bluuebunny/crossref_metadata_2025_split huggingface dataset:
Species fluctuations sustained by a cyclic succession at the edge of chaos
Authors: Benincà Elisa , Ballantine Bill , Ellner Stephen P. , Huisman Jef 
Published: April 2015

Significance
The intuitive and popular idea of a balance of nature has been criticized, because species interactions may generate nonequilibrium dynamics, such as oscillations and chaos. However, field evidence of chaos in ecosystems is rare. We report on a coastal community that has displayed striking fluctuations in the abundances of barnacles, mussels, and algae for more than 20 y. Data analysis reveals that these fluctuations reflect a cyclic succession alternating between stabilizing and chaotic dynamics during the species replacement. These results are supported by a simple patch-occupancy model, which predicts very similar dynamics when exposed to seasonal variation. Our findings provide a field demonstration of nonequilibrium coexistence of competing species through a cyclic succession at the edge of chaos.
Causal effects of the early caregiving environment on development of stress response systems in children
Authors: McLaughlin Katie A. , Sheridan Margaret A. , Tibu Florin , Fox Nathan A. , Zeanah Charles H. , Nelson Charles A. 
Published: April 2015

Significance
Disruptions in stress response system functioning are thought to be a central mechanism by which exposure to adverse early-life environments influences human development. Although rodent models support this possibility, results from human studies have been decidedly mixed. Using data from an experimental study examining whether random assignment to a caregiving environment alters development of the autonomic nervous system and hypothalamic–pituitary–adrenal axis in humans, we provide causal evidence for persistent effects of the early caregiving environment on stress response system functioning in humans with effects that differ markedly from those observed in rodent models. We also provide evidence of a sensitive period in human development during which the environment is particularly likely to alter stress response system development.
Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye
Authors: Jia Yali , Bailey Steven T. , Hwang Thomas S. , McClintic Scott M. , Gao Simon S. , Pennesi Mark E. , Flaxel Christina J. , Lauer Andreas K. , Wilson David J. , Hornegger Joachim , Fujimoto James G. , Huang David 
Published: April 2015

Significance
Retinal vascular diseases are a leading cause of blindness. Optical coherence tomography (OCT) has become the standard imaging modality for evaluating fluid accumulation in these diseases and for guiding treatment. However, fluorescein angiography (FA) is still required for initial evaluation of retinal ischemia and choroidal neovascularization, which are not visible in conventional structural OCT. The limitations of FA include poor penetration of fluorescence through blood and pigment, inability to determine the depth of the pathology due to its two-dimensional nature, and some uncommon but potentially severe complications. As a noninvasive three-dimensional alternative, OCT angiography may be used in routine screening and monitoring to provide new information for clinical diagnosis and management.
X-ray phase-contrast tomography with a compact laser-driven synchrotron source
Authors: Eggl Elena , Schleede Simone , Bech Martin , Achterhold Klaus , Loewen Roderick , Ruth Ronald D. , Pfeiffer Franz 
Published: April 2015

Significance
Absorption-based X-ray tomography suffers from low contrast for soft tissue. Over the last few years, it has been shown that grating-based phase-contrast X-ray tomography can overcome this limitation. Here we present, to our knowledge, the first phase-contrast tomography acquired at a compact light source, a recently developed compact synchrotron based on inverse Compton scattering.
The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo
Authors: Neugebauer Judith M. , Kwon Sunjong , Kim Hyung-Seok , Donley Nathan , Tilak Anup , Sopory Shailaja , Christian Jan L. 
Published: April 2015

Significance
Bone morphogenetic proteins (BMPs) are made as inactive precursor proteins that dimerize and are cleaved to generate a bioactive ligand along with prodomain fragments that lack signaling activity. BMP ligands signal as either homodimers, or as heterodimers that display significantly higher activity in vivo. Recombinant homodimeric BMP ligands are used clinically to stimulate bone healing, but this requires supraphysiological doses due to the short half-life of the implanted protein. The current studies demonstrate that properties intrinsic to the BMP4 prodomain contribute to the formation and activity of BMP homodimers and heterodimers in vivo. Understanding how the prodomain regulates the activity of the ligand when it is made in vivo may lead to changes in the way BMP ligands are used clinically.
Role for RNA:DNA hybrids in origin-independent replication priming in a eukaryotic system
Authors: Stuckey Ruth , García-Rodríguez Néstor , Aguilera Andrés , Wellinger Ralf Erik 
Published: April 2015

Significance
R-loop formation has been related to genome instability and human disease, yet the role of R-loops in replication priming remains to be explored in the eukaryotic genome. This investigation discloses that transcription-dependent R-loops have the potential to initiate origin-independent replication events in ribosomal DNA. Taken together, our data suggest that R-loops contribute to transcription-driven endoreplication events and alterations in genome copy number.
Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis
Authors: Ebert Gregor , Allison Cody , Preston Simon , Cooney James , Toe Jesse G. , Stutz Michael D. , Ojaimi Samar , Baschuk Nikola , Nachbur Ueli , Torresi Joseph , Silke John , Begley C. Glenn , Pellegrini Marc 
Published: April 2015

Significance
Current antiviral treatments for chronic hepatitis B virus (HBV) infection are effective in suppressing production of virus, but they have poor efficacy in promoting the elimination of infection. Hence, most patients with chronic HBV infection are maintained on antiviral therapies indefinitely. There is much interest in identifying treatments that promote the clearance of infected hepatocytes, thus purging the HBV DNA reservoir in the liver. Here, we show that the clinical-stage drug birinapant, which antagonizes host cell inhibitor of apoptosis proteins (cIAPs), preferentially promotes the killing of HBV-infected hepatocytes in a mouse model of HBV. Therefore, birinapant and other antagonists of cIAPs may be efficacious in the treatment of chronic HBV infection and may promote elimination of virus.
Noninvasive imaging of immune responses
Authors: Rashidian Mohammad , Keliher Edmund J. , Bilate Angelina M. , Duarte Joao N. , Wojtkiewicz Gregory R. , Jacobsen Johanne Tracey , Cragnolini Juanjo , Swee Lee Kim , Victora Gabriel D. , Weissleder Ralph , Ploegh Hidde L. 
Published: April 2015

Significance
Tumors are often surrounded and invaded by bone marrow-derived cells. Imaging the infiltration of such immune cells into tumors may therefore be an attractive means of detecting tumors or of tracking the response to anticancer therapy. We show that it is possible to detect these cells noninvasively by positron emission tomography (PET) via the surface markers displayed by them. The ability to monitor the immune response in the course of therapy will enable early determination of the efficacy of treatment and will inform decisions as to whether treatment should be stopped or continued. Noninvasive monitoring could therefore change how therapies are applied and assessed, to the benefit of many patients.
Error, signal, and the placement of Ctenophora sister to all other animals
Authors: Whelan Nathan V. , Kocot Kevin M. , Moroz Leonid L. , Halanych Kenneth M. 
Published: April 2015

Significance
Traditional interpretation of animal phylogeny suggests traits, such as mesoderm, muscles, and neurons, evolved only once given the assumed placement of sponges as sister to all other animals. In contrast, placement of ctenophores as the first branching animal lineage raises the possibility of multiple origins of many complex traits considered important for animal diversification and success. We consider sources of potential error and increase taxon sampling to find a single, statistically robust placement of ctenophores as our most distant animal relatives, contrary to the traditional understanding of animal phylogeny. Furthermore, ribosomal protein genes are identified as creating conflict in signal that caused some past studies to recover a sister relationship between ctenophores and cnidarians.
Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice
Authors: Hathaway Catherine K. , Gasim Adil M. H. , Grant Ruriko , Chang Albert S. , Kim Hyung-Suk , Madden Victoria J. , Bagnell C. Robert , Jennette J. Charles , Smithies Oliver , Kakoki Masao 
Published: April 2015

Significance
About one third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below normal transforming growth factor (TGF) β1 expression ameliorates the nephropathy and decreased glomerular filtration rate resulting from long-standing type 1 diabetes, while above normal TGFβ1 expression makes both worse. Reducing TGFβ1 expression in the glomerulus is more important in avoiding the decrease in glomerular filtration rate than altering expression in the tubule, while expression in the tubule is more important in controlling interstitial fibrosis and albuminuria. Suppressing TGFβ1 action in the kidney as a whole, or specifically in podocytes, could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes.
siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown
Authors: Randeria Pratik S. , Seeger Mark A. , Wang Xiao-Qi , Wilson Heather , Shipp Desmond , Mirkin Chad A. , Paller Amy S. 
Published: April 2015

Significance
Diabetic patients often suffer from impaired wound healing, which can develop into nonhealing diabetic ulcers, facilitate bacterial infections, and necessitate amputation. Current strategies for treatment have failed to achieve the anticipated efficacy and do not address the fundamental molecular abnormalities that prevent efficient wound closure. In this work, we introduce a previously unidentified approach to treating diabetic wound healing by using topically delivered spherical nucleic acids to effect the knockdown of ganglioside-monosialic acid 3 (GM3) synthase, a mediator of impaired wound healing, in type 2 diabetic mice. In addition to laying the groundwork for developing a therapy for a debilitating condition, this work also validates the critical role of GM3 in diabetic wound healing.
Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation
Authors: Rotem Asaf , Janzer Andreas , Izar Benjamin , Ji Zhe , Doench John G. , Garraway Levi A. , Struhl Kevin 
Published: April 2015

Significance
The paper describes an assay for cellular transformation that involves growth in low attachment (GILA). This assay is comparable to the gold-standard soft-agar assay, but it is much easier to perform and is suitable for high-throughput drug and genetic screens. We describe such screens for drugs and genes that selectively inhibit or increase transformation, but not proliferation. Such molecules are unlikely to be found through conventional drug screening. Lastly, we demonstrate the ability of Food and Drug Administration-approved noncancer drugs to selectively kill ovarian cancer cells derived from patients with chemotherapy-resistant disease, suggesting this approach may provide useful information for personalized cancer treatment.
Unraveling functional significance of natural variations of a human galectin by glycodendrimersomes with programmable glycan surface
Authors: Zhang Shaodong , Moussodia Ralph-Olivier , Vértesy Sabine , André Sabine , Klein Michael L. , Gabius Hans-Joachim , Percec Virgil 
Published: April 2015

Significance
Lectins are endogenous sugar receptors involved in diverse physiological and disease-associated processes. The functional consequences of naturally occurring single-nucleotide polymorphism and alternative splicing in lectins has been explored using glycodendrimersomes, a versatile test system with programmable glycan (complex carbohydrates) display. Importantly, glycodendrimersomes facilitate quantitative determination of lectin-mediated cross-linking, a hallmark of their activity. Threshold and kinetic effects measured for a human galectin associated with autoimmune disease document the sensitivity of the test system and highlight its potential as a new and highly versatile supramolecular sensor for biomedical applications.
Heterologous production of l-lysine ε-oxidase by directed evolution using a fusion reporter method
Authors: Matsui Daisuke , Asano Yasuhisa 
Published: April 2015

Abstract
For the heterologous production of l-lysine ε-oxidase (LodA), we constructed a new plasmid carrying LodA gene fused in-frame with an antibiotic (phleomycine) resistant gene. The new plasmid was randomly mutated and the mutated plasmids were transformed into Escherichia coli BL21 (DE3) harboring lodB, which encodes a protein (LodB) acting in posttranslational modification of LodA, and active mutants were selected by phleomycin resistance and oxidase activities. One soluble LodA variant isolated by this method contained six silent mutations and one missense mutation. At these mutation points, the codon adaptations at Lys92, Ala550, and Thr646, and the amino acid substitution at His286 to Arg contributed to the production of its functional form. The active form of LodA variant was induced by post-modification of LodB in the heterologous coexpression, and the activity increased with additional NaCl and heat treatment. This is the first report of heterologous production of LodA by random mutagenesis.
Otolith fluctuating asymmetry: a misconception of its biological relevance?
Authors: Díaz-Gil Carlos , Palmer Miquel , Catalán Ignacio A. , Alós Josep , Fuiman Lee A. , García Elena , Gil María del Mar , Grau Amalia , Kang Andrew , Maneja Rommel H. , Mohan John A. , Morro Bernat , Schaffler Jason J. , Buttay Lucie , Riera-Batle Inmaculada , Tolosa Borja , Morales-Nin Beatriz 
Published: April 2015

Abstract
For decades, disruption of the bilateral symmetry of body structures has been related to underperformance and, hence, to fitness. In fish, this concept coupled with the claimed evidence for increased fluctuating asymmetry (FA) of pairs of hard structures, such as otoliths under conditions of stress, has led to the use of otolith FA (OFA) as a proxy for individual fitness and population success. Interpreting those significant differences in OFA in relation to stress-inducing environments and using them to identify suboptimal conditions for survival is especially appealing in the context of, for example, assessing climate change using historical otolith collections. Despite several works that give evidence to support the usefulness of OFA approach, we report on a number of unpublished and published datasets from a wide range of both, wild populations and experimental designs that show no correlation between OFA and any of the usual indicators of fitness or between OFA and expected stress gradients. Our results suggest that there may be a strong bias in the published literature towards positive relationships, despite the enormous importance of negative results for understanding the significance of OFA. These results might shed light on the interpretability of OFA in both laboratory and field studies.
Associations between healthcare quality and use of electronic health record functions in ambulatory care
Authors: Ancker Jessica S , Kern Lisa M , Edwards Alison , Nosal Sarah , Stein Daniel M , Hauser Diane , Kaushal Rainu ,   with the HITEC Investigators
Published: April 2015

AbstractObjectives Contemporary electronic health records (EHRs) offer a wide variety of features, creating opportunities to influence healthcare quality in different ways. This study was designed to assess the relationship between physician use of individual EHR functions and healthcare quality.Materials and Methods Sixty-five providers eligible for “meaningful use” were included. Data were abstracted from office visit records during the study timeframe (183 095 visits with 61 977 patients). Three EHR functions were considered potential predictors: acceptance of best practice alerts, use of order sets, and viewing panel-level reports. Eighteen clinical quality measures from the “meaningful use” program were abstracted.Results Use of condition-specific best-practice alerts and order sets was associated with better scores on clinical quality measures capturing processes in diabetes, cancer screening, tobacco cessation, and pneumonia vaccination. For example, providers above the median in use of tobacco-related alerts had higher performance on tobacco cessation intervention metrics (median 80.6% vs. 66.7%; P &lt; .001), and providers above the median in use of diabetes order sets had higher quality on diabetes low density lipoprotein (LDL) testing (68.2% vs. 59.5%; P == .001). Post hoc examination of the results showed that the positive associations were with measures of healthcare processes (such as rates of LDL testing), whereas there were no positive associations with measures of healthcare outcomes (such as LDL levels).Discussion Among primary care providers in the ambulatory setting using a single EHR, intensive use of certain EHR functions was associated with increased adherence to recommended care as measured by performance on electronically reported “meaningful use” quality measures. This study is relevant to current policy as it uses quality metrics constructed by contemporary certified EHR technology, and quantitative EHR use metrics rather than self-reported use.Conclusion In the early stages of the “meaningful use” program, use of specific EHR functions was associated with higher performance on healthcare process metrics.
Nuclear composition of magnetized gamma-ray burst jets
Authors: Shibata Sanshiro , Tominaga Nozomu 
Published: April 2015

Abstract
We investigate the fraction of metal nuclei in the relativistic jets of gamma-ray bursts associated with core-collapse supernovae. We simulate the fallback in jet-induced explosions with two-dimensional relativistic hydrodynamics calculations and the jet acceleration with steady, radial, relativistic magnetohydrodynamics calculations, and derive the detailed nuclear composition of the jet by post-processing calculation. We found that if the temperature at the jet launch site is above 4.7 × 109 K, quasi-statistical equilibrium is established and heavy nuclei are dissociated into light particles such as 4He during the acceleration of the jets. The criterion for the survival of metal nuclei is written in terms of the isotropic jet luminosity as $L_{\rm j}^{\rm iso} \lesssim 3.9 \times 10^{50} ( R_{\rm i}/10^{7}\ {\rm cm})^2$(1 + σi) erg s−1, where Ri and σi are the initial radius of the jets and the initial magnetization parameter, respectively. If the jet is initially dominated by radiation field (i.e., σi ≪ 1) and the isotropic luminosity is relatively high ($L_{\rm j}^{\rm iso} \gtrsim 4 \times 10^{52}$ erg s−1), the metal nuclei cannot survive in the jet. On the other hand, if the jet is mainly accelerated by magnetic field (i.e., σi ≫ 1), metal nuclei initially contained in the jet can survive without serious dissociation even in the case of a high-luminosity jet. If the jet contains metal nuclei, the dominant nuclei are 28Si, 16O, and 32S and the mean mass number can be 〈A〉 ∼ 25.
Efficient genotype compression and analysis of large genetic variation datasets
Authors: Layer Ryan M. , Kindlon Neil , Karczewski Konrad J. , Quinlan Aaron R. ,   Exome Aggregation Consortium
Published: April 2015

ABSTRACTThe economy of human genome sequencing has catalyzed ambitious efforts to interrogate the genomes of large cohorts in search of new insight into the genetic basis of disease. This manuscript introduces Genotype Query Tools (GQT) as a new indexing strategy and toolset that addresses an analytical bottleneck by enabling interactive analyses based on genotypes, phenotypes and sample relationships. Speed improvements are achieved by operating directly on a compressed genotype index without decompression. GQT’s data compression ratios increase favorably with cohort size and relative analysis performance improves in kind. We demonstrate substantial performance improvements over state-of-the-art tools using datasets from the 1000 Genomes Project (46 fold), the Exome Aggregation Consortium (443 fold), and simulated datasets of up to 100,000 genomes (218 fold). Furthermore, we show that this indexing strategy facilitates population and statistical genetics measures such as principal component analysis and burden tests. Based on its computational efficiency and by complementing existing toolsets, GQT provides a flexible framework for current and future analyses of massive genome datasets.
Relationship between LD Score and Haseman-Elston Regression
Authors: Bulik-Sullivan Brendan 
Published: April 2015

AbstractEstimating SNP-heritability from summary statistics using LD Score regression provides a convenient alternative to standard variance component models, because LD Score regression is computationally very fast and does not require individual genotype data. However, the mathematical relationship between variance component methods and LD Score regression is not clear; in particular, it is not known in general how much of an increase in standard error one incurs by working with summary data instead of individual genotypes.In this paper, I show that in samples of unrelated individuals, LD Score regression with constrained intercept is essentially the same as Haseman-Elston (HE) regression, which is currently the state-of-the-art method for estimating SNP-heritability from ascertained case/control samples. Similar results hold for SNP-genetic correlation.