bluuebunny/crossref_metadata_2025 huggingface dataset:
Enterprising Women: Independence, Finance and Virago Press, c.1976–93
Authors: Withers D -M
Published: November 2019

Virago Press were established in 1972 and became one of the twentieth century’s most enduring publishing brands. As a women-led enterprise, articulations of independence have defined key moments in Virago’s history. This article explores two moments when the company re-structured as independent, in 1976 and 1987. To become successful, Virago had to overcome barriers that have historically hindered women’s participation in business, namely limited social capital and difficulties accessing finance. Virago founder Carmen Callil’s friendship with publisher Paul Hamlyn and printing entrepreneur Robert Gavron embedded Virago in networks of male entrepreneurial knowledge that helped shape the evolution of the company. Such networks were vital to Virago securing investment from Rothschilds Ventures Limited in 1987 who were, at that time, leading figures in the UK’s growing private equity industry. This article contributes to growing historical understanding of the synergies between financial, arts and culture industries in the 1980s. It argues that while this era offered new opportunities for women to participate in business, such participation was tempered by new forms of legal and financial discipline that re-calibrated existing gender inequalities within business cultures. Due to the time periods under consideration, this article also analyses how entrepreneurial practices and opportunities for women changed dramatically with the onset of Thatcher’s ‘Enterprise Culture’.
Exploring students’ proof comprehension of the Cauchy Generalized Mean Value Theorem
Authors: Kolahdouz Fahimeh , Radmehr Farzad , Alamolhodaei Hassan
Published: November 2019

Undergraduate students majoring in mathematics often face difficulties in comprehending mathematical proofs. Inspired by a number of studies related to students’ proof comprehension, and Mejia-Ramos et al.’s study in particular, a test was designed in relation to the proof comprehension of the Cauchy Generalized Mean Value Theorem (CGMVT). The test mainly focused on (a.) investigating students’ understanding of relations between the statements within the CGMVT proof and (b.) the relations between the CGMVT and other theorems. Thirty-five first-year university students voluntarily participated in this study. In addition, 10 of these students were subsequently interviewed to seek their opinion about the test. Test results indicated that most of the students lacked an understanding of the relations between the mathematical statements within the CGMVT proof, and the relations between the CGMVT and other theorems. The results of interviews showed that this type of assessment was new to students and helped them to improve their insights into mathematical proofs. The findings suggested such a test design could be used more frequently in assessments to aid instructors’ understanding of students’ proof comprehension and to teach students how mathematical proofs should be learned.
Pseudorivibacter rhizosphaerae gen. nov., sp. nov., isolated from rhizosphere soil of Camellia sinensis (L.) O. Ktze and emended description of the genus Rivibacter
Authors: Zhou Xing-Kui , Li Qing-Qing , Dong Li-Min , Yang Deng-Qiang , Liu Lan , Fang Bao-Zhu , Jeon Che Ok , Li Wen-Jun , Duan Yan-Qing
Published: November 2019

A Gram-stain-negative, facultative anaerobic, motile and straight rod-shaped bacterium, designated strain C1-9T, was isolated from rhizosphere soil of Camellia sinensis (L.) O. Ktze collected from a tea garden in Huize, south-western PR China. Cells were oxidase-positive and catalase-negative. Growth occurred at 20–40 °C and pH 6.0–10.0, with an optimal growth at 30 °C and pH 7.0. The respiratory quinone was detected as ubiquinone-8 (Q-8). The major fatty acids were identified as summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), C16 : 0 and summed feature 8 (C18 : 1ω7c or C18 : 1ω6c). The cellular polar lipids contained phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, three unidentified phospholipids, two unidentified lipids, one unidentified aminophospholipid and one unidentified aminolipid. The polyamine types were detected as 1,8-diaminooctane and 2-hydroxyputrescine. The genomic DNA G+C content was 68.6 mol%. Based on the results of 16S rRNA gene sequence analysis, strain C1-9T (MF687442) showed highest sequence similarity to

Rivibacter subsaxonicus

DSM 19570T (97.1 %). The phylogenetic tree based on 16S rRNA gene sequences showed that strain C1-9T clustered close to

R. subsaxonicus

DSM 19570T,

Methylibium petroleiphilum

CCTCC AB 2014193T and species belonging to the genera

Rhizobacter

and

Piscinibacter

. The phylogenomic tree indicated that strain C1-9T formed a clade with

R. subsaxonicus

. The average nucleotide identity value was 76.0 % between strain C1-9T and

R. subsaxonicus

DSM 19570T, which is lower than the prokaryotic species delineation threshold of 95.0–96.0 %. The polyphasic taxonomic characteristics indicated that strain C1-9T represents a novel species of a new genus within the order

Burkholderiales

, for which the name Pseudorivibacter rhizosphaerae gen. nov., sp. nov. (type strain C1-9T = KCTC 62325T=CGMCC 1.13864T) is proposed.
Boosting Chinese healthcare service providers’ utilization of behavioural and pharmacotherapy interventions for cigarette smoking cessation by ‘WeChat WeQuit’ program
Authors: Liao Yanhui , Wang Yunfei , Wu Zhenzhen , Liu Yuhang , Wang Chudong , Tang Jinsong
Published: November 2019

Introduction

In China, standard smoking cessation practices are rarely used by healthcare service providers (HSPs). WeChat, a popular social media app, has been widely used in China.

Methods

In this single-blind, randomized trial, undertaken in China with 8-week interventions and follow-up to 52 weeks, about 2,200 providers from different health care settings will be randomly selected to the intervention or control group. This trial will be conducted in China between June 2018 to October 2019. The intervention group will receive regular smoking cessation training program messages by the professional team to 8 weeks and follow to 52 weeks. A hard copy of the manual will be sent to each provider from the intervention group by mail after randomization. The Control group will only communicate by themselves and receive thanks messages for 8 weeks, and follow-up to 52 weeks. The trial will be carried out in two phases. The first phase is the pilot study (n=200, 8-week intervention and follow-up to 16 weeks) and the second is the main study (n=2000, 8-week intervention and follow-up to 52 weeks). The primary outcome measure will be the utilization rate of behavioural and pharmacotherapy interventions for smoking patients from 8 to 52 weeks. This trial is registered atClinicalTrials.gov(numberNCT03556774).

Conclusions

This program will be the first evidence-based educational program in smoking cessation designed specifically for the improvement of Chinese HSPs’ utilization of behavioural and pharmacotherapy interventions for cigarette smoking cessation in health care settings by the ‘WeChat WeQuit’ program.

Implications

This protocol may show that ‘WeChat WeQuit’ training program will be effective in increasing the provision of effective tobacco cessation interventions by Chinese-speaking HSPs, especially therapists, to patients with cigarette smoking, which will provide valuable insights into bridging the gap between need and services for smoking cessation in China. Overall, we believe this program will be likely to have very substantial public health benefits if it would provide a widely accessible and efficacious smoking cessation information for Chinese HSPs.
Access to internet, smartphone usage, and acceptability of mobile health technology among cancer patients
Authors: Potdar Rashmika , Thomas Arun , DiMeglio Matthew , Mohiuddin Kamran , Djibo Djeneba Audrey , Laudanski Krzysztof , Dourado Claudia M. , Leighton John Charles , Ford Jean G.
Published: November 2019

Purpose

The use of mobile health (mHealth) technologies to augment patient care, enables providers to communicate remotely with patients enhancing the quality of care and patient engagement. Few studies addressed barriers to its implementation, especially in medically underserved populations.

Methods

A cross-sectional study of 151 cancer patients was conducted at an academic medical center in the United States. A trained interviewer performed structured interviews regarding the barriers and facilitators of patients’ current and desired utilization of technology for healthcare services.

Results

Of the 151 participants, 35.8% were male and ages ranged from 21-104 years. Only 73.5% of participants currently have daily access to internet, and 68.2% currently own a smartphone capable of displaying mobile applications. Among all participants, utilization of a daily mHealth application was significantly higher in patients with a college-level degree (OR; 2.78, p<0.01) and lower in older patients (OR; 0.05, p<0.01). Differences in utilization when adjusted for current smartphone use and daily access to internet were nonsignificant. Among smartphone users, the desire to increase cancer knowledge was associated with a higher likelihood of utilizing a mHealth application (OR; 261.53, p<0.01).

Conclusion

The study suggests the access to mobile technology is the predominant determinant of utilization. Healthcare organizations should consider these factors when launching patient engagement platforms.
Targeted Memory Reactivation Increases Memory Recall: A Meta-analysis
Authors: Lieber Thomas
Published: November 2019

abstract

Research on Targeted Memory Reactivation (TMR) shows that it’s a successful for increasing memory recall. However, As of yet no systematic study had been conducted to evaluate to what extend TMR can increase recall. This study used a comprehensive literature search to attempt to find all studies conducted in which TMR is used to increase memory recall. Methodological quality, study characteristics and where possible descriptive statistics were extracted from the studies. In total, 41 studies were identified, 26 of which included enough descriptive data to be included in the meta-analysis. The results indicated that the average methodological quality was good. Furthermore, TMR significantly increased memory recall. The subgroup analysis for modality was not significant, while the subgroup analysis for type of memory did yield a significant result. Overall, TMR seems to have small to medium effect on memory recall, is independent of modality and depends on memory.
Image memorability is predicted by discriminability and similarity in different stages of a convolutional neural network
Authors: Koch Griffin E. , Akpan Essang , Coutanche Marc N.
Published: November 2019

The features of an image can be represented at multiple levels – from its low-level visual properties to high-level meaning. What drives some images to be memorable while others are forgettable? We address this question across two behavioral experiments. In the first, different layers of a convolutional neural network (CNN), which represent progressively higher levels of features, were used to select the images that would be shown to 100 participants through a form of prospective assignment. Here, the discriminability/similarity of an image with others, according to different CNN layers dictated the images presented to different groups, who made a simple indoor vs. outdoor judgment for each scene. We find that participants remember more scene images that were selected based on their low-level discriminability or high-level similarity. A second experiment replicated these results in an independent sample of fifty participants, with a different order of post-encoding tasks. Together, these experiments provide evidence that both discriminability and similarity, at different visual levels, predict image memorability.
Adversarial generation of gene expression data
Authors: Viñas Ramon , Andrés-Terré Helena , Liò Pietro , Bryson Kevin
Published: November 2019

The problem of reverse engineering gene regulatory networks from high-throughput expression data is one of the biggest challenges in bioinformatics. In order to benchmark network inference algorithms, simulators of well-characterized expression datasets are often required. However, existing simulators have been criticized because they fail to emulate key properties of gene expression data.

In this study we address two problems. First, we propose mechanisms to faithfully assess the realism of a synthetic gene expression dataset. Second, we design an adversarial simulator of expression data, gGAN, based on a Generative Adversarial Network. We show that our model outperforms existing simulators by a large margin, achieving realism scores that are up to 17 times higher than those of GeneNetWeaver and SynTReN. More importantly, our results show that gGAN is, to our best knowledge, the first simulator that passes the Turing test for gene expression data proposed by Maier et al. (2013).
Neighbor GWAS: incorporating neighbor genotypic identity into genome-wide association studies of field herbivory
Authors: Sato Yasuhiro , Yamamoto Eiji , Shimizu Kentaro K. , Nagano Atsushi J.
Published: November 2019

An increasing number of field studies have shown that the phenotype of an individual plant depends not only on its genotype but also on those of neighboring plants; however, this fact is not taken into consideration in genome-wide association studies (GWAS). Based on the Ising model of ferromagnetism, we incorporated neighbor genotypic identity into a regression model, named “Neighbor GWAS”. Our simulations showed that the effective range of neighbor effects could be estimated using an observed phenotype from when the proportion of phenotypic variation explained (PVE) by neighbor effects peaked. The spatial scale of the first nearest neighbors gave the maximum power to detect the causal variants responsible for neighbor effects, unless their effective range was too broad. However, if the effective range of the neighbor effects was broad and minor allele frequencies were low, there was collinearity between the self and neighbor effects. To suppress the false positive detection of neighbor effects, the fixed effect and variance components involved in the neighbor effects should be tested in comparison with a standard GWAS model. We applied neighbor GWAS to field herbivory data from 199 accessions of Arabidopsis thaliana and found that neighbor effects explained 8% more of the PVE of the observed damage than standard GWAS. The neighbor GWAS method provides a novel tool that could facilitate the analysis of complex traits in spatially structured environments and is available as an R package at CRAN (https://cran.rproject.org/package=rNeighborGWAS).
Light dependent activation of the GCN2 kinase under cold and salt stress is mediated by the photosynthetic status of the chloroplast
Authors: Lokdarshi Ansul , Morgan Philip W. , Franks Michelle , Emert Zoe , Emanuel Catherine , von Arnim Albrecht G
Published: November 2019

Regulation of cytosolic mRNA translation is a key node for rapid adaptation to environmental stress conditions. In yeast and animals, phosphorylation of the α-subunit of eukaryotic translation initiation factor eIF2 is the most thoroughly characterized event in regulating global translation under stress. In plants, the GCN2 kinase (General Control Non-derepressible-2) is the only known kinase for eIF2α. GCN2 is activated under a variety of stresses including reactive oxygen species. Here we provide new evidence that the GCN2 kinase in Arabidopsis is also activated rapidly and in a light dependent manner by cold and salt treatments. These treatments alone did not repress global mRNA ribosome loading in a major way. The activation of GCN2 was attenuated by inhibitors of photosynthesis and antioxidants, suggesting that it is gated by the redox poise or the reactive oxygen status of the chloroplast. In keeping with these results, gcn2 mutant seedlings were more sensitive than wild type to both cold and salt in a root elongation assay. These data suggest that cold and salt stress may both affect the status of the cytosolic translation apparatus via the conserved GCN2-eIF2α module. The potential role of the GCN2 kinase pathway in the global repression of translation under abiotic stress will be discussed.
Climate associated genetic variation in Fagus sylvatica and potential responses to climate change in the French Alps
Authors: Capblancq Thibaut , Morin Xavier , Gueguen Maya , Renaud Julien , Lobreaux Stéphane , Bazin Eric
Published: November 2019

Local adaptation patterns have been found in many plants and animals, highlighting the genetic heterogeneity of species along their range of distribution. In the next decades, global warming must induce a change in the selective pressures that drive this adaptive variation, forcing a reshuffling of the underlying adaptive allele distributions. For species with low dispersion capacity and long generation time such as trees, the rapidity of the change could imped the migration of beneficial alleles and lower their capacity to track the changing environment. Identifying the main selective pressures driving the adaptive genetic variation is thus necessary when investigating species capacity to respond to global warming. In this study, we investigate the adaptive landscape of Fagus sylvatica along a gradient of populations in the French Alps. Using a ddRAD-seq approach, we identified 7,000 SNPs from 570 individuals across 36 different sites. An RDA-derived method allowed us to identify several SNPs that were strongly associated with climatic gradients; moreover, we defined the primary selective gradients along the natural populations of F. sylvatica in the Alps. Strong effects of elevation and humidity, which contrast north-western and south-eastern site, were found and were believed to be important drivers of genetic adaptation. Finally, simulations of future genetic landscapes that used these findings predicted a severe range contraction and a shift towards higher altitudes for F. sylvatica in the Alps and allowed to identify populations at risk, which could be helpful for future management plans.
Microbe-metabolite associations linked to the rebounding murine gut microbiome post-colonization with vancomycin resistant Enterococcus faecium
Authors: Mu Andre , Carter Glen P. , Li Lucy , Isles Nicole S. , Vrbanac Alison F. , Morton James T. , Jarmusch Alan K. , De Souza David P. , Narayana Vinod K. , Kanojia Komal , Nijagal Brunda , McConville Malcolm J. , Knight Rob , Howden Benjamin P. , Stinear Timothy P.
Published: November 2019

Vancomycin resistant Enterococcus faecium (VREfm) is an emerging antibiotic resistant pathogen. Strain-level investigations are beginning to reveal the molecular mechanisms used by VREfm to colonize regions of the human bowel. However, the role of commensal bacteria during VREfm colonization, in particular following antibiotic treatment, remains largely unknown. We employed amplicon 16S rRNA gene sequencing and metabolomics in a murine model system to try and investigate functional roles of the gut microbiome during VREfm colonization. First-order taxonomic shifts between Bacteroidetes and Tenerricutes within the gut microbial community composition were detected both in response to pretreatment using ceftriaxone, and to subsequent VREfm challenge. Using neural networking approaches to find co-occurrence profiles of bacteria and metabolites, we detected key metabolome features associated with butyric acid during and after VREfm colonization. These metabolite features were associated with Bacteroides, indicative of a transition towards a pre-antibiotic naïve microbiome. This study shows the impacts of antibiotics on the gut ecosystem, and the progression of the microbiome in response to colonisation with VREfm. Our results offer insights towards identifying potential non-antibiotic alternatives to eliminate VREfm through metabolic re-engineering to preferentially select for Bacteroides.

Importance

This study demonstrates the importance and power of linking bacterial composition profiling with metabolomics to find the interactions between commensal gut bacteria and a specific pathogen. Knowledge from this research will inform gut microbiome engineering strategies, with the aim of translating observations from animal models to human-relevant therapeutic applications.
Cluster-permutation statistical analysis for high-dimensional brain-wide functional connectivity mapping
Authors: Sanchez-Bornot Jose M. , Lopez Maria E. , Bruña Ricardo , Maestu Fernando , Youssofzadeh Vahab , Yang Su , McLean Paula L. , Prasad Girijesh , Wong-Lin KongFatt
Published: November 2019

Brain functional connectivity (FC) analyses based on magnetoencephalographic (MEG) signals have yet to exploit the intrinsic high-dimensional information. Typically, these analyses are constrained to regions of interest to avoid the curse of dimensionality, which leads to conservative hypothesis testing. We removed such constraint by extending cluster-permutation statistics for high-dimensional MEG-FC analyses. We demonstrated the feasibility of this approach by identifying MEG-FC resting-state changes in mild cognitive impairment (MCI), a prodromal stage of Alzheimer’s disease. We found dense clusters of increased connectivity strength in MCI compared to healthy controls (hypersynchronization), in delta (1-4 Hz) and higher-theta (6-8 Hz) bands oscillations. These clusters mainly consisted of interactions between occipitofrontal and occipitotemporal regions in the left hemisphere and could potentially be used as neuromarkers of early progression in Alzheimer’s disease. Our novel approach can be used to generate high-resolution statistical FC maps for neuroimaging studies in general.
Ultrasound Echogenicity is Associated with Achilles Tendon Fatigue Damage in a Cadaveric Loading Model
Authors: Schmidt Elaine C. , Hullfish Todd J. , O’Connor Kathryn M. , Hast Michael W. , Baxter Josh R.
Published: November 2019

Achilles tendon disorders are among the most difficult sports-related injuries to predict with current diagnostic tools. The purpose of this study was to identify a clinically useful marker for early tendon damage. We hypothesized that alterations in mean echogenicity are linked with changes in vitro tendon mechanics. To test our hypothesis, we harvested Achilles tendons from 10 fresh-frozen cadaveric feet and cyclically fatigued them using a universal test frame while we continuously acquired ultrasound images. Throughout this fatigue protocol, we applied 2 stress tests every 500 loading cycles to quantify changes in ultrasound imaging echogenicity. We continued this fatigue protocol until each tendon either failed completely or survived 150,000 cycles. Tendons that failed during the fatigue loading (6/10) underwent greater changes in mean echogenicity compared to tendons that did not fail (P = 0.031). These tendons that failed during fatigue loading demonstrated greater changes in mean echogenicity that surpassed 1.0%; whereas survivor tendons exhibited less than 0.5% changes in mean echogenicity. We found that changes in mean echogenicity measured with ultrasound increased proportionally with increased tendon damage. The magnitude of these changes was relatively small (<1.5% change in mean echogenicity) but may be an effective predictor of tendon failure. Mean echogenicity is a promising marker for quantifying fatigue damage in cadaveric Achilles tendons during a stress test. Although these changes cannot be detected with the naked eye, computer-based predictive models may effectively assess risk of tendon damage in physically active adults.

Level of evidence

Controlled laboratory experiment
FtsW exhibits distinct processive motions driven by either septal cell wall synthesis or FtsZ treadmilling in E. coli
Authors: Yang Xinxing , McQuillen Ryan , Lyu Zhixin , Phillips-Mason Polly , De La Cruz Ana , McCausland Joshua W. , Liang Hai , DeMeester Kristem E. , Santiago Cintia C. , Grimes Catherine L. , de Boer Piet , Xiao Jie
Published: November 2019

During bacterial cell division, synthesis of new septal peptidoglycan (sPG) is crucial for successful cytokinesis and cell pole morphogenesis. FtsW, a SEDS (Shape, Elongation, Division and Sporulation) family protein and an indispensable component of the cell division machinery in all walled bacterial species, was recently identified in vitro as a new monofunctional peptidoglycan glycosyltransferase (PGTase). FtsW and its cognate monofunctional transpeptidase (TPase) class B penicillin binding protein (PBP3 or FtsI in E. coli) may constitute the essential, bifunctional sPG synthase specific for new sPG synthesis. Despite its importance, the septal PGTase activity of FtsW has not been documented in vivo. How its activity is spatiotemporally regulated in vivo has also remained unknown. Here we investigated the septal PGTase activity and dynamics of FtsW in E. coli cells using a combination of single-molecule imaging and genetic manipulations. We show that FtsW exhibits robust activity to incorporate an N-acetylmuramic acid analog at septa in the absence of other known PGTases, confirming FtsW as the essential septum-specific PGTase in vivo. Notably, we identified two populations of processive moving FtsW molecules at septa. A fast-moving population is driven by the treadmilling dynamics of FtsZ and independent of sPG synthesis. A slow-moving population is driven by active sPG synthesis and independent of FtsZ’s treadmilling dynamics. We further identified that FtsN, a potential sPG synthesis activator, plays an important role in promoting the slow-moving, sPG synthesis-dependent population. Our results support a two-track model, in which inactive sPG synthase molecules follow the fast treadmilling “Z-track” to be distributed along the septum; FtsN promotes their release from the “Z-track” to become active in sPG synthesis on the slow “sPG-track”. This model explains how the spatial information is integrated into the regulation of sPG synthesis activity and suggests a new mechanistic framework for the spatiotemporal coordination of bacterial cell wall constriction.
Head Stabilization During Standing in People with Persisting Symptoms after Mild Traumatic Brain Injury
Authors: Fino Peter C. , Raffegeau Tiphanie E , Parrington Lucy , Peterka Robert J , King Laurie A.
Published: November 2019

Increased postural sway is often observed in people with mild traumatic brain injury (mTBI), but our understanding of how individuals with mTBI control their head during stance is limited. The purpose of this study was to determine if people with mTBI exhibit increased sway at the head compared with healthy controls. People with persisting symptoms after mTBI (n = 59, 41 women) and control participants (n = 63, 38 women) stood quietly for one minute in four conditions: eyes open on a firm surface (EO-firm), eyes closed on a firm surface (EC-firm), eyes open on a foam pad (EO-foam), and eyes closed on foam (EC-foam). Inertial sensors at the head, sternum, and lumbar region collected tri-axial accelerations. Root-mean-square (RMS) accelerations in anteroposterior (AP) and mediolateral (ML) directions. Sway ratios between the head and sternum, head and lumbar, and sternum and lumbar region, were compared between groups. Temporal coupling of anti-phase motion between the upper and lower body angular accelerations was assessed with magnitude squared coherence and cross-spectral phase angles. People with mTBI demonstrated greater sway than controls across conditions and directions. During foam-surface conditions, the control group, but not the mTBI group, reduced ML sway at their head and trunk relative to their lumbar by increasing the expression of an anti-phase hip strategy within the frontal plane. These results are consistent with suggestions of inflexible or inappropriate postural control in people with mTBI.
Transcription factors protect from DNA re-methylation during reprograming of primordial germ cells and pre-implantation embryos
Authors: Kremsky Isaac , Corces Victor G.
Published: November 2019

A growing body of evidence suggests that certain phenotypic traits of epigenetic origin can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization. By integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNA-seq data collected during multiple stages of primordial germ cell and preimplantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global reprogramming, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germ line and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global de-methylation, become de-methylated during global de-methylation, and then become re-methylated. The results suggest that transcription factors can act as carriers of epigenetic information during germ cell and pre-implantation development by ensuring that the methylation status of CpGs is maintained after reprogramming of DNA methylation. Based on our findings, we propose a model in which transcription factor binding during the re-methylation phases of primordial germ cell and pre-implantation development allow epigenetic information to be maintained trans-generationally even at sites where DNA methylation is lost during global de-methylation.
Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory deficits in rats
Authors: Westbrook Sara R. , Dwyer Megan R. , Cortes Laura R. , Gulley Joshua M.
Published: November 2019

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration (SA) in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h SA sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (OR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats exhibited modest deficits in OiP compared to adult-onset rats, but there was no sex difference in this effect and no groups differed in OR. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and subsequent dysfunction of PFC-dependent cognition.
Extracellular DNA controls expression ofPseudomonas aeruginosagenes involved in nutrient utilization, metal homeostasis, acid pH tolerance, and virulence
Authors: Lewenza Shawn , Johnson Lori , Charron-Mazenod Laetitia , Hong Mia , Mulcahy-O’Grady Heidi
Published: November 2019

Pseudomonas aeruginosagrows in extracellular DNA-enriched biofilms and infection sites. Extracellular DNA (eDNA) is generally considered a structural biofilm polymer required for aggregation and biofilm maturation. In addition, eDNA can sequester divalent metal cations, acidify the growth media, and serve as a nutrient source. Here we determine the transcriptome of planktonicP. aeruginosagrown in the presence of eDNA using RNA-seq. Transcriptome analysis identified 89 induced genes and 76 repressed genes in the presence of eDNA (FDR<0.05), and transcriptionalluxfusions were used to confirm eDNA regulation. A large number of eDNA-induced genes appear to be involved in utilizing DNA as a nutrient. Several eDNA-induced genes are also induced by acidic pH 5.5, and growth in the presence of eDNA or acidic pH promoted an acid tolerance response inP. aeruginosa. ThecyoABCDEterminal oxidase is induced at pH 5.5 and contributed to the acid tolerance phenotype. Quantitative metal analysis confirmed that DNA binds to diverse metals, which helps explain why many genes involved in a general uptake of metals were controlled by eDNA. Growth in the presence of eDNA also promoted intracellular bacterial survival and influenced virulence and during the acute infection model of fruit flies. The diverse functions of the eDNA-regulated genes underscore the important role of this extracellular polymer in promoting antibiotic resistance, virulence, acid tolerance, and nutrient utilization; phenotypes that contribute to long-term survival.
Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes
Authors: Mordaunt Charles E. , Jianu Julia M. , Laufer Ben , Zhu Yihui , Dunaway Keith W. , Bakulski Kelly M. , Feinberg Jason I. , Volk Heather E. , Lyall Kristen , Croen Lisa A. , Newschaffer Craig J. , Ozonoff Sally , Hertz-Picciotto Irva , Fallin M. Daniele , Schmidt Rebecca J. , LaSalle Janine M.
Published: November 2019

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth.

Results

We identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development.

Conclusions

At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD, and provides novel insights for early diagnosis and therapy.
Neurocognitive mechanisms of social inferences in typical and autistic adolescents
Authors: Rosenblau Gabriela , Korn Christoph W. , Dutton Abigail , Lee Daeyeol , Pelphrey Kevin A.
Published: November 2019

Background

Many of our efforts in social interactions are dedicated to learning about others. Adolescents with autism have core deficits in social learning, but a mechanistic understanding of these deficits and how they relate to neural development is lacking. The current study aimed to specify how adolescents with and with autism represent and acquire social knowledge and how these processes are implemented in neural activity.

Methods

Typically developing (TD) adolescents (N=26) and adolescents with autism (N=20) rated in the MR scanner how much three peers liked a variety of items and received trial-by-trial feedback about the peer’s actual preference ratings. In a separate study, we established the preferences of a new sample of adolescents (N=99), used to examine population preference structures. Using computational models, we tested whether participants in the MR study relied on preference structures during learning and how model predictions were implemented in brain activity.

Results

TD adolescents relied on average population preferences and prediction error (PE) updating. Importantly, PE updating was scaled by the similarity between items. In contrast, preferences of adolescents with autism were best described by a No-learning model that relied only on participants own preferences for each item. Model predictions were encoded in neural activity. TD adolescents encoded PEs in the putamen and adolescents with autism showed greater encoding of own preferences in the angular gyrus.

Conclusions

We specified how adolescents represent and update social knowledge during learning. Our findings indicate that adolescents with ASD rely only on their own preferences when making social inferences.
Designing combination therapies using multiple optimal controls
Authors: Sharp Jesse A , Browning Alexander P , Mapder Tarunendu , Baker Christopher M , Burrage Kevin , Simpson Matthew J
Published: November 2019

Strategic management of populations of interacting biological species routinely requires interventions combining multiple treatments or therapies. This is important in key research areas such as ecology, epidemiology, wound healing and oncology. Despite the well developed theory and techniques for determining single optimal controls, there is limited practical guidance supporting implementation of combination therapies. In this work we use optimal control theory to calculate optimal strategies for applying combination therapies to a model of acute myeloid leukaemia. We consider various combinations of continuous and bang-bang (discrete) controls, and we investigate how the control dynamics interact and respond to changes in the weighting and form of the pay-off characterising optimality. We demonstrate that the optimal controls respond non-linearly to treatment strength and control parameters, due to the interactions between species. We discuss challenges in appropriately characterising optimality in a multiple control setting and provide practical guidance for applying multiple optimal controls. Code used in this work to implement multiple optimal controls is available on GitHub.
The network structure and eco-evolutionary dynamics of CRISPR-induced immune diversification
Authors: Pilosof Shai , Alcalá-Corona Sergio A. , Wang Tong , Kim Ted , Maslov Sergei , Whitaker Rachel , Pascual Mercedes
Published: November 2019

As a heritable sequence-specific adaptive immune system, CRISPR-Cas is a powerful force shaping strain diversity in host-virus systems. While the diversity of CRISPR alleles has been explored, the associated structure and dynamics of host-virus interactions have not. We explore the role of CRISPR in mediating the interplay between host-virus interaction structure and eco-evolutionary dynamics in a computational model and compare results with three empirical datasets from natural systems. We show that the structure of the networks describing who infects whom and the degree to which strains are immune, are respectively modular (containing groups of hosts and viruses that interact strongly) and weighted-nested (specialist hosts are more susceptible to subsets of viruses that in turn also infect the more generalist hosts with many spacers matching many viruses). The dynamic interplay between these networks influences transitions between dynamical regimes of virus diversification and host control. The three empirical systems exhibit weighted-nested protection networks, a pattern our theory shows is indicative of hosts able to suppress virus diversification. Previously missing from studies of microbial host-pathogen systems, the protection network plays a key role in the coevolutionary dynamics.
Uncoupling splicing from transcription using antisense oligonucleotides reveals a dual role for I exon donor splice sites in antibody class switching
Authors: Marchalot Anne , Ashi Mohamad Omar , Lambert Jean-Marie , Srour Nivine , Delpy Laurent , Le Pennec Soazig
Published: November 2019

Class switch recombination (CSR) changes antibody isotype by replacing Cμ constant exons with different constant exons located downstream on the immunoglobulin heavy (IgH) locus. During CSR, transcription through specific switch (S) regions and processing of noncoding germline transcripts (GLTs) are essential for the targeting of Activation-Induced cytidine Deaminase (AID). While CSR to IgG1 is abolished in mice lacking Iγ1 exon donor splice site (dss), many questions remain regarding the importance of I exon dss recognition in CSR. To further clarify the role of I exon dss in CSR, we first evaluated RNA polymerase II (RNA pol II) loading and chromatin accessibility in S regions after activation of mouse B cells lacking Iγ1 dss. We found that deletion of Iγ1 dss markedly reduced RNA pol II pausing and active chromatin marks in the Sγ1 region. We then challenged the post-transcriptional function of I exon dss in CSR by using antisense oligonucleotides (ASO) masking I exon dss on GLTs. Treatment of stimulated B cells with an ASO targeting Iγ1 dss, in the acceptor Sγ1 region, or Iμ dss, in the donor Sμ region, did not decrease germline transcription but strongly inhibited constitutive splicing and CSR to IgG1. Altogether, this study reveals that the recognition of I exon dss first supports RNA pol II pausing and the opening of chromatin in targeted S regions and that GLTs splicing events using constitutive I exon dss appear mandatory for the later steps of CSR, most likely by guiding AID to S regions.
Colony volatiles and substrate-borne vibrations entrain circadian rhythms and are potential mediators of social synchronization in honey bee colonies
Authors: Siehler Oliver , Bloch Guy
Published: November 2019

Internal circadian clocks organize animal behavior and physiology and are entrained by ecologically-relevant external time-givers such as light and temperature cycles. In the highly social honey bee, social time-givers are important and can override photic entrainment, but the cues mediating social synchronization are unknown. Here we tested whether substrate-borne vibrations and hive volatiles can mediate social synchronization in honey bees. We first placed newly-emerged worker bees on the same or on a different substrate on which we placed cages with foragers entrained to ambient day- night cycles, while minimizing transfer of volatiles between cages. In the second experiment, we exposed young bees to constant airflow coming from either a free-foraging colony or a similar size control hive containing only empty combs, while minimizing transfer of substrate-borne vibrations between cages. After five days, we individually isolated each focal bee in an individual cage in an environmental chamber, and monitored locomotor activity. We repeated each experiment five times, each trail with bees from a different source colony, monitoring a total of more than 1000 bees representing diverse genotypes. We found that bees placed on the same substrate as foragers showed a stronger phase coherence; and in 3 of 5 trials their phase was more similar to that of foragers, compared to bees placed on a different substrate. In the second experiment, bees exposed to air from a colony showed a stronger phase coherence, and in 4 out of 5 trial their phase was more similar to that of foragers, compared to control bees exposed to air from an empty hive. These findings lend credence to the hypothesis that surrogates of activity such as substrate-borne vibrations, and volatile cues entrain circadian rhythms in natural free-foraging honey bee colonies.
AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity
Authors: Abdelbaki Ahmed , Akman H. Begum , Poteau Marion , Grant Rhys , Gavet Olivier , Guarguaglini Giulia , Lindon Catherine
Published: November 2019

Activity of AURKA is controlled through multiple mechanisms including phosphorylation, ubiquitin-mediated degradation, and allosteric interaction with TPX2. Activity peaks at mitosis before AURKA is degraded during mitotic exit in a process strictly dependent on APC/C coactivator FZR1. We used FZR1 knockout cells (FZR1KO) and a novel FRET-based AURKA biosensor to investigate how activity is regulated in absence of destruction. We found that AURKA activity in FZR1KO cells dropped at mitotic exit as rapidly as in parental cells, despite absence of destruction. Unexpectedly, TPX2 was degraded normally in FZR1KO cells. Overexpression of an N-terminal TPX2 fragment sufficient for AURKA binding, but not degraded at mitotic exit, caused delay in AURKA inactivation. We conclude that AURKA inactivation in mitotic exit is determined not by its own degradation but by degradation of TPX2 and therefore dependent on CDC20 rather than FZR1. The biosensor revealed that FZR1 instead suppresses AURKA activity in interphase and is critically required for assembly of the interphase mitochondrial network after mitosis.
A high-quality genome assembly of the North American Song Sparrow, Melospiza melodia
Authors: Louha Swarnali , Ray David A. , Winker Kevin , Glenn Travis
Published: November 2019

The song sparrow, Melospiza melodia, is one of the most widely distributed species of songbirds found in North America. It has been used in a wide range of behavioral and ecological studies. This species’ pronounced morphological and behavioral diversity across populations makes it a favorable candidate in several areas of biomedical research. We have generated a high-quality de novo genome assembly of M. melodia using Illumina short read sequences from genomic and in vitro proximity-ligation libraries. The assembled genome is 978.3 Mb, with a coverage of 24.9×, N50 scaffold size of 5.6 Mb and N50 contig size of 31.7 Kb. Genes within our genome assembly are largely complete, with 87.5% full-length genes present out of a set of 4,915 universal single-copy orthologs present in most avian genomes. We annotated our genome assembly and constructed 15,086 gene models, a majority of which have high homology to related birds, Taeniopygia guttata and Junco hyemalis. In total, 83% of the annotated genes are assigned with putative functions. Furthermore, only ~7% of the genome is found to be repetitive; these regions and other non-coding functional regions are also identified. The high-quality M. melodia genome assembly and annotations we report will serve as a valuable resource for facilitating studies on genome structure and evolution that can contribute to biomedical research and serve as a reference in population genomic and comparative genomic studies of closely related species.