bluuebunny/crossref_metadata_2025 huggingface dataset:
Zika Virus Causes Acute Infection and Inflammation in the Ovary of Mice Without Apparent Defects in Fertility
Authors: Caine Elizabeth A , Scheaffer Suzanne M , Broughton Darcy E , Salazar Vanessa , Govero Jennifer , Poddar Subhajit , Osula Augustine , Halabi Jacques , Skaznik-Wikiel Malgorzata E , Diamond Michael S , Moley Kelle H
Published: May 2019

Background

Zika virus (ZIKV) has become a global concern because infection of pregnant mothers was linked to congenital birth defects. Zika virus is unique from other flaviviruses, because it is transmitted vertically and sexually in addition to by mosquito vectors. Prior studies in mice, nonhuman primates, and humans have shown that ZIKV targets the testis in males, resulting in persistent infection and oligospermia. However, its effects on the corresponding female gonads have not been evaluated.

Methods

In this study, we assessed the effects of ZIKV on the ovary in nonpregnant mice.

Results

During the acute phase, ZIKV productively infected the ovary causing accumulation of CD4+ and virus-specific CD8+ T cells. T cells protected against ZIKV infection in the ovary, as higher viral burden was measured in CD8−/− and TCRβδ−/− mice. Increased cell death and tissue inflammation in the ovary was observed during the acute phase of infection, but this normalized over time.

Conclusions

In contrast to that observed with males, minimal persistence and no long-term consequences of ZIKV infection on ovarian follicular reserve or fertility were demonstrated in this model. Thus, although ZIKV replicates in cells of the ovary and causes acute oophoritis, there is rapid resolution and no long-term effects on fertility, at least in mice.
Aligning Epistemology and Writing: A Literary Analysis of Qualitative Research
Authors: Mahé Anne-Laure
Published: May 2019

This article examines writing as the last link in the epistemology-theory-methodology alignment. Although political scientists dedicate a great deal of their time to writing, conversations on this topic remain scarce within international relations and political science overall. Notably absent are analyses of the actual writing choices scholars make and what these mean for the knowledge they produce. This article uses the tools of literary analysis to take a closer look at the mechanics of three published academic articles in the fields of international relations and comparative politics. It focuses on how qualitative interviews are written, demonstrates how authors can conceal or reveal the dialogical dimension, and examines how they deal with the conundrum of the representation of research participants. This kind of reflexive analysis reveals the epistemological foundations of a given research article and can be used to identify instances of misrepresentation and misalignment. As such, it is an important tool for the improvement of academic writing.
Prepartum fatty acid supplementation in sheep. IV. Effect of calcium salts with eicosapentaenoic acid and docosahexaenoic acid in the maternal and finishing diet on lamb liver and adipose tissue during the lamb finishing period1
Authors: Coleman Danielle N , Carranza Martin Ana C , Jin Yukun , Lee Kichoon , Relling Alejandro E
Published: May 2019

The objective of this study was to evaluate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation to ewes during late gestation on finishing lamb liver and adipose tissue fatty acid (FA) profile and gene expression. Lambs born from ewes supplemented with Ca salts of EPA + DHA, or palm FA distillate (PFAD) high in palmitic and oleic acid at 0.39% DM during the last 50 d of gestation were used. Lambs were weaned at 61 d of age and adapted to a high concentrate diet for 1.5 mo. After adaptation, 74 lambs (28 pens) were blocked by sex and BW and used in a 2 × 2 factorial arrangement of treatments using the factors of dam supplementation (DS) and lamb supplementation (LS) of Ca salts of EPA + DHA or PFAD at 1.48% DM. Lambs were slaughtered after 42 d and liver and adipose tissue collected for FA and gene expression analysis. Liver concentrations of EPA and DHA were greater (P < 0.01) with LS of EPA + DHA vs. PFAD during the finishing period. In adipose tissue, a lamb × dam interaction was observed for EPA (P = 0.02) and DHA (P = 0.04); LS of EPA + DHA increased EPA and DHA, but the increase was greatest in lambs born from ewes supplemented with PFAD. No lamb × dam treatment interactions were observed for gene expression in liver tissue (P > 0.10). Hepatic mRNA abundance of hormone-sensitive lipase (HSL; P = 0.01) was greater in lambs born from EPA + DHA ewes vs. lambs from PFAD ewes. mRNA expression of stearoyl-CoA desaturase (P < 0.01), fatty acid synthase (P = 0.01), Δ5-desaturase (P < 0.01), and Δ6-desaturase (P < 0.01) were decreased in liver of EPA + DHA lambs. A significant lamb × dam diet interaction was observed for elongation of very long chain fatty acid 2 in adipose tissue (P = 0.01); lambs supplemented with the same FA as their dams had lower expression. Expression of HSL tended (P = 0.08) to be decreased in adipose of EPA + DHA lambs born from EPA + DHA ewes. The changes in mRNA expression suggest that lipogenesis decreased, and lipolysis increased in lamb liver with EPA + DHA vs. PFAD supplementation during the finishing period. In adipose tissue, changes suggest that lipogenesis decreased in lambs born from EPA + DHA supplemented dams and supplemented with EPA + DHA during the finishing period. In addition, these results suggest an interaction between supplementation of FA to dams during late gestation on lamb response of adipose tissue, but not liver, to FA supplementation during the finishing period.
Family Networks and Distributive Politics
Authors: Fafchamps Marcel , Labonne Julien
Published: May 2019

We study the distribution of public services by local politicians when political support spreads through social networks. We sketch a model showing that incumbents target goods and services to individuals who would lead to the largest aggregate loss of support if they stopped supporting the incumbent. Those individuals have high betweenness centrality. Using data on 3.6 million households from the Philippines, we show that households with high betweenness centrality receive a greater number of public services from their local government. This result is robust to the inclusion of controls for program eligibility, detailed measure of family wealth and elite status, family ties with politicians, and other measures of centrality.
Basel and the IASB: Accountability Interdependencies and Consequences for Prudential Regulation
Authors: Riepe Jan
Published: May 2019

Accountability is a key concern for international standard setters. If transnational actors set standards instead of national democratic authorities, then the standard setters might suffer from ‘apparent’ deficits in their democratic accountability and oversight. Consequently, most international standard setters rely on different processes to enhance their accountability and transparency to mitigate concerns about their own standards. Ensuring accountability is already a major challenge for a single or homogenous set of rules or standards. So how can a supranational body design legitimate rules that rest on the standards of another very different supranational standard setter? This study examines the accountability and transparency concerns from the interaction of supranational standard setters that have different objectives. Therefore, I investigate the processes of prudential regulation based on the capital adequacy standard of the Basel Committee on Banking Supervision that relies on the financial accounting standards set by the International Accounting Standards Board. The results show flaws with respect to accountability in the regulatory process that involves another standard setter and how the prudential regulator reacts to these flaws to ensure a higher degree of accountability in its banking regulation.
Inherited Institutions: Cooperation in the Light of Democratic Legitimacy
Authors: Langenbach Pascal , Tausch Franziska
Published: May 2019

We experimentally investigate whether the procedural history of a sanctioning institution affects cooperation in a social dilemma. Subjects inherit the institutional setting from a previous generation of subjects who either decided on the implementation of the institution democratically by majority vote or were exogenously assigned a setting. In order to isolate the impact of the voting procedure, no information about the cooperation history is provided. In line with existing empirical evidence, we observe that in the starting generation cooperation is higher (lower) with a democratically chosen (rejected) institution, as compared to the corresponding, randomly imposed setting. In the second generation, we find no positive effect of the democratic procedural history on cooperation when the institution is implemented. Yet, the vote-based rejection of the institution leads to (marginally) less cooperation in the second generation.
Parental Self-Control as a Moderator of the Association Between Family Conflict and Type 1 Diabetes Management
Authors: Campbell MaryJane S , Berg Cynthia A , Wiebe Deborah J
Published: May 2019

Objective

To examine whether parental self-control (i.e., parents’ ability to regulate their emotions, cognitions, and behaviors) moderates the detrimental association between type 1 diabetes (T1D)-specific family conflict and adherence and HbA1c, such that conflict is most detrimental when parental self-control is low.

Methods

One hundred and forty-nine adolescents diagnosed with T1D (Mage = 14.09; 53% female) reported on their T1D-specific conflict with their mothers and fathers and their adherence to the T1D regimen at two time points (6 months apart). Mothers and fathers reported on their self-control. Glycated hemoglobin (HbA1c) was obtained from the medical record at both time points.

Results

Higher adolescent-reported conflict with father was associated concurrently with higher HbA1c and lower adherence only for fathers with low self-control (ps < .05). Higher adolescent-reported conflict with mother was also associated concurrently with lower adherence only for mothers with lower self-control (p < .05); no significant moderation was found for mothers’ self-control in predicting HbA1c. Longitudinal analyses indicated family conflict with mother predicted changes in adherence and HbA1c, but there were no significant moderating effects of either mother or father self-control.

Conclusions

Lower parental self-control may prevent parents from handling diabetes-related family conflict in a productive manner. We discuss the implications of parental self-control as an intervention target for health care professionals working with adolescents with T1D and their families.
Detecting baryon acoustic oscillations in dark matter from kinematic weak lensing surveys
Authors: Ding Zhejie , Seo Hee-Jong , Huff Eric , Saito Shun , Clowe Douglas
Published: May 2019

We investigate the feasibility of extracting baryon acoustic oscillations (BAO) from cosmic shear tomography. We particularly focus on the BAO scale precision that can be achieved by future spectroscopy-based, kinematic weak lensing (KWL) surveys in comparison to the traditional photometry-based weak lensing surveys. We simulate cosmic shear tomography data of such surveys with a few simple assumptions to focus on the BAO information, extract the spatial power spectrum, and constrain the recovered BAO feature. Due to the small shape noise and the shape of the lensing kernel, we find that a Dark Energy Task Force Stage IV version of such KWL survey can detect the BAO feature in dark matter by 3σ and measure the BAO scale at the precision level of 4 per cent, while it will be difficult to detect the feature in photometry-based weak lensing surveys. With a more optimistic assumption, a KWL-Stage IV could achieve a ${\sim } 2{{\ \rm per\ cent}}$ BAO scale measurement with 4.9σ confidence. A built-in spectroscopic galaxy survey within such KWL survey will allow cross-correlation between galaxies and cosmic shear, which will tighten the constraint beyond the lower limit we present in this paper and therefore possibly allow a detection of the BAO scale bias between galaxies and dark matter.
Intraspecific Variation in Microsatellite Mutation Profiles in Daphnia magna
Authors: Ho Eddie K H , Macrae Fenner , Latta Leigh C , Benner Maia J , Sun Cheng , Ebert Dieter , Schaack Sarah
Published: May 2019

Microsatellite loci (tandem repeats of short nucleotide motifs) are highly abundant in eukaryotic genomes and often used as genetic markers because they can exhibit variation both within and between populations. Although widely recognized for their mutability and utility, the mutation rates of microsatellites have only been empirically estimated in a few species, and have rarely been compared across genotypes and populations within a species. Here, we investigate the dynamics of microsatellite mutation over long- and short-time periods by quantifying the starting abundance and mutation rates for microsatellites for six different genotypes of Daphnia magna, an aquatic microcrustacean, collected from three populations (Finland, Germany, and Israel). Using whole-genome sequences of these six starting genotypes, descendent mutation accumulation (MA) lines, and large population controls (non-MA lines), we find each genotype exhibits a distinctive initial microsatellite profile which clusters according to the population-of-origin. During the period of MA, we observe motif-specific, highly variable, and rapid microsatellite mutation rates across genotypes of D. magna, the average of which is order of magnitude greater than the recently reported rate observed in a single genotype of the congener, Daphnia pulex. In our experiment, genotypes with more microsatellites starting out exhibit greater losses and those with fewer microsatellites starting out exhibit greater gains—a context-dependent mutation bias that has not been reported previously. We discuss how genotype-specific mutation rates and spectra, in conjunction with evolutionary forces, can shape both the differential accumulation of repeat content in the genome and the evolution of mutation rates.
DNAvisualization.org: a serverless web tool for DNA sequence visualization
Authors: Lee Benjamin D , Timony Michael A , Ruiz Pablo
Published: May 2019

Raw DNA sequences contain an immense amount of meaningful biological information. However, these sequences are hard for humans to intuitively interpret. To solve this problem, a number of methods have been proposed to transform DNA sequences into two-dimensional visualizations. DNAvisualization.org implements several of these methods in a cost effective and performant manner via a novel, entirely serverless architecture. By taking advantage of recent developments in serverless parallel computing and selective data retrieval, the website is able to offer users the ability to visualize up to thirty 4.5 Mb DNA sequences simultaneously using one of five supported methods and to export these visualizations in a variety of publication-ready formats.
Validation of the GARD™skin Assay for Assessment of Chemical Skin Sensitizers: Ring Trial Results of Predictive Performance and Reproducibility
Authors: Johansson Henrik , Gradin Robin , Johansson Angelica , Adriaens Els , Edwards Amber , Zuckerstätter Veronika , Jerre Anders , Burleson Florence , Gehrke Helge , Roggen Erwin L
Published: May 2019

Proactive identification of chemicals with skin sensitizing properties is a key toxicological endpoint within chemical safety assessment, as required by legislation for registration of chemicals. In order to meet demands of increased animal welfare and facilitate increased testing efficiency also in nonregulatory settings, considerable efforts have been made to develop nonanimal approaches to replace current animal testing. Genomic Allergen Rapid Detection (GARD™) is a state-of-the-art technology platform, the most advanced application of which is the assay for assessment of skin sensitizing chemicals, GARD™skin. The methodology is based on a dendritic cell (DC)-like cell line, thus mimicking the mechanistic events leading to initiation and modulation of downstream immunological responses. Induced transcriptional changes are measured following exposure to test chemicals, providing a detailed evaluation of cell activation. These changes are associated with the immunological decision-making role of DCs in vivo and include among other phenotypic modifications, up-regulation of co-stimulatory molecules, induction of cellular and oxidative stress pathways and xenobiotic responses, and provide a holistic readout of substance-induced DC activation. Here, results from an inter-laboratory ring trial of GARD™skin, conducted in compliance with OECD guidance documents and comprising a blinded chemical test set of 28 chemicals, are summarized. The assay was found to be transferable to naïve laboratories, with an inter-laboratory reproducibility of 92.0%. The within-laboratory reproducibility ranged between 82.1% and 88.9%, whereas the cumulative predictive accuracy across the 3 laboratories was 93.8%. It was concluded that GARD™skin is a robust and reliable method for the identification of skin sensitizing chemicals and suitable for stand-alone use or as a constituent of integrated testing. These data form the basis for the regulatory validation of GARD™skin.
Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury
Authors: Holman Natalie S , Church Rachel J , Nautiyal Manisha , Rose Kelly A , Thacker Sarah E , Otieno Monicah A , Wolf Kristina K , LeCluyse Edward , Watkins Paul B , Mosedale Merrie
Published: May 2019

Most idiosyncratic drug-induced liver injury appears to result from an adaptive immune attack on the liver. Recent evidence suggests that the T-cell response may be facilitated by the loss of immune tolerance. In this study, we explored the hypothesis that constitutively released hepatocyte-derived exosomes (HDE) are important for maintaining normal liver immune tolerance. Exosomes were isolated from the conditioned medium of primary human hepatocytes via polymer precipitation. Mock controls were prepared by processing fresh medium that was not hepatocyte exposed with precipitation reagent. THP-1 monocytes were then treated with HDE or an equivalent volume of mock control for 24 h, followed by a 6-h stimulation with LPS. HDE exposure resulted in a significant decrease in the LPS-induced media levels of interleukin-1β and interleukin-8. Gene expression profiling performed in THP-1 cells just prior to LPS-induced stimulation identified a significant decrease among genes associated with innate immune response. MicroRNA (miRNA) profiling was performed on the HDE to identify exosome contents that may drive immune suppression. Many of the predicted mRNA target genes for the most abundant microRNAs in HDE were among the differentially expressed genes in THP-1 cells. Taken together, our data suggest that HDE play a role in maintaining normal liver immune tolerance. Future experiments will explore the possibility that drugs causing idiosyncratic liver injury promote the loss of homeostatic HDE signaling.
Differential Sensitivity to In Vitro Inhibition of Cytochrome P450 Aromatase (CYP19) Activity Among 18 Freshwater Fishes
Authors: Doering Jon A , Villeneuve Daniel L , Fay Kellie A , Randolph Eric C , Jensen Kathleen M , Kahl Michael D , LaLone Carlie A , Ankley Gerald T
Published: May 2019

There is significant concern regarding potential impairment of fish reproduction associated with endocrine disrupting chemicals. Aromatase (CYP19) is a steroidogenic enzyme involved in the conversion of androgens to estrogens. Inhibition of aromatase by chemicals can result in reduced concentrations of estrogens leading to adverse reproductive effects. These effects have been extensively investigated in a small number of laboratory model fishes, such as fathead minnow (Pimephales promelas), Japanese medaka (Oryzias latipes), and zebrafish (Danio rerio). But, differences in sensitivity among species are largely unknown. Therefore, this study took a first step toward understanding potential differences in sensitivity to aromatase inhibitors among fishes. Specifically, a standard in vitro aromatase inhibition assay using subcellular fractions of whole tissue homogenates was used to evaluate the potential sensitivity of 18 phylogenetically diverse species of freshwater fish to the nonsteroidal aromatase inhibitor fadrozole. Sensitivity to fadrozole ranged by more than 52-fold among these species. Five species were further investigated for sensitivity to up to 4 additional nonsteroidal aromatase inhibitors, letrozole, imazalil, prochloraz, and propiconazole. Potencies of each of these chemicals relative to fadrozole ranged by up to 2 orders of magnitude among the 5 species. Fathead minnow, Japanese medaka, and zebrafish were among the least sensitive to all the investigated chemicals; therefore, ecological risks of aromatase inhibitors derived from these species might not be adequately protective of more sensitive native fishes. This information could guide more objective ecological risk assessments of native fishes to chemicals that inhibit aromatase.
Papaya Ringspot Virus Isolates From Papaya in Bangladesh: Detection, Characterization, and Distribution
Authors: Hamim Islam , Al Rwahnih Maher , Borth Wayne B. , Suzuki Jon Y. , Melzer Michael J. , Wall Marisa M. , Green James C. , Hu John S.
Published: May 2019

Papaya ringspot virus (PRSV) is the major constraint to papaya (Carica papaya) production in Bangladesh. Disease symptoms occurred in 90 to 100% of the plants surveyed. Full-length genomes of PRSV strains from severely infected papaya plants were determined using the Illumina NextSeq 500 platform, followed by Sanger DNA sequencing of viral genomes obtained by reverse-transcription PCR(RT-PCR). The genome sequences of two distinct PRSV strains, PRSV BD-1 (10,300 bp) and PRSV BD-2 (10,325 bp) were 74 and 83% identical to each other, respectively, at the nucleotide and amino acid levels. PRSV BD-1 and PRSV BD-2 were 74 to 75% and 79 to 88% identical, respectively, to other full-length PRSV sequences at the nucleotide level. Based on phylogenetic analysis, PRSV BD-2 was most closely related to PRSV-Meghalaya (MF356497) from papaya in India. PRSV BD-1 formed a branch distinct from the other PRSV sequences based on nucleotide and amino acid sequence comparisons. Comparisons of the genome sequences of these two strains with other sequenced PRSV genomes indicated two putative recombination events in PRSV BD-2. One recombinant event contained a 2,766-nucleotide fragment highly identical to PRSV-Meghalaya (MF356497). The other recombinant event contained a 5,105-nucleotide fragment highly identical to PRSV-China (KY933061). The occurrence rates of PRSV BD-1 and PRSV BD-2 in the sampled areas of Bangladesh were approximately 19 and 69%, respectively. Plants infected with both strains (11%) exhibited more severe symptoms than plants infected with either strain alone. The full-length genome sequences of these new PRSV strains and their distribution provide important information regarding the dynamics of papaya ringspot virus infections in papaya in Bangladesh.
Pharmacologically targeting a novel pathway of sodium iodide symporter trafficking to enhance radioiodine uptake
Authors: Fletcher Alice , Read Martin L. , Thornton Caitlin E.M. , Larner Dean P. , Poole Vikki L. , Brookes Katie , Nieto Hannah R. , Alshahrani Mohammed , Thompson Rebecca J. , Lavery Gareth G. , Campbell Moray J. , Boelaert Kristien , Turnell Andrew S. , Smith Vicki E. , McCabe Christopher J.
Published: May 2019

Radioiodine treatment fails ≥25% of patients with thyroid cancer and has been proposed as a potential treatment for breast cancer. Cellular iodide uptake is governed by the sodium iodide symporter (NIS), which is frequently mislocalized in thyroid and breast tumours. However, the trafficking of NIS to the plasma membrane (PM) is ill-defined. Through mass spectrometry, co-immunoprecipitation, cell surface biotinylation and proximity ligation assays we identify two proteins which control NIS subcellular trafficking: ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP). HiLo microscopy revealed ARF4 enhanced NIS trafficking in co-incident PM vesicles, governed by a C-terminal VXPX motif, whilst papillary thyroid cancers (PTC) demonstrate repressed ARF4 expression. In contrast, VCP, the central protein in ER-associated degradation, specifically bound NIS and decreased its PM localization. Five chemically distinct allosteric VCP inhibitors all overcame VCP-mediated repression of NIS function. In mice, two re-purposed FDA-approved VCP inhibitors significantly enhanced radioiodine uptake into thyrocytes, whilst human primary thyrocytes showed similar increases. Critically, PTC patients with high tumoural VCP expression who received radioiodine had strikingly worse disease-free survival. These studies now delineate the mechanisms of NIS trafficking, and for the first time open the therapeutic possibility of systemically enhancing radioiodine uptake in patients via FDA-approved drugs.

One Sentence Summary

Novel NIS interactors ARF4 and VCP alter NIS trafficking in vitro, and FDA-approved VCP inhibitors can significantly enhance radioiodine uptake.
Inhibition of host Lactate dehydrogenase A by a small-molecule limitsMycobacterium tuberculosisgrowth and potentiates bactericidal activity of isoniazid
Authors: Krishnamoorthy Gopinath , Kaiser Peggy , Abed Ulrike Abu , Weiner January , Moura-Alves Pedro , Brinkmann Volker , Kaufmann Stefan H. E.
Published: May 2019

Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate. Increased lactate turnover is shared by malignant and immune cells. Hypoxic lung granuloma inMycobacterium tuberculosis-infected animals present elevated levels ofLdhaand lactate. Such alteration in metabolic milieu could influence the outcome of interactions betweenM. tuberculosisand its infected immune cells. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for Tuberculosis (TB) disease progression and its potential as a host-directed therapeutic target. To this end, we administered FX11, a small-molecule NADH-competitive LDHA inhibitor, toM. tuberculosisinfected C57BL/6J mice and Nos2−/−mice with hypoxic necrotizing lung TB lesions mimicking human pathology more closely. FX11 did not inhibitM. tuberculosisgrowth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limitedM. tuberculosisreplication and onset of necrotic lesions in Nos2−/−mice. In this model, Isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant subpopulation. This adverse effect was corrected by adjunct FX11 treatment and augmented the INH-derived bactericidal effect againstM. tuberculosis. Our findings therefore support LDHA as a potential target for host-directed adjunctive TB therapy and encourage further investigations into the underlying mechanism.

IMPORTANCE

Tuberculosis (TB) continues to be a global health threat of critical dimension. Standard TB drug treatment is prolonged and cumbersome. Inappropriate treatment or non-compliance results in emergence of drug-resistantMycobacterium tuberculosisstrains (MDR-TB) that render current treatment options ineffective. Targeting the host immune system as adjunct therapy to augment bacterial clearance is attractive as it is also expected to be effective against MDR-TB. Here, we provide evidence that pharmaceutical blockade of host lactate dehydrogenase A (LDHA) by a small-molecule limitsM. tuberculosisgrowth and reduces pathology. Notably, LDHA inhibition potentiates the effect of Isoniazid, a first-line anti-TB drug. Hence, its implications of our findings for short-term TB treatment are profound. In sum, our findings establish murine LDHA as a potential target for host-directed TB therapy.
Origin of the bidirectionality of cerebrospinal fluid flow and impact on long-range transport between brain and spinal cord
Authors: Thouvenin Olivier , Keiser Ludovic , Cantaut-Belarif Yasmine , Carbo-Tano Martin , Verweij Frederik , Jurisch-Yaksi Nathalie , Bardet Pierre-Luc , Niel Guillaume Van , Gallaire François , Wyart Claire
Published: May 2019

The circulation of cerebrospinal fluid (CSF) plays pivotal roles for body axis formation and brain development. During embryogenesis, CSF is rich in particles and proteins and flows bidirectionally in the central canal. The origins of bidirectional flow and its impact on development are unknown. Experiments combined with modeling and simulations demonstrate that the bidirectionality of CSF flow is generated locally by caudally-polarized motile cilia confined to the ventral wall of the central canal. Such active bidirectional flow of the CSF accelerates the long-range transport of particles propagating rostrally and caudally. In addition, spontaneous muscle contractions increase local CSF flow and consequently enhance long-range transport of extracellular lipidic particles. Focal ablation of the channel connecting brain ventricles to the central canal reduces embryo length, indicating that long-range transport contributes to embryonic growth. Our study also demonstrates that at this early stage, motile cilia ensure the proper formation of the central canal.
Rewiring of transcriptional networks as a major event leading to the diversity of asexual multicellularity in fungi
Authors: Etxebeste Oier , Otamendi Ainara , Garzia Aitor , Espeso Eduardo A. , Cortese Marc S.
Published: May 2019

Complex multicellularity (CM) is characterized by the generation of three-dimensional structures that follow a genetically controlled program. CM emerged at least five times in evolution, one of them in fungi. There are two types of CM programs in fungi, leading, respectively, to the formation of sexual or asexual spores. Asexual spores foment the spread of mycoses, as they are the main vehicle for dispersion. In spite of this key dependence, there is great morphological diversity of asexual multicellular structures in fungi. To advance the understanding of the mechanisms that control initiation and progression of asexual CM and how they can lead to such a remarkable morphological diversification, we studied 503 fungal proteomes, representing all phyla and subphyla, and most known classes. Conservation analyses of 33 regulators of asexual development suggest stepwise emergence of transcription factors. While velvet proteins constitute one of the most ancient systems, the central regulator BrlA emerged late in evolution (with the class eurotiomycetes). Some factors, such as MoConX4, seem to be species-specific. These observations suggest that the emergence and evolution of transcriptional regulators rewire transcriptional networks. This process could reach the species level, resulting in a vast diversity of morphologies.

One-sentence summary

A study of the evolution of regulators that control the production of asexual spores in fungi.
Genetic Resilience of a Once Endangered Species, Tibetan Antelope (Pantholops hodgsonii)
Authors: Shi Yue , Chen Jiarui , Su Jianping , Zhang Tongzuo , Wasser Samuel K.
Published: May 2019

Population reduction is generally assumed to reduce the population’s genetic diversity and hence its ability to adapt to environmental change. However, if life history traits that promote gene flow buffer populations from such impacts, conservation efforts should aim to maintain those traits in vulnerable species. Tibetan antelope (Pantholops hodgsonii) has experienced population reduction by 95% due to poaching during the 20thcentury. We hypothesize that opportunities for gene flow provided by their sex-specific migration buffered their genetic diversity from the poaching impacts. We measured the mtDNA (control region, CR) and nuDNA (microsatellites or STRs) diversity, population differentiation, along with the change in effective population size (pre-poaching era vs. post-poaching era) and tested for a genetic bottleneck. Our results showed that Tibetan antelope maintained considerable genetic diversity in both mtDNA CR and STR markers (Hd= 0.9970 and Hobs= 0.8446, respectively), despite a marked reduction in post-poaching effective population size 368.9 (95% CI of 249.3 - 660.6) compared to the pre-poaching average (4.93×103- 4.17×104). Post-poached populations also had low population structure and showed no evidence of a genetic bottleneck. Pairwise Fstvalues using CR haplotype frequencies were higher than those using STR allele frequencies, suggesting different degrees of gene flow mediated by females and males. This study suggests that the Tibetan antelope’s sex-specific migration buffered their loss of genetic diversity in the face of severe demographic decline. These findings highlight the importance of recognizing the traits likely to maintain genetic diversity and promoting conservation efforts that allow them to be exercised. For Tibetan antelope, this requires assuring that their migration routes remain unobstructed by growing human disturbances while continuing to enforce anti-poaching law enforcement efforts.
Novel functions of Kaposi’s sarcoma herpesvirus viral FLICE inhibitory protein
Authors: Herold Kevin , Ruffin Ayana , Constantine Mathew , Causey Amerria , Mitchell Ashley E. , Chmura Jennifer C. , Moorad Razia , Ehrlich Elana S.
Published: May 2019

KSHV viral FLICE inhibitory protein (vFLIP) is a potent activator of NF-κB signaling and an inhibitor of apoptosis and autophagy. Inhibition of vFLIP function and NF-κB signaling promotes lytic reactivation. Here we provide evidence for a novel function of vFLIP in promoting NFκB signaling through inhibition of the DUB activity of the negative regulator, A20. We demonstrate interaction of vFLIP with the Itch/A20 ubiquitin editing complex. We have identified a SUMO interaction motif in vFLIP that is required for NF-κB activation. Mutation of the SIM in BAC16 resulted in increased spontaneous RTA expression and loss of spindle cell morphology. Our results suggest a role for SUMO in mediating vFLIP function and provide evidence for vFLIP modulation of the negative regulation of NF-κB signaling by A20. Our results provide further insight into the function of vFLIP and SUMO in the regulation of NF-κB signaling and the latent lytic transition.
Differentiation between wild and domesticated Ungulates based on ecological niches
Authors: Hendrix Elke , Vos Rutger
Published: May 2019

The domestication of flora and fauna is one of the most significant transitions in humankind’s history. It changed human societies drastically with alterations in biodiversity, atmospheric composition and land use. Humans have domesticated relatively few large animals and all of them belong to the Ungulates, though they are only 15 species of the ±150 that the entire group comprises. This can partially be explained by behavioral and life history pre-adaptations, e.g. social group structure, mating behavior, parent-young interaction, feeding behavior, and response to humans. The other dimension of proposed pre-adapatations concerns the biomes from which domesticated Ungulates originate. Here we test whether environmental preferences i.e. niches and related niche traits, differentiate between wild and domesticated Ungulates. We used three methods to determine the niche dimensions for each species and calculate overlap in niche space between them. Two methods are based on MaxEnt ecological niche models and one method uses raw occurrence data. Our results show that there is no weighted combination of environmental traits that clusters all domesticated Ungulates to the exclusion of all wild ones. On the contrary, domesticated Ungulates are overdispersed in niche space, indicating that the major pre-adaptations for domestication are not directly related to the abiotic niche. However, phylogenetic generalized linear modelling of selected niche dimensions does predict domestication significantly. We conclude that further research of other traits is needed.
Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein
Authors: Eshraghi Mehdi , Karunadharma Pabalu , Blin Juliana , Shahani Neelam , Ricci Emiliano , Michel Audrey , Urban Nicolai , Galli Nicole , Rao Sumitha Rajendra , Sharma Manish , Florescu Katie , Subramaniam Srinivasa
Published: May 2019

The regulators that stall ribosome translocation are poorly understood. We find that polyglutamine-expanded mutant Huntingtin (mHtt), the Huntington’s disease (HD) causing protein, promotes ribosome stalling and physiologically suppresses protein synthesis. A comprehensive, genome-wide analysis of ribosome footprint profiling (Ribo-Seq) revealed widespread ribosome stalling on mRNA transcripts and a shift in the distribution of ribosomes toward the 5’ end, with single-codon unique pauses on selected mRNAs in HD cells. In Ribo-Seq, we found fragile X mental retardation protein (FMRP), a known regulator of ribosome stalling, translationally upregulated and it co-immunoprecipitated with mHtt in HD cells and postmortem brain. Depletion of FMRP gene,Fmr1, however, did not affect the mHtt-mediated suppression of protein synthesis or ribosome stalling in HD cells. Consistent with this, heterozygous deletion ofFmr1in Q175FDN-Het mouse model, Q175FDN-Het;Fmr1+/–, showed no discernable phenotype, but a subtle deficit in motor skill learning. On the other hand, depletion of mHtt, which binds directly to ribosomes in an RNase-sensitive manner, enhanced global protein synthesis, increased ribosome translocation and decreased stalling. This mechanistic knowledge advances our understanding of the inhibitory role of mHtt in ribosome translocation and may lead to novel target(s) identification and therapeutic approaches that modulate ribosome stalling in HD.

One Sentence Summary

Huntington’s disease (HD) protein, mHtt, binds to ribosomes and affects their translocation and promotes stalling independent of the fragile X mental retardation protein.
MEK1/2 in Rhabdomyosarcoma
Authors: Crawford Kenneth A. , Cleary Megan M. , Ricker Cora A. , Svalina Matthew N. , Shern John F. , Chen Hung-I Harry , Berlow Noah E. , Keller Charles , Li Guangheng
Published: May 2019

Alveolar and embryonal rhabdomyosarcoma (RMS) are soft-tissue cancers that affect children, adolescents, and young adults. Sometimes referred to as muscle cancer, RMS is a cancer of muscle and non-muscle origin that phenocopies incompletely differentiated myoblasts or activated satellite (muscle stem) cells. Interestingly, embryonal RMS (ERMS) has been observed to undergo terminal myogenic differentiation in response to stress induced by chemotherapy and radiation therapy4, 9, 24. Given the propensity of rhabdomyosarcoma to differentiation, in this report we explore the use of differentiation therapy combining MEK inhibitor (MEKi) cobimetinib and chemotherapy as a strategy to halt RMS growth. We evaluated a representative panel of RMS cell lines with cobimetinib and chemotherapy in two dosing schedules that mimic clinical use followed by cell growth evaluation and high content analysis (differentiation) assays. We uncovered that cobimetinib does not have significant additive or synergistic effects on cell differentiation or cell growth with chemotherapy in RMS and can have unanticipated antagonistic effects; specifically, pre-exposure of cobimetinib to cells can decrease the effectiveness of chemotherapy-mediated cell growth inhibition in vitro. Although differentiation-therapy is still a potential viable strategy in RMS, our data do not support MEKi/chemotherapy co-treatment in this context.
Genic evidence that gnetophytes are sister to all other seed plants
Authors: Zhang Yinzhi , Liu Zhiming
Published: May 2019

Gnetophytes, comprising three relict genera, Gnetum, Welwitchia and Ephedra, are a morphologically diverse and enigmatic assemblage among seed plants. Despite recent progress on phylogenomic analyses or the insights from the recently decoded Gnetum genome, the relationship between gnetophytes and other seed plant lineages is still one of the outstanding, unresolved questions in plant sciences. Here, we showed that phylogenetic studies from nuclear genes support the hypothesis that places gnetophytes as sister to all other extant seed plants and so this hypothesis should not be ruled out according to phylogenetic inference based on nuclear genes. However, this extraordinarily difficult phylogenetic problem might never be solved by phylogenetic inference based gene tree under various artificial selection. Hence, we adopted a novel approach, comparing gene divergence among different lineages, to solve the conflicts by showing that gnetophytes actually did not gained a set of genes like the most recent common ancestor (MRCA) of other seed plants. This distinct gene evolution pattern could not be explained by random gene lost as in other seed plants but should be interpreted by the early divergence of gnetophytes from rest of seed plants. With such a placement, the gymnosperms are paraphyletic and there should be three distinct groups of living seed plants: gnetophytes, non-gnetophytes gymnosperms and angiosperms.
Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics
Authors: Krieger Teresa G , Tirier Stephan M , Park Jeongbin , Eisemann Tanja , Peterziel Heike , Angel Peter , Eils Roland , Conrad Christian
Published: May 2019

Glioblastoma multiforme (GBM) are devastating neoplasms with high invasive capacity. GBM has been difficult to study in vitro. Therapeutic progress is also limited by cellular heterogeneity within and between tumors. To address these challenges, we present an experimental model using human cerebral organoids as a scaffold for patient-derived glioblastoma cell invasion. By tissue clearing and confocal microscopy, we show that tumor cells within organoids extend a network of long microtubes, recapitulating the in vivo behavior of GBM. Single-cell RNA-seq of GBM cells before and after co-culture with organoid cells reveals transcriptional changes implicated in the invasion process that are coherent across patient samples, indicating that GBM cells reactively upregulate genes required for their dispersion. Functional therapeutic targets are identified by an in silico receptor-ligand pairing screen detecting potential interactions between GBM and organoid cells. Taken together, our model has proven useful for studying GBM invasion and transcriptional heterogeneity in vitro, with applications for both pharmacological screens and patient-specific treatment selection at a time scale amenable to clinical practice.
Glycosylation-dependent enhanced cell-binding and infectivity through DC-SIGN in the West African Ebola virus Makona
Authors: Lasala Fátima , Luczkowiak Joanna , Kremer Leonor , Casasnovas Jose M , Delgado Rafael
Published: May 2019

Since its discovery in Zaire in 1976, most ebolavirus outbreaks described occurred mainly in remote and poorly communicated areas of Central Africa and affected a limited number of individuals. Nonetheless, the Ebola epidemic that began in West Africa at the end of 2013 spread rapidly and reached an unprecedented scale. This epidemic was caused by the Makona variant of Zaire ebolavirus (EBOV). Monitoring of the EBOV Makona evolution throughout the epidemic identified the A82V substitution in the EBOV glycoprotein (GP) at the beginning of the epidemic, which correlated with its rapid spread. The Makona GP-V82 variant exhibits slightly higher human and primate cell infectivity. Host factors responsible for the enhanced transmission of EBOV Makona have yet to be identified. Here we show that the GP A82V substitution increases EBOV avidity for its DC-SIGN lectin receptor, which enhances cell-binding and infectivity of dendritic cells and macrophages, the primary cell subsets infected during the initial stages of the disease. Using a pseudotype lentivirus system, we identified two GP N-linked glycosylation responsible of the augmented Makona GP-V82 cell infection. Crystal structures indicated how the GP A82V substitution drives exposure of a key glycan and facilitates lectin recognition. Thus, DC-SIGN might be an important host determinant for the unique dissemination of EBOV during the 2013-2016 epidemic, which likely promoted host-to-host transmission by enhancing viral infection of dendritic cells in the skin and mucosa. This study also reveals that variations in virus envelope glycosylations can be a common pathway for virus adaptation to human transmission.

Synopsis

The Zaire ebolavirus (EBOV) Makona, responsible of the largest outbreak of Ebola virus disease (EVD) in West Africa from 2013-2016, displayed a glycosylation-dependent enhancement of binding and subsequent infectivity in cells expressing the DC-SIGN surface lectin.
Effect of high-salt diet on mean arterial pressure, renal epithelial sodium channels and aquaporin subunits expression levels in Spontaneously Hypertensive Rats
Authors: Ramachandran Chitra Devi , Gholami Khadijeh , Lam Sau-Kuen , Mustafa Mohd Rais , Hoe See-Ziau
Published: May 2019

An increase in blood pressure (BP) by a high-salt (HS) diet may involve the changes in the expression of epithelium sodium channels (ENaCs) and aquaporins (AQPs) in the kidney which affect the sodium- and water-handling mechanisms. In the present study, spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were exposed to HS and regular-salt (RS) diets for 6 weeks and fluid intake was monitored. After 6 weeks, mean arterial pressure (MAP) and plasma hormonal activity of atrial natriuretic peptide (ANP), levels of angiotensin II (Ang II), aldosterone and arginine vasopressin (AVP) were determined. The expression of mRNA and protein levels of ENaC and AQP subunits in kidneys were quantified by real-time PCR and Western blotting. High-salt diet caused higher MAP only in SHRs and higher fluid intake in both strains of rats when compared with their respective controls on RS diet. The plasma levels of Ang II and aldosterone were low in both SHRs and WKY rats fed with HS diet. Meanwhile, plasma ANP activity was high in both strains of rats on HS diet; whilst the AVP showed vice versa effects. The renal expression of mRNA and protein levels of α- and γ-ENaCs was lowered by HS diet in both SHRs and WKY rats. Although β-ENaC mRNA and protein expression levels were depressed in SHRs but they were enhanced in WKY rats. On the other hand, AQP-1, 2 and 7 mRNA and protein expression levels were lowered in both strains of rats fed with HS diet, while that of AQP-3, 4 and 6 showed no significant changes. The suppression of mRNA and protein expression levels of ENaC and AQP subunits suggests that the HS-induced increase in the MAP of SHRs may not be due to the renal sodium and water retention solely.
Factors affecting pathogenicity of the turfgrass dollar spot pathogen in natural and model hosts
Authors: Rioux R.A. , Stephens C.M. , Kerns J.P.
Published: May 2019

Clarireediasp. (formerly calledSclerotinia homoeocarpa), the fungal pathogen that causes dollar spot of turfgrasses, produces oxalic acid but the role of this toxin inClarireediasp. pathogenesis is unknown. In the current study, whole plant inoculation assays were used to evaluate pathogenesis ofClarireediasp. in various model hosts and investigate the role of oxalic acid in dollar spot disease. These assays revealed that both host endogenous oxalate content and pathogen-produced oxalic acid influence the timing and magnitude of symptom development. In time-course expression analysis, oxalate oxidase and related defense-associated germin-like protein genes in creeping bentgrass showed strong up-regulation starting at 48-72 hpi, indicating that germin-like protein genes are most likely involved in defense following initial contact with the pathogen and demonstrating the importance of oxalic acid inClarireediasp. pathogenesis. Overall, the results of these studies suggest that oxalic acid and host endogenous oxalate content are important for pathogenesis byClarireediasp. and may be associated with the transition from biotrophy to necrotrophy during host infection.