulated as a linear program. Leveraging these results, we propose a scalable iterative algorithm for the systematic design of sparse, small gain feedback strategies that stabilize the evolutionary dynamics of a generic disease model. We achieve the desired feedback structure by augmenting the optimization problems with ℓ1and ℓ2regularization terms, and illustrate our method on an example inspired by an experimental study aimed at finding appropriate HIV neutralizing antibody therapy combinations in the presence of escape mutants.
Speciation and introgression betweenMimulus nasutusandMimulus guttatus
Authors: Brandvain Yaniv , Kenney Amanda M. , Flagel Lex , Coop Graham , Sweigart Andrea L. 
Published: November 2013

ABSTRACTMimulus guttatusandM. nasutusare an evolutionary and ecological model sister species pair differentiated by ecology, mating system, and partial reproductive isolation. Despite extensive research on this system, the history of divergence and differentiation in this sister pair is unclear. We present and analyze a novel population genomic data set which shows thatM. nasutus“budded” off of a central CalifornianM. guttatuspopulation within the last 200 to 500 thousand years. In this time, theM. nasutusgenome has accrued numerous genomic signatures of the transition to predominant selfing. Despite clear biological differentiation, we document ongoing, bidirectional introgression. We observe a negative relationship between the recombination rate and divergence betweenM. nasutusand sympatricM. guttatussamples, suggesting that selection acts againstM. nasutusancestry inM. guttatus.
Microenvironmental variables must influence intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity
Authors: Scott Jacob G. , Hjelmeland Anita B. , Chinnaiyan Prakash , Anderson Alexander R. A. , Basanta David 
Published: November 2013

AbstractSince the discovery of tumour initiating cells (TICs) in solid tumours, studies focussing on their role in cancer initiation and progression have abounded. The biological interrogation of these cells continues to yield volumes of information on their pro-tumourigenic behaviour, but actionable generalised conclusions have been scarce. Further, new information suggesting a dependence of tumour composition and growth on the microenvironment has yet to be studied theoretically. To address this point, we created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue with a simple microenvironment. Using the model we explored the phenotypic traits inherent to the tumour initiating cells and the effect of the microenvironment on tissue growth. We identify the regions in phenotype parameter space where TICs are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour maintenance. As our parameters and model are non-specific, they could apply to any tissue TIC and do not assume specific genetic mutations. Targeting these phenotypic traits could represent a generalizable therapeutic strategy across cancer types. Further, we find that the microenvironmental variable does not strongly effect the outcomes, suggesting a need for direct feedback from the microenvironment onto stem-cell behaviour in future modelling endeavours.Author SummaryIn this paper, we present a mathematical/computational model of a tumour growing according to the canonical cancer stem-cell hypothesis with a simplified microenvironment. We explore the parameters of this model and find good agreement between our model and other theoretical models in terms of the intrinsic cellular parameters, which are difficult to study biologically. We find, however, disagreement between novel biological data and our model in terms of the microenvironmental changes. We conclude that future theoretical models of stem-cell driven tumours must include specific feedback from the microenvironment onto the individual cellular behavior. Further, we identify several cell intrinsic parameters which govern loss of homeostasis into a state of uncontrolled growth.
Population genomics of parallel hybrid zones in the mimetic butterflies,H. melpomeneandH. erato
Authors: Nadeau Nicola J. , Ruiz Mayté , Salazar Patricio , Counterman Brian , Medina Jose Alejandro , Ortiz-Zuazaga Humberto , Morrison Anna , McMillan W. Owen , Jiggins Chris D. , Papa Riccardo 
Published: November 2013

ABSTRACTHybrid zones can be valuable tools for studying evolution and identifying genomic regions responsible for adaptive divergence and underlying phenotypic variation. Hybrid zones between subspecies ofHeliconiusbutterflies can be very narrow and are maintained by strong selection acting on colour pattern. The co-mimetic speciesH. eratoandH. melpomenehave parallel hybrid zones where both species undergo a change from one colour pattern form to another. We use restriction associated DNA sequencing to obtain several thousand genome wide sequence markers and use these to analyse patterns of population divergence across two pairs of parallel hybrid zones in Peru and Ecuador. We compare two approaches for analysis of this type of data; alignment to a reference genome andde novoassembly, and find that alignment gives the best results for species both closely (H. melpomene) and distantly (H. erato,∼15% divergent) related to the reference sequence. Our results confirm that the colour pattern controlling loci account for the majority of divergent regions across the genome, but we also detect other divergent regions apparently unlinked to colour pattern differences. We also use association mapping to identify previously unmapped colour pattern loci, in particular theRolocus. Finally, we identify within our sample a new cryptic population ofH. timaretain Ecuador, which occurs at relatively low altitude and is mimetic withH. melpomene malleti.
Genome-wide targets of selection: female response to experimental removal of sexual selection inDrosophila melanogaster
Authors: Innocenti Paolo , Flis Ilona , Morrow Edward H. 
Published: November 2013

ABSTRACTDespite the common assumption that promiscuity should in general be favored in males, but not in females, to date there is no consensus on the general impact of multiple mating on female fitness. Notably, very little is known about the genetic and physiological features underlying the female response to sexual selection pressures. By combining an experimental evolution approach with genomic techniques, we investigated the effects of single and multiple matings on female fecundity and gene expression. We experimentally manipulated the mating system in replicate populations ofDrosophila melanogasterby removing sexual selection, with the aim of testing differences in short term post-mating effects of females evolved under different mating strategies. We show that monogamous females suffer decreased fecundity, a decrease that was partially recovered by experimentally reversing the selection pressure back to the ancestral promiscuous state. The post-mating gene expression profiles of monogamous females differ significantly from promiscuous females, involving 9% of the genes tested. These transcripts are active in several tissues, mainly ovaries, neural tissues and midgut, and are involved in metabolic processes, reproduction and signaling pathways. Our results demonstrate how the female post-mating response can evolve under different mating systems, and provide novel insights into the genes targeted by sexual selection in females, by identifying a list of candidate genes responsible for the decrease in female fecundity in the absence of promiscuity.
A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction
Authors: Watterson Steven , Guerriero Maria Luisa , Blanc Mathieu , Mazein Alexander , Loewe Laurence , Robertson Kevin A , Gibbs Holly , Shui Guanghou , Wenk Markus R , Hillston Jane , Ghazal Peter 
Published: November 2013

Graphical AbstractHighlightsWe model the cholesterol biosynthesis pathway and its regulationThe innate immune response leads to a suppression of flux through the pathwayStatin inhibitors show a different mode of suppression to the immune responseStatin inhibitor suppression is less robust and less specific than immune suppressionAsbtractThe cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalyzing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus infection or treated with IFNγ, we show that, under these assumptions, coordinate down regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation. Finally, the results from our models have implications for future pharmaceutical therapies intended to target cholesterol production with greater specificity and fewer off target effects, suggesting that this can be achieved by mimicking the coordinated down-regulation observed in immunological responses.
Universality and predictability in molecular quantitative genetics
Authors: Nourmohammad Armita , Held Torsten , Lässig Michael 
Published: November 2013

AbstractMolecular traits, such as gene expression levels or protein binding affinities, are increasingly accessible to quantitative measurement by modern high-throughput techniques. Such traits measure molecular functions and, from an evolutionary point of view, are important as targets of natural selection. We review recent developments in evolutionary theory and experiments that are expected to become building blocks of a quantitative genetics of molecular traits. We focus onuniversalevolutionary characteristics: these are largely independent of a trait’s genetic basis, which is often at least partially unknown. We show that universal measurements can be used to infer selection on a quantitative trait, which determines its evolutionary mode of conservation or adaptation. Furthermore, universality is closely linked to predictability of trait evolution across lineages. We argue that universal trait statistics extends over a range of cellular scales and opens new avenues of quantitative evolutionary systems biology.
Negative autoregulation matches production and demand in synthetic transcriptional networks
Authors: Franco Elisa , Giordano Giulia , Forsberg Per-Ola , Murray Richard M. 
Published: November 2013

AbstractWe propose a negative feedback architecture that regulates activity of artificial genes, or “genelets”, to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the “error” between the circuit output concentration and its actual demand. This two-device system is experimentally implemented usingin vitrotranscriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system, and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times.
Gappy TotalReCaller for RNASeq Base-Calling and Mapping
Authors: Mishra Bud 
Published: November 2013

AbstractUnderstanding complex mammalian biology depends crucially on our ability to define a precise map of all the transcripts encoded in a genome, and to measure their relative abundances. A promising assay depends on RNASeq approaches, which builds on next generation sequencing pipelines capable of interrogating cDNAs extracted from a cell. The underlying pipeline starts with base-calling, collect the sequence reads and interpret the raw-read in terms of transcripts that are grouped with respect to different splice-variant isoforms of a messenger RNA. We address a very basic problem involved in all of these pipeline, namely accurate Bayesian base-calling, which could combine the analog intensity data with suitable underlying priors on base-composition in the transcripts. In the context of sequencing genomic DNA, a powerful approach for base-calling has been developed in the TotalReCaller pipeline. For these purposes, it uses a suitable reference whole-genome sequence in a compressed self-indexed format to derive its priors. However, TotalReCaller faces many new challenges in the transcriptomic domain, especially since we still lack a fully annotated library of all possible transcripts, and hence a sufficiently good prior. There are many possible solutions, similar to the ones developed for TotalReCaller, in applications addressing de novo sequencing and assembly, where partial contigs or string-graphs could be used to boot-strap the Bayesian priors on base-composition. A similar approach would be applicable here too, partial assembly of transcripts can be used to characterize the splicing junctions or organize them in incompatibility graphs and then used as priors for TotalReCaller. The key algorithmic techniques for this purpose have been addressed in a forthcoming paper on Stringomics. Here, we address a related but fundamental problem, by assuming that we only have a reference genome, with certain intervals marked as candidate regions for ORF (Open Reading Frames), but not necessarily complete annotations regarding the 5’ or 3’ termini of a gene or its exon-intron structure. The algorithms we describe find the most accurate base-calls of a cDNA with the best possible segmentation, all mapped to the genome appropriately.
A structural classification of candidate oscillators and multistationary systems
Authors: Blanchini Franco , Franco Elisa , Giordano Giulia 
Published: November 2013

AbstractMolecular systems are uncertain: the variability of reaction parameters and the presence of unknown interactions can weaken the predictive capacity of solid mathematical models. However, strong conclusions on the admissible dynamic behaviors of a model can often be achieved without detailed knowledge of its specific parameters. In particular, starting with Thomas' conjectures, loop–based criteria have been largely used to characterize oscillatory and multistationary dynamic outcomes in systems with a sign definite Jacobian.We build on the rich literature focused on the identification of potential oscillatory and multistationary behaviors based on parameter–free criteria. We propose a classification for sign–definite non autocatalytic biological networks which summarize several existing results in the literature, adding new results when necessary. We define candidate oscillators and multistationary systems based on their admissible transitions to instability. We introduce four categories: strong/weak candidate oscillatory/multistationary systems, which correspond to networks in which all/some of the existing feedback loops are negative/positive. We provide necessary and sufficient conditions characterizing strong and weak candidate oscillators and multistationary systems based on the exclusive or simultaneous presence of positive and negative loops in their linearized dynamics. We also consider the case in which the overall system is the connection of several stable aggregate monotone components, providing conditions in terms of positive/negative loops in a suitable network with aggregate monotone systems as nodes.Most realistic examples of biological networks fall in the gray area of systems in which both positive and negative cycles are present: therefore, both oscillatory and bistable behavior are in principle possible. Native systems with a large number of components are often interconnections of monotone modules, where negative/positive loops among modules characterize oscillatory and bistable behaviors, in agreement with our results. Finally, we note that many canonical example circuits exhibiting oscillations or bistability fall in the categories of strong candidate oscillators/multistationary systems.
ROS accumulation in cotton ovule epidermal cells is necessary for fiber initiation
Authors: Pang Mingxiong , Sanford Nicholas , Wilkins Thea A 
Published: November 2013

AbstractCotton (Gossypium hirsutum) fiber, an extremely elongated and thickened single cell of the seed epidermis, is the world’s most important natural and economical textile fiber. UnlikeArabidopsisleaf trichomes, fiber initials are randomly developed and frequently form in adjacent seed epidermal cells and follow no apparent pattern. Numerous publications suggested cotton fiber development shares a similar mechanism withArabidopsisleaf trichome development. Here we show that H2O2 accumulation in cotton ovule epidermal cells by NBT staining ovules at different development stages between TM1 and N1n2, a lintless-fuzzless doubled mutant originated from TM1. In contrast,Arabidopsisand cotton leaf trichomes do not show H2O2 content. By adding DPI (H2O2 inhibitor) and SHAM (H2O2 activator) in vitro ovule cultures, we show fiber initiation directly involves with H2O2 accumulation. We propose that the directional accumulation of H2O2 in cotton ovule epidermal cell is the drive for fiber initiation, elongation.