bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mathematical modeling links benefits of short and long antibiotic treatment to details of infection
Authors: Paupério Francisco F. S. , Ganusov Vitaly V. , Gjini Erida 
Published: February 2019

AbstractAntibiotics are the major tool for treating bacterial infections. With rising antibiotic resistance in microbes, strategies that limit further evolution and spread of drug resistance are urgently needed, in individuals and populations. While classical recommendations favor longer and aggressive treatments, more recent studies and clinical trials advocate for moderate regimens. In this debate, two axes of aggressive treatment have typically been conflated: treatment intensity and treatment duration, the latter being rarely addressed by mathematical models. Here, by using a simple mathematical model of a generic bacterial infection, controlled by host’s immune response, we investigate the role of treatment timing and antibiotic efficacy in determining optimal duration of treatment. We show that even in such simple mathematical model, it is impossible to select for universally optimal treatment duration. In particular, short (3 day) or long (7 day) treatments may be both beneficial depending on treatment onset, on the criterion used, and on the antibiotic efficacy. This results from the dynamic trade-off between immunity and resistance in acute, self-limiting infections, and uncertainty relating symptoms to the start of infection. We find that treatment timing can shift the trend between resistance selection and length of antibiotic exposure in individual hosts. We propose that major advances in predicting impact of antibiotics on bacterial infections must come from deeper experimental understanding of bacterial infection dynamics in humans. To guide rational therapy, mathematical models need to be constrained by data, including details of pathology and symptom thresholds in patients, and of host immune control of infection.
Discovery of several thousand highly diverse circular DNA viruses
Authors: Tisza Michael J. , Pastrana Diana V. , Welch Nicole L. , Stewart Brittany , Peretti Alberto , Starrett Gabriel J. , Pang Yuk-Ying S. , Krishnamurthy Siddharth R. , Pesavento Patricia A. , McDermott David H. , Murphy Philip M. , Whited Jessica L. , Miller Bess , Brenchley Jason M. , Rosshart Stephan P. , Rehermann Barbara , Doorbar John , Ta’ala Blake A. , Pletnikova Olga , Troncoso Juan , Resnick Susan M. , Bolduc Ben , Sullivan Matthew B. , Varsani Arvind , Segall Anca M. , Buck Christopher B. 
Published: February 2019

SummaryAlthough it is suspected that there are millions of distinct viral species, fewer than 9,000 are catalogued in GenBank’s RefSeq database. We selectively enriched for and amplified the genomes of circular DNA viruses in over 70 animal samples, ranging from cultured soil nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2,500 circular genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA viruses and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these “dark matter” sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere.
Modeling epistasis in mice and yeast using the proportion of two or more distinct genetic backgrounds: evidence for “polygenic epistasis”
Authors: Rau Christoph D. , Gonzales Natalia M. , Bloom Joshua S. , Park Danny , Ayroles Julien , Palmer Abraham A. , Lusis Aldons J. , Zaitlen Noah 
Published: February 2019

AbstractBackgroundThe majority of quantitative genetic models used to map complex traits assume that alleles have similar effects across all individuals. Significant evidence suggests, however, that epistatic interactions modulate the impact of many alleles. Nevertheless, identifying epistatic interactions remains computationally and statistically challenging. In this work, we address some of these challenges by developing a statistical test forpolygenic epistasisthat determines whether the effect of an allele is altered by the global genetic ancestry proportion from distinct progenitors.ResultsWe applied our method to data from mice and yeast. For the mice, we observed 49 significant genotype-by-ancestry interaction associations across 14 phenotypes as well as over 1,400 Bonferroni-corrected genotype-by-ancestry interaction associations for mouse gene expression data. For the yeast, we observed 92 significant genotype-by-ancestry interactions across 38 phenotypes. Given this evidence of epistasis, we test for and observe evidence of rapid selection pressure on ancestry specific polymorphisms within one of the cohorts, consistent with epistatic selection.ConclusionsUnlike our prior work in human populations, we observe widespread evidence of ancestry-modified SNP effects, perhaps reflecting the greater divergence present in crosses using mice and yeast.Author SummaryMany statistical tests which link genetic markers in the genome to differences in traits rely on the assumption that the same polymorphism will have identical effects in different individuals. However, there is substantial evidence indicating that this is not the case. Epistasis is the phenomenon in which multiple polymorphisms interact with one another to amplify or negate each other’s effects on a trait. We hypothesized that individual SNP effects could be changed in a polygenic manner, such that the proportion of as genetic ancestry, rather than specific markers, might be used to capture epistatic interactions. Motivated by this possibility, we develop a new statistical test that allowed us to examine the genome to identify polymorphisms which have different effects depending on the ancestral makeup of each individual. We use our test in two different populations of inbred mice and a yeast panel and demonstrate that these sorts of variable effect polymorphisms exist in 14 different physical traits in mice and 38 phenotypes in yeast as well as in murine gene expression. We use the term “polygenic epistasis” to distinguish these interactions from the more conventional two- or multi-locus interactions.
Classical conditioning drives learned reward prediction signals in climbing fibers across the lateral cerebellum
Authors: Heffley William , Hull Court 
Published: February 2019

AbstractClassical models of cerebellar learning posit that climbing fibers operate according to a supervised learning rule to instruct changes in motor output by signaling the occurrence of movement errors. However, cerebellar output is also associated with non-motor behaviors, and recently with modulating reward association pathways in the VTA. To test how the cerebellum processes reward related signals in the same type of classical conditioning behavior typically studied to evaluate reward processing in the VTA and striatum, we have used calcium imaging to visualize instructional signals carried by climbing fibers across the lateral cerebellum before and after learning. We find distinct climbing fiber responses in three lateral cerebellar regions that can each signal reward prediction, but not reward prediction errors per se. These instructional signals are well suited to guide cerebellar learning based on reward expectation and enable a cerebellar contribution to reward driven behaviors.
An evolutionarily conserved mechanism for production of secondary meristems in land plants
Authors: Yasui Yukiko , Tsukamoto Shigeyuki , Sugaya Tomomi , Nishihama Ryuichi , Wang Quan , Yamato Katsuyuki T. , Fukaki Hidehiro , Mimura Tetsuro , Kubo Hiroyoshi , Theres Klaus , Kohchi Takayuki , Ishizaki Kimitsune 
Published: February 2019

AbstractA variety of plants in diverse taxa can reproduce asexually via vegetative propagation, in which clonal propagules with new meristem(s) are generated directly from vegetative organs. A basal land plant, Marchantia polymorpha, develops clonal propagules, gemmae, in a specialized receptacle, gemma cup. Here we report an R2R3-MYB transcription factor, designated GEMMA CUP-ASSOCIATED MYB 1 (GCAM1), which is an essential regulator of gemma cup development in M. polymorpha. Although gemma cups are a characteristic gametophyte organ for vegetative reproduction in a taxonomically restricted group of liverwort species, phylogenetic and interspecific complementation analyses supported the orthologous relationship of GCAM1 to regulatory factors for axillary meristem formation, e.g. Arabidopsis RAXs and tomato Blind, in angiosperm sporophytes. The present findings in M. polymorpha suggest an ancient acquisition of a regulatory mechanism for production of secondary meristems, and the use of the mechanism for diverse developmental programs during land plant evolution.
The relationship between neural variability and neural oscillations
Authors: Daniel Edan , Meindertsma Thomas , Arazi Ayelet , Donner Tobias H. , Dinstein Ilan 
Published: February 2019

AbstractNeural activity fluctuates over time, creating considerable variability across trials. This trial-by-trial neural variability is dramatically reduced (“quenched”) after the presentation of sensory stimuli. Likewise, the power of neural oscillations, primarily in the alpha-beta band, is also reduced. Despite their similarity, these phenomena have been discussed independently. We hypothesized that the two phenomena are tightly coupled. To test this, we examined magnetoencephalography (MEG) recordings of healthy subjects viewing repeated presentations of a visual stimulus. The timing, amplitude, and spatial topography of variability-quenching and power suppression were remarkably similar. Neural variability quenching was eliminated by excluding the alpha-beta band from the recordings, but not by excluding other frequency-bands. Moreover, individual magnitudes of alpha-beta band power explained 86% of between-subject differences in variability quenching. In contrast, inter-trial-phase-coherence (ITPC) was not correlated with variability quenching. These results reveal that neural variability quenching reflects stimulus-induced changes in the power of alpha-beta band oscillations.
Recombination and mutational robustness in neutral fitness landscapes
Authors: Klug Alexander , Park Su-Chan , Krug Joachim 
Published: February 2019

AbstractMutational robustness quantifies the effect of random mutations on fitness. When mutational robustness is high, most mutations do not change fitness or have only a minor effect on it. From the point of view of fitness landscapes, robust genotypes form neutral networks of almost equal fitness. Using deterministic population models it has been shown that selection favors genotypes inside such networks, which results in increased mutational robustness. Here we demonstrate that this effect is massively enhanced by recombination. Our results are based on a detailed analysis of mesa-shaped fitness landscapes, where we derive precise expressions for the dependence of the robustness on the landscape parameters for recombining and non-recombining populations. In addition, we carry out numerical simulations on different types of random holey landscapes as well as on an empirical fitness landscape. We show that the mutational robustness of a genotype generally correlates with its recombination weight, a new measure that quantifies the likelihood for the genotype to arise from recombination. We argue that the favorable effect of recombination on mutational robustness is a highly universal feature that may have played an important role in the emergence and maintenance of mechanisms of genetic exchange.Author summaryTwo long-standing and seemingly unrelated puzzles in evolutionary biology concern the ubiquity of sexual reproduction and the robustness of organisms against genetic perturbations. Using a theoretical approach based on the concept of a fitness landscape, in this article we argue that the two phenomena may in fact be closely related. In our setting the hereditary information of an organism is encoded in its genotype, which determines it to be either viable or non-viable, and robustness is defined as the fraction of mutations that maintain viability. Previous work has demonstrated that the purging of non-viable genotypes from the population by natural selection leads to a moderate increase in robustness. Here we show that genetic recombination acting in combination with selection massively enhances this effect, an observation that is largely independent of how genotypes are connected by mutations. This suggests that the increase of robustness may be a major driver underlying the evolution of sexual recombination and other forms of genetic exchange throughout the living world.
An insect serotonin receptor mediates cellular immune responses and its inhibition by phenylethylamide derivatives from bacterial secondary metabolites
Authors: Hasan Ariful , Yeom Hyun-Suk , Ryu Jaewook , Bode Helge B. , Kim Yonggyun 
Published: February 2019

AbstractSerotonin (5-hydroxytryptamine: 5-HT) is a biogenic monoamine that mediates immune responses and modulates nerve signal in insects.Se-5HTR, a specific receptor of serotonin, has been identified in the beet armyworm,Spodoptera exigua.It is classified into subtype 7 among known 5HTRs.Se-5HTRwas expressed in all developmental stages ofS. exigua.It was expressed in all tested tissues of larval stage. Its expression was up-regulated in hemocytes and fat body in response to immune challenge. RNA interference (RNAi) ofSe-5HTRexhibited significant immunosuppression by preventing cellular immune responses such as phagocytosis and nodulation. Treatment with an inhibitor (SB-269970) specific to 5HTR subtype 7 resulted in significant immunosuppression. Such immunosuppression was also induced by bacterial secondary metabolites derived fromXenorhabdusandPhotorhabdus. To determine specific bacterial metabolites inhibiting Se-5HTR, this study screened 37 bacterial secondary metabolites with respect to cellular immune responses associated with Se-5HTR and selected 10 potent inhibitors. These 10 selected compounds competitively inhibited cellular immune responses against 5-HT and shared phenylethylamide (PEA) chemical skeleton. Subsequently, 46 PEA derivatives were screened and resulting potent chemicals were used to design a compound to be highly inhibitory against Se-5HTR. The designed compound was chemically synthesized. It showed high immunosuppressive activities along with specific and competitive inhibition activity for Se-5HTR. This study reports the first 5HT receptor fromS. exiguaand provides its specific inhibitor designed from bacterial metabolites and their derivatives.Author SummarySerotonin (5-hydroxytryptamine: 5-HT) plays a crucial role in mediating nerve and immune signals in insects. Interruption of 5-HT signal leads to malfunctioning of various insect physiological processes. Se-5HTR, a 5-HT receptor of beet armyworm,Spodoptera exigua,was identified and classified as subtype 7 (5-HT7) of 5-HT receptors. A specific inhibitor (SB-269970) for 5-HT7highly inhibited immune responses such as phagocytosis and nodulation mediated by Se-5HTR. Two entomopathogenic bacteria,XenorhabdusandPhotorhabdus,could secrete potent inhibitors against immune responses mediated by 5-HTR. Bacterial secondary metabolites were screened against Se-5HTR-mediating immune responses. Most of resulting compounds shared phenylethylamide (PEA) chemical skeleton. Subsequent screening using PEA derivatives supported the importance of this chemical skeleton. Based on their relative inhibitory activities, a compound was designed and synthesized. This novel compound possessed high inhibitory activities against Se-5HTR-mediating immune responses and exhibited competitive inhibition with 5-HT.
Molecular signaling involved in immune system activation against root-knot nematodes by bio-control agents in tomato plants
Authors: Molinari Sergio , Leonetti Paola 
Published: February 2019

AbstractThe expression of key defense genes was detected in roots and leaves of tomato plants until the 12thday after treatments with a mixture of beneficial bio-control agents (BCAs), as soil-drenches. The expression of the same genes was monitored in pretreated plants at the 3rdand 7thday since the inoculation with the root-knot nematodeMeloidogyne incognita.Genes dependent on SA-signaling, such as the Pathogenesis Related Genes,PR1, PR3,andPR5,were systemically over-expressed at the earliest stages of BCA-root interaction. BCA pre-treatment primed plants against root-knot nematodes. The expression ofPR-genes and of the gene encoding for the enzyme 1-aminocyclopropane-1-carboxylic acid (ACC) oxidase (ACO), which catalyzes the last step of ethylene biosynthesis, was systemically enhanced after nematode inoculation in primed plants. Defense related enzyme activities, such as endochitinase and glucanase, were higher in roots of BCA-treated than in those of untreated plants, as well. On the contrary, the expression of genes dependent on JA/ET-signaling, such as Jasmonate Ethylene Response Factor 3 (JERF3), did not increase after nematode inoculation in primed plants. The antioxidant system, as indicated by catalase gene expression and ascorbate peroxidase activity, was repressed in infected colonized roots. Therefore, Systemic Acquired Resistance (SAR), and not Induced Systemic Resistance (ISR), is proposed as the molecular signaling that is activated by BCA priming at the earliest stages of root-nematode interaction. Such BCA-induced activation of the plant immune system did not directly act against nematode motile juveniles penetrating and moving inside the roots. It resulted in a drastically decreased number of sedentary individuals and, then, in an augmented ability of the plants to contrast feeding site building by invasive juveniles.
The PAAFID project: exploring the perspectives of autism in adult females among intellectual disability healthcare professionals
Authors: Tromans Samuel , Chester Verity , Kapugama Chaya , Elliott Amy , Robertson Sarah , Barrett Mary 
Published: February 2019

Purpose
The purpose of this paper is to explore the perspectives of healthcare professionals on autism in adult females with intellectual disability (ID), including regarding the gender ratio of autism, the clinical manifestation of autism in females, and the recognition, screening and diagnosis of autism.

Design/methodology/approach
The questionnaire was developed following a review of the relevant literature and distributed to professionals within three healthcare trusts as well as members of two clinical research groups. The questionnaire was completed by 80 ID healthcare professionals. Data were aggregated and analysed using Microsoft Excel.

Findings
ID healthcare professionals had a lack of recognition of the smaller gender ratio of autism in patients with ID as compared to those without ID. Most respondents reported believing that autism manifests differently in females; with women demonstrating a greater ability to mask their symptoms. A considerable proportion of participants reported feeling less confident in recognising, screening and diagnosing autism in female patients, with many endorsing a wish for additional training in this area.

Practical implications
These findings suggest that ID healthcare professionals are keen to improve their skills in providing services for women with autism. Training programmes at all levels should incorporate the specific needs of women with ASD, and individual professionals and services should actively seek to address these training needs in order to promote best practice and better outcomes for women with autism.

Originality/value
This is the first published questionnaire exploring the perspectives of healthcare professionals regarding autism in adult females with ID.
Mediator assisted simultaneous negotiations with multiple customers for order acceptance decision
Authors: Piya Sujan 
Published: February 2019

PurposeThe purpose of this paper is to develop a framework for the manufacturer of a make-to-order company to simultaneously negotiate with multiple customers through mediator to achieve order acceptance decisions (OADs).Design/methodology/approachThe paper developed mathematical models for the manufacturer, as well as customers to revise their offers during negotiations. Moreover, the paper also proposed a method for the mediator to carry out his assigned duties to assist in negotiation. In the decision process, mediator acts as a bridge between the manufacturer and customers to reach an agreement. A numerical example is enumerated to illustrate the working mechanism and superiority of proposed framework as compared to the framework where simultaneous negotiations are carried out without the presence of mediator.FindingsIterative method of negotiation conducted without mediator leads to delay in reaching agreement as the aspiration level of manufacturer offer and counter-offer of customer will never cross each other. In addition, the party who submits the offer first may suffer as the opponent can take the advantage of his/her offer during negotiation, thereby, derailing the issue of fairness. Introducing mediator between the manufacturer and the customer for their negotiations could overcome these two issues. Numerical analysis clearly illustrates that, in average, the rounds of negotiation to reach an agreement can be reduced by 22 percent using proposed negotiation framework. In addition, the fairness in negotiations can be improved by 33 percent with the incorporation of mediator.Originality/valueThrough continuing research efforts in this domain, certain models and strategies have been developed for negotiation. Iterative method of negotiations without mediator will help neither the manufacturer nor the customer in terms of fairness and negotiations round to reach an agreement. To the best of the author’s knowledge, so far, this is the first instance of research work in the domain of OAD and negotiation framework that attempts to incorporate mediator for simultaneous negotiation between manufacturer and customers on multiple issues simultaneously.