bluuebunny/crossref_metadata_2025 huggingface dataset:
Guidance for Studies Evaluating the Accuracy of Rapid Tuberculosis Drug-Susceptibility Tests
Authors: Georghiou Sophia B , Schumacher Samuel G , Rodwell Timothy C , Colman Rebecca E , Miotto Paolo , Gilpin Christopher , Ismail Nazir , Rodrigues Camilla , Warren Rob , Weyer Karin , Zignol Matteo , Arafah Sonia , Cirillo Daniela Maria , Denkinger Claudia M
Published: April 2019

The development and implementation of rapid molecular diagnostics for tuberculosis (TB) drug-susceptibility testing is critical to inform treatment of patients and to prevent the emergence and spread of resistance. Optimal trial planning for existing tests and those in development will be critical to rapidly gather the evidence necessary to inform World Health Organization review and to support potential policy recommendations. The evidence necessary includes an assessment of the performance for TB and resistance detection as well as an assessment of the operational characteristics of these platforms. The performance assessment should include analytical studies to confirm the limit of detection and assay ability to detect mutations conferring resistance across globally representative strains. The analytical evaluation is typically followed by multisite clinical evaluation studies to confirm diagnostic performance in sites and populations of intended use. This paper summarizes the considerations for the design of these analytical and clinical studies.
A modal extension of Jaśkowski’s discussive logic $\textbf{D}_\textbf{2}$
Authors: Mruczek-Nasieniewska Krystyna , Nasieniewski Marek , Pietruszczak Andrzej
Published: April 2019

In Jaśkowski’s model of discussion, discussive connectives represent certain interactions that can hold between debaters. However, it is not possible within the model for participants to use explicit modal operators. In the paper we present a modal extension of the discussive logic $\textbf{D}_{\textbf{2}}$ that formally corresponds to an extended version of Jaśkowski’s model of discussion that permits such a use. This logic is denoted by $\textbf{m}\textbf{D}_{\textbf{2}}$. We present philosophical motivations for the formulation of this logic. We also give syntactic characterizations of the logic and propose a comparison with certain other modal systems. In particular, we prove that $\textbf{m}\textbf{D}_{\textbf{2}}$ is neither normal nor regular. On the basis of the axiomatization of $\textbf{D}_{\textbf{2}}$, we give an axiomatization of $\textbf{m}\textbf{D}_{\textbf{2}}$. We also give another axiomatization which is not based on the axiomatization of $\textbf{D}_{\textbf{2}}$. Furthermore, we give a natural Kripke-style semantics for $\textbf{m}\textbf{D}_{\textbf{2}}$ and prove the respective adequacy theorems.
Exact Inference in Long-Horizon Predictive Quantile Regressions with an Application to Stock Returns
Authors: Gungor Sermin , Luger Richard
Published: April 2019

We develop an exact and distribution-free procedure to test for quantile predictability at several prediction horizons and quantile levels jointly, while allowing for an endogenous predictive regressor with any degree of persistence. The approach proceeds by combining together the quantile regression t-statistics from each considered prediction horizon and quantile level, and uses Monte-Carlo resampling techniques to control the familywise error rate in finite samples. A simulation study confirms that the proposed inference procedure is indeed level-correct and that testing several quantile levels jointly can deliver more power to detect predictability. In an empirical application to excess stock returns, we find that the default yield spread predicts the right tail while the short-term interest rate predicts the center of the return distribution. This predictability evidence is stronger at shorter rather than longer horizons.
Gone in 60 seconds: Sub-lethal Effects of Metofluthrin Vapors on Behavior and Fitness of Resistant and Field Strains of Aedes aegypti (Diptera: Culicidae)
Authors: Bibbs Christopher S , Bloomquist Jeffrey R , Hahn Daniel A , Kaufman Phillip E , Xue Rui-De
Published: April 2019

Spatial repellents can reduce fecundity and interrupt oviposition behavior in Aedes aegypti. Yet, it is unclear if short exposure times, resistant phenotypes, and other aspects of spatial repellents can impact these effects on mosquito reproduction. To address these issues, pyrethroid susceptible, pyrethroid resistant, and field strains of Ae. aegypti were used to evaluate the extent to which fecundity and oviposition behavior are affected following metofluthrin exposure. Mosquitoes were exposed for 60 s to a sub-lethal dose (LC30) of metofluthrin before blood feeding and allowed 72 h to become gravid before evaluation in an oviposition bioassay for an additional 72 h. Metofluthrin-exposed susceptible, field, and to a lesser extent resistant strain Ae. aegypti showed oviposition across fewer containers, less egg yield, less egg viability, and reduced larval survivorship in hatched eggs compared to unexposed cohorts. Susceptible mosquitoes retained some eggs at dissection following bioassays, and in one case, melanized eggs retained in the female. Treated resistant and field strain F1 larvae hatched significantly earlier than unexposed cohorts and resulted in increased larval mortality in the first 3 d after oviposition. Upon laying, the treated field strain had incompletely melanized eggs mixed in with viable eggs. The treated field strain also had the lowest survivorship of larvae reared from bioassay eggs. These results indicate that metofluthrin could succeed in reducing mosquito populations via multiple mechanisms besides acute lethality. With the available safety data, pre-existing spatial repellent registration, and possibilities for other outdoor delivery methods, metofluthrin is a strong candidate for transition into broader mosquito abatement operations.
Establishment of mixed plantations of Pinus sylvestris var. mongolica and Populus × xiaozhuanica may not be appropriate: evidence from litter decomposition
Authors: Song Huan-Huan , Yan Tao , Zeng De-Hui
Published: April 2019

Aims

Mongolian pine (Pinus sylvestris var. mongolica) and Xiaozhuan poplar (Populus × xiaozhuanica) are two predominant afforestation tree species in the semi-arid sandy lands of northeast China, which are characterized by poor soil nutrients. Plant litter decomposition plays a critical role in regulating nutrient cycling in terrestrial ecosystems. Admixture of broadleaf litter to conifer litter is expected to improve litter decomposition and soil fertility, and thus productivity. However, the effects on the decomposition of litter mixture of the above two tree species are not well understood. Therefore, it is essential to assess the decomposition performance of litter mixture with the aim of improving forest nutrient management and the establishment of mixed plantation. Appropriate forest management practice is critical for the sustainability of site productivity in plantation forests.

Methods

We conducted a field litterbag decomposition transplant experiment for single pine litter, single poplar litter and their mixture in a pine stand, a poplar stand and an adjacent grassland for 16 months in the Keerqin Sandy Lands, northeast China.

Important Findings

After 16 months of incubation, there remained significantly more litter mass of pine (73.8%) than of poplar (67.2%). The mass remaining was positively correlated with litter carbon (C):nitrogen (N), C:phosphorus (P) and lignin:N ratios, and negatively with litter N and P concentrations, which suggests that initial litter chemical properties were an important factor affecting litter decay. Generally, net N and P immobilizations were observed during decomposition. This indicates that litter decomposition in this area was N-limited as N was progressively immobilized, and then tended to induce P limitation. Thus, we strongly recommend prohibiting litter harvesting by local residents to maintain soil fertility in this nutrient-poor area. Our results do not support the home-field advantage hypothesis, as illustrated by the fact that, in most cases, mass loss of litter from native habitat was comparable to that in transplanted habitats during decomposition. Furthermore, a dominant additive effect was detected, indicating that the establishment of mixed plantation may not be appropriate for these two species.
Misreporting Among Reluctant Respondents
Authors: Bach Ruben L , Eckman Stephanie , Daikeler Jessica
Published: April 2019

Many surveys aim to achieve high response rates to keep bias due to nonresponse low. However, research has shown that the relationship between the nonresponse rate and nonresponse bias is small. In fact, high response rates may lead to measurement error, if respondents with low response propensities provide survey responses of low quality. In this paper, we explore the relationship between response propensity and measurement error, specifically, motivated misreporting, the tendency to give inaccurate answers to speed through an interview. Using data from four surveys conducted in several countries and modes, we analyze whether motivated misreporting is worse among those respondents who were the least likely to respond to the survey. Contrary to the prediction of our theoretical model, we find only limited evidence that reluctant respondents are more likely to misreport.
Tiny grains shining bright in the gaps of Herbig Ae transitional discs
Authors: Birchall Eloise K , Ireland Michael J , Federrath Christoph , Monnier John D , Kraus Stefan , Willson Matthew , Kraus Adam L , Rizzuto Aaron , Agnew Matthew T , Maddison Sarah T
Published: April 2019

This work presents a study of two Herbig Ae transitional discs, Oph IRS 48 and HD 169142; which both have reported rings in their dust density distributions. We use Keck-II/NIRC2 adaptive optics imaging observations in the L′ filter (3.8 $\mu$m) to probe the regions of these discs inwards of ${\sim }20\, \mathrm{au}$ from the star. We introduce our method for investigating these transitional discs, which takes a forward modelling approach: making a model of the disc (using the Monte Carlo radiative transfer code radmc3d), convolving it with point spread functions of calibrator stars, and comparing the convolved models with the observational data. The disc surface density parameters are explored with a Monte Carlo Markov Chain technique. Our analysis recovers emission from both of the discs interior to the well-known optically thick walls, modelled as a ring of emission at ${\sim }15\, \mathrm{au}$ in Oph IRS 48, and ${\sim }7\, \mathrm{au}$ for HD 169142, and identifies asymmetries in both discs. Given the brightness of the near-symmetric rings compared to the reported companion candidates, we suggest that the reported companion candidates can be interpreted as slightly asymmetric disc emission or illumination.
Predictably missing satellites: subhalo abundances in Milky Way-like haloes
Authors: Fielder Catherine E , Mao Yao-Yuan , Newman Jeffrey A , Zentner Andrew R , Licquia Timothy C
Published: April 2019

On small scales there have been a number of claims of discrepancies between the standard cold dark matter (CDM) model and observations. The ‘missing satellites problem’ infamously describes the overabundance of subhaloes from CDM simulations compared to the number of satellites observed in the Milky Way. A variety of solutions to this discrepancy have been proposed; however, the impact of the specific properties of the Milky Way halo relative to the typical halo of its mass has yet to be explored. Motivated by recent studies that identified ways in which the Milky Way is atypical, we investigate how the properties of dark matter haloes with mass comparable to our Galaxy’s – including concentration, spin, shape, and scale factor of the last major merger – correlate with the subhalo abundance. Using zoom-in simulations of Milky Way-like haloes, we build two models of subhalo abundance as functions of host halo properties. From these models we conclude that the Milky Way most likely has fewer subhaloes than the average halo of the same mass. We expect up to 30 per cent fewer subhaloes with low maximum rotation velocities ($V_{\rm max}^{\rm sat} \sim 10$ km s−1) at the 68 per cent confidence level and up to 52 per cent fewer than average subhaloes with high rotation velocities ($V_{\rm max}^{\rm sat} \gtrsim 30$ km s−1, comparable to the Magellanic Clouds) than would be expected for a typical halo of the Milky Way’s mass. Concentration is the most informative single parameter for predicting subhalo abundance. Our results imply that models tuned to explain the missing satellites problem assuming typical subhalo abundances for our Galaxy may be overcorrecting.
The footprint of cometary dust analogues – II. Morphology as a tracer of tensile strength and application to dust collection by the Rosetta spacecraft
Authors: Ellerbroek L E , Gundlach B , Landeck A , Dominik C , Blum J , Merouane S , Hilchenbach M , John H , van Veen H A
Published: April 2019

The structure of cometary dust is a tracer of growth processes in the formation of planetesimals. Instrumentation on board the Rosetta mission to comet 67P/Churyumov–Gerasimenko captured dust particles and analysed them in situ. However, these deposits are a product of a collision within the instrument. We conducted laboratory experiments with cometary dust analogues, simulating the collection process by Rosetta instruments (specifically COSIMA, MIDAS). In Paper I, we reported that velocity is a key driver in determining the appearance of deposits. Here in Paper II, we use materials with different monomer sizes, and study the effect of tensile strength on the appearance of deposits. We find that mass transfer efficiency increases from ∼1 up to ∼10 per cent with increasing monomer diameter from 0.3 to 1.5 $\mu\mathrm{ m}$ (i.e. tensile strength decreasing from ∼12 to ∼3 kPa), and velocities increasing from 0.5 to 6 m s−1. Also, the relative abundance of small fragments after impact is higher for material with higher tensile strength. The degeneracy between the effects of velocity and material strength may be lifted by performing a closer study of the deposits. This experimental method makes it possible to estimate the mass transfer efficiency in the COSIMA instrument. Extrapolating these results implies that more than half of the dust collected during the Rosetta mission has not been imaged. We analysed two COSIMA targets containing deposits from single collisions. The collision that occurred closest to perihelion passage led to more small fragments on the target.
TNRC6 proteins modulate hepatitis C virus replication by spatially regulating the binding of miR-122/Ago2 complexes to viral RNA
Authors: Li You , Wang Li , Rivera-Serrano Efraín E , Chen Xian , Lemon Stanley M
Published: April 2019

The liver-specific microRNA, miR-122, is an essential host factor for replication of the hepatitis C virus (HCV). miR-122 stabilizes the positive-strand HCV RNA genome and promotes its synthesis by binding two sites (S1 and S2) near its 5′ end in association with Ago2. Ago2 is essential for both host factor activities, but whether other host proteins are involved is unknown. Using an unbiased quantitative proteomics screen, we identified the TNRC6 protein paralogs, TNRC6B and TNRC6C, as functionally important but redundant components of the miR-122/Ago2 host factor complex. Doubly depleting TNRC6B and TNRC6C proteins reduced HCV replication in human hepatoma cells, dampening miR-122 stimulation of viral RNA synthesis without reducing the stability or translational activity of the viral RNA. TNRC6B/C were required for optimal miR-122 host factor activity only when S1 was able to bind miR-122, and restricted replication when S1 was mutated and only S2 bound by miR-122. TNRC6B/C preferentially associated with S1, and TNRC6B/C depletion enhanced Ago2 association at S2. Collectively, these data suggest a model in which TNRC6B/C regulate the assembly of miR-122/Ago complexes on HCV RNA, preferentially directing miR-122/Ago2 to S1 while restricting its association with S2, thereby fine-tuning the spatial organization of miR-122/Ago2 complexes on the viral genome.
Bacterial genome architecture shapes global transcriptional regulation by DNA supercoiling
Authors: El Houdaigui Bilal , Forquet Raphaël , Hindré Thomas , Schneider Dominique , Nasser William , Reverchon Sylvie , Meyer Sam
Published: April 2019

DNA supercoiling acts as a global transcriptional regulator in bacteria, that plays an important role in adapting their expression programme to environmental changes, but for which no quantitative or even qualitative regulatory model is available. Here, we focus on spatial supercoiling heterogeneities caused by the transcription process itself, which strongly contribute to this regulation mode. We propose a new mechanistic modeling of the transcription-supercoiling dynamical coupling along a genome, which allows simulating and quantitatively reproducing in vitro and in vivo transcription assays, and highlights the role of genes’ local orientation in their supercoiling sensitivity. Consistently with predictions, we show that chromosomal relaxation artificially induced by gyrase inhibitors selectively activates convergent genes in several enterobacteria, while conversely, an increase in DNA supercoiling naturally selected in a long-term evolution experiment with Escherichia coli favours divergent genes. Simulations show that these global expression responses to changes in DNA supercoiling result from fundamental mechanical constraints imposed by transcription, independently from more specific regulation of each promoter. These constraints underpin a significant and predictable contribution to the complex rules by which bacteria use DNA supercoiling as a global but fine-tuned transcriptional regulator.
Research on Youth and Young Adult Tobacco Use, 2013–2018, From the Food and Drug Administration–National Institutes of Health Tobacco Centers of Regulatory Science
Authors: Perry Cheryl L , Creamer MeLisa R , Chaffee Benjamin W , Unger Jennifer B , Sutfin Erin L , Kong Grace , Shang Ce , Clendennen Stephanie L , Krishnan-Sarin Suchitra , Pentz Mary Ann
Published: April 2019

The Tobacco Regulatory Science Program is a collaborative research effort between the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). In 2013, the NIH funded 14 Tobacco Centers of Regulatory Science (TCORS), which serve as partners in establishing research, training, and professional development programs to guide FDA. Each of the fourteen TCORS, and two other NIH-funded research programs, the Center for the Evaluation of Nicotine in Cigarettes (CENIC) and the Consortium on Methods Evaluating Tobacco (COMET), pursued specific research themes relevant to FDA’s priorities. A key mandate for FDA is to reduce tobacco use among young people. This article is a review of the peer-reviewed research, including published and in-press manuscripts, from the TCORS, CENIC, and COMET, which provides specific data or other findings on youth (ages 10–18 years) and/or young adults (ages 18–34 years), from 2013 to 2018. Citations of all TCORS, CENIC, and COMET articles from September 2013 to December 2017 were collected by the TCORS coordinating center, the Center for Evaluation and Coordination of Training and Research. Additional citations up to April 30, 2018 were requested from the principal investigators. A scoring rubric was developed and implemented to assess study type, primary theme, and FDA priority area addressed by each article. The major subareas and findings from each priority area are presented. There were 766 articles in total, with 258 (34%) focusing on youth and/or young adults. Findings relevant to FDA from this review concern impact analysis, toxicity, health effects, addiction, marketing influences, communications, and behavior.

Implications

The Tobacco Centers of Regulatory Science, CENIC, and COMET have had a high output of scientific articles since 2013. These Centers are unique in that the FDA supports science specifically to guide future regulatory actions. The 258 articles that have focused on youth and/or young adults are providing data for regulatory actions by the FDA related to the key priority areas such as the addictiveness of non-cigarette products, the effects of exposure to electronic cigarette marketing on initiation and cessation, and the impact of flavored products on youth and young adult tobacco use. Future regulations to reduce tobacco use will be guided by the cumulative evidence. These Centers are one innovative mechanism to promote important outcomes to advance tobacco regulatory science.
In situ and experimental evidence for effects of elevated pH on protistan and metazoan grazers
Authors: Hansen Benni W , Andersen Christian M B , Hansen Per J , Nielsen Torkel G , Vismann Bent , Tiselius Peter
Published: April 2019

Plankton succession was studied in a hyper-eutrophic stratified estuary, Mariager Fjord, Denmark. Above the pycnocline (15 m) pH increased from 8.5 to 9.2 and the oxygen increased to super saturation after 5 d of sunny weather due to high primary production. The protistan grazers were dominated by heterotrophic dinoflagellates and mixotrophic and heterotrophic ciliates. Metazooplankton was dominated by meroplankton, rotifers and the copepod, Acartia tonsa, all with a relatively low biomass. Cirriped nauplii occupied the upper strata while polychaete larvae populated the whole water column. Bivalve larvae occurred occasionally above the pycnocline even at very high pH. In pH challenge experiments, the mixotrophic ciliate Mesodinium rubrum was the least pH tolerant species, followed by Strombidium spp., which did not cope well with seawater pH > 8.5. Some heterotrophic dinoflagellates were more tolerant with net growth at pH > 9. The predominant rotifer Synchaeta sp. tolerated up to pH 9.5 and the copepod survived pH 10 but stopped producing eggs at pH 9.5 with unaffected egg hatching success. The polychaete and cirriped larvae tolerated pH 9.5, but bivalve larvae showed decreased survival already at pH 8.5. In situ distribution patterns and pH challenge experiments suggest that pH indeed contribute to structuring zooplankton distribution.
EVALUATION AND STATISTICAL ANALYSIS OF THE USE OF INFOGRAPHICS IN RADIOLOGY EDUCATION
Authors: Takashima Ryuta , Ito Mari , Chida Takanori , Watanabe Toshiyuki , Toyama Takahiko , Yaginuma Taira , Anzai Takahiro , Hiyama Toru , Iimoto Takeshi , Fujii Hirofumi
Published: April 2019

Interest in the need for systematic radiology education has increased since the Fukushima Daiichi nuclear disaster. Practice and attitude surveys on radiology education have been previously undertaken and indicate that there is currently limited quantitative knowledge on the use of radiation and radiological consequences. Although maintenance of an education system and measurements of its effects on knowledge levels have been conducted, no novel developments have been made in the methods of measurement. In this study, we measured the effect of the infographics to develop more effective educational materials and lecture methods in radiology education. In addition, we quantitatively evaluated the effects of using infographics on changes in knowledge levels using statistical analysis.
Map2k7 Haploinsufficiency Induces Brain Imaging Endophenotypes and Behavioral Phenotypes Relevant to Schizophrenia
Authors: Openshaw Rebecca L , Thomson David M , Thompson Rhiannon , Penninger Josef M , Pratt Judith A , Morris Brian J , Dawson Neil
Published: April 2019

c-Jun N-terminal kinase (JNK) signaling contributes to functional plasticity in the brain and cognition. Accumulating evidence implicates a role for MAP kinase kinase 7 (MAP2K7), a JNK activator encoded by the Map2k7 gene, and other JNK pathway components in schizophrenia (ScZ). Mice haploinsufficient for Map2k7 (Map2k7+/− mice) display ScZ-relevant cognitive deficits, although the mechanisms are unclear. Here we show that Map2k7+/− mice display translationally relevant alterations in brain function, including hippocampal and mesolimbic system hypermetabolism with a contrasting prefrontal cortex (PFC) hypometabolism, reminiscent of patients with ScZ. In addition Map2k7+/− mice show alterations in functional brain network connectivity paralleling those reported in early ScZ, including PFC and hippocampal hyperconnectivity and compromised mesolimbic system functional connectivity. We also show that although the cerebral metabolic response to ketamine is preserved, the response to dextroamphetamine (d-amphetamine) is significantly attenuated in Map2k7+/− mice, supporting monoamine neurotransmitter system dysfunction but not glutamate/NMDA receptor (NMDA-R) dysfunction as a consequence of Map2k7 haploinsufficiency. These effects are mirrored behaviorally with an attenuated impact of d-amphetamine on sensorimotor gating and locomotion, whereas similar deficits produced by ketamine are preserved, in Map2k7+/− mice. In addition, Map2k7+/− mice show a basal hyperactivity and sensorimotor gating deficit. Overall, these data suggest that Map2k7 modifies brain and monoamine neurotransmitter system function in a manner relevant to the positive and cognitive symptoms of ScZ.
Suspicious Mothering: Maternal Labor and Marriage Migration in South Korea
Authors: Yi Sohoon
Published: April 2019

Inspired by theories of marginalized women’s maternal labor, this article contributes to the literature on the relationship between borders and parenting in Asia. After marital breakdown, marriage migrants in South Korea can extend their stay if they have South Korean children and can present evidence of mothering to the immigration authorities. This article presents a socio-legal analysis of cross-border mothering through in-depth interviews with migrants and relevant stakeholders. Taking cross-border mothering as a site where state intervention encounters migrant subjectivity, I examine maternal norms and scrutiny imposed by immigration authorities and performative maternal labor of migrant mothers.
The Molecular Clock in the Evolution of Protein Structures
Authors: Pascual-García Alberto , Arenas Miguel , Bastolla Ugo
Published: April 2019

The molecular clock hypothesis, which states that substitutions accumulate in protein sequences at a constant rate, plays a fundamental role in molecular evolution but it is violated when selective or mutational processes vary with time. Such violations of the molecular clock have been widely investigated for protein sequences, but not yet for protein structures. Here, we introduce a novel statistical test (Significant Clock Violations) and perform a large scale assessment of the molecular clock in the evolution of both protein sequences and structures in three large superfamilies. After validating our method with computer simulations, we find that clock violations are generally consistent in sequence and structure evolution, but they tend to be larger and more significant in structure evolution. Moreover, changes of function assessed through Gene Ontology and InterPro terms are associated with large and significant clock violations in structure evolution. We found that almost one third of significant clock violations are significant in structure evolution but not in sequence evolution, highlighting the advantage to use structure information for assessing accelerated evolution and gathering hints of positive selection. Clock violations between closely related pairs are frequently significant in sequence evolution, consistent with the observed time dependence of the substitution rate attributed to segregation of neutral and slightly deleterious polymorphisms, but not in structure evolution, suggesting that these substitutions do not affect protein structure although they may affect stability. These results are consistent with the view that natural selection, both negative and positive, constrains more strongly protein structures than protein sequences. Our code for computing clock violations is freely available at https://github.com/ugobas/Molecular_clock.
A Novel Open Access Web Portal for Integrating Mechanistic and Toxicogenomic Study Results
Authors: Sutherland Jeffrey J , Stevens James L , Johnson Kamin , Elango Navin , Webster Yue W , Mills Bradley J , Robertson Daniel H
Published: April 2019

Applying toxicogenomics to improving the safety profile of drug candidates and crop protection molecules is most useful when it identifies relevant biological and mechanistic information that highlights risks and informs risk mitigation strategies. Pathway-based approaches, such as gene set enrichment analysis, integrate toxicogenomic data with known biological process and pathways. Network methods help define unknown biological processes and offer data reduction advantages. Integrating the 2 approaches would improve interpretation of toxicogenomic information. Barriers to the routine application of these methods in genome-wide transcriptomic studies include a need for “hands-on” computer programming experience, the selection of 1 or more analysis methods (eg pathway analysis methods), the sensitivity of results to algorithm parameters, and challenges in linking differential gene expression to variation in safety outcomes. To facilitate adoption and reproducibility of gene expression analysis in safety studies, we have developed Collaborative Toxicogeomics, an open-access integrated web portal using the Django web framework. The software, developed with the Python programming language, is modular, extensible and implements “best-practice” methods in computational biology. New study results are compared with over 4000 rodent liver experiments from Drug Matrix and open TG-GATEs. A unique feature of the software is the ability to integrate clinical chemistry and histopathology-derived outcomes with results from gene expression studies, leading to relevant mechanistic conclusions. We describe its application by analyzing the effects of several toxicants on liver gene expression and exemplify application to predicting toxicity study outcomes upon chronic treatment from expression changes in acute-duration studies.
Spermine Is a Potent Plant Defense Activator Against Gray Mold Disease on Solanum lycopersicum, Phaseolus vulgaris, and Arabidopsis thaliana
Authors: Seifi Hamed S. , Zarei Adel , Hsiang Tom , Shelp Barry J.
Published: April 2019

Polyamines (PAs) are ubiquitous aliphatic amines that play important roles in growth, development, and environmental stress responses in plants. In this study, we report that exogenous application of spermine (Spm) is effective in the induction of resistance to gray mold disease, which is caused by the necrotrophic fungal pathogen Botrytis cinerea, on tomato (Solanum lycopersicum), bean (Phaseolus vulgaris), and Arabidopsis thaliana. High throughput transcriptome analysis revealed a priming role for the Spm molecule in the genus Arabidopsis, resulting in strong upregulation of several important defense-associated genes, particularly those involved in systemic-acquired resistance. Microscopic analysis confirmed that Spm application potentiates endogenous defense responses in tomato leaves through the generation of reactive oxygen species and the hypersensitive response, which effectively contained B. cinerea growth within the inoculated area. Moreover, co-application of Spm and salicylic acid resulted in a synergistic effect against the pathogen, leading to higher levels of resistance than those induced by separate applications of the two compounds. The Spm plus salicylic acid treatment also reduced infection in systemic nontreated leaves of tomato plants. Our findings suggest that Spm, particularly when applied in combination with salicylic acid, functions as a potent plant defense activator that leads to effective local and systemic resistance against B. cinerea.
Identification of novel epitopes in serotype O foot-and-mouth disease virus by in vitro immune selection
Authors: Mahapatra Mana , Upadhyaya Sasmita , Parida Satya
Published: April 2019

Foot-and-mouth disease virus (FMDV) displays various epitopes on the capsid outer surface. In addition to the five neutralizing antigenic sites, there is evidence of the existence of other, yet unidentified, epitopes that are believed to play a role in antibody-mediated protection. Previous attempts to identify these epitopes revealed two additional substitutions at positions VP2-74 and -191 (5M2/5 virus) to be of antigenic significance. However, complete resistance to neutralization was not obtained in the neutralization assay, indicating the existence of other, undisclosed epitopes. Results from this study provides evidence of at least two new neutralizing epitopes involving residues VP3-116 and -195 around the threefold axis that have significant impact on the antigenic nature of the virus. These findings extend our knowledge of the surface features of the FMDV capsid known to elicit neutralizing antibodies, and should help with rational vaccine design.
Improvement in serological diagnosis of pertussis by external quality assessment
Authors: Markey Kevin , Douglas-Bardsley Alex , Asokanathan Cathy , Fry Norman K. , Barkoff Alex-Mikael , Bacci Sabrina , Ködmön Csaba , He Qiushui
Published: April 2019

Purpose. Serological analysis is an essential tool for the diagnosis of pertussis or whooping cough, disease surveillance and the evaluation of vaccine effectiveness against

Bordetella pertussis

. Accurate measurement of anti-pertussis toxin (anti-PT) IgG antibody levels in sera is essential. These measurements are usually performed using immunological methods such as ELISA and multiplex immunoassays. However, there are a large number of different assay systems available, and therefore standardization and harmonization between the methods are needed to obtain comparable data.

Methodology. In collaboration with ECDC, the EUPert-LabNet network has organized three External Quality Assessment (EQA) schemes (2010, 2012 and 2016), which initially identified the diverse range of techniques and reagents being used throughout Europe. This manuscript discusses the findings of each of the EQA rounds and their impact on the participating laboratories.

Results. The studies have shown an increasing number of laboratories (from 65% to 92%) using only the recommended coating antigen, purified PT, in immunoassays, as this allows exact quantification of serum anti-PT IgG and since PT is only produced by

Bordetella pertussis

this prevents cross-reactivity with other species. There has also been an increase in the numbers of laboratories (from 59% to 92%), including a WHO reference serum in their assays, which allows anti-PT IgG concentrations to be measured in International Units, thus enabling the comparison of results from different methods and laboratories. In addition, manufacturers have also considered these recommendations when they produce commercial ELISA kits.

Conclusion. The three EQA rounds have resulted in greater harmonization in methods among different laboratories, showing a significant improvement of the ELISA methods used for serodiagnosis of pertussis.
Stem cell delivery to kidney via minimally invasive ultrasound-guided renal artery injection in mice
Authors: Thin May Zaw , Ogunldade Olumide , Comenge Joan , Patrick P. Stephen , Stuckey Daniel J. , L.David Anna , Lévy Raphaël , Lythgoe Mark F. , Beard Paul , Kalber Tammy L.
Published: April 2019

Cell-based therapies are promising treatments for various kidney diseases. However, the major hurdle in initiating therapeutic responses is the inefficiency of injection routes to deliver cells to the kidney parenchyma. Systemic injection, such as intravenous injection only delivers a small proportion of cells to the kidney. Whereas direct delivery, such as renal artery injection require surgical procedures. A minimally invasive renal artery injection was therefore developed to enhance cell delivery to kidney. In this study, luciferase expressing human adipocyte derived stem cells (ADSC) were labelled with gold nanorods (GNR) and injected into the renal artery using ultrasound guidance. The ADSCs were tracked using bioluminescence and photoacoustic imaging serially over 7 days. Imaging confirmed that the majority of signal was within the kidney, indicative of successful injection and that signal remained stable for 3 days. Histology showed co-localization of GNRs with ADSC staining throughout the kidney with no indication of injury caused by injection. These findings demonstrate that ultrasound-guided renal artery injection is feasible in mice and can successfully deliver a large proportion of cells which are retained within the kidney for 3 days. Therefore, the techniques developed here will be useful for optimising cell therapy in kidney diseases.
Predicting the short-term success of human influenza A variants with machine learning
Authors: Hayati Maryam , Biller Priscila , Colijn Caroline
Published: April 2019

Seasonal influenza viruses are constantly changing, and produce a different set of circulating strains each season. Small genetic changes can accumulate over time and result in antigenically different viruses; this may prevent the body’s immune system from recognizing those viruses. Due to rapid mutations, in particular in the hemagglutinin gene, seasonal influenza vaccines must be updated frequently. This requires choosing strains to include in the updates to maximize the vaccines’ benefits, according to estimates of which strains will be circulating in upcoming seasons. This is a challenging prediction task. In this paper we use longitudinally sampled phylogenetic trees based on hemagglutinin sequences from human influenza viruses, together with counts of epitope site polymorphisms in hemagglutinin, to predict which influenza virus strains are likely to be successful. We extract small groups of taxa (subtrees) and use a suite of features of these subtrees as key inputs to the machine learning tools. Using a range of training and testing strategies, including training on H3N2 and testing on H1N1, we find that successful prediction of future expansion of small subtrees is possible from these data, with accuracies of 0.71-0.85 and a classifier ‘area under the curve’ (AUC) 0.75-0.9.
Simulation of multiple microenvironments shows a putative role of RPTPs on the control of Epithelial-to-Mesenchymal Transition
Authors: Pais Ricardo Jorge
Published: April 2019

Epithelial-to-Mesenchymal Transition (EMT) together with Mesenchymal-to-Epithelial Transition (MET) are two natural processes thought to participate in the process of metastasis. Multiple signals from the microenvironment have been reported to drive EMT. However, microenvironment signals that control EMT and promote MET are still unknown. Here, we analysed a regulatory network of EMT involving 8 microenvironment signals to evaluate the role of cell contact signals on the switching between Epithelial and Mesenchymal-like phenotypes. The results demonstrated that RPTP activation by cell contacts have the potential to control EMT and promote MET in the presence of 5 EMT driving signals under physiological scenarios. These simulations also showed that hypoxia inhibits the RPTPs capacity of controlling EMT. In this case, FAT4 activation by cell contacts functions as an alternative control mechanism of EMT except under chronic inflammation, providing a theoretical explanation for the observed correlation between hypoxia and metastasis under chronic inflammation. Taken together, we propose here a natural control mechanism of EMT that supports the idea that this process is tightly regulated by the microenvironment.

Highlights

Cell contact dependent RPTP inhibit EMT and triggers MET in the presence of 5 EMT driving signals in silico.

A proposed molecular mechanism for the control of EMT by cell contact dependent RPTPs.

A proposed explanation for the observed MET in vitro and the correlation between hypoxia and metastasis in vivo.
The number sense is an emergent property of a deep convolutional neural network trained for object recognition
Authors: DeWind Nicholas K.
Published: April 2019

Humans and many non-human animals have the “number sense,” an ability to estimate the number of items in a set without counting. This innate sense of number is hypothesized to provide a foundation for more complex numerical and mathematical concepts. Here I investigated whether we also share the number sense with a deep convolutional neural network (DCNN) trained for object recognition. These in silico networks have revolutionized machine learning over the last seven years, allowing computers to reach human-level performance on object recognition tasks for the first time. Their architecture is based on the structure of mammalian visual cortex, and after they are trained, they provide a highly predictive model of responses in primate visual cortex, suggesting deep homologies. I found that the DCNN demonstrates three key hallmarks of the number sense: numerosity-selective units (analogous to biological neurons), the behavioral ratio effect, and ordinality over representational space. Because the DCNN was not trained to enumerate, I conclude that the number sense is an emergent property of the network, the result of some combination of the network architecture and the constraint to develop the complex representational structure necessary for object recognition. By analogy I conclude that the number sense in animals was not necessarily the result of direct selective pressure to enumerate but might have “come for free” with the evolution of a complex visual system that evolved to identify objects and scenes in the real world.
PyRanges: efficient comparison of genomic intervals in Python
Authors: Stovner Endre Bakken , Sætrom Pål
Published: April 2019

Complex genomic analyses often use sequences of simple set operations like intersection, overlap, and nearest on genomic intervals. These operations, coupled with some custom programming, allow a wide range of analyses to be performed. To this end, we have written PyRanges, a data structure for representing and manipulating genomic intervals and their associated data in Python. Run single-threaded on binary set operations, PyRanges is in median 2.3-9.6 times faster than the popular R GenomicRanges library and is equally memory efficient; run multi-threaded on 8 cores, our library is up to 123 times faster. PyRanges is therefore ideally suited both for individual analyses and as a foundation for future genomic libraries in Python.

Availability

PyRanges is available open-source under the MIT license at https://github.com/biocore-NTNU/pyranges and documentation exists at https://biocore-NTNU.github.io/pyranges/

Contact

endrebak85@gmail.com

Supplementary information

Supplementary data are available.
The pace of life: Time, temperature, and a biological theory of relativity
Authors: Neuheimer Anna B.
Published: April 2019

For living things, time proceeds relative to body temperature. In this contribution, I describe the biochemical underpinnings of this “biological time” and formalize the Biological Theory of Relativity (BTR). Paralleling Einstein’s Special Theory of Relativity, the BTR describes how time progresses across temporal frames of reference, contrasting temperature-scaled biological time with our more familiar (and constant) “calendar” time measures. By characterizing the relationship between these two time frames, the BTR allows us to position observed biological variability on a relevant time-scale. In so doing, we are better able to explain observed variation (both temperature-dependent and -independent), make predictions about the timing of biological phenomena, and even manipulate the biological world around us. The BTR presents a theoretical framework to direct future work regarding an entire landscape of fundamental biological questions across space, time and species.
Presynaptic MAST Kinase Controls Bidirectional Post-Synaptic Responses to Convey Stimulus Valence in C. elegans
Authors: Nakano Shunji , Ikeda Muneki , Tsukada Yuki , Fei Xianfeng , Suzuki Takamasa , Ahluwalia Rhea , Sano Ayana , Kondo Rumi , Ihara Kunio , Hashimoto Koichi , Higashiyama Tetsuya , Mori Ikue
Published: April 2019

Presynaptic plasticity is known to modulate the strength of synaptic transmission. However, it remains unknown whether regulation in presynaptic neurons alters the directionality –positive or negative-of postsynaptic responses. We report here that the C. elegans homologs of MAST kinase, Stomatin and Diacylglycerol kinase act in a thermosensory neuron to elicit in its postsynaptic neuron an excitatory or inhibitory response that correlates with the valence of thermal stimuli. By monitoring neural activity of the valence-coding interneuron in freely behaving animals, we show that the alteration between excitatory and inhibitory responses of the interneuron is mediated by controlling the balance of two opposing signals released from the presynaptic neuron. These alternative transmissions further generate opposing behavioral outputs necessary for the navigation on thermal gradients. Our findings reveal the previously unrecognized capability of presynaptic regulation to evoke bidirectional postsynaptic responses and suggest a molecular mechanism of determining stimulus valence.
Understanding requires tracking: noise and knowledge interact in bilingual comprehension
Authors: Blanco-Elorrieta Esti , Ding Nai , Pylkkänen Liina , Poeppel David
Published: April 2019

Understanding speech in noise is a fundamental challenge for speech comprehension. This perceptual demand is amplified in a second language: it is a common experience in bars, train stations, and other noisy environments that degraded signal quality severely compromises second language comprehension. Through a novel design, paired with a carefully selected participant profile, we independently assessed signal-driven and knowledge-driven contributions to the brain bases of first versus second language processing. We were able to dissociate the neural processes driven by the speech signal from the processes that come from speakers’ knowledge of their first versus second languages. The neurophysiological data show that in combination with impaired access to top-down linguistic information in the second language, the locus of bilinguals’ difficulty in understanding second language speech in noisy conditions arises from a failure to successfully perform a basic, low-level process: cortical entrainment to speech signals above the syllabic level.

Significance statement

Over half of the world’s population is multilingual. Although proficiency in a second language improves over time, even to the point of reaching native-like proficiency, one persistent difficulty is understanding a second language in noisy environments (e.g. in crowds, train stations, etc.). We examined this processing impairment using a novel frequency-tagging paradigm with magnetoencephalography (MEG). We found that the reason underlying bilinguals’ difficulty in understanding second language speech in noisy conditions is induced by a failure to neurally track the operations reflecting structure (i.e., phrase) building.