bluuebunny/crossref_metadata_2025 huggingface dataset:
Fine tuning of hormonal signaling is linked to dormancy status in sweet cherry flower buds
Authors: Vimont Noémie , Schwarzenberg Adrian , Domijan Mirela , Donkpegan Armel S. L. , Beauvieux Rémi , le Dantec Loïck , Arkoun Mustapha , Jamois Frank , Yvin Jean-Claude , Wigge Philip A. , Dirlewanger Elisabeth , Cortijo Sandra , Wenden Bénédicte
Published: September 2018

In temperate trees, optimal timing and quality of flowering directly depend on adequate winter dormancy progression, regulated by a combination of chilling and warm temperatures. Physiological, genetic and functional genomic studies have shown that hormones play a key role in bud dormancy establishment, maintenance and release. We combined physiological, transcriptional analyses, quantification of abscisic acid (ABA) and gibberellins (GAs), and modelling to further investigate how these signaling pathways are associated with dormancy progression in the flower buds of two sweet cherry cultivars.

Our results demonstrated that GA-associated pathways have distinct functions and may be differentially related with dormancy. In addition, ABA levels rise at the onset of dormancy, associated with enhanced expression of ABA biosynthesisPavNCEDgenes, and decreased prior to dormancy release. Following the observations that ABA levels are correlated with dormancy depth, we identifiedPavUG71B6, a sweet cherryUDP-GLYCOSYLTRANSFERASEgene that up-regulates active catabolism of ABA to ABA-GE and may be associated with low ABA content in the early cultivar. Subsequently, we modelled ABA content and dormancy behavior in three cultivars based on the expression of a small set of genes regulating ABA levels. These results strongly suggest the central role of ABA pathway in the control of dormancy progression and open up new perspectives for the development of molecular-based phenological modelling.
Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 are associated with gestational duration
Authors: Liu Xueping , Helenius Dorte , Skotte Line , Beaumont Robin N. , Wielscher Matthias , Geller Frank , Juodakis Julius , Mahajan Anubha , Bradfield Jonathan P. , Lin Frederick T.J. , Vogelezang Suzanne , Bustamante Mariona , Ahluwalia Tarunveer S. , Pitkänen Niina , Wang Carol A. , Bacelis Jonas , Borges Maria C. , Zhang Ge , Bedell Bruce A. , Rossi Robert M. , Skogstrand Kristin , Peng Shouneng ,   Early Growth Genetics (EGG) Consortium,   iPSYCH-BROAD Working Group, Thompson Wesley K. , Appadurai Vivek , Lawlor Debbie A. , Kalliala Ilkka , Power Christine , McCarthy Mark I. , Boyd Heather A. , Marazita Mary L. , Hakonarson Hakon , Hayes M. Geoffrey , Scholtens Denise M. , Rivadeneira Fernando , Jaddoe Vincent W.V. , Vinding Rebecca K. , Bisgaard Hans , Knight Bridget A. , Pahkala Katja , Raitakari Olli , Helgeland Øyvind , Johansson Stefan , Njølstad Pål R. , Fadista João , Schork Andrew , Nudel Ron , Miller Daniel E. , Chen Xiaoting , Weirauch Matthew T. , Mortensen Preben Bo , Børglum Anders D. , Nordentoft Merete , Mors Ole , Hao Ke , Ryckman Kelli K. , Hougaard David M. , Kottyan Leah C. , Pennell Craig E. , Lyytikainen Leo-Pekka , Bønnelykke Klaus , Vrijheid Martine , Felix Janine F. , Lowe William L. , Grant Struan F.A. , Hyppönen Elina , Jacobsson Bo , Jarvelin Marjo-Riitta , Muglia Louis J. , Murray Jeffrey C. , Freathy Rachel M. , Werge Thomas M. , Melbye Mads , Buil Alfonso , Feenstra Bjarke
Published: September 2018

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. We conducted a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 was associated with gestational duration; the association was replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,536 mother-child pairs showed that the association was driven by fetal rather than maternal genotype. Functional experiments showed that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
D.sort: template based automatic spike sorting tool
Authors: Belkhiri Madeny , Kvitsiani Duda
Published: September 2018

Understanding how populations of neurons represent and compute internal or external variables requires precise and objective metrics for tracing the individual spikes that belong to a given neuron. Despite recent progress in the development of accurate and fast spike sorting tools, the scarcity of ground truth data makes it difficult to settle on the best performing spike sorting algorithm. Besides, the use of different configurations of electrodes and ways to acquire signal (e.g. anesthetized, head fixed, freely behaving animal recordings, tetrode vs. silicone probes, etc.) makes it even harder to develop a universal spike sorting tool that will perform well without human intervention. Some of the prevalent problems in spike sorting are: units separating due to drift, clustering bursting cells, and dealing with nonstationarity in background noise. The last is particularly problematic in freely behaving animals where the noises from the electrophysiological activity of hundreds or thousands of neurons are intermixed with noise arising from movement artifacts. We address these problems by developing a new spike sorting tool that is based on a template matching algorithm. The spike waveform templates are used to perform normalized cross correlation (NCC) with an acquired signal for spike detection. The normalization addresses problems with drift, bursting, and nonstationarity of noise and provides normative scoring to compare different units in terms of cluster quality. Our spike sorting algorithm, D.sort, runs on the graphic processing unit (GPU) to accelerate computations. D.sort is a freely available software package (https://github.com/1804MB/Kvistiani-lab_Dsort).
Novel regression methods for metacognition
Authors: Kristensen Simon Bang , Sandberg Kristian , Bibby Bo Martin
Published: September 2018

Metacognition is an important component in basic science and clinical psychology, often studied through complex, cognitive experiments. While Signal Detection Theory (SDT) provides a popular and pervasive framework for modelling responses from such experiments, a shortfall remains that it cannot in a straightforward manner account for the often complex designs. Additionally, SDT does not provide direct estimates of metacognitive ability. This latter shortcoming has recently been sought remedied by introduction of a measure for metacognitive sensitivity dubbed meta-d’. The need for a flexible regression model framework remains, however, which should also incorporate the new sensitivity measure. In the present paper, we argue that a straightforward extension of SDT is obtained by identifying the model with the proportional odds model, a widely implemented, ordinal regression technique. We go on to develop a formal statistical framework for metacognitive sensitivity by defining a model that combines standard SDT with meta-d’ in a latent variable model. We show how this agrees with the literature on meta-d’ and constitutes a practical framework for extending the model. We supply several teoretical considerations on the model, including closed-form approximate estimates of meta-d’ and optimal weighing of response-specific meta-sensitivities. We discuss regression analysis as an application of the obtained model and illustrate our points through simulations. Lastly, we presentR-software that implements the model. Our methods and their implementation extend the computational possibilities of SDT and meta-dand are useful for theoretical and practical researchers of metacognition.
Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a non-phosphorous allosteric inhibitor
Authors: Vidilaseris Keni , Kiriazis Alexandros , Turku Ainoleena , Khattab Ayman , Johansson Niklas G. , Leino Teppo O. , Kiuru Paula S. , af Gennäs Gustav Boije , Meri Seppo , Yli-Kauhaluoma Jari , Xhaard Henri , Goldman Adrian
Published: September 2018

Membrane-bound pyrophosphatases are homodimeric integral membrane proteins that hydrolyse pyrophosphate into orthophosphates, coupled to the active transport of protons or sodium ions across membranes. They are important in the life cycle of bacteria, archaea, plants, and protist parasites, but no homologous proteins exist in vertebrates, making them a promising drug target. Here, we report the first non-phosphorous allosteric inhibitor (Ki of 1.8 ± 0.3 μM) of the thermophilic bacterium Thermotoga maritima membrane-bound pyrophosphatase and its bound structure at 3.7 Å resolution together with the substrate analogue imidodiphosphate. The unit cell contains two protein homodimers, each binding a single inhibitor dimer near the exit channel, creating a hydrophobic clamp that inhibits the movement of β-strand 1–2 during pumping, and thus preventing the hydrophobic gate from opening. This asymmetry of inhibitor binding with respect to each homodimer provide the first clear demonstration of asymmetry in the catalytic cycle of membrane-bound pyrophosphatases.
SilentMutations (SIM): a tool for analyzing long-range RNA-RNA interactions in viral genomes and structured RNAs
Authors: Desirò Daniel , Hölzer Martin , Ibrahim Bashar , Marz Manja
Published: September 2018

Background

A single nucleotide change in the coding region can alter the amino acid sequence of a protein. In consequence, natural or artificial sequence changes in viral RNAs may have various effects not only on protein stability, function and structure but also on viral replication.

In recent decades, several tools have been developed to predict the effect of mutations in structured RNAs such as viral genomes or non-coding RNAs. Some tools use multiple point mutations and also take coding regions into account. However, none of these tools was designed to specifically simulate the effect of mutations on viral long-range interactions.

Results

Here, we developedSilentMutations (SIM), an easy-to-use tool to analyze the effect of multiple point mutations on the secondary structures of two interacting viral RNAs. The tool can simulate disruptive and compensatory mutants of two interacting single-stranded RNAs. This allows a fast and accurate assessment of key regions potentially involved in functional long-range RNA-RNA interactions and will eventually help virologists and RNA-experts to design appropriate experiments.

SIMonly requires two interacting single-stranded RNA regions as input. The output is a plain text file containing the most promising mutants and a graphical representation of all interactions.

Conclusion

We applied our tool on two experimentally validated influenza A virus and hepatitis C virus interactions and we were able to predict potential double mutants forin vitrovalidation experiments.

Availability

The source code and documentation ofSIMare freely available at github.com/desiro/silentMutations.
Therapeutic Treatment of Aerosolized Staphylococcal Enterotoxin B in Nonhuman Primates with two Monoclonal Antibodies
Authors: Verreault Daniel , Ennis Jane , Whaley Kevin , Killeen Stephanie Z. , Karauzum Hatice , Aman M.Javad , Holtsberg Rick , Doyle-Meyers Lara , Didier Peter J. , Zeitlin Larry , Roy Chad J.
Published: September 2018

Staphylococcal enterotoxin B (SEB) is a protein exotoxin found on the cell surface ofStaphylococcus aureusthat is the source for multiple pathologies in man. When purified and concentrated in aerosol form, SEB can cause an acute and often fatal intoxication, and thus is considered a biological threat agent. There are currently no vaccines or treatments approved for human use. Studies in rodent models of SEB intoxication show that antibody therapy may be a promising treatment strategy, however many have used antibodies only prophylactically or well before any clinical signs of intoxication are apparent. We assessed and compared the protective efficacy of two monoclonal antibodies, Ig121 and c19F1, when administered after aerosol exposure in a uniformly lethal nonhuman primate model of SEB intoxication. Rhesus macaques were challenged using small particle aerosols of SEB, and then were infused intravenously with a single dose of either Ig121 or c19F1 (10 mg/kg) at either 0.5, 2 or 4 hours postexposure. Onset of clinical signs, hematological, and cytokine response in untreated controls confirmed the acute onset and potency of the toxin used in the challenge. All animals administered either Ig121 or c19F1 survived SEB challenge, whereas the untreated controls succumbed to SEB intoxication 30-48 hours postexposure. These results represent the successful therapeuticin vivoprotection by two investigational drugs against SEB in a severe nonhuman primate disease model and punctuate the therapeutic value of monoclonal antibodies hold when faced with treatment options for SEB-induced toxicity in a postexposure setting.

One Sentence Summary: Two high-affinity monoclonal antibodies were tested for therapeutic efficacy using a rhesus macaque challenge model of aerosolized SEB
Assessing the blood-host plasticity and dispersal rate of the malaria vector Anopheles coluzzii
Authors: Orsborne James , Furuya-Kanamori Luis , Jeffries Claire L. , Kristan Mojca , Mohammed Abdul Rahim , Afrane Yaw A. , O’Reilly Kathleen , Massad Eduardo , Drakeley Chris , Walker Thomas , Yakob Laith
Published: September 2018

Difficulties with observing the dispersal of insect vectors in the field have hampered understanding of several aspects of their behaviour linked to disease transmission. Here, a novel method based on detection of blood-meal sources is introduced to inform two critical and understudied mosquito behaviours: plasticity in the malaria vector’s blood-host choice and vector dispersal. Strategically located collections of Anopheles coluzzii from a malaria-endemic village of southern Ghana showed statistically significant variation in host species composition of mosquito blood-meals. Trialling a new sampling approach gave the first estimates for the remarkably local spatial scale across which host choice is plastic. Using quantitative PCR, the blood-meal digestion was then quantified for field-caught mosquitoes and calibrated according to timed blood digestion in colony mosquitoes. We demonstrate how this new ‘molecular Sella score’ approach can be used to estimate the dispersal rate of blood-feeding vectors caught in the field.
Detection of adaptive divergence in populations of the stream mayflyEphemera strigatawith machine learning
Authors: Li Bin , Yaegashi Sakiko , Carvajal Thaddeus M , Gamboa Maribet , Watanabe Kozo
Published: September 2018

Adaptive divergence is a key mechanism shaping the genetic variation of natural populations. A central question linking ecology with evolutionary biology concerns the role of environmental heterogeneity in determining adaptive divergence among local populations within a species. In this study, we examined adaptive the divergence among populations of the stream mayflyEphemera strigatain the Natori River Basin in northeastern Japan. We used a genome scanning approach to detect candidate loci under selection and then applied a machine learning method (i.e. Random Forest) and traditional distance-based redundancy analysis (dbRDA) to examine relationships between environmental factors and adaptive divergence at non-neutral loci. We also assessed spatial autocorrelation at neutral loci to quantify the dispersal ability ofE. strigata. Our main findings were as follows: 1) random forest shows a higher resolution than traditional statistical analysis for detecting adaptive divergence; 2) separating markers into neutral and non-neutral loci provides insights into genetic diversity, local adaptation and dispersal ability and 3)E. strigatashows altitudinal adaptive divergence among the populations in the Natori River Basin.
A systematic review and meta-analysis of the human blood index of the major African malaria vectors
Authors: Orsborne James , Furuya-Kanamori Luis , Jeffries Claire L. , Kristan Mojca , Mohammed Abdul Rahim , Afrane Yaw A. , O’Reilly Kathleen , Massad Eduardo , Drakeley Chris , Walker Thomas , Yakob Laith
Published: September 2018

BACKGROUND

The proportion of mosquito blood-meals that are of human origin, referred to as the ‘human blood index’ or HBI, is a key determinant of malaria transmission. We conducted a systematic review of the HBI for the major African malaria vectors.

RESULTS

Evidence is presented for higher HBI among Anopheles gambiae (M/S forms and An. coluzzii/An. gambiae s.s. are not distinguished for most studies and therefore combined) as well as An. funestus when compared with An. arabiensis (prevalence odds ratio adjusted for collection location [i.e. indoor or outdoor]: 1.62; 95%CI 1.09-2.42; 1.84; 95%CI 1.35-2.52, respectively). This finding is keeping with the entomological literature which describes An. arabiensis to be more zoophagic than the other major African vectors. However, analysis also revealed that HBI was more associated with location of mosquito captures (R2=0.29) than with mosquito (sibling) species (R2=0.11).

CONCLUSIONS

Our findings call into question the appropriateness of current methods of assessing host preferences among disease vectors and have important implications for strategizing vector control.
Characterization of deep neural network features by decodability from human brain activity
Authors: Horikawa Tomoyasu , Aoki Shuntaro C. , Tsukamoto Mitsuaki , Kamitani Yukiyasu
Published: September 2018

Achievements of near human-level performances in object recognition by deep neural networks (DNNs) have triggered a flood of comparative studies between the brain and DNNs. Using a DNN as a proxy for hierarchical visual representations, our recent study found that human brain activity patterns measured by functional magnetic resonance imaging (fMRI) can be decoded (translated) into DNN feature values given the same inputs. However, not all DNN features are equally decoded, indicating a gap between the DNN and human vision. Here, we present a dataset derived through the DNN feature decoding analyses including fMRI signals of five human subjects during image viewing, decoded feature values of DNNs (AlexNet and VGG19), and decoding accuracies of individual DNN features with their rankings. The decoding accuracies of individual features were highly correlated between subjects, suggesting the systematic differences between the brain and DNNs. We hope the present dataset will contribute to reveal the gap between the brain and DNNs and provide an opportunity to make use of the decoded features for further applications.
Functional Specialization is Independent of Microstructural Variation in Cerebellum but Not in Cerebral Cortex
Authors: Guell Xavier , Schmahmann Jeremy D , Gabrieli John DE
Published: September 2018

The human brain is understood to follow fundamental principles linking form (such as microstructure and anatomical connectivity) to function (perceptual, motor, cognitive, emotional, and other processes). Most of this understanding is based on knowledge of the cerebral cortex, where functional specialization is thought to be closely linked to microstructural variation as well as anatomical connectivity. The Universal Cerebellar Transform (UCT) theory has posited that the cerebellum has a different form-function organization in which microstructure is uniform, and in which functional specialization is determined solely by anatomical connectivity with extracerebellar structures. All cerebellar functions may thus be subserved by a common microstructural - and hence computational - substrate. Here we tested this hypothesis by measuring microstructural variation and functional specialization as indexed by magnetic resonance imaging in 1003 healthy humans. Cerebral cortex exhibited the expected pattern of microstructure-function correlation, but functional specialization was independent of microstructural variation in the cerebellum. These findings support the idea that cerebellar functional specialization is not determined by microstructure, and hence that cerebellar functions may be computationally constant across domains.

SIGNIFICANCE STATEMENT

The cerebellum is estimated to contain more than half the neurons in the human brain, is known to be involved in motoric, cognitive, and emotional functions, and is implicated in many neurological and neuropsychological disorders, but remains far less studied than the cerebral cortex. The Universal Cerebellar Transform (UCT) theory posits that one uniform computation underlies all cerebellar functions across multiple domains, but testing that idea has been difficult. Here we find that unlike the cerebral cortex, in which microstructural variation is associated with functional variation, the cerebellum exhibits relatively uniform microstructure across functionally distinct regions. These findings support UCT theory, and draw a sharp distinction between form-function relations in the cerebellum versus the cerebral cortex.
poreTally: run and publish de novo Nanopore assembler benchmarks
Authors: de Lannoy Carlos , Risse Judith , de Ridder Dick
Published: September 2018

Nanopore sequencing is a novel approach to nucleic acid analysis that generates long, error-prone reads. Since device components, base calling software and best practices for sample preparation are updated frequently and extensively, the nature of the produced data also changes frequently. As a result, peer-reviewed publications on de novo assembly pipeline benchmarking efforts are quickly rendered outdated by the next major improvement to the sequencing platforms. To provide the user community with a faster, more flexible alternative to peer-reviewed benchmark papers for de novo assembly tool performance we constructed poreTally, a comprehensive benchmarking tool. poreTally automatically assembles a given read set using several often-used assembly pipelines, analyzes the resulting assemblies for correctness and continuity, and finally generates a quality report. Results can immediately be shared with peers in a Github/Gitlab repository. Furthermore, we aim to give a more inclusive overview of assembly pipeline performance than any individual research group can, by offering users the possibility to submit their results to a collective benchmarking effort. poreTally is available on Github.
Discovery and characterization of variance QTLs in human induced pluripotent stem cells
Authors: Sarkar Abhishek K. , Tung Po-Yuan , Blischak John D. , Burnett Jonathan E. , Li Yang I. , Stephens Matthew , Gilad Yoav
Published: September 2018

Quantification of gene expression levels at the single cell level has revealed that gene expression can vary substantially even across a population of homogeneous cells. However, it is currently unclear what genomic features control variation in gene expression levels, and whether common genetic variants may impact gene expression variation. Here, we take a genome-wide approach to identify expression variance quantitative trait loci (vQTLs). To this end, we generated single cell RNA-seq (scRNA-seq) data from induced pluripotent stem cells (iPSCs) derived from 53 Yoruba individuals. We collected data for a median of 95 cells per individual and a total of 5,447 single cells, and identified 241 mean expression QTLs (eQTLs) at 10% FDR, of which 82% replicate in bulk RNA-seq data from the same individuals. We further identified 14 vQTLs at 10% FDR, but demonstrate that these can also be explained as effects on mean expression. Our study suggests that dispersion QTLs (dQTLs) which could alter the variance of expression independently of the mean can have larger fold changes, but explain less phenotypic variance than eQTLs. We estimate 424 individuals as a lower bound to achieve 80% power to detect the strongest dQTLs in iPSCs. These results will guide the design of future studies on understanding the genetic control of gene expression variance.

Author summary

Common genetic variation can alter the level of average gene expression in human tissues, and through changes in gene expression have downstream consequences on cell function, human development, and human disease. However, human tissues are composed of many cells, each with its own level of gene expression. With advances in single cell sequencing technologies, we can now go beyond simply measuring the average level of gene expression in a tissue sample and directly measure cell-to-cell variance in gene expression. We hypothesized that genetic variation could also alter gene expression variance, potentially revealing new insights into human development and disease. To test this hypothesis, we used single cell RNA sequencing to directly measure gene expression variance in multiple individuals, and then associated the gene expression variance with genetic variation in those same individuals. Our results suggest that effects on gene expression variance are smaller than effects on mean expression, relative to how much the phenotypes vary between individuals, and will require much larger studies than previously thought to detect.
A comparative study of ‘safe and just operating space’ for the south and south-east Asian countries
Authors: Roy Ajishnu , Pramanick Kousik
Published: September 2018

The world is presently maintaining a delicate balance of continuing well-being and social development for the people through consumption of biophysical resources of nature without topping global average per capita availability. In this paper, we have framed a per capita top-down framework to survey national‘safe and just operating space’ (NSJOS) for the countries of south and southeast Asia to understand past variations and as a consequence, the present scenario. Amalgamating 27 indicators, all regarding Sustainable Development Goals (except – SDG 17), in consort with their respective environmental boundaries or desirable social development thresholds, this study explores into both biophysical (for ecological stress) and social development (for social deprivation) attributes of 19 countries of south and southeast Asia. This analysis shows, only 2 have remained either unchanged (political voice) or declining (social equity) among the 12 dimensions of social development in countries of this region. The remaining 10 dimensions of social development showing positive progress and will meet corresponding desired thresholds of United Nations Sustainable Development Goals 2015. All the 7 indicators showing tendencies of overconsumption of biophysical resources, that might be leading to exceeding per capita global average planetary boundaries in forthcoming future. However, ecological boundaries have remained protected to a decent degree so far for these countries. The challenge would be to maintain and increase the pace of social development and bringing it in equal strata of a global standard in future without depleting drivers of these, i.e. biophysical resources. National policy adaptations are crucial if these countries of south and southeast Asia desire to bring about adequacy in biophysical resources reserve whilst granting social equity in access and exploitation of these resources for the people towards the persistant social development in impending decades.
Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection
Authors: Yu Tai-Yuan , Kimble Michael , Symington Lorraine S
Published: September 2018

The Mre11-Rad50-Xrs2NBS1 complex plays important roles in the DNA damage response by activating the Tel1ATM kinase and catalyzing 5’-3’ resection at DNA double-strand breaks (DSBs). To initiate resection, Mre11 endonuclease nicks the 5’ strands at DSB ends in a reaction stimulated by Sae2CtIP. Accordingly, Mre11-nuclease deficient (mre11-nd) and sae2Δ mutants are expected to exhibit similar phenotypes; however, we found several notable differences. First, sae2Δ cells exhibit greater sensitivity to genotoxins than mre11-nd cells. Second, sae2Δ is synthetic lethal with sgs1Δ, whereas the mre11-nd sgs1Δ mutant is viable. Third, Sae2 attenuates the Tel1-Rad53CHK2 checkpoint and antagonizes Rad953BP1 accumulation at DSBs independent of Mre11 nuclease. We show that Sae2 competes with other Tel1 substrates, thus reducing Rad9 binding to chromatin and to Rad53. We suggest that persistent Sae2 binding at DSBs in the mre11-nd mutant counteracts the inhibitory effects of Rad9 and Rad53 on Exo1 and Dna2-Sgs1 mediated resection, accounting for the different phenotypes conferred by mre11-nd and sae2Δ mutations. Collectively, these data show a resection initiation independent role for Sae2 at DSBs by modulating the DNA damage checkpoint.
Flavor-Cyber-Agriculture: Optimization of plant metabolites in an open-source control environment through surrogate modeling
Authors: Johnson Arielle J. , Meyerson Elliot , de la Parra John , Savas Timothy L. , Miikkulainen Risto , Harper Caleb B.
Published: September 2018

Food production in conventional agriculture faces numerous challenges such as reducing waste, meeting demand, maintaining flavor, and providing nutrition. Contained environments under artificial climate control, or cyber-agriculture, could in principle be used to meet many of these challenges. Through such environments, phenotypic expression of the plant---mass, edible yield, flavor, and nutrients---can be actuated through a “climate recipe,” where light, water, nutrients, temperature, and other climate and ecological variables are optimized to achieve a desired result. This paper describes a method for doing this optimization for the desired result of flavor by combining cyber-agriculture, metabolomic phenotype (chemotype) measurements, and machine learning. In a pilot experiment, (1) environmental conditions, i.e. photoperiod and ultraviolet (UV) light (known to affect production of flavor-active molecules in edible plants) were applied under different regimes to basil plants (Ocimum basilicum) growing inside a hydroponic farm with an open-source design; (2) flavor-active volatile molecules were measured in each plant using gas chromatography-mass spectrometry (GC-MS); and (3) symbolic regression was used to construct a surrogate model of this chemistry from the input environmental variables, and this model was used to discover new combinations of photoperiod and UV light to increase this chemistry. These new combinations, or climate recipes, were then implemented in the hydroponic farm, and several of them resulted in a marked increase in volatiles over control. The process also led to two important insights: it demonstrated a “dilution effect”, i.e. a negative correlation between weight and desirable chemical species, and it discovered the surprising effect that a 24-hour photoperiod of photosynthetic-active radiation, the equivalent of all-day light, induces the most flavor molecule production in basil. In this manner, surrogate optimization through machine learning can be used to discover effective recipes for cyber-agriculture that would be difficult and time-consuming to find using hand-designed experiments.
Effects of two centuries of global environmental variation on phenology and physiology of Arabidopsis thaliana
Authors: DeLeo Victoria L. , Menge Duncan N. L. , Hanks Ephraim M. , Juenger Thomas E. , Lasky Jesse R.
Published: September 2018

Intraspecific trait variation is caused by genetic and plastic responses to environment. This intraspecific diversity is captured in immense natural history collections, giving us a window into trait variation across continents and through centuries of environmental shifts. Here we tested if hypotheses based on life history and the leaf economics spectrum explain intraspecific trait changes across global spatiotemporal environmental gradients. We measured phenotypes on a 216-year time series of Arabidopsis thaliana accessions from across the native range and applied spatially varying coefficient models to quantify region-specific trends in trait coordination and trait responses to climate gradients. All traits exhibited significant change across space and/or through time. For example, δ15N decreased over time across much of the range and leaf C:N increased, consistent with predictions based on anthropogenic changes in land use and atmosphere. Plants were collected later in the growing season in more recent years in many regions, possibly because populations shifted toward more spring germination and summer flowering as opposed to fall germination and spring flowering. When climate variables were considered, collection dates were earlier in warmer years, while summer rainfall had opposing associations with collection date depending on regions. There was only a modest correlation among traits, indicating a lack of a single life history/physiology axis. Nevertheless, leaf C:N was low for summer- versus spring-collected plants, consistent with a life history-physiology axis from slow-growing winter annuals to fast-growing spring/summer annuals. Regional heterogeneity in phenotype trends indicates complex responses to spatiotemporal environmental gradients potentially due to geographic genetic variation and climate interactions with other aspects of environment. Our study demonstrates how natural history collections can be used to broadly characterize trait responses to environment, revealing heterogeneity in response to anthropogenic change.
Highly Mutable Linker Regions Regulate HIV-1 Rev Function and Stability
Authors: Jayaraman Bhargavi , Fernandes Jason D , Yang Shumin , Smith Cynthia , Frankel Alan D
Published: September 2018

The HIV-1 protein Rev is an essential viral regulatory protein that facilitates the nuclear export of intron-containing viral mRNAs. Its sequence is organized into short, structured, functionally well-characterized motifs joined by less understood linker regions. We recently carried out a competitive deep mutational scanning study, which determined the relative fitness of every amino acid at every position of Rev in replicating viruses. This study confirmed many known constraints in Rev’s established interaction motifs, but also identified positions of mutational plasticity within these regions as well as in surrounding linker regions. Here, we probe the mutational limits of these linkers by designing and testing the activities of multiple truncation and mass substitution mutations. We find that these regions possess previously unknown structural, functional or regulatory roles, not apparent from systematic point mutational approaches. Specifically, the N- and C-termini of Rev contribute to protein stability; mutations in a turn that connects the two main helices of Rev have different effects in nuclear export assays and viral replication assays; and a linker region which connects the second helix of Rev to its nuclear export sequence has structural requirements for function. Thus, we find that Rev function extends beyond its characterized motifs, and is in fact further tuned by determinants within seemingly plastic portions of its sequence. At the same time, Rev’s ability to tolerate many of these massive truncations and substitutions illustrates the overall mutational and functional robustness inherent in this viral protein.

Author Summary (non-technical summary)

HIV-1 Rev is an essential viral protein that controls a critical step in the HIV life cycle. It is responsible for transporting viral mRNA messages from the nucleus to the cytoplasm where they can contribute to the formation new virus particles. In order to understand how different regions of the Rev protein sequence are involved in its function, we introduced truncations and mass substitution mutations in the protein sequence and tested their effect on protein function. Through this study, we not only confirmed previous work highlighting known functionally important regions in Rev, but also found that a large portion of Rev, with little known functional roles influence Rev function and stability. We also show that although protein sequence is critical to its function, Rev can tolerate large variations to its sequence without disrupting its function significantly.
Parliament2: Fast Structural Variant Calling Using Optimized Combinations of Callers
Authors: Zarate Samantha , Carroll Andrew , Krashenina Olga , Sedlazeck Fritz J , Jun Goo , Salerno William , Boerwinkle Eric , Gibbs Richard
Published: September 2018

Here we present Parliament2 – a structural variant caller which combines multiple best-in-class structural variant callers to create a highly accurate callset. This captures more events than the individual callers achieve independently. Parliament2 uses a call-overlap-genotype approach that is highly extensible to new methods and presents users the choice to run some or all of Breakdancer, Breakseq, CNVnator, Delly, Lumpy, and Manta to run. Parliament2 applies an additional parallelization framework to speed certain callers and executes these in parallel, taking advantage of the different resource requirements to complete structural variant calling much faster than running the programs individually. Parliament2 is available as a Docker container, which pre-installs all required dependencies. This allows users to run any caller with easy installation and execution. This Docker container can easily be deployed in cloud or local environments and is available as an app on DNAnexus.
An exploration of Prevotella-rich microbiomes in HIV and men who have sex with men
Authors: Armstrong Abigail JS , Shaffer Michael , Nusbacher Nichole M , Griesmer Christine , Fiorillo Suzanne , Schneider Jennifer M , Neff C Preston , Li Sam X , Fontenot Andrew P , Campbell Thomas , Palmer Brent E , Lozupone Catherine A
Published: September 2018

Background

Gut microbiome characteristics associated with HIV infection are of intense research interest but a deep understanding has been challenged by confounding factors across studied populations. Notably, a Prevotella-rich microbiome described in HIV-infected populations is now understood to be common in men who have sex with men (MSM) regardless of HIV status, but driving factors and potential health implications are unknown.

Results

Here we further define the MSM-associated gut microbiome and describe compositional differences between the fecal microbiomes of Prevotella-rich MSM and non-MSM that may underlie observed pro-inflammatory properties. Furthermore, we show relatively subtle gut microbiome changes in HIV infection in MSM and women that include an increase in potential pathogens that is ameliorated with antiretroviral therapy (ART). Lastly, using a longitudinal cohort, we describe microbiome changes that happen after ART initiation.

Conclusions

This study provides an in-depth characterization of microbiome differences that occur in a US population infected with HIV and demonstrates the degree to which these differences may be driven by lifestyle factors, ART and HIV infection itself. Understanding microbiome compositions that occur with sexual behaviors that are high-risk for acquiring HIV and untreated and ART-treated HIV infection will guide the investigation of immune and metabolic functional implications to ultimately target the microbiome therapeutically.
Cell wall inhibitors increase the accumulation of rifampicin in Mycobacterium tuberculosis
Authors: McNeil Matthew B. , Chettiar Somsundaram , Awasthi Divya , Parish Tanya
Published: September 2018

There is a need for new combination regimens for tuberculosis. Identifying synergistic drug combinations can avoid toxic side effects and reduce treatment times. Using a fluorescent rifampicin conjugate, we demonstrated that synergy between cell wall inhibitors and rifampicin was associated with increased accumulation of rifampicin. Increased accumulation was also associated with increased cellular permeability.
Neural circuit repair by low-intensity magnetic stimulation requires cryptochrome
Authors: Dufor Tom , Grehl Stephanie , Tang Alexander D , Doulazmi Mohamed , Traoré Massiré , Debray Nicolas , Dubacq Caroline , Deng Zhi-De , Mariani Jean , Lohof Ann M , Sherrard Rachel M
Published: September 2018

Magnetic brain stimulation is a promising treatment in neurology and psychiatry, but clinical outcomes are variable. Unfortunately, mechanisms underlying magnetic stimulation effects are ill-defined, which impedes the development of stimulation protocols appropriate for different neurological conditions. Here we show,in vivoandex vivo, that repetitive transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with complex patterns being particularly effective, and its mechanism requires the presence of cryptochrome (Cry), a putative magneto-receptor. Effective LI-rTMS patterns altered expression of Cry target genes known to promote neuronal repair. Because LI-rTMS generates electric fields too weak to depolarise neurons, these findings indicate that the magnetic field itself induces the repair. Our data open a new framework for magnetic stimulation - cryptochrome-mediated molecular and structural neuroplasticity. This information suggests new routes to treatments specific for each neurological disease.
Connexin-43 dependent ATP release mediates macrophage activation during peritonitis
Authors: Dosch Michel , Zindel Joël , Jebbawi Fadi , Melin Nicolas , Sanchez-Taltavull Daniel , Stroka Deborah , Candinas Daniel , Beldi Guido
Published: September 2018

Peritonitis is the consequence of bacterial spillage into a sterile environment by gastrointestinal hollow-organ perforation that may lead to fulminant sepsis. Outcome of peritonitis-induced sepsis critically depends on macrophage activation by extracellular ATP release and associated para- and autocrine signaling via purinergic receptors. Mechanisms that mediate and control ATP release, however, are poorly understood. Here we show that TLR-2 and -4 agonists trigger ATP release via Connexin-43 (CX43) hemichannels in peritoneal macrophages leading to poor survival during sepsis. In humans, CX43 expression was upregulated on macrophages isolated from the peritoneal cavity in patients with intraperitoneal infection but not in healthy controls. Using a murine caecal ligation and puncture (CLP) model, we identified increased CX43 expression in activated infiltrating peritoneal, hepatic and pulmonary macrophages. Conditional MAC-CX43 KO Lyz2cre/creCx43flox/flox mice were developed to specifically assess the CX43 impact in macrophages. Both macrophage-specific CX43 deletion (using Lyz2cre/creCx43flox/flox mice) or pharmacological CX43 blockade were associated with reduced cytokine secretion by macrophages in response to LPS and CLP. This was ultimately resulting in increased survival in Lyz2cre/creCx43flox/flox mice and after pharmacological blockade. Specific inhibition of the purinergic receptor P2RY1 abrogated CX43 elicited cytokine responses. In conclusion, inhibition of autocrine ATP signaling via CX43 on macrophages and P2RY1 improves sepsis outcome in experimental peritonitis.

Brief Summary

Connexin-43-mediated ATP release from macrophages in response to TLR-4 and -2 agonists modulates autocrine activation of macrophages in a P2Y1-dependent manner, ultimately determining sepsis survival.
TheC. elegansCHP1 homolog,pbo-1, functions in innate immunity by regulating the pH of the intestinal lumen
Authors: Benomar Saida , Bender Aaron , Peterson Blake R. , Chandler Josephine R. , Ackley Brian D.
Published: September 2018

Caenorhabditis elegansare soil-dwelling nematodes and models for understanding innate immunity and infection. Previous work has described a regularly-timed pH change in the intestine ofCaenorhabditis eleganscalled the pH wave. To characterize this wave and its function in the worm, we developed a novel fluorescent dye (KR35) that accumulates in the intestine and sensitively responds to dynamic changes in pH. Here, we use KR35 to show that mutations in the Ca2+-binding protein, PBO-1 abrogate the pH wave, causing the anterior intestine to be constantly acidic. Surprisingly,pbo-1mutants were also more susceptible to infection by several bacterial pathogens. We could suppress pathogen susceptibility inpbo-1mutants by treating the animals with pH-buffering bicarbonate, suggesting the pathogen susceptibility is a function of the acidity of the intestinal pH. Furthermore, we use KR35 to show that pathogens completely neutralize the pH in the intestine of wild type, but notpbo-1mutants.C. elegansis known to increase production of reactive oxygen species (ROS), such as H2O2,in response to pathogens, which is an important component of pathogen defense. We show thatpbo-1mutants exhibited decreased H2O2in response to pathogens, which could also be partially restored inpbo-1animals treated with bicarbonate. Ultimately, our results support a model wherebypbo-1functions during infection to permit pH changes in the intestine that are important for fighting pathogens.

Author Summary

Innate immunity is critical for host defense against pathogens. However, questions remain about how the host senses and responds to pathogen invasion. Using a pH-sensitive fluorescent dye and aCaenorhabditis eleganspathogen infection model we show that pathogens induce changes in pH of the worm intestine. We also show that intestinal pH directly affects production of reactive oxygen species (e.g. H2O2) important for pathogen defense. Our results show that pH regulation is an important component of the innate immune response to pathogens.