bluuebunny/crossref_metadata_2025 huggingface dataset:
ARE VALUE OF INFORMATION METHODS READY FOR PRIME TIME? AN APPLICATION TO ALTERNATIVE TREATMENT STRATEGIES FOR NSTEMI PATIENTS
Authors: Kent Seamus , Briggs Andrew , Eckermann Simon , Berry Colin
Published: December 2013

Objectives:The use of value of information methods to inform trial design has been widely advocated but there have been few empirical applications of these methods and there is little evidence they are widely used in decision making. This study considers the usefulness of value of information models in the context of a real clinical decision problem relating to alternative diagnostic strategies for patients with a recent non-ST elevated myocardial infarction.

Methods:A pretrial economic model is constructed to consider the cost-effectiveness of two competing strategies: coronary angiography alone or in conjunction with fractional flow reserve measurement. A closed-form solution to the expected benefits of information is used with optimal sample size estimated for a range of models reflecting increasingly realistic assumptions and alternative decision contexts.

Results:Fractional flow reserve measurement is expected to be cost-effective with an incremental cost-effectiveness ratio of GBP 1,621, however, there is considerable uncertainty in this estimate and consequently a large expected value to reducing this uncertaintyviaa trial. The recommended sample size is strongly affected by the reality of the assumptions of the expected value of information (EVI) model and the decision context.

Conclusions:Value of information models can provide a simple and flexible approach to clinical trial design and are more consistent with the constraints and objectives of the healthcare system than traditional frequentist approaches. However, the variation in sample size estimates demonstrates that it is essential that appropriate model parameters and decision contexts are used in their application.
IS TREATMENT OF DEPRESSION COST-EFFECTIVE IN PEOPLE WITH DIABETES? A SYSTEMATIC REVIEW OF THE ECONOMIC EVIDENCE
Authors: Jeeva Farheen , Dickens Christopher , Coventry Peter , Bundy Christine , Davies Linda
Published: December 2013

Objectives: Depression is common in diabetes and linked to a wide range of adverse outcomes. UK policy indicates that depression should be treated using conventional psychological treatments in a stepped care framework. This review aimed to identify current economic evidence of psychological treatments for depression among people with diabetes.

Method: Electronic search strategies (conducted in MEDLINE, EMBASE, PsycINFO, CINAHL, NHS EED) combined clinical and economic search terms to identify full economic evaluations of the relevant interventions. Prespecified screening and inclusion criteria were used. Standardized data extraction and critical appraisal were conducted and the results summarized qualitatively.

Results: Excluding duplicates, 1,516 studies for co-morbid depression and diabetes were screened. Four economic evaluations were identified. The studies found that the interventions improved health status, reduced depression and were cost-effective compared with usual care. The studies were all U.S.-based and evaluated collaborative care programs that included psychological therapies. Critical appraisal indicated limitations with the study designs, analysis and results for all studies.

Conclusions: The review highlighted the paucity of evidence in this area. The four studies indicated the potential of interventions to reduce depression and be cost-effective compared with usual care. Two studies reported costs per QALY gained of USD 267 to USD 4,317, whilst two studies reported the intervention dominated usual care, with net savings of USD 440 to USD 612 and net gains in patient free days or QALYs.
A MODEL FOR HTA PRIORITY SETTING: EXPERIENCE IN LITHUANIA
Authors: Jankauskiene Danguole , Petronyte Gintare
Published: December 2013

Objectives: To promote the further development of HTA, this study aims to design a model for HTA priority setting, which would address national needs for a country with little experience in the field of HTA, and assess its feasibility for the health system.

Methods: Literature search and review, as well as qualitative research have been used in the design and testing of the model for HTA priority setting. To test the model and the methodology, a three-round Delphi study was conducted in 2011 in the form of an electronic questionnaire, which was distributed to the panel of eleven national experts. The panel was composed of experts representing various fields of the health care sector: policy-makers, health care service professionals and academics, with diverse professional roles.

Results: The designed model consists of four stages: (i) selection of experts for the panel, (ii) indication and selection of health policy topics, (iii) identification of health technologies, and (iv) priority setting. Three rounds of the Delphi study were performed to test the model and reach expert consensus on a list of health technologies for assessment, including pharmaceuticals, vaccines, medical devices, diagnostic methods, public health interventions, organizational systems, etc.

Conclusions: Based on the Delphi technique as a method for consensus building, the model for HTA priority setting was developed for Lithuania; however, it could also be used for other countries with little experience in the field of HTA.
A monoclonal antibody interferes with TIMP-2 binding and incapacitates the MMP-2-activating function of multifunctional, pro-tumorigenic MMP-14/MT1–MMP
Authors: Shiryaev S A , Remacle A G , Golubkov V S , Ingvarsen S , Porse A , Behrendt N , Cieplak P , Strongin A Y
Published: December 2013

Matrix metalloproteinases (MMPs) and, especially membrane type 1 (MT1)-MMP/MMP-14, are promising drug targets in malignancies. In contrast with multiple small-molecule and protein pan-inhibitors of MT1–MMP cleavage activity, the murine 9E8 monoclonal antibody targets the MMP-2-activating function of cellular MT1–MMP alone, rather than the general proteolytic activity and the pro-migratory function of MT1–MMP. Furthermore, the antibody does not interact in any detectable manner with other members of the membrane type (MT)-MMP family. The mechanism of this selectivity remained unknown. Using mutagenesis, binding and activity assays, and modeling in silico, we have demonstrated that the 9E8 antibody recognizes the MT-loop structure, an eight residue insertion that is specific for MT–MMPs and that is distant from the MT1–MMP active site. The binding of the 9E8 antibody to the MT-loop, however, prevents tissue inhibitor of metalloproteinases-2 (TIMP-2) association with MT1–MMP. As a result, the 9E8 antibody incapacitates the TIMP-2-dependent MMP-2-activating function alone rather than the general enzymatic activity of human MT1–MMP. The specific function of the 9E8 antibody we determined directly supports an essential, albeit paradoxical, role of the protein inhibitor (TIMP-2) in MMP-2 activation via a unique membrane-tethered mechanism. In this mechanism, the formation of a tri-molecular MT1–MMPTIMP-2MMP-2 complex is required for both the capture of the soluble MMP-2 proenzyme by cells and then its well-controlled conversion into the mature MMP-2 enzyme. In sum, understanding of the structural requirements for the 9E8 antibody specificity may pave the way for the focused design of the inhibitory antibodies against other individual MMPs.
Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment
Authors: Takatsu Kanae , Miyaoku Kaori , Roy Shimi Rani , Murono Yuki , Sago Tomohiro , Itagaki Hideyuki , Nakamura Masaru , Tokumoto Toshinobu
Published: December 2013

This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.
A simple, rapid and reliable UFLC-MS/MS method for the determination of dendrobine in rat plasma and its application to a pharmacokinetic study
Authors: Chen Xiaomin , Zhang Shuangshuang , Ma Jianshe , Hu Shuping , Shi Shaohua , Xiang Zheng
Published: December 2013

A sensitive, simple and rapid UFLC-MS/MS method was developed and validated for the determination of dendrobine in rat plasma.
Non-destructive descriptions of carotenoids in feathers using Raman spectroscopy
Authors: Thomas Daniel B. , McGraw Kevin J. , James Helen F. , Madden Odile
Published: December 2013

Raman spectroscopy coupled with multivariate statistics can identify the most abundant carotenoid in a feather without sample destruction.
A fluorescence assay that detects long branches in the starch polysaccharide amylopectin
Authors: Beeren Sophie R. , Hindsgaul Ole
Published: December 2013

Regions of consecutive α(1–4)-glucopyranose units in amylopectin are detected by turn-on fluorescence by extraction of amphiphilic probes from fluorescence-quenched spermidine-stabilised micelles.
Retracted Article: Determination of chemical affinity of graphene oxide nanosheets with radionuclides investigated by macroscopic, spectroscopic and modeling techniques
Authors: Ding Congcong , Cheng Wencai , Sun Yubing , Wang Xiangke
Published: December 2013

The chemical affinity of graphene oxide nanosheets with radionuclides (Eu(iii) and U(vi)) was determined by macroscopic, spectroscopic and modeling techniques.
Tactics for probing aryne reactivity: mechanistic studies of silicon–oxygen bond cleavage during the trapping of (HDDA-generated) benzynes by silyl ethers
Authors: Hoye Thomas R. , Baire Beeraiah , Wang Tao
Published: December 2013

Mechanistic features of the trapping reaction of an HDDA-generated aryne by pendant silyl ethers were probed using, e.g., an intramolecular clock reaction (cf. k2).
Improved technique for etching overcladding layer of perfluorinated polymer optical fibre by chloroform and water
Authors: Hayashi N. , Mizuno Y. , Nakamura K.
Published: December 2013

A simple technique is developed for etching the overcladding layer of a perfluorinated graded‐index polymer optical fibre by the combined use of chloroform and water. The boundary between the two liquids can mitigate the evaporation of chloroform, leading to a much lower loss than that of the conventional technique which does not employ water. The effectiveness of this method is verified by Brillouin signal measurement and infrared thermometry.
Melting dynamics of large ice balls in a turbulent swirling flow
Authors: Machicoane N. , Bonaventure J. , Volk R.
Published: December 2013

We study the melting dynamics of large ice balls in a turbulent von Kármán flow at very high Reynolds number. Using an optical shadowgraphy setup, we record the time evolution of particle sizes. We study the heat transfer as a function of the particle scale Reynolds number \documentclass[12pt]{minimal}\begin{document}$\mbox{\textit {Re}}_{D}$\end{document}ReD for three cases: fixed ice balls melting in a region of strong turbulence with zero mean flow, fixed ice balls melting under the action of a strong mean flow with lower fluctuations, and ice balls freely advected in the whole apparatus. For the fixed particles cases, heat transfer is observed to be much stronger than in laminar flows, the Nusselt number behaving as a power law of the Reynolds number: \documentclass[12pt]{minimal}\begin{document}$\mbox{\textit {Nu}} \propto \mbox{\textit {Re}}_{D}^{0.8}$\end{document}Nu∝ReD0.8. For freely advected ice balls, the turbulent transfer is further enhanced and the Nusselt number is proportional to the Reynolds number \documentclass[12pt]{minimal}\begin{document}$\mbox{\textit {Nu}} \propto \mbox{\textit {Re}}_{D}$\end{document}Nu∝ReD. Furthermore, the surface heat flux is found to be independent of the particles size, leading to an ultimate regime of heat transfer reached when the thermal boundary layer is fully turbulent.
90-degree polarization switching in BaTiO3 crystals without domain wall motion
Authors: Li Y. W. , Scott J. F. , Fang D. N. , Li F. X.
Published: December 2013

We report 90° polarization switching in a BaTiO3 crystal without domain wall (DW) motion by prefabricating samples with interlocking domains via compression. During electric re-poling of the depoled and aged crystals, 90° domain nucleation still exists, but 90° DW motion is inhibited by the strong constraints from surrounding domains, leading to DW-free 90° polarization switching. The measured coercive field of 500 V/mm for the DW-free 90° switching is close to the intrinsic values and much larger than that of 80 V/mm via 90° DW motion. Compared to the rather difficult domain-free 180° polarization switching in ultrathin films, 90° DW-free switching is easier.
Slow dynamics of ablated zone observed around the density fluctuation ridge of fluid medium
Authors: Koizumi Masato , Kulinich Sergei A. , Shimizu Yoshiki , Ito Tsuyohito
Published: December 2013

In-situ shadowgraph images were recorded to follow and study processes during laser ablation of Sn targets in pressurized carbon dioxide medium. The dynamics of the low-density region with a bubble-like structure forming by ablated Sn in CO2 at different pressures was studied. The lifetime of the region is shown to be pressure-dependent, being the longest near the density fluctuation ridge of the medium, i.e., at 8.8 MPa at 40 °C. The present work is to report on the slower dynamics of ablated zone near the medium density fluctuation maximum, which can be used in nanoparticle synthesis and processing.
Pulsed laser deposited Si on multilayer graphene as anode material for lithium ion batteries
Authors: Radhakrishnan Gouri , Adams Paul M. , Foran Brendan , Quinzio Michael V. , Brodie Miles J.
Published: December 2013

Pulsed laser deposition and chemical vapor deposition were used to deposit very thin silicon on multilayer graphene (MLG) on a nickel foam substrate for application as an anode material for lithium ion batteries. The as-grown material was directly fabricated into an anode without a binder, and tested in a half-cell configuration. Even under stressful voltage limits that accelerate degradation, the Si-MLG films displayed higher stability than Si-only electrodes. Post-cycling images of the anodes reveal the differences between the two material systems and emphasize the role of the graphene layers in improving adhesion and electrochemical stability of the Si.
Increasing the reactive surface area of a Li three dimensional negative electrode by morphology control
Authors: Oliveira J. C. R. E. , Braga M. H.
Published: December 2013

The theoretical grounds establishing the ideal composition, temperature, and time to attain the highest interconnected interface area within a liquid miscibility gap were developed. A three dimension (3D) negative electrode (having low polarization, low density, and interconnected channels) based on the Li-LiH system is proposed for Li conversion batteries. Using the Gibbs free energy of the Li-LiH liquid phase and phase field simulations, we determined the corresponding 3D morphology finding the ideal conditions to increase the electrode's reactive surface area. The optimal morphology was obtained for the composition xH = 0.413 (in the Li-H system).
Negative thermal expansion and compressibility of Sc1–xYxF3 (x≤0.25)
Authors: Morelock Cody R. , Greve Benjamin K. , Gallington Leighanne C. , Chapman Karena W. , Wilkinson Angus P.
Published: December 2013

Scandium fluoride displays isotropic negative thermal expansion (NTE) from at least 10 to 1100 K and retains a cubic ReO3-type structure over this range; the NTE is most pronounced at low temperatures. Control of thermal expansion was explored by forming Sc1–xYxF3 (x≤0.25), which were characterized with synchrotron powder diffraction at ambient pressure from 100 to 800 K. The behavior of the solid solutions under pressure (≤0.276 GPa) was also examined while heating from 298 to 523 K. Insertion of the relatively large Y3+ ion into ScF3 results in a cubic-to-rhombohedral phase transition upon cooling from ambient temperature to 100 K, even at low substitution levels (5%). The coefficient of thermal expansion (CTE) of the solid solutions in the rhombohedral phase is strongly dependent on both composition and temperature; however, above 400 K, where all samples are cubic, the CTE appears to be largely independent of composition. The isothermal bulk modulus and CTE of ScF3, but not those of the solid solutions, are independent of temperature and pressure, respectively. Yttrium substitution lowers the bulk modulus, even at temperatures where the samples are cubic. Finally, the solid solutions stiffen upon heating.
A facile microfluidic strategy for measuring interfacial tension
Authors: Zhou Hongbo , Yao Yuan , Chen Qiang , Li Gang , Yao Shuhuai
Published: December 2013

We report a facile method for measuring interfacial tension (IFT, γ) of immiscible fluids using a microfluidic device. The IFT is determined by monitoring the pressure drop across a microchannel, where a pair of modified Laplace sensors (formed by tapered channels) are connected, and the curvatures of the interfaces in the tapered channels. The method was tested with the model oil/water systems, and the results agreed well with a commercial tensiometry. We expect this method to be easily implemented in common microfluidic laboratories and supply a low-cost and fast way for interfacial tension measurement.
Acoustically assisted spin-transfer-torque switching of nanomagnets: An energy-efficient hybrid writing scheme for non-volatile memory
Authors: Biswas Ayan K. , Bandyopadhyay Supriyo , Atulasimha Jayasimha
Published: December 2013

We show that the energy dissipated to write bits in spin-transfer-torque random access memory can be reduced by an order of magnitude if a surface acoustic wave (SAW) is launched underneath the magneto-tunneling junctions (MTJs) storing the bits. The SAW-generated strain rotates the magnetization of every MTJs' soft magnet from the easy towards the hard axis, whereupon passage of a small spin-polarized current through a target MTJ selectively switches it to the desired state with > 99.99% probability at room temperature, thereby writing the bit. The other MTJs return to their original states at the completion of the SAW cycle.
Metabolic and endocrine profiles of primiparous beef cows grazing native grassland. 1. Relationships between body condition score at calving and metabolic profiles during the transition period
Authors: Soca P. , Carriquiry M. , Claramun M. , Gestido V. , Meikle A.
Published: December 2013

The body condition score (BCS) at calving has been postulated as the main factor in the interaction of nutrition and reproduction in beef-cow ecosystems. The objective of the present study was to analyse the effect of BCS at calving on endocrine and metabolic profiles during the transition period in primiparous Hereford cows (n = 56) grazing native grassland. Cow BCS was registered and plasma insulin, insulin-like growth factor-I (IGF-I) and metabolites (concentrations of urea, albumin, cholesterol, total protein, non-esterified fatty acids (NEFA)) were determined in plasma from –30 to +45 days postpartum (DPP). The effect of BCS at calving (low ≤3.5 and moderate ≥4; 1–8 visual scale) on BCS evolution and hormone and metabolite concentrations were analysed using a time repeated-measures analysis. Cow BCS, NEFA, urea and IGF-I profiles were affected (P < 0.05) by the BCS at calving and DPP interaction, while insulin tended (P = 0.06) to be affected only by BCS at calving. The low-BCS cows presented a smaller loss of BCS during the prepartum than did moderate-BCS cows, and a delayed BCS recovery during the postpartum. The increase in plasma NEFA was greater (P < 0.05) and started earlier during the prepartum period in the low-BCS cows. Protein concentrations increased during prepartum to +30 DPP, while albumin and urea concentrations were maintained until calving and decreased during the postpartum. Urea concentrations were greater (P < 0.05) during prepartum in low-BCS cows. Concentrations of IGF-I and insulin were greater (P < 0.05) in moderate- than low-BCS cows during prepartum, but did not differ between the groups after calving. No effects were observed in calf weight or milk production at +45 DPP. The association between BCS during prepartum and at calving with the endocrine and metabolic profiles (positive: insulin, IGF-I; negative: NEFA and urea) reflected a better nutritional status and plasticity to negative energy balance on moderate cows. This different endocrine milieu did not affect calf weight and/or milk production. In conclusion, the BCS at calving affected the metabolic and endocrine profile during the transition period of primiparous beef cows grazing native grassland.
Voiceless stop aspiration in Yucatan Spanish
Authors: Michnowicz Jim , Carpenter Lindsey
Published: November 2013

Previous research has indicated that in Yucatan Spanish, /ptk/ are aspirated at greater levels than in other varieties, a feature attributed to contact with Yucatec Maya, a language that has both aspirated and ejective voiceless stops. The current study presents the first quantitative, acoustic, variationist investigation of the linguistic and social factors that constrain aspiration (as measured by VOT) in Yucatan Spanish. Analyses, conducted using mixed-effects statistical models, indicate that VOT values are longer in stressed syllables and phrase initially, and also before non-low vowels. Regarding social factors, men consistently favor longer VOT, along with older speakers. While no significant result was obtained based on language background (Maya-Spanish bilinguals vs. Spanish monolinguals), there is evidence of the influence of language and dialect contact on the observed patterns. Further results and conclusions are discussed.
The role of intuition in the translation process
Authors: Hubscher-Davidson Séverine
Published: November 2013

This paper explores the psychological construct of intuition and its influence in decision-making behavior. Intuition was defined by Jung (1971) as a primary mode of perception operating subconsciously. As opposed to sensing personality types who prefer concrete details, intuitive personality types prefer to acquire information by imagining possibilities (Myers and Myers 1995). In this paper, an analysis of verbalization data from a translation process study is discussed in order to demonstrate the influence of intuition on decision-making during the translation process and to explore the implications of this influence. Recent studies have found that intuition plays a role in learning and decision-making tasks involving affect (Laborde et al. 2010: 786). Intuition is therefore here viewed as a potentially vital component of translator behavior which could predict individuals’ translating effectiveness.
The diplomacy of partition revisited: African−Asian relations and the economic diplomacy of security
Authors: Mwagiru Makumi
Published: December 2013

This paper examines the promising relations between Africa and the emerging Asian powers. The most significant event in African international relations was the Berlin Conference of 1884–1885, which amongst other things partitioned Africa and imposed the Westphalian state system on Africa. This imposition is still being felt today through the military engagements in African politics, the latest being Mali. The emerging Asian powers have enjoyed a relationship with Africa based on mutual sympathies as was characterized by the Non-Aligned Movement. While these historical relations are still being used as a rationale for emerging Africa−Asia relations, lately these sympathies have been transfigured in the Asian power searches for economic and human security survival. The paper argues that the foreign and economic policies of the emerging Asian powers in Africa in effect are turning the clock back and economically re-partitioning Africa. The paper argues that this trend of relations, while useful for Asia, is detrimental to Africa, and hence needs to be revisited. The paper concludes that at the end of the day, relations between Africa and the emerging Asian powers must be based on the need for both to maintain their identity and interests in mutually fulfilling ways. The failure to do so will entrench the emergent (economic) partition of Africa, with all its attendant consequences for its future and for Africa−Asia relations.
ABACUS: an entropy-based cumulative bivariate statistic robust to rare variants and different direction of genotype effect
Authors: Di Camillo Barbara , Sambo Francesco , Toffolo Gianna , Cobelli Claudio
Published: November 2013

Motivation: In the past years, both sequencing and microarray have been widely used to search for relations between genetic variations and predisposition to complex pathologies such as diabetes or neurological disorders. These studies, however, have been able to explain only a small fraction of disease heritability, possibly because complex pathologies cannot be referred to few dysfunctional genes, but are rather heterogeneous and multicausal, as a result of a combination of rare and common variants possibly impairing multiple regulatory pathways. Rare variants, though, are difficult to detect, especially when the effects of causal variants are in different directions, i.e. with protective and detrimental effects.

Results: Here, we propose ABACUS, an Algorithm based on a BivAriate CUmulative Statistic to identify single nucleotide polymorphisms (SNPs) significantly associated with a disease within predefined sets of SNPs such as pathways or genomic regions. ABACUS is robust to the concurrent presence of SNPs with protective and detrimental effects and of common and rare variants; moreover, it is powerful even when few SNPs in the SNP-set are associated with the phenotype. We assessed ABACUS performance on simulated and real data and compared it with three state-of-the-art methods. When ABACUS was applied to type 1 and 2 diabetes data, besides observing a wide overlap with already known associations, we found a number of biologically sound pathways, which might shed light on diabetes mechanism and etiology.

Availability and implementation: ABACUS is available at http://www.dei.unipd.it/∼dicamill/pagine/Software.html.

Contact:  barbara.dicamillo@dei.unipd.it

Supplementary information:  Supplementary data are available at Bioinformatics online.
Employee Shareholder ‘Status’: Dismantling the Contract of Employment
Authors: Prassl Jeremias
Published: November 2013

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

The 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

The 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.
Comparative analysis of microbiome between accurately identified 16S rDNA and quantified bacteria in simulated samples
Authors: Wang Haiyin , Du Pengcheng , Li Juan , Zhang Yuanyuan , Zhang Wen , Han Na , Woo Patrick C. Y. , Chen Chen
Published: November 2013

Although 16S rRNA gene (rDNA) sequencing is the gold standard for categorizing bacteria or characterizing microbial communities its clinical utility is limited by bias in metagenomic studies, in either the experiments or the data analyses. To evaluate the efficiency of current metagenomic methods, we sequenced seven simulated samples of ten bacterial species mixed at different concentrations. The V3 region of 16S rDNA was targeted and used to determine the distribution of bacterial species. The number of target sequences in individual simulated samples was in the range 1–1000 to provide a better reflection of natural microbial communities. However, for a given bacterial species present in the same proportion but at different concentrations, the observed percentage of 16S rDNAs was similar, except at very low concentrations that cannot be detected by real-time PCR. These results confirmed that the comparative microbiome in a sample characterized by 16S rDNA sequencing is sufficient to detect not only potential infectious pathogens, but also the relative proportion of 16S rDNA in the sample.
A Population Genetic Signature of Polygenic Local Adaptation
Authors: Berg Jeremy J , Coop Graham
Published: November 2013

Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We use a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model, we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of QST/FST comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.
A Scalable Formulation for Engineering Combination Therapies for Evolutionary Dynamics of Disease
Authors: Jonsson Vanessa , Rantzer Anders , Murray Richard M.
Published: November 2013

It 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

Mimulus 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.
A filter-flow perspective of hematogenous metastasis offers a non-genetic paradigm for personalized cancer therapy
Authors: Scott Jacob G , Fletcher Alexander G , Maini Philip K , Anderson Alexander R A , Gerlee Philip
Published: November 2013

Background: Research into mechanisms of hematogenous metastasis has largely become genetic in focus, attempting to understand the molecular basis of `seed-soil' relationships. However, preceding this biological mechanism is the physical process of dissemination of circulating tumour cells (CTCs) in the circulatory network. We utilize a novel, network perspective of hematogenous metastasis and a large dataset on metastatic patterns to shed new light on this process. %a fundamental gap in our knowledge of this process. Experimental Design: The metastatic efficiency index (MEI), previously suggested by Weiss, quantifies the process of hematogenous metastasis by taking the ratio of metastatic incidence for a given primary-target organ pair and the relative blood flow between the two sites. In this paper we extend the methodology by taking into account the reduction in CTC number that occurs in capillary beds and a novel network model of CTC flow. Results: By applying this model to a dataset of metastatic incidence, we show that the MEI depends strongly on the assumptions of micrometastatic lesions in the lung and liver. Utilizing this framework we can represent different configurations of metastatic disease and offer a rational method for identifying patients with oligometastatic disease for inclusion in future trials. Conclusions:We show that our understanding of the dynamics of CTC flow is significantly lacking, and that this specifically precludes our ability to predict metastatic patterns in individual patients. Our formalism suggests an opportunity to go a step further in metastatic disease characterization by including the distribution of CTCs at staging, offering a rational method of trial design for oligometastatic disease.
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

Since 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 Summary

In 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

Hybrid 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

Despite 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 genome wide dosage suppressor network reveals genetic robustness and a novel mechanism for Huntingtons disease
Authors: Patra Biranchi , Kon Yoshiko , Yadav Gitanjali , Sevold Anthony , Frumkin Jesse P , Vallabhajosyula Ravishankar R , Hintze Arend , Østman Bjørn , Schossau Jory , Bhan Ashish , Marzolf Bruz , Tamashiro Jenna K , Kaur Amardeep , Baliga Nitin S , Grayhack Elizabeth J , Adami Christoph , Galas David J , Raval Alpan , Phizicky Eric M , Ray Animesh
Published: November 2013

Mutational robustness is the extent to which an organism has evolved to withstand the effects of deleterious mutations. We explored the extent of mutational robustness in the budding yeast by genome wide dosage suppressor analysis of 53 conditional lethal mutations in cell division cycle and RNA synthesis related genes, revealing 660 suppressor interactions of which 642 are novel. This collection has several distinctive features, including high co-occurrence of mutant-suppressor pairs within protein modules, highly correlated functions between the pairs, and higher diversity of functions among the co-suppressors than previously observed. Dosage suppression of essential genes encoding RNA polymerase subunits and chromosome cohesion complex suggest a surprising degree of functional plasticity of macromolecular complexes and the existence of degenerate pathways for circumventing potentially lethal mutations. The utility of dosage-suppressor networks is illustrated by the discovery of a novel connection between chromosome cohesion-condensation pathways involving homologous recombination, and Huntingtons disease.