bluuebunny/crossref_metadata_2025 huggingface dataset:
The base rate principle and the fairness principle in social judgment
Authors: Cao Jack , Banaji Mahzarin R.
Published: June 2016

Significance

In the absence of individuating facts, beliefs about individuals can either use base rates to maximize statistical likelihood or uphold fairness to maximize equal opportunity. But once individuating facts become known, neither base rates nor fairness should drive beliefs. Only the facts should matter. Whereas explicit beliefs rationally follow this prescription, implicit beliefs do not. Despite learning individuating facts about a particular male and female that rendered base rates inapplicable, implicit beliefs still relied on base rates. These findings are important not just for theories of social cognition and Bayesian updating, but also for crafting policies that will minimize the undesired impact of stereotypes on decisions about the worth and capabilities of specific individuals.
Stochastic steps in secondary active sugar transport
Authors: Adelman Joshua L. , Ghezzi Chiara , Bisignano Paola , Loo Donald D. F. , Choe Seungho , Abramson Jeff , Rosenberg John M. , Wright Ernest M. , Grabe Michael
Published: June 2016

Significance

The potential energy stored in ion gradients across cell membranes drives nutrients in and out of cells by cotransport proteins, e.g., uphill glucose accumulation in cells by sodium cotransporters. Insight into the mechanism of cotransport has been obtained from high-resolution atomic structures of the transporters, but further progress requires dynamic information about ion and substrate movements through the proteins. We have used multiple long molecular-dynamic simulations and electrophysiological assays to explore the dynamics of the transport cycle. Ligands bound to sodium-dependent glucose transporters are released to the cytoplasm stochastically, whereas release to the external solution is ordered with sugar first. The order of events is intimately tied to how the protein converts the energy stored in an ion gradient into a sugar gradient.
Budgerigars and zebra finches differ in how they generalize in an artificial grammar learning experiment
Authors: Spierings Michelle J. , ten Cate Carel
Published: June 2016

Significance

Human language learning is based on learning abstract grammatical structures. Whether any nonhuman animal can detect such structures is a contentious issue. We tested zebra finches and budgerigars on whether experience with auditory strings with different grammatical structures resulted in learning these structures. Both species were able to distinguish the differently structured strings but did so very differently. Zebra finches attended to the ordinal positions of specific items in a string. In contrast, budgerigars detected the underlying structure and used this structure to classify correctly strings consisting of fully novel items. This ability to perceive the abstract relation between items is comparable to analogical reasoning, something long thought to be unique for humans and known from only a few species.
Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation
Authors: Braun Christian J. , Bruno Peter M. , Horlbeck Max A. , Gilbert Luke A. , Weissman Jonathan S. , Hemann Michael T.
Published: June 2016

Significance

Tumor development is accompanied by widespread genomic and transcriptional changes. The mere acquisition of this information has greatly outpaced our capability to functionally study the biological roles of altered genes. This dilemma highlights the necessity to develop technologies that facilitate a rapid functional prioritization among lists of altered genes. Here, we use catalytically dead Cas9 to specifically activate or inactivate the transcription of genes in mouse models of cancer. This approach allows us to study the impact of gene-level changes in vivo and to systematically screen for novel genetic mediators of treatment relapse. We expect that this approach can be used to systematically dissect the biological role of cancer-related genes, a process critical to identifying new cancer drug targets.
Cardiac myosin light chain is phosphorylated by Ca
2+
/calmodulin-dependent and -independent kinase activities
Authors: Chang Audrey N. , Mahajan Pravin , Knapp Stefan , Barton Hannah , Sweeney H. Lee , Kamm Kristine E. , Stull James T.
Published: June 2016

Significance

Chronic heart failure is associated with decreased cardiac myosin light chain kinase (MLCK; cMLCK) expression and myosin regulatory light chain (RLC) phosphorylation, similar to heart failure associated with mutations in numerous sarcomeric proteins. Although ablation of cMLCK expression reduces RLC phosphorylation sufficiently to cause heart failure, the residual phosphorylation indicates that another kinase also phosphorylates RLC. We find that MLCK4 is also expressed abundantly in cardiac muscle, and structural analyses indicate that it is a Ca
2+
/calmodulin (CaM)-independent kinase, in contrast to Ca
2+
/CaM-stimulated cMLCK. Biochemical kinetic analyses confirmed these structural predictions. These studies define distinct regulation of cMLCK and MLCK4 activities to affect RLC phosphorylation, and lay the foundation for RLC phosphorylation as a therapeutic target for heart failure.
Arabidopsis
cryptochrome 1 functions in nitrogen regulation of flowering
Authors: Yuan Shu , Zhang Zhong-Wei , Zheng Chong , Zhao Zhong-Yi , Wang Yu , Feng Ling-Yang , Niu Guoqi , Wang Chang-Quan , Wang Jian-Hui , Feng Hong , Xu Fei , Bao Fang , Hu Yong , Cao Ying , Ma Ligeng , Wang Haiyang , Kong Dong-Dong , Xiao Wei , Lin Hong-Hui , He Yikun
Published: June 2016

Significance

Overapplication of nitrogen (N) fertilizer causes delayed flowering and negatively impacts the function and composition of natural ecosystems and climate. In this study, we demonstrate that flowering time variations regulated by altered nitrogen levels are mediated by two key factors: ferredoxin-NADP
+
-oxidoreductase (FNR1) and the blue-light receptor cryptochrome 1 (CRY1). Nitrogen regulates
FNR1
expression, thereby contributing to changes in NADPH/NADP
+
and ATP/AMP ratios, which in turn activates adenosine monophosphate-activated protein kinase to modulate nuclear CRY1 abundance, which further acts in the N signal input pathway to affect central clock function and flowering time. A better understanding of N-regulated floral transition will offer biotechnological solutions to improve sustainable agriculture.
Global threat to agriculture from invasive species
Authors: Paini Dean R. , Sheppard Andy W. , Cook David C. , De Barro Paul J. , Worner Susan P. , Thomas Matthew B.
Published: June 2016

Significance

A key scientific and policy challenge relating to invasive species at the world level is to understand and predict which countries are most vulnerable to the threat of invasive species. We present an analysis of the threat from almost 1,300 agricultural invasive species to the world (124 countries). The analysis examines the global distribution of these species, international trade flows, and each country’s main agricultural production crops, to determine potential invasion and impact of these invasive species. We found the most vulnerable countries to be from Sub-Saharan Africa, while those countries representing the greatest threat to the rest of the world (given the invasive species they already contain, and their trade patterns) to be the United States and China.
Oxytocin, the peptide that bonds the sexes also divides them
Authors: Gao Shan , Becker Benjamin , Luo Lizhu , Geng Yayuan , Zhao Weihua , Yin Yu , Hu Jiehui , Gao Zhao , Gong Qiyong , Hurlemann Rene , Yao Dezhong , Kendrick Keith M.
Published: June 2016

Significance

To interpret and respond appropriately to social cues is a fundamental aspect of human nature that becomes impaired in many mental disorders. The past decade has witnessed unprecedented excitement across neuroscience, psychology, and psychiatry regarding the role of oxytocin in human social cognition and its potential therapeutic use. There is also a considerable long-established public interest in behavioral sex differences and the molecular and brain mechanisms responsible. The current findings provide the first mechanistic explanation, to our knowledge, for how this key social molecule has evolved sex-dependent actions on amygdala function to influence the salience and attractiveness of positive social attributes in women but negative ones in men.
Highly efficient primed spacer acquisition from targets destroyed by the
Escherichia coli
type I-E CRISPR-Cas interfering complex
Authors: Semenova Ekaterina , Savitskaya Ekaterina , Musharova Olga , Strotskaya Alexandra , Vorontsova Daria , Datsenko Kirill A. , Logacheva Maria D. , Severinov Konstantin
Published: June 2016

Significance

Clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR associated (Cas) immunity relies on adaptive acquisition of spacers from foreign DNA into prokaryotes genomes. Efficient “primed” acquisition leads to selective intake of extra spacers from DNA molecules recognized by Cas proteins complexed with CRISPR RNAs partially matching foreign DNA. In contrast, fully matching targets are destroyed without new spacer acquisition. We show that when the rate of degradation of DNA with fully and partially matching targets is made equal, fully matching protospacers stimulate primed adaptation much more efficiently than partially matching ones. Thus, different outcomes of CRISPR-Cas response to two kinds of targets are caused by much more rapid destruction of fully matching targets rather than by structural differences in complexes formed on fully and partially matching targets.
Epigenetic modification ofOXTand human sociability
Authors: Haas Brian W. , Filkowski Megan M. , Cochran R. Nick , Denison Lydia , Ishak Alexandra , Nishitani Shota , Smith Alicia K.
Published: June 2016

Significance

Elucidating the genetic and biological substrates of social behavior serves to advance the way basic human nature is understood and improves the way genetic and biological markers can be used to prevent, diagnose, and treat people with impairments in social cognition and behavior. This study shows that epigenetic modification of the structural gene for oxytocin (OXT) is an important factor associated with individual differences in social processing, including self-report, behavior, and brain function and structure in humans.
Structure of a phleboviral envelope glycoprotein reveals a consolidated model of membrane fusion
Authors: Halldorsson Steinar , Behrens Anna-Janina , Harlos Karl , Huiskonen Juha T. , Elliott Richard M. , Crispin Max , Brennan Benjamin , Bowden Thomas A.
Published: June 2016

Significance

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a deadly tick-borne viral pathogen. Since first being reported in China in 2009, SFTSV has spread throughout South Korea and Japan, with mortality rates reaching up to 30%. The surface of the SFTSV virion is decorated by two glycoproteins, Gn and Gc. Here, we report the atomic-level structure of the Gc glycoprotein in a conformation formed during uptake of the virion into the host cell. Our analysis reveals the conformational changes that the Gc undergoes during host cell infection and provides structural evidence that these rearrangements are conserved with otherwise unrelated alpha- and flaviviruses.
Economic impact of refugees
Authors: Taylor J. Edward , Filipski Mateusz J. , Alloush Mohamad , Gupta Anubhab , Rojas Valdes Ruben Irvin , Gonzalez-Estrada Ernesto
Published: June 2016

Significance

The number of refugees displaced by civil conflict or natural disasters is on the rise. Economic impacts of refugees on host countries are controversial and little understood, because data have not been available and the question of refugee impacts does not lend itself to conventional impact evaluation methods. We use a unique Monte Carlo simulation approach with microdata from refugee and host-country surveys to obtain the first estimates of refugee camps’ impacts on surrounding host-country economies and to compare impacts of cash versus in-kind refugee aid. An additional refugee increases total real income within a 10-km radius around two cash camps by significantly more than the aid the refugee receives. Impacts around a camp receiving in-kind (food) aid are smaller.
Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease
Authors: Horii Mariko , Li Yingchun , Wakeland Anna K. , Pizzo Donald P. , Nelson Katharine K. , Sabatini Karen , Laurent Louise Chang , Liu Ying , Parast Mana M.
Published: June 2016

Significance

Human pluripotent stem cells (hPSCs) continue to be underappreciated as a model for studying trophoblast differentiation. In this study, we provide a reproducible, two-step protocol by which hPSCs can be differentiated into bipotential cytotrophoblast (CTB) stem-like cells and subsequently into functional, terminally differentiated trophoblasts. In addition, we provide evidence that the response of hPSC-derived CTBs to low oxygen is similar to that of primary CTBs. Finally, using trisomy 21-affected hPSCs, we show, for the first time to our knowledge, that hPSCs can model a trophoblast differentiation defect. We propose that hPSCs are superior to other currently available models for studying human trophoblast differentiation.
Effect of physician disclosure of specialty bias on patient trust and treatment choice
Authors: Sah Sunita , Fagerlin Angela , Ubel Peter
Published: June 2016

Significance

Disclosure policies, intended to protect consumers, are a popular solution across a range of industries such as health care, financial investments, mortgages, and other services in which professional advisors may suffer from potential bias from misaligned incentives. Using field data (recorded transcripts of surgeon–patient consultations) and a randomized controlled laboratory experiment, we examine and find that disclosures of specialty bias increase patients’ trust and their likelihood of choosing a treatment in accordance with the physicians’ specialty. Professionals and policy makers should be aware of the implications on advisee trust and choice when advocating for the disclosure of advisor bias.
Elementary quantum mechanics of the neutron with an electric dipole moment
Authors: Baym Gordon , Beck D. H.
Published: June 2016

Significance

A permanent electric dipole moment of the neutron, a manifestation of the violation of time-reversal symmetry in nature, is an important clue to physics beyond the standard model, and is the subject of a number of ongoing large-scale experimental efforts. Although, in the absence of external electric fields, the dipole moment must lie along the neutron spin, the neutron dipole moment and spin are independent; e.g., the external electric field in Compton scattering on the neutron induces a component of the dipole moment parallel to the field. How then should one think generally about the neutron electric dipole moment, including time-reversal violation, within elementary quantum mechanics, and in particular when interpreting experimental searches for a permanent moment?
BBX21, an
Arabidopsis
B-box protein, directly activates
HY5
and is targeted by COP1 for 26S proteasome-mediated degradation
Authors: Xu Dongqing , Jiang Yan , Li Jigang , Lin Fang , Holm Magnus , Deng Xing Wang
Published: June 2016

Significance

CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) and ELONGATED HYPOCOTYL 5 (HY5) are two central regulators of photomorphogenesis. COP1 destabilizes HY5 to repress photomorphogenesis in darkness. On light illumination, accumulated HY5 regulates the expression of a large number of genes to optimize photomorphogenesis. Thus, COP1-HY5 defines a regulatory hub for light control of seedling development. In this work, our data indicate that BBX21 is a key component involved in the COP1-HY5 regulatory hub. BBX21 is controlled by COP1 via its E3 ubiquitin ligase activity in darkness. In the light, BBX21 promotes photomorphogenesis by binding to the promoter of
HY5
and activating
HY5
expression.
MiR-137 affects melanin synthesis in mouse melanocyte by repressing the expression ofc-KitandTyrp2inSCF/c-Kitsignaling pathway
Authors: Jiang Shan , Yu Xiuju , Dong Changsheng
Published: June 2016

Previously, we created miR-137 overexpressing transgenic mice that produced lighten color phenotypes including gray mice phenotype. However, the miR-137 functional role in coat color regulation is still not well understood. In this study, the quantity of melanin granule and the relative expression of TYRP2 in gray miR-137 overexpression transgenic mouse skin were significantly lower than that in C57BL/6J black mouse skin. The mRNA and protein expression level of c-Kit and c-Kit downstream gene Tyrp2 in miR-137 expression plasmid-transfected melanocytes were significantly down-regulated comparing with that of the control melanocytes. In melanocytes, miR-137 overexpression could decrease the enhanced expression of c-Kit and Tyrp2 and the increased melanin production caused by UV treatment. The target relationship of miR-137 and c-Kit was identified by luciferase assay. The results suggest that miR-137 could inhibit melanogenesis in mouse skin melanocytes by repressing the expression of c-Kit and Tyrp2 in SCF/c-Kit signaling pathway.
Conceptual study of an ICRH traveling-wave antenna system for low-coupling conditions as expected in DEMO
Authors: Ragona R. , Messiaen A.
Published: June 2016

For the central heating of a fusion reactor ion cyclotron radio frequency heating (ICRH) is the first choice method as it is able to couple RF power to the ions without density limit. The drawback of this heating method is the problem of excitation of the magneto-sonic wave through the plasma boundary layer from the antenna located along the wall, without exceeding its voltage standoff. The amount of coupling depends on the antenna excitation and the surface admittance at the antenna output due to the plasma profile. The paper deals with the optimization of the antenna excitation by the use of sections of traveling-wave antennas (TWAs) distributed all along the reactor wall between the blanket modules. They are mounted and fed in resonant ring system(s). First, the physics of the coupling of a strap array is studied by simple models and the coupling code ANTITER II. Then, after the study of the basic properties of a TWA section, its feeding problem is solved by hybrids driving them in resonant ring circuit(s). The complete modeling is obtained from the matrices of the TWA sections connected to one of the feeding hybrid(s). The solution is iterated with the coupling code to determine the loading for a reference low-coupling ITER plasma profile. The resulting wave pattern up to the plasma bulk is derived. The proposed system is totally load resilient and allows us to obtain a very selective exciting wave spectrum. A discussion of some practical implementation problems is added.
Free-boundary ideal MHD stability of W7-X divertor equilibria
Authors: Nührenberg C.
Published: June 2016

Plasma configurations describing the stellarator experiment Wendelstein 7-X (W7-X) are computationally established taking into account the geometry of the test-divertor unit and the high-heat-flux divertor which will be installed in the vacuum chamber of the device (Gasparotto et al 2014 Fusion Eng. Des. 89 2121). These plasma equilibria are computationally studied for their global ideal magnetohydrodynamic (MHD) stability properties. Results from the ideal MHD stability code cas3d (Nührenberg 1996 Phys. Plasmas
3 2401), stability limits, spatial structures and growth rates are presented for free-boundary perturbations. The work focusses on the exploration of MHD unstable regions of the W7-X configuration space, thereby providing information for future experiments in W7-X aiming at an assessment of the role of ideal MHD in stellarator confinement.
Rotational shear effects on edge harmonic oscillations in DIII-D quiescent H-mode discharges
Authors: Chen Xi , Burrell K.H. , Ferraro N.M. , Osborne T.H. , Austin M.E. , Garofalo A.M. , Groebner R.J. , Kramer G.J. , Luhmann N.C. , McKee G.R. , Muscatello C.M. , Nazikian R. , Ren X. , Snyder P.B. , Solomon W.M. , Tobias B.J. , Yan Z.
Published: June 2016

In the quiescent H-mode (QH-mode) regime, edge harmonic oscillations (EHOs) play an important role in avoiding transient edge localized mode (ELM) power fluxes by providing benign and continuous edge particle transport. A detailed theoretical, experimental and modeling comparison has been made of low-n (n  ⩽  5) EHO in DIII-D QH-mode plasmas. The calculated linear eigenmode structure from the extended magentoohydrodynamics (MHD) code M3D-C1 matches closely the coherent EHO properties from external magnetics data and internal measurements using the ECE, BES, ECE-Imaging and microwave imaging reflectometer (MIR) diagnostics, as well as the kink/peeling mode properties found by the ideal MHD code ELITE. Numerical investigations indicate that the low-n EHO-like solutions from M3D-C1 are destabilized by rotation and/or rotational shear while high-n modes are stabilized. This effect is independent of the rotation direction, suggesting that EHOs can be destabilized in principle with rotation in either direction. The modeling results are consistent with observations of EHO, support the proposed theory of the EHO as a low-n kink/peeling mode destabilized by edge E  ×  B rotational shear, and improve our understanding and confidence in creating and sustaining QH-mode in present and future devices.
Integrated gene set analysis for microRNA studies
Authors: Garcia-Garcia Francisco , Panadero Joaquin , Dopazo Joaquin , Montaner David
Published: June 2016

Motivation: Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis. Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario.

Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes.

Results: We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action.

Availability and Implementation: The proposed methodology was implemented in the Bioconductor library mdgsa. http://bioconductor.org/packages/mdgsa. For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna

Contact: david.montaner@gmail.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
RTCR: a pipeline for complete and accurate recovery of T cell repertoires from high throughput sequencing data
Authors: Gerritsen Bram , Pandit Aridaman , Andeweg Arno C. , de Boer Rob J.
Published: June 2016

Motivation: High Throughput Sequencing (HTS) has enabled researchers to probe the human T cell receptor (TCR) repertoire, which consists of many rare sequences. Distinguishing between true but rare TCR sequences and variants generated by polymerase chain reaction (PCR) and sequencing errors remains a formidable challenge. The conventional approach to handle errors is to remove low quality reads, and/or rare TCR sequences. Such filtering discards a large number of true and often rare TCR sequences. However, accurate identification and quantification of rare TCR sequences is essential for repertoire diversity estimation.

Results: We devised a pipeline, called Recover TCR (RTCR), that accurately recovers TCR sequences, including rare TCR sequences, from HTS data (including barcoded data) even at low coverage. RTCR employs a data-driven statistical model to rectify PCR and sequencing errors in an adaptive manner. Using simulations, we demonstrate that RTCR can easily adapt to the error profiles of different types of sequencers and exhibits consistently high recall and high precision even at low coverages where other pipelines perform poorly. Using published real data, we show that RTCR accurately resolves sequencing errors and outperforms all other pipelines.

Availability and Implementation: The RTCR pipeline is implemented in Python (v2.7) and C and is freely available at http://uubram.github.io/RTCR/along with documentation and examples of typical usage.

Contact:  b.gerritsen@uu.nl
A simple model predicts UGT-mediated metabolism
Authors: Dang Na Le , Hughes Tyler B. , Krishnamurthy Varun , Swamidass S. Joshua
Published: June 2016

Motivation: Uridine diphosphate glucunosyltransferases (UGTs) metabolize 15% of FDA approved drugs. Lead optimization efforts benefit from knowing how candidate drugs are metabolized by UGTs. This paper describes a computational method for predicting sites of UGT-mediated metabolism on drug-like molecules.

Results: XenoSite correctly predicts test molecule’s sites of glucoronidation in the Top-1 or Top-2 predictions at a rate of 86 and 97%, respectively. In addition to predicting common sites of UGT conjugation, like hydroxyl groups, it can also accurately predict the glucoronidation of atypical sites, such as carbons. We also describe a simple heuristic model for predicting UGT-mediated sites of metabolism that performs nearly as well (with, respectively, 80 and 91% Top-1 and Top-2 accuracy), and can identify the most challenging molecules to predict on which to assess more complex models. Compared with prior studies, this model is more generally applicable, more accurate and simpler (not requiring expensive quantum modeling).

Availability and implementation: The UGT metabolism predictor developed in this study is available at http://swami.wustl.edu/xenosite/p/ugt.

Contact: swamidass@wustl.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
The Space of Freedom in a Context of War, Exile and Endless Instability: A Sociolinguistic Approach to Autobiographical Narratives on Catalan Exile
Authors: Iglésias-Franch Narcís
Published: June 2016

In the recent numerous publications on the autobiographies of Catalan writers who went into exile in 1939, themes such as memory, identity crisis or travel have been studied in depth. In this article, I propose a sociolinguistic interpretation of a series of autobiographical works by exiled authors such as Xavier Benguerel, Lluís Ferran de Pol and Antoni Rovira i Virgili. According to the theoretical framework of sociolinguistic studies, autobiographical narratives can be analysed using three different approaches: first, the way authors narrate how ‘things’ are or were; second, how ‘things’ or events were experienced; and, finally, the ways in which ‘things’ or events are narrated. Language is not only historical data or an individual experience which authors narrate in their autobiographical narratives. This sociolinguistic approach to the autobiographical narratives of Catalan exiles shows the close link between language and identity, and between language and morality.
Pervasive microRNA Duplication in Chelicerates: Insights from the Embryonic microRNA Repertoire of the Spider
Parasteatoda tepidariorum
Authors: Leite Daniel J. , Ninova Maria , Hilbrant Maarten , Arif Saad , Griffiths-Jones Sam , Ronshaugen Matthew , McGregor Alistair P.
Published: June 2016

MicroRNAs are small (∼22 nt) noncoding RNAs that repress translation and therefore regulate the production of proteins from specific target mRNAs. microRNAs have been found to function in diverse aspects of gene regulation within animal development and many other processes. Among invertebrates, both conserved and novel, lineage specific, microRNAs have been extensively studied predominantly in holometabolous insects such as Drosophila melanogaster . However little is known about microRNA repertoires in other arthropod lineages such as the chelicerates. To understand the evolution of microRNAs in this poorly sampled subphylum, we characterized the microRNA repertoire expressed during embryogenesis of the common house spider Parasteatoda tepidariorum . We identified a total of 148 microRNAs in P. tepidariorum representing 66 families. Approximately half of these microRNA families are conserved in other metazoans, while the remainder are specific to this spider. Of the 35 conserved microRNAs families 15 had at least two copies in the P. tepidariorum genome. A BLAST-based approach revealed a similar pattern of duplication in other spiders and a scorpion, but not among other chelicerates and arthropods, with the exception of a horseshoe crab. Among the duplicated microRNAs we found examples of lineage-specific tandem duplications, and the duplication of entire microRNA clusters in three spiders, a scorpion, and in a horseshoe crab. Furthermore, we found that paralogs of many P. tepidariorum microRNA families exhibit arm switching, which suggests that duplication was often followed by sub- or neofunctionalization. Our work shows that understanding the evolution of microRNAs in the chelicerates has great potential to provide insights into the process of microRNA duplication and divergence and the evolution of animal development.
Effects of combined radiofrequency field exposure on amyloid-beta–induced cytotoxicity in HT22 mouse hippocampal neurones
Authors: Lee Jong-Sun , Kim Jeong-Yub , Kim Hee-Jin , Kim Jeong Cheol , Lee Jae-Seon , Kim Nam , Park Myung-Jin
Published: June 2016

Alzheimer's disease (AD) is the most common progressive and irreversible neurodegenerative disease and it is caused by neuronal death in the brain. Recent studies have shown that non-ionizing radiofrequency (RF) radiation has some beneficial cognitive effects in animal models of AD. In this study, we examined the effect of combined RF radiation on amyloid-beta (Aβ)–induced cytotoxicity in HT22 rat hippocampal neurons. Treatment with Aβ suppressed HT22 cell proliferation in a concentration-dependent manner. RF exposure did not affect cell proliferation, and also had a marginal effect on Aβ-induced suppression of growth in HT22 cells. Cell cycle analysis showed that Aβ decreased the G1 fraction and increased the subG1 fraction, indicating increased apoptosis. Accordingly, Aβ increased the annexin V/propidium iodide (PI)–positive cell fraction and the degradation of poly (ADP ribose) polymerase and caspase-3 in HT22 cells. However, RF alone and the combination of Aβ and RF did not affect these events significantly. Aβ increased reactive oxygen species (ROS) generation, thereby suppressing cell proliferation. This was abrogated by N-acetylcysteine (NAC) treatment, indicating that Aβ-induced ROS generation is the main cause of suppression of proliferation. NAC also restored Aβ-induced annexin V/PI–positive cell populations. However, RF did not have a significant impact on these events. Finally, Aβ stimulated the ataxia telangiectasia and Rad3-related protein/checkpoint kinase 1 DNA single-strand breakage pathway, and enhanced beta-site amyloid precursor protein expression; RF had no effect on them. Taken together, our results demonstrate that RF exposure did not significantly affect the Aβ-induced decrease of cell proliferation, increase of ROS production, or induction of cell death in these cells.
Human Immunodeficiency Virus and Allergic Bronchopulmonary Aspergillosis: Case Report and Review of Literature
Authors: Galiatsatos Panagis , Melia Michael T. , Silhan Leann L.
Published: June 2016

Allergic bronchopulmonary aspergillosis (ABPA) results from a hypersensitivity response to airways colonization with Aspergillus fumigatus, and it occurs most often in individuals with asthma or cystic fibrosis. Allergic bronchopulmonary aspergillosis is an indolent, but potentially progressive, disease in patients. In patients infected with human immunodeficiency virus (HIV), ABPA is rare, and its description in the literature is limited to case reports. We describe the occurrence of ABPA in a 37-year-old woman with well controlled HIV infection. This represents the first documented case of ABPA in an HIV-infected patient whose only pulmonary comorbidity included the ramifications of prior acute respiratory distress syndrome due to Pneumocystis jirovecii pneumonia. We also review prior case reports of ABPA in HIV-infected patients and consider risk factors for its development.
Therapeutic Trial of Rifabutin After Rifampicin-Associated DRESS Syndrome in Tuberculosis-Human Immunodeficiency Virus Coinfected Patients
Authors: Lehloenya Rannakoe J. , Dlamini Sipho , Muloiwa Rudzani , Kakande Betty , Ngwanya Mzudumile R. , Todd Gail , Dheda Keertan
Published: June 2016

Elimination of a rifamycin from the treatment regimen for tuberculosis negatively impacts outcomes. Cross-reactivity between the rifamycins after drug eruptions is unclear. We report 6 consecutive human immunodeficiency virus-infected patients with rifampicin-associated drug rash with eosinophilia and systemic symptoms (DRESS) syndrome confirmed on diagnostic rechallenge. The patients subsequently tolerated rifabutin. These data inform clinical management of tuberculosis-associated drug reactions.
Clearance of Vancomycin-Resistant Enterococcus Concomitant With Administration of a Microbiota-Based Drug Targeted at Recurrent Clostridium difficile Infection
Authors: Dubberke Erik R. , Mullane Kathleen M. , Gerding Dale N. , Lee Christine H. , Louie Thomas J. , Guthertz Harriet , Jones Courtney
Published: June 2016

Background.  Vancomycin-resistant Enterococcus (VRE) is a major healthcare-associated pathogen and a well known complication among transplant and immunocompromised patients. We report on stool VRE clearance in a post hoc analysis of the Phase 2 PUNCH CD study assessing a microbiota-based drug for recurrent Clostridium difficile infection (CDI).

Methods.  A total of 34 patients enrolled in the PUNCH CD study received 1 or 2 doses of RBX2660 (microbiota suspension). Patients were requested to voluntarily submit stool samples at baseline and at 7, 30, and 60 days and 6 months after the last administration of RBX2660. Stool samples were tested for VRE using bile esculin azide agar with 6 µg/mL vancomycin and Gram staining. Vancomycin resistance was confirmed by Etest.

Results.  VRE status (at least 1 test result) was available for 30 patients. All stool samples for 19 patients (63.3%, mean age 61.7 years, 68% female) tested VRE negative. Eleven patients (36.7%, mean age 75.5 years, 64% female) were VRE positive at the first test (baseline or 7-day follow-up). Of these patients, 72.7%, n = 8 converted to negative as of the last available follow-up (30 or 60 days or 6 months). Of the other 3: 1 died (follow-up data not available); 1 patient remained positive at all follow-ups; 1 patient retested positive at 6 months with negative tests during the interim.

Conclusions.  Although based on a small sample size, this secondary analysis demonstrated the possibility of successfully converting a high percentage of VRE-positive patients to negative in a recurrent CDI population with RBX2660.
Host Biomarkers Are Associated With Response to Therapy and Long-Term Mortality in Pediatric Severe Malaria
Authors: Conroy Andrea L. , Hawkes Michael , McDonald Chloe R. , Kim Hani , Higgins Sarah J. , Barker Kevin R. , Namasopo Sophie , Opoka Robert O. , John Chandy C. , Liles W. Conrad , Kain Kevin C.
Published: June 2016

Background.  Host responses to infection are critical determinants of disease severity and clinical outcome. The development of tools to risk stratify children with malaria is needed to identify children most likely to benefit from targeted interventions.

Methods.  This study investigated the kinetics of candidate biomarkers of mortality associated with endothelial activation and dysfunction (angiopoietin-2 [Ang-2], soluble FMS-like tyrosine kinase-1 [sFlt-1], and soluble intercellular adhesion molecule-1 [sICAM-1]) and inflammation (10 kDa interferon γ-induced protein [CXCL10/IP-10] and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) in the context of a randomized, double-blind, placebo-controlled, parallel-arm trial evaluating inhaled nitric oxide versus placebo as adjunctive therapy to parenteral artesunate for severe malaria. One hundred eighty children aged 1–10 years were enrolled at Jinja Regional Referral Hospital in Uganda and followed for up to 6 months.

Results.  There were no differences between the 2 study arms in the rate of biomarker recovery. Median levels of Ang-2, CXCL10, and sFlt-1 were higher at admission in children who died in-hospital (n = 15 of 180; P < .001, P = .027, and P = .004, respectively). Elevated levels of Ang-2, sTREM-1, CXCL10, and sICAM-1 were associated with prolonged clinical recovery times in survivors. The Ang-2 levels were also associated with postdischarge mortality (P < .0001). No biomarkers were associated with neurodisability.

Conclusions.  Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.
Expected constraints on models of the epoch of reionization with the variance and skewness in redshifted 21 cm-line fluctuations
Authors: Kubota Kenji , Yoshiura Shintaro , Shimabukuro Hayato , Takahashi Keitaro
Published: June 2016

The redshifted 21 cm-line signal from neutral hydrogen in the intergalactic medium (IGM) gives a direct probe of the epoch of reionization (EoR). In this paper, we investigate the potential of the variance and skewness of the probability distribution function of the 21 cm brightness temperature for constraining EoR models. These statistical quantities are simple, easy to calculate from the observed visibility, and thus suitable for the early exploration of the EoR with current telescopes such as the Murchison Widefield Array (MWA) and LOw Frequency ARray (LOFAR). We show, by performing Fisher analysis, that the variance and skewness at z = 7–9 are complementary to each other to constrain the EoR model parameters such as the minimum virial temperature of halos which host luminous objects, ionizing efficiency, and mean free path of ionizing photons in the IGM. Quantitatively, the constraining power highly depends on the quality of the foreground subtraction and calibration. We give a best case estimate of the constraints on the parameters, neglecting the systematics other than the thermal noise.
Notes on the birth–death prior with fossil calibrations for Bayesian estimation of species divergence times
Authors: dos Reis Mario
Published: June 2016

Constructing a multi-dimensional prior on the times of divergence (the node ages) of species in a phylogeny is not a trivial task, in particular, if the prior density is the result of combining different sources of information such as a speciation process with fossil calibration densities. Yang & Rannala (2006
Mol. Biol. Evol
. 23, 212–226. (
doi:10.1093/molbev/msj024
)) laid out the general approach to combine the birth–death process with arbitrary fossil-based densities to construct a prior on divergence times. They achieved this by calculating the density of node ages without calibrations conditioned on the ages of the calibrated nodes. Here, I show that the conditional density obtained by Yang & Rannala is misspecified. The misspecified density can sometimes be quite strange-looking and can lead to unintentionally informative priors on node ages without fossil calibrations. I derive the correct density and provide a few illustrative examples. Calculation of the density involves a sum over a large set of labelled histories, and so obtaining the density in a computer program seems hard at the moment. A general algorithm that may provide a way forward is given.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
Bayesian phylogenetic estimation of fossil ages
Authors: Drummond Alexei J. , Stadler Tanja
Published: June 2016

Recent advances have allowed for both morphological fossil evidence and molecular sequences to be integrated into a single combined inference of divergence dates under the rule of Bayesian probability. In particular, the fossilized birth–death tree prior and the Lewis-Mk model of discrete morphological evolution allow for the estimation of both divergence times and phylogenetic relationships between fossil and extant taxa. We exploit this statistical framework to investigate the internal consistency of these models by producing phylogenetic estimates of the age of each fossil in turn, within two rich and well-characterized datasets of fossil and extant species (penguins and canids). We find that the estimation accuracy of fossil ages is generally high with credible intervals seldom excluding the true age and median relative error in the two datasets of 5.7% and 13.2%, respectively. The median relative standard error (RSD) was 9.2% and 7.2%, respectively, suggesting good precision, although with some outliers. In fact, in the two datasets we analyse, the phylogenetic estimate of fossil age is on average less than 2 Myr from the mid-point age of the geological strata from which it was excavated. The high level of internal consistency found in our analyses suggests that the Bayesian statistical model employed is an adequate fit for both the geological and morphological data, and provides evidence from real data that the framework used can accurately model the evolution of discrete morphological traits coded from fossil and extant taxa. We anticipate that this approach will have diverse applications beyond divergence time dating, including dating fossils that are temporally unconstrained, testing of the ‘morphological clock', and for uncovering potential model misspecification and/or data errors when controversial phylogenetic hypotheses are obtained based on combined divergence dating analyses.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
A mixed relaxed clock model
Authors: Lartillot Nicolas , Phillips Matthew J. , Ronquist Fredrik
Published: June 2016

Over recent years, several alternative relaxed clock models have been proposed in the context of Bayesian dating. These models fall in two distinct categories: uncorrelated and autocorrelated across branches. The choice between these two classes of relaxed clocks is still an open question. More fundamentally, the true process of rate variation may have both long-term trends and short-term fluctuations, suggesting that more sophisticated clock models unfolding over multiple time scales should ultimately be developed. Here, a mixed relaxed clock model is introduced, which can be mechanistically interpreted as a rate variation process undergoing short-term fluctuations on the top of Brownian long-term trends. Statistically, this mixed clock represents an alternative solution to the problem of choosing between autocorrelated and uncorrelated relaxed clocks, by proposing instead to combine their respective merits. Fitting this model on a dataset of 105 placental mammals, using both node-dating and tip-dating approaches, suggests that the two pure clocks, Brownian and white noise, are rejected in favour of a mixed model with approximately equal contributions for its uncorrelated and autocorrelated components. The tip-dating analysis is particularly sensitive to the choice of the relaxed clock model. In this context, the classical pure Brownian relaxed clock appears to be overly rigid, leading to biases in divergence time estimation. By contrast, the use of a mixed clock leads to more recent and more reasonable estimates for the crown ages of placental orders and superorders. Altogether, the mixed clock introduced here represents a first step towards empirically more adequate models of the patterns of rate variation across phylogenetic trees.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
A molecular palaeobiological exploration of arthropod terrestrialization
Authors: Lozano-Fernandez Jesus , Carton Robert , Tanner Alastair R. , Puttick Mark N. , Blaxter Mark , Vinther Jakob , Olesen Jørgen , Giribet Gonzalo , Edgecombe Gregory D. , Pisani Davide
Published: June 2016

Understanding animal terrestrialization, the process through which animals colonized the land, is crucial to clarify extant biodiversity and biological adaptation. Arthropoda (insects, spiders, centipedes and their allies) represent the largest majority of terrestrial biodiversity. Here we implemented a molecular palaeobiological approach, merging molecular and fossil evidence, to elucidate the deepest history of the terrestrial arthropods. We focused on the three independent, Palaeozoic arthropod terrestrialization events (those of Myriapoda, Hexapoda and Arachnida) and showed that a marine route to the colonization of land is the most likely scenario. Molecular clock analyses confirmed an origin for the three terrestrial lineages bracketed between the Cambrian and the Silurian. While molecular divergence times for Arachnida are consistent with the fossil record, Myriapoda are inferred to have colonized land earlier, substantially predating trace or body fossil evidence. An estimated origin of myriapods by the Early Cambrian precedes the appearance of embryophytes and perhaps even terrestrial fungi, raising the possibility that terrestrialization had independent origins in crown-group myriapod lineages, consistent with morphological arguments for convergence in tracheal systems.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.
Species relationships and divergence times in beeches: new insights from the inclusion of 53 young and old fossils in a birth–death clock model
Authors: Renner S. S. , Grimm Guido W. , Kapli Paschalia , Denk Thomas
Published: June 2016

The fossilized birth–death (FBD) model can make use of information contained in multiple fossils representing the same clade, and we here apply this model to infer divergence times in beeches (genus
Fagus
), using 53 fossils and nuclear sequences for all nine species. We also apply FBD dating to the fern clade Osmundaceae, with about 12 living species and 36 fossils.
Fagus
nuclear sequences cannot be aligned with those of other Fagaceae, and we therefore use Bayes factors to choose among alternative root positions. The crown group of
Fagus
is dated to 53 (62–43) Ma; divergence of the sole American species to 44 (51–39) Ma and divergence between Central European
F. sylvatica
and Eastern Mediterranean
F. orientalis
to 8.7 (20–1.8) Ma, unexpectedly old. The FBD model can accommodate fossils as sampled ancestors or as extinct or unobserved lineages; however, this makes its raw output, which shows all fossils on short or long branches, problematic to interpret. We use hand-drawn depictions and a bipartition network to illustrate the uncertain placements of fossils. Inferred speciation and extinction rates imply approximately 5× higher evolutionary turnover in
Fagus
than in Osmundaceae, fitting a hypothesized low turnover in plants adapted to low-nutrient conditions.

This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.