bluuebunny/crossref_metadata_2025_split huggingface dataset:
Justifying reimbursement for Alzheimer's diagnostics and treatments: Seeking alignment on evidence
Authors: Foster Norman L. , Hackett Judith S.M. , White Greg , Chenevert Sherri , Svarvar Patrick , Bain Lisa , Carrillo Maria C. 
Published: June 2014

AbstractThe increasing cost of health care combined with expensive new drugs and diagnostics is leading to more frequent gaps between regulatory and subsequent reimbursement approval decisions. As a result, persons with Alzheimer's disease may have difficulty accessing the benefit of medical advances. In contrast to the long history and established structure for drug approval, payer decision making is dispersed, not standardized, and perspectives on necessary evidence and the evaluation of this evidence differ and are often poorly defined. Particularly challenging is how to demonstrate the value of drugs and diagnostics for patients who do not yet have significant functional decline. Although discussions to develop consensus continue, clinical trials should begin to incorporate health system and patient‐oriented outcomes. In some situations, additional studies designed to demonstrate value and comparative effectiveness will be needed. Such studies should examine outcomes of representative populations in community settings. To assure scientific advances in diagnosis and treatment benefit in patients, developing evidence to support reimbursement will become as important as obtaining regulatory approval.
A continuous stable isotope record from the penultimate glacial maximum to the Last Interglacial (159–121 ka) from Tana Che Urla Cave (Apuan Alps, central Italy)
Authors: Regattieri Eleonora , Zanchetta Giovanni , Drysdale Russell N. , Isola Ilaria , Hellstrom John C. , Roncioni Adriano 
Published: June 2014

AbstractRelatively few radiometrically dated records are available for the central Mediterranean spanning the marine oxygen isotope stage 6–5 (MIS 6–5) transition and the first part of the Last Interglacial. Two flowstone cores from Tana che Urla Cave (TCU, central Italy), constrained by 19 U/Th ages, preserve an interval of continuous speleothem deposition between ca. 159 and 121 ka. A multiproxy record (δ18O, δ13C, growth rate and petrographic changes) obtained from this flowstone preserves significant regional-scale hydrological changes through the glacial/interglacial transition and multi-centennial variability (interpreted as alternations between wetter and drier periods) within both glacial and interglacial stages. The glacial stage shows a wetter period between ca. 154 and 152 ka, while the early to middle Last Interglacial period shows several drying events at ca. 129, 126 and 122 ka, which can be placed in the wider context of climatic instability emerging from North Atlantic marine and NW European terrestrial records. The TCU record also provides important insights into the evolution of local environmental conditions (i.e. soil development) in response to regional and global-scale climate events.
A low energy ion source for electron capture spectroscopy
Authors: Tusche C. , Kirschner J. 
Published: June 2014

We report on the design of an ion source for the production of single and double charged Helium ions with kinetic energies in the range from 300 eV down to 5 eV. The construction is based on a commercial sputter ion gun equipped with a Wien-filter for mass/charge separation. Retardation of the ions from the ionizer potential (2 keV) takes place completely within the lens system of the sputter gun, without modification of original parts. For 15 eV He+ ions, the design allows for beam currents up to 30 nA, limited by the space charge repulsion in the beam. For He2 + operation, we obtain a beam current of 320 pA at 30 eV, and 46 pA at 5 eV beam energy, respectively. In addition, operating parameters can be optimized for a significant contribution of metastable He*+ (2s) ions.
SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool
Authors: Karthigeyan Dhanasekaran , Siddhanta Soumik , Kishore Annavarapu Hari , Perumal Sathya S. R. R. , Ågren Hans , Sudevan Surabhi , Bhat Akshay V. , Balasubramanyam Karanam , Subbegowda Rangappa Kanchugarakoppal , Kundu Tapas K. , Narayana Chandrabhas 
Published: June 2014

Significance
Surface-enhanced Raman spectroscopy along with molecular dynamics simulation is shown to be a useful tool for understanding drug binding to therapeutic proteins. Herein, the selective binding of felodipine to human Aurora A kinase is employed as a test system to demonstrate this powerful technique. Preliminary knowledge of the protein structure makes this approach robust for drug discovery.
Ten best resources on conditional cash transfers
Authors: Marshall Caroline , Hill Peter S 
Published: June 2014

Abstract
The world’s economy is in a fragile state. Although cautiously recovering from a global recession, unemployment rates and poverty levels remain high. At the same time, food and fuel crises have resulted in skyrocketing commodity costs, straining household budgets even further than before. In the wake of these financial pressure points, there has been increased focus on social safety net programmes. More recently, Brazil’s ‘Bolsa Familia’ conditional cash transfer (CCT) programme has celebrated its tenth-year anniversary, renewing focus on this particular aspect of social transfer programmes. This essay examines one particular aspect of these social safety net programmes: CCTs. CCT programmes are useful social programmes that have had demonstrable effects on many different populations. However, they are not a ‘magic bullet’ against poverty, and their image has suffered from unreasonable expectations of their impacts. This 10 best list is an ideal starting point from which a potential user can begin to understand CCTs. There remain significant gaps in the literature behind CCTs, with a particular need for much more research on emerging areas such as impacts on gender, long-term school and health outcomes, methods for increasing efficiency and adapting conditionalities within cultural contexts, among others. However, this list can function as a starting point from which the reader can gain an understanding and appreciation for what we believe to be one of the most innovative social programmes for addressing poverty worldwide.
Reconstructing the Chelyabinsk event: pre-impact orbital evolution
Authors: de la Fuente Marcos C. , de la Fuente Marcos R. 
Published: June 2014

Abstract
The Chelyabinsk superbolide was the largest known natural object to enter the Earth's atmosphere since the Tunguska event in 1908 and it has become a template to understand, manage and mitigate future impacts. Although the event has been documented in great detail, the actual pre-impact orbit of the parent body is still controversial. Here, we revisit this topic using an improved Monte Carlo approach that includes the coordinates of the impact point to compute the most probable solution for the pre-impact orbit (a = 1.62 au, e = 0.53, i = 3 $_{.}^{\circ}$97, Ω = 326 $_{.}^{\circ}$45 and ω = 109 $_{.}^{\circ}$71). We also check all the published solutions using a simple yet robust statistical test to show that many of them have problems to cause an impact at the right time. We use the improved orbit and N-body simulations to revisit the dynamical status of a putative Chelyabinsk asteroid family and confirm that it could be linked to resonant asteroids 2007 BD7 and 2011 EO40. In addition, and as the classification of Chelyabinsk meteorites is well established, a search for meteorite falls of the same chondrite group and petrologic type gives some evidence for the existence of an associated LL5 chondrite cluster.
Near-field limits on the role of faint galaxies in cosmic reionization
Authors: Boylan-Kolchin Michael , Bullock James S. , Garrison-Kimmel Shea 
Published: June 2014

Abstract
Reionizing the Universe with galaxies appears to require significant star formation in low-mass haloes at early times, while local dwarf galaxy counts tell us that star formation has been minimal in small haloes around us today. Using simple models and the ELVIS simulation suite, we show that reionization scenarios requiring appreciable star formation in haloes with Mvir ≈ 108 M⊙ at z = 8 are in serious tension with galaxy counts in the Local Group. This tension originates from the seemingly inescapable conclusion that 30–60 haloes with Mvir &gt; 108 M⊙ at z = 8 will survive to be distinct bound satellites of the Milky Way at z = 0. Reionization models requiring star formation in such haloes will produce dozens of bound galaxies in the Milky Way's virial volume today (and 100–200 throughout the Local Group), each with ≳105 M⊙ of old stars (≳13 Gyr). This exceeds the stellar mass function of classical Milky Way satellites today, even without allowing for the (significant) post-reionization star formation observed in these galaxies. One possible implication of these findings is that star formation became sharply inefficient in haloes smaller than ∼109 M⊙ at early times, implying that the high-z luminosity function must break at magnitudes brighter than is often assumed (at MUV ≃ −14). Our results suggest that the James Webb Space Telescope (and possibly even the Hubble Space Telescope with the Frontier Fields) may realistically detect the faintest galaxies that drive reionization. It remains to be seen how these results can be reconciled with the most sophisticated simulations of early galaxy formation at present, which predict substantial star formation in Mvir ∼ 108 M⊙ haloes during the epoch of reionization.
Detecting pairwise correlations in spike trains: an objective comparison of methods and application to the study of retinal waves
Authors: Cutts Catherine S , Eglen Stephen J 
Published: June 2014

AbstractCorrelations in neuronal spike times are thought to be key to processing in many neural systems. Many measures have been proposed to summarise these correlations and of these the correlation index is widely used and is the standard in studies of spontaneous retinal activity. We show that this measure has two undesirable properties: it is unbounded above and confounded by firing rate. We list properties needed for a measure to fairly quantify and compare correlations and we propose a novel measure of correlation — the Spike Time Tiling Coefficient. This coefficient, the correlation index and 33 other measures of correlation of spike times are blindly tested for the required properties on synthetic and experimental data. On the basis of this, we propose a measure (the Spike Time Tiling Coefficient) to replace the correlation index. To demonstrate the benefits of this measure, we re-analyse data from seven key studies which previously used the correlation index to investigate the nature of spontaneous activity. We re-analyse data fromβ2(KO) andβ2(TG) mutants, mutants lacking connexin isoforms and also the age-dependent changes in wild type andβ2(KO) correlations. Re-analysis of the data using the proposed measure can significantly change the conclusions. It leads to better quantification of correlations and therefore better inference from the data. We hope that the proposed measure will have wide applications, and will help clarify the role of activity in retinotopic map formation.
Genetic dissection of courtship song variation using the Drosophila Synthetic Population Resource
Authors: Pischedda Alison , Cochrane Veronica A. , Cochrane Wesley G. , Turner Thomas 
Published: June 2014

AbstractConnecting genetic variation to trait variation is a grand challenge in biology. Natural populations contain a vast reservoir of fascinating and potentially useful variation, but it is unclear if the causal alleles will generally have large enough effects for us to detect. Without knowing the effect sizes or allele frequency of typical variants, it is also unclear what methods will be most successful. Here, we use a multi-parent advanced intercross population (the Drosophila Synthetic Population Resource) to map natural variation inDrosophilacourtship song traits. Most additive genetic variation in this population can be explained by a modest number of highly resolved QTL. Mapped QTL are universally multiallelic, suggesting that individual genes are “hotspots” of natural variation due to a small target size for major mutations and/or filtering of variation by positive or negative selection. Using quantitative complementation in randomized genetic backgrounds, we provide evidence that one causal allele is harbored in the geneFhos, making this one of the few genes associated with behavioral variation in any taxon.
Formalization of Genome Interval Relations
Authors: Mungall Chris J. 
Published: June 2014

AbstractIn order to take full advantage of next generation genomics data, I need informatics methods to be based on agreed uponformally specifiedstandards that can be implemented easily in a uniform fashion without ambiguity. These standards should be encoded as logical formulae, so that provably correct and efficient decision procedures can be used for query answering and validation.In this paper I present the core of such a standard for sequence data: a collection of definitions of relations that hold between genomic intervals, and an alegbra for performing operations upon these intervals. I show how these relations can be used to extend formalize concepts in the Sequence Ontology (SO).
Regulatory vs. helper CD4+T-cell ratios and the progression of HIV/AIDS disease
Authors: Ndifon Wilfred , Dushoff Jonathan , Coombs Daniel 
Published: June 2014

AbstractThe causes of individual variability in the length of time between human immunodeficiency virus (HIV) infection and the development of AIDS are incompletely understood. Here, we present a novel hypothesis: that the relative magnitude of responses to HIV mediated by CD4+T regulatory (Treg) cells vs. CD4+T effector (Teff) cells is a critical determinant of variability in AIDS progression rates. We use a simple mathematical model to show that this hypothesis can plausibly explain three qualitatively different outcomes of HIV infection – fast or slow progression to AIDS, and long-term non-progression to AIDS – based on individual variation in underlying T-cell response. This hypothesis also provides a unifying explanation for various other empirical observations, suggesting in particular that both aging and certain dual infections increase the rate of AIDS progression because they increase the strength of the Treg cell response. We discuss potential therapeutic implications of our results.
Long-term balancing selection inLAD1maintains a missense trans-species polymorphism in humans, chimpanzees and bonobos
Authors: Teixeira João C. , de Filippo Cesare , Weihmann Antje , Meneu Juan R. , Racimo Fernando , Dannemann Michael , Nickel Birgit , Fischer Anne , Halbwax Michel , Andre Claudine , Atencia Rebeca , Meyer Matthias , Parra Genís , Pääbo Svante , Andrés Aida M. 
Published: June 2014

AbstractBalancing selection maintains advantageous genetic and phenotypic diversity in populations. When selection acts for long evolutionary periods selected polymorphisms may survive species splits and segregate in present-day populations of different species. Here, we investigate the role of long-term balancing selection in the evolution of protein-coding sequences in theHomo-Panclade. We sequenced the exome of 20 humans, 20 chimpanzees and 20 bonobos and detected eight coding trans-species polymorphisms (trSNPs) that are shared among the three species and have segregated for approximately 14 million years of independent evolution. While the majority of these trSNPs were found in three genes of the MHC cluster, we also uncovered one coding trSNP (rs12088790) in the geneLAD1. All these trSNPs show clustering of sequences by allele rather than by species and also exhibit other signatures of long-term balancing selection, such as segregating at intermediate frequency and lying in a locus with high genetic diversity. Here we focus on the trSNP inLAD1, a gene that encodes for Ladinin-1, a collagenous anchoring filament protein of basement membrane that is responsible for maintaining cohesion at the dermal-epidermal junction; the gene is also an autoantigen responsible for linear IgA disease. This trSNP results in a missense change (Leucine257Proline) and, besides altering the protein sequence, is associated with changes in gene expression ofLAD1.
Reconstructing subclonal composition and evolution from whole genome sequencing of tumors
Authors: Deshwar Amit G. , Vembu Shankar , Yung Christina K. , Jang Gun Ho , Stein Lincoln , Morris Quaid 
Published: June 2014

AbstractTumors often contain multiple, genetically distinct subpopulations of cancerous cells. These so-called subclonal populations are defined by distinct somatic mutations that include point mutations such as single nucleotide variants and small indels - collectively called simple somatic mutations (SSMs) - as well as larger structural changes that result in copy number variations (CNVs). In some cases, the genotype and prevalence of these subpopulations can be reconstructed based on high-throughput, short-read sequencing of DNA in one or more tumor samples. To date, no automated SSM-based subclonal reconstructions have been attempted on WGS data; and CNV-based reconstructions are limited to tumors with two or fewer cancerous subclonal populations and with a small number of CNVs.We describe a new automated method, PhyloWGS, that can be applied to WGS data from one or more tumor samples to perform subclonal reconstruction based on both CNVs and SSMs. PhyloWGS successfully recovers the composition of mixtures of a highly rearranged TGCA cell line when a CNV-based method fails. On WGS data with average read depth of 40 from five time-series chronic lymphocytic leukemia samples, PhyloWGS recovers the same tumor phylogeny previously reconstructed using deep targeted resequencing. To further explore the limits of WGS-based subclonal reconstruction, we ran PhyloWGS on simulated data: PhyloWGS can reliably reconstruct as many as three cancerous subpopulations based on 30-50x coverage WGS data from a single tumor sample with 10’s to 1000’s of SSMs per subpopulation. At least five cancerous subpopulations can be reconstructed if provided with read depths of 200 or more.PhyloWGS is the first automated method that can be applied to WGS tumor data that accurately reconstructs the frequency, genotype and phylogeny of the subclonal populations based on both SSMs and CNVs. It also provides a principled, automated approach to combining overlapping SSM and CNV data. By demonstrating the utility of PhyloWGS on medium depth WGS data, including from examples with highly rearranged chromosomes, we have greatly expanded the range of tumors for which subclonal reconstruction is possible.
Subdigital adhesive pad morphology varies in relation to structural habitat use in the Namib Day Gecko
Authors: Collins Clint E. , Russell Anthony P. , Higham Timothy E. 
Published: June 2014

Summary

Morphological features that lead to increased locomotor performance, such as faster sprint speed, are thought to evolve in concert with habitat use. The latter depends on available habitat structure and how the animal moves within that habitat. Thus, this behavioural variation will impact how natural selection acts on locomotion and morphology.

Quantifying the interplay between escape behaviour and locomotor morphology across habitats that vary in structural composition could reveal how selection acts on locomotion at local levels. Substrate features, such as incline and topographical variation, are likely key drivers of morphological and functional disparity among terrestrial animals. We investigated the impact of habitat variation and escape behaviour on morphology, including the adhesive system, of Rhoptropus afer, a diurnal and cursorial gecko from Namibia. Substrate incline and topographical variation are likely important for this pad‐bearing gecko due to the trade‐off between adhering and sprinting (i.e. using adhesion results in decreased sprint speed).

We corroborate the hypothesis that the adhesive system exhibits the greatest degree of reduction in populations that utilize the flattest terrain during an escape. Our findings suggest that the adhesive apparatus is detrimental to rapid locomotion on relatively horizontal surfaces and may thus be counterproductive to the evasion of predators in such situations. A broad scale analysis of geckos would determine whether diversity of adhesive morphology is driven primarily by habitat use.

Phenotypic plasticity of the adhesive system and interspecific competition are plausible candidates for driving our results. However, it is unclear whether the differences we observed have a genetic basis. Future work should focus on how variation of the adhesive system impacts downstream locomotor components such as kinematics and mechanics and how the integration of these traits is related to habitat use.
Stereoscopy and Scanning Electron Microscopy of Brazil Nut (Bertholletia excelsa H.B.K.) Shell, Brown Skin, and Edible Part: Part One—Healthy Nut
Authors: Scussel Vildes M. , Manfio Daniel , Savi Geovana D. , Moecke Elisa H.S. 
Published: June 2014

AbstractIn this article, tissue layers and cells characteristics of the Brazil nut (Bertholletia excelsa H.B.K.) shell (tegument), brown skin (testae), and edible part (cotyledons) were identified by stereoscopy (SM) and scanning electron microscopies (SEM). (a) The shell (a lignin rich, protective wall) varies in thickness throughout the nut structure and comprises different tissue types (total 3)/texture (hard/mid‐hard/soft), layers (2 to 5), colors (light to dark brown and white to cream), cell shape (amorphous/flattened on both surfaces; polygonal and cylindrical with thick, porous primary and secondary wall in cross‐section), and vascular distribution (helically and polyedrical thickened vessels at soft tissue and locule/channel structures). These variations are observed either in the shell faces, face corners, nut tips, or locule in testae. (b) The brown skin (shell nut part linked to both the shell and edible part) is made of flattened irregular‐shaped parenchymal cells distributed in several layers with more flexible fibrous, thinner wall tissue than shell. It has both rough and smooth shiny texture on the upper and lower surfaces, respectively. However, the nut (c) edible part, that is the nut storage tissue, shows several different tissue/cell layers starting from epidermis (double/triple cells sequence of round and palisade shapes) layer–the endosperm tissue. The parenchymal tissues show cells of irregular shape with small and larger sizes distributed in regular and randomly layers, respectively, separated by a short meristem tissue layer. The cortex cells increase in size as they approach the cotyledons junction. The Brazil nut part's tissue layers and cells were identified by the SM and SEM microscopy methods applied, which provides knowledge for further understanding of nut alterations that may occur either in the forest or during the factory processing.