bluuebunny/crossref_metadata_2025 huggingface dataset:
Low but genetically variable male remating ability in a tropicalDrosophiladespite substantial fitness benefits
Authors: Saxon Andrew D. , Jones Natalie E. , O’Brien Eleanor K. , Bridle Jon R.
Published: December 2018

Mating success is the main source of fitness variation in males, meaning that males should capitalise on all opportunities for mating. Strong selection on male mating success should also reduce genetic variation in male mating traits relative to other traits. We quantified mating latency, mating duration and productivity in males of the tropical fruitfly,Drosophila birchii, from 30 isofemale lines collected from across two elevational gradients, when they were given opportunities to mate with up to four females consecutively. Male remating rates were low compared to otherDrosophila(only 14 – 27% of males achieved a fourth mating), with mean mating durations approximately doubling across successive copulations. However, although successive remating produced progressively fewer offspring, it consistently increased overall male reproductive success, with males that mated four times more than doubling offspring number compared to males mating only once. We also found no reduction in the productivity of sons emerging from later matings, indicating a sustained cumulative fitness benefit to remating. Heritable variation was observed for most traits (H2= 0.035 – 0.292) except mating latency, but there was no divergence in trait means with elevation. The observed restricted remating ability of maleD. birchii, despite the clear benefits of remating, may be due to a low encounter rate with females in the field, leading to high investment per gamete (or ejaculate). However, it remains unclear why genetic variation in these traits is high, given we observe no variation in these traits across elevational gradients known to affect local population density.
doepipeline: a systematic approach to optimizing multi-level and multi-step data processing workflows
Authors: Svensson Daniel , Sjögren Rickard , Sundell David , Sjödin Andreas , Trygg Johan
Published: December 2018

Background

Selecting the proper parameter settings for bioinformatic software tools is challenging. Not only will each parameter have an individual effect on the outcome, but there are also potential interaction effects between parameters. Both of these effects may be difficult to predict. To make the situation even more complex, multiple tools may be run in a sequential pipeline where the final output depends on the parameter configuration for each tool in the pipeline. Because of the complexity and difficulty of predicting outcomes, in practice parameters are often left at default settings or set based on personal or peer experience obtained in a trial and error fashion. To allow for the reliable and efficient selection of parameters for bioinformatic pipelines, a systematic approach is needed.

Results

We presentdoepipeline, a novel approach to optimizing bioinformatic software parameters, based on core concepts of the Design of Experiments methodology and recent advances in subset designs. Optimal parameter settings are first approximated in a screening phase using a subset design that efficiently spans the entire search space, then optimized in the subsequent phase using response surface designs and OLS modeling.doepipelinewas used to optimize parameters in four use cases; 1) de-novo assembly, 2) scaffolding of a fragmented genome assembly, 3) k-mer taxonomic classification of Oxford Nanopore Technologies MinION reads, and 4) genetic variant calling. In all four cases,doepipelinefound parameter settings that produced a better outcome with respect to the characteristic measured when compared to using default values. Our approach is implemented and available in the Python packagedoepipeline.

Conclusions

Our proposed methodology provides a systematic and robust framework for optimizing software parameter settings, in contrast to labor- and time-intensive manual parameter tweaking. Implementation indoepipelinemakes our methodology accessible and user-friendly, and allows for automatic optimization of tools in a wide range of cases. The source code ofdoepipelineis available athttps://github.com/clicumu/doepipelineand it can be installed through conda-forge.
Measuring Granger-causal effects in multivariate time series by system editing
Authors: Pascual-Marqui Roberto D. , Biscay Rolando J. , Bosch-Bayard Jorge , Faber Pascal , Kinoshita Toshihiko , Kochi Kieko , Milz Patricia , Nishida Keiichiro , Yoshimura Masafumi
Published: December 2018

1.

What is the role of each node in a system of many interconnected nodes? This can be quantified by comparing the dynamics of the nodes in the intact system, with their modified dynamics in the edited system, where one node is deleted. In detail, the spectra are calculated from a causal multivariate autoregressive model for the intact system. Next, without re-estimation, one node is deleted from the model and the modified spectra at all other nodes are re-calculated. The change in spectra from the edited system to the intact system quantifies the role of the deleted node, giving a measure of its Granger-causal effects (CFX) on the system. A generalization of this novel measure is available for networks (i.e. for groups of nodes), which quantifies the role of each network in a system of many networks. For the sake of reproducible research, program codes (PASCAL), executable file, and toy data in human readable format are included in the supplementary material.
Predicting synergism of cancer drug combinations using NCI-ALMANAC data
Authors: Sidorov Pavel , Naulaerts Stefan , Ariey-Bonnet Jérémy , Pasquier Eddy , Ballester Pedro J.
Published: December 2018

Background

Drug combinations are of great interest for cancer treatment. Unfortunately, the discovery of synergistic combinations by purely experimental means is only feasible on small sets of drugs.In silicomodeling methods can substantially widen this search by providing tools able to predict which of all possible combinations in a large compound library are synergistic. Here we investigate to which extent drug combination synergy can be predicted by exploiting the largest available dataset to date (NCI-ALMANAC, with over 290,000 synergy determinations).

Methods

Each cell line is modeled using primarily two machine learning techniques, Random Forest (RF) and Extreme Gradient Boosting (XGBoost), on the datasets provided by NCI-ALMANAC. This large-scale predictive modeling study comprises more than 5000 pair-wise drug combinations, 60 cell lines, 4 types of models and 5 types of chemical features. The application of a powerful, yet uncommonly used, RF-specific technique for reliability prediction is also investigated.

Results

The evaluation of these models shows that it is possible to predict the synergy of unseen drug combinations with high accuracy (Pearson correlations between 0.43 and 0.86 depending on the considered cell line, with XGBoost providing slightly better predictions than RF). We have also found that restricting to the most reliable synergy predictions results in at least two-fold error decrease with respect to employing the best learning algorithm without any reliability estimation. Alkylating agents, tyrosine kinase inhibitors and topoisomerase inhibitors are the drugs whose synergy with other partner drugs are better predicted by the models.

Conclusions

Despite its leading size, NCI-ALMANAC comprises an extremely small part of all conceivable combinations. Given their accuracy and reliability estimation, the developed models should drastically reduce the number of requiredin vitrotests by predictingin silicowhich of the considered combinations are likely to be synergistic.
The regulation of HAD-like phosphatases by signaling pathways modulates cellular resistance to the metabolic inhibitor, 2-deoxyglucose
Authors: Defenouillère Quentin , Verraes Agathe , Laussel Clotilde , Friedrich Anne , Schacherer Joseph , Léon Sébastien
Published: December 2018

Cancer cells display an altered metabolism with an increased glycolysis and glucose uptake. Anti-cancer strategies targeting glycolysis through metabolic inhibitors have been considered. Particularly, the glucose analogue 2-deoxyglucose (2DG) is imported into cells and phosphorylated into 2DG-6-phosphate, a toxic by-product that inhibits glycolysis. Recent data suggest that 2DG has additional effects in the cell, and resistance to 2DG has also been observed. Using yeast as a model, we engaged an unbiased, mass-spectrometry-based approach to probe the cellular effects of 2DG on the proteome and study resistance mechanisms. This revealed that two 2DG-6-phosphate phosphatases, Dog1 and Dog2, are induced upon exposure to 2DG and participate in 2DG detoxication. 2DG induces Dog2 by upregulating several signaling pathways, such as the MAPK (Hog1/p38)-based stress-responsive pathway, the Unfolded Protein Response (UPR) triggered by 2DG-induced ER stress, and the MAPK (Slt2)-based Cell Wall Integrity pathway. Thus, 2DG-induced interference with cellular signaling rewires the expression of these endogenous phosphatases to promote 2DG resistance. Consequently, loss of the UPR or CWI pathways leads to hypersensitivity to 2DG. In contrast,DOG2is transcriptionally repressed by glucose availability in a Snf1/AMPK-dependent manner, and mutants impaired in this pathway are 2DG-resistant. The characterization and genome resequencing of spontaneous 2DG-resistant mutants revealed thatDOG2overexpression is a common strategy to achieve 2DG resistance. The human Dog2 orthologue, HDHD1, also displays 2DG-6-phosphate phosphatase activityin vitro, and its overexpression confers 2DG resistance in HeLa cells, which has important implications for potential future chemotherapies involving 2DG.
Challenging the function of motor inhibition: Does it really assist action selection?
Authors: Quoilin Caroline , Fievez Fanny , Duque Julie
Published: December 2018

By applying transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) in muscles of the contralateral hand during reaction time (RT) tasks, many studies have reported a strong suppression of MEPs during action preparation, a phenomenon called preparatory inhibition. Several hypotheses have been put forward regarding the role of this inhibition, with the predominant view suggesting that it would help action selection. However, this assumption is still a matter of debate. Here, we aimed at directly addressing this idea by comparing MEPs in a task that required subjects to select a finger response within a set of predefined options (choice RT task: left or right index finger abduction) or when subjects simply had to provide the same finger response on every trial, in the absence of choice (simple RT task). Moreover, we minimized any effect that could be associated with other forms of inhibition. In both versions of the task, TMS was applied on both M1 (double-coil protocol) at several time points between the go signal and the left or right index finger response, eliciting MEPs bilaterally in the prime mover (index finger agonist) and in an irrelevant muscle (pinky agonist). Overall, MEP suppression was moderate in this study; it was only found for the irrelevant muscle. As such, MEPs in the index agonist were facilitated when elicited in a responding hand (e.g. left MEPs preceding left responses) and remained mostly unchanged in a non-responding hand (e.g. left MEPs preceding right responses). In contrast, MEPs were almost always suppressed in the pinky muscle when elicited in the non-responding hand and sometimes also in the responding hand. Importantly, this effect was more consistent in the choice than in the simple RT task, supporting the view that preparatory inhibition may assist action selection. Moreover, the fact that it sometimes concerned the responding hand is coherent with the idea of a global process, suppressing broadly the motor system.
Embedding the Skin Conductance Response into the Brain Connectivity Framework: Monoaminergic Signaling Visible Through the Lenses of Computational Modeling
Authors: Branković Saša
Published: December 2018

Relying on evidence for the functional, neurochemical, and spectral parallelism between the late event-related potentials, delta oscillatory brain responses, and the skin conductance response (SCR) system the hypotheses about the existence of the SCR-related brain oscillations and their connectivity with the SCR system have been here suggested. In contrast to classical approach to event-related oscillations which relies on either stimulus- or response-locked time reference, an approach assigned as “oscillatory process-related oscillations” has been introduced. The method enables us to overcome the variability of latency period of the SCR. The hypothesis about the existence of the SCR-related brain oscillations and their delta nature has been confirmed through the grand averaging method. An unexpected finding was the complex nature of the SCR-related oscillations: in addition to the two second EEG segment which was correlated with the SCR system signals they also comprised an initial 200 ms segment uncorrelated with the SCR. The hypothesis about the connectivity between the SCR system and the respective delta brain oscillatory response has been operationalized through a multiple time series regression model. The predictor set consists of the SCR, its first three derivatives, and their mutual interactions. The Monte Carlo test of the causal link between the SCR system signals and the related delta EEG signal demonstrated significance in more than half of the participants. The findings have been considered from the standpoints of the segmental structure of the EEG, monoaminergic signaling and recently emerged the “brain-body dynamic syncytium” hypothesis.
Population-wide copy number variation calling using variant call format files from 6,898 individuals
Authors: Png Grace , Suveges Daniel , Park Young-Chan , Walter Klaudia , Kundu Kousik , Ntalla Ioanna , Tsafantakis Emmanouil , Karaleftheri Maria , Dedoussis George , Zeggini Eleftheria , Gilly Arthur
Published: December 2018

Motivation

Copy number variants (CNVs) are large deletions or duplications at least 50 to 200 base pairs long. They play an important role in multiple disorders, but accurate calling of CNVs remains challenging. Most current approaches to CNV detection use raw read alignments, which are computationally intensive to process.

Results

We use a regression tree-based approach to call CNVs from whole-genome sequencing (WGS, > 18x) variant call-sets in 6,898 samples across four European cohorts, and describe a rich large variation landscape comprising 1,320 CNVs. 61.8% of detected events have been previously reported in the Database of Genomic Variants. 23% of high-quality deletions affect entire genes, and we recapitulate known events such as theGSTM1andRHDgene deletions. We test for association between the detected deletions and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the detected CNVs. We describe the LD structure and copy number variation underlying the association between levels of the CCL3 protein and a complex structural variant (MAF = 0.15, p = 3.6×10-12) affectingCCL3L3, a paralog of theCCL3gene. We also identify acis-association between a low-frequencyNOMO1deletion and the protein product of this gene (MAF = 0.02, p = 2.2×10-7), for which nocis-ortrans-single nucleotide variant-driven protein quantitative trait locus (pQTL) has been documented to date. This work demonstrates that existing population-wide WGS call-sets can be mined for CNVs with minimal computational overhead, delivering insight into a less well-studied, yet potentially impactful class of genetic variant.

Availability

The regression tree based approach, UN-CNVc, is available as an R and bash executable on GitHub athttps://github.com/agilly/un-cnvc.

Contact

eleftheria.zeggini@helmholtz-muenchen.de;arthur.gilly@helmholtz-muenchen.de

Supplementary Information

Supplementary information is appended.
An event-based paradigm for analyzing fluorescent astrocyte activity uncovers novel single-cell and population-level physiology
Authors: Wang Yizhi , DelRosso Nicole V. , Vaidyanathan Trisha , Reitman Michael , Cahill Michelle K. , Mi Xuelong , Yu Guoqiang , Poskanzer Kira E.
Published: December 2018

Recent work examining astrocytic physiology centers on fluorescence imaging approaches, due to development of sensitive fluorescent indicators and observation of spatiotemporally complex calcium and glutamate activity. However, the field remains hindered in fully characterizing these dynamics, both within single cells and at the population-level, because of the insufficiency of current region-of-interest-based approaches to describe activity that is often spatially unfixed, size-varying, and propagative. Here, we present a paradigm-shifting analytical framework that releases astrocyte biologists from ROI-based tools. Astrocyte Quantitative Analysis (AQuA) software enables users to take an event-based approach to accurately capture and quantify the irregular activity observed in astrocyte imaging datasets. We apply AQuA to a range of ex vivo and in vivo imaging data, and uncover previously undescribed physiological phenomena in each. Since AQuA is data-driven and based on machine learning principles, it can be applied across model organisms, fluorescent indicators, experimental modes, and imaging resolutions and speeds, enabling researchers to elucidate fundamental astrocyte physiology.
Dual-color volumetric imaging of neural activity of cortical columns
Authors: Han Shuting , Yang Weijian , Yuste Rafael
Published: December 2018

To capture the emergent properties of neural circuits, high-speed volumetric imaging of neural activity at cellular resolution is desirable. But while conventional two-photon calcium imaging is a powerful tool to study population activity in vivo, it is restrained to two-dimensional planes. Expanding it to 3D while maintaining high spatiotemporal resolution appears necessary. Here, we developed a two-photon microscope with dual-color laser excitation that can image neural activity in a 3D volume. We imaged the neuronal activity of primary visual cortex from awake mice, spanning from L2 to L5 with 10 planes, at a rate of 10 vol/sec, and demonstrated volumetric imaging of L1 long-range PFC projections and L2/3 somatas. Using this method, we map visually-evoked neuronal ensembles in 3D, finding a lack of columnar structure in orientation responses and revealing functional correlations between cortical layers which differ from trial to trial and are missed in sequential imaging. We also reveal functional interactions between presynaptic L1 axons and postsynaptic L2/3 neurons. Volumetric two-photon imaging appears an ideal method for functional connectomics of neural circuits.
A role for gut microbiota in m6A epitranscriptomic mRNA modifications in different host tissues
Authors: Jabs Sabrina , Becavin Christophe , Nahori Marie-Anne , Guerinau Vincent , Touboul David , Ghozlane Amine , Dillies Marie-Agnes , Cossart Pascale
Published: December 2018

The intestinal microbiota modulates host physiology and gene expression via mechanisms that are not fully understood. A recently discovered layer of gene expression regulation is N6-methyladenosine (m6A) modification of mRNA. To unveil if this epitranscriptomic mark in part mediates the impact of the gut microbiota on the host, we analyzed m6A-modifications in transcripts of mice displaying either a conventional, or a modified, or no gut flora. We discovered that the microbiota has a strong influence on m6A-modifications in the cecum, and also, albeit to a lesser extent, in the liver. We furthermore show that a single commensal bacterium, Akkermansia muciniphila, can affect specific m6A modifications. Together, we report here epitranscriptomic modifications as an unexpected level of interaction in the complex interplay between commensal bacteria and their host.
Sensorimotor conflicts alter perceptual and action monitoring
Authors: Faivre Nathan , Vuillaume Laurene , Bernasconi Fosco , Salomon Roy , Blanke Olaf , Cleeremans Axel
Published: December 2018

Bodily self-consciousness is defined as a set of prereflective representations of integrated bodily signals giving rise to self-identification, self-location and first-person perspective. While bodily self-consciousness is known to modulate perception, little is known about its influence on higher-level cognitive processes. Here, we manipulated bodily self-consciousness by applying sensorimotor conflicts while participants performed a perceptual task followed by confidence judgments. Results showed that sensorimotor conflicts altered perceptual monitoring by decreasing metacognitive performance. In a second experiment, we replicated this finding and extended our results by showing that sensorimotor conflicts also altered action monitoring, as measured implicitly through intentional binding. In a third experiment, we showed that effects on perceptual monitoring were induced specifically by sensorimotor conflicts related to the trunk and not to the hand. Taken together, our results suggest that bodily self-consciousness may serve as a scaffold for perceptual and action monitoring.
PSI controls tim splicing and circadian period in Drosophila
Authors: Foley Lauren , Ling Jinli , Joshi Radhika , Evantal Naveh , Kadener Sebastian , Emery Patrick
Published: December 2018

The Drosophila circadian pacemaker consists of transcriptional feedback loops subjected to both post-transcriptional and post-translational regulation. While post-translational regulatory mechanisms have been studied in detail, much less is known about circadian post-transcriptional control. To have a better understanding of the role and mechanisms of circadian post-transcriptional regulation, we targeted 364 RNA binding and RNA associated proteins with RNA interference. Among the 43 genes we identified was the alternative splicing regulator P-element somatic inhibitor (PSI). PSI downregulation shortens the period of circadian rhythms both in the brain and in peripheral tissues. Interestingly, we found that PSI regulates the thermosensitive alternative splicing of timeless (tim), promoting splicing events favored at warm temperature over those increased at cold temperature. Moreover, the period of circadian behavior was insensitive to PSI downregulation when flies could produce functional TIM proteins only from a transgene that cannot form the thermosensitive splicing isoforms. Therefore, we conclude that PSI regulates the period of Drosophila circadian rhythms through its modulation of the tim splicing pattern.
Convergent Allostery in Ribonucleotide Reductase
Authors: Thomas William C. , Brooks F. Phil , Burnim Audrey A. , Bacik John-Paul , Stubbe JoAnne , Kaelber Jason T. , Chen James Z. , Ando Nozomi
Published: December 2018

Ribonucleotide reductases (RNRs) use a conserved radical-based mechanism to catalyze the conversion of ribonucleotides to deoxyribonucleotides. Within the RNR family, class Ib RNRs are notable for being largely restricted to bacteria, including many pathogens, and for lacking an evolutionarily mobile ATP-cone domain that allosterically controls overall activity. In this study, we report the emergence of a new and unexpected mechanism of activity regulation in the sole RNR of the model organism Bacillus subtilis. Using a hypothesis-driven structural approach that combines the strengths of small-angle X-ray scattering (SAXS), crystallography, and cryo-electron microscopy (cryo-EM), we describe the reversible interconversion of six unique structures, including a flexible, active tetramer and two novel, inhibited filaments. These structures reveal the conformational gymnastics necessary for RNR activity and the molecular basis for its control via an evolutionarily convergent form of allostery.
Specific inflammatory and mitochondrial signatures characterise the WSB/EiJ mice diet-induced obesity resistance capacity: Supplementary Material
Authors: Terrien Jérémy , Seugnet Isabelle , Seffou Bolaji , Herrero Maria J , Bowers James , Chamas Lamis , Decherf Stéphanie , Duvernois-Berthet Evelyne , Djediat Chakib , Ducos Bertrand , Demeneix Barbara A. , Clerget-Froidevaux Marie-Stéphanie
Published: December 2018

Energy balance disruption due to excess of food is considered to be one of the major players in the current worldwide obesity pandemic. In rodents, a high fat diet (HFD) induces not only obesity, but also inflammation and mitochondrial dysfunctions. To identify factors underlying diet-induced obesity (DIO) resistance we compared the wild-derived mouse strain WSB/EiJ, characterized by a striking resistance to DIO, with the more DIO-sensitive C57BL/6J strain. We analysed circulating levels of lipids, cytokines and adipokines as well as hypothalamic markers of inflammatory status and mitochondrial activity in both strains exposed to HFD for three days (3d) or eight weeks (8wk). To identify hypothalamic genes potentially involved in these differential regulations, we analysed the expression levels of 86 genes related to inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from hypothalamic nuclei of the two strains of mice, under the different HFD treatments. After 3d and 8wk HFD, C57BL/6J mice, in contrast to WSB/EiJ, displayed significantly increased body weight gain, circulating levels of leptin, cholesterol, HDL and LDL. WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. Principal Component Analysis and gene ontology analysis of gene expression data allowed identifying the metabolic pathways involved. Strain-specific differential expression of several individual hypothalamic genes as well as differential effects of HFD between strains reinforced these results. Thus, adaptation to metabolic stress in the DIO-resistant WSB/EiJ strain implicates enhanced lipid metabolism, lower peripheral and hypothalamic inflammatory status and higher mitochondrial activity than in the C57BL/6J strain. These results point to the involvement of the hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.
Plasticity and the role of mass-scaling in allocation, morphology and anatomical trait responses to above and belowground resource limitation in cultivated sunflower (Helianthus annuus L.)
Authors: Wang Yan , Donovan Lisa A. , Temme Andries A.
Published: December 2018

In the face of resource limitations, plants show plasticity in multiple trait categories, including biomass allocation, morphology and anatomy, yet inevitably also grow less. The extent to which passive mass-scaling plays a role in trait responses that contribute to increased potential for resource acquisition are poorly understood. Here we assessed the role of mass-scaling on the direction, magnitude and coordination of trait plasticity to light and/or nutrient limitation in cultivated sunflower (Helianthus annuus).

We grew seedlings of ten sunflower genotypes for three weeks in a factorial of light (50% shade) and nutrient (10% supply) limitation in the greenhouse and measured a suite of allocational, morphological and anatomical traits for leaves, stems, fine roots, and tap roots.

Under resource limitation, plants were smaller and more biomass was allocated to the organ capturing the most limiting resource, as expected. Traits varied in the magnitude of plasticity and the extent to which the observed response was passive (scaled with plant mass) and/or had an additional active component. None of the allocational responses were primarily passive. Plastic changes to specific leaf area and specific root length were primarily active, and adjusted towards more acquisitive trait values under light and nutrient limitation, respectively. For many traits, the observed response was a mixture of active and passive components, and for some traits the active adjustment was antagonistic to the direction of passive adjustment, e.g. stem height, and tap root and stem theoretical hydraulic conductance. Passive scaling with size played a major role in the coordinated response to light, but correcting for mass clarified that the active responses to both limitations were more similar in magnitude, although still resource and organ specific.

Our results demonstrate that both passive plasticity and active plasticity can contribute to increased uptake capacity for limiting resources in a manner that is resource, organ and trait specific. Indeed, passive adjustments (scaling with mass) of traits due to resource stress extends well beyond just mass allocation traits. For a full understanding of plants response to environmental stress both passive and active plasticity needs to be taken into account.
Differential dominance of an allele of the Drosophila tßh gene challenges standard genetic techniques
Authors: Damrau Christine , Colomb Julien , Brembs Björn
Published: December 2018

The biogenic amine octopamine (OA) and its precursor tyramine (TA) are involved in controlling a plethora of different physiological and behavioral processes. Thetyramine-ß-hydroxylase(tßh) gene encodes the enzyme catalyzing the last synthesis step from TA to OA. Here, we report differential dominance (from recessive to overdominant) of the putative nulltßhnM18allele in two behavioral measures in Buridan’s paradigm (walking speed and stripe deviation) and a proboscis extension assay in the fruit flyDrosophila melanogaster. The behavioral analysis of transgenictßhexpression experiments in mutant and wild type flies as well as of OA- and TA-receptor mutants revealed a complex interaction of both aminergic systems. Our analysis suggests that the different neuronal networks responsible for the three phenotypes show differential sensitivity totßhgene expression levels. The evidence suggests that this sensitivity is brought about by a TA/OA opponent system modulating the involved neuronal circuits. This conclusion entails important implications for standard transgenic techniques, commonly used in functional genetics.
Pyrophosphate modulates stress responses via SUMOylation
Authors: Patir-Nebioglu Görkem , Andrés Zaida , Krebs Melanie , Fink Fabian , Drzewicka Katarzyna , Stankovic-Valentin Nicolas , Segami Shoji , Schuck Sebastian , Büttner Michael , Hell Rüdiger , Maeshima Masayoshi , Melchior Frauke , Schumacher Karin
Published: December 2018

Pyrophosphate (PPi), a byproduct of macromolecule biosynthesis is maintained at low levels by soluble inorganic pyrophosphatases (sPPase) found in all eukaryotes. In plants, H+-pumping pyrophosphatases (H+-PPase) convert the substantial energy present in PPi into an electrochemical gradient. We show here, that both cold- and heat stress sensitivity of fugu5 mutants lacking the major H+-PPase isoform AVP1 is caused by reduced SUMOylation. In addition, we show that increased PPi concentrations interfere with SUMOylation in yeast and we provide evidence that SUMO activating E1-enzymes are inhibited by micromolar concentrations of PPi in a non-competitive manner. Taken together, our results do not only provide a mechanistic explanation for the beneficial effects of AVP1 overexpression in plants but they also highlight PPi as an important integrator of metabolism and stress tolerance in eukaryotes.
The genetic basis of hindwing eyespot number variation in Bicyclus anynana butterflies
Authors: Rivera-Colón Angel G , Westerman Erica , van Belleghem Steven , Monteiro Antonia , Papa Riccardo
Published: December 2018

The underlying genetic changes that regulate the appearance and disappearance of repeated traits, or serial homologs, remain poorly understood. One hypothesis is that variation in genomic regions flanking master regulatory genes, also known as input-output genes, controls variation in trait number, making the locus of evolution almost predictable. Other hypotheses implicate genetic variation in up-stream or downstream loci of master control genes. Here, we use the butterfly Bicyclus anynana, a species which exhibits natural variation in eyespot number on the dorsal hindwing, to test these two hypotheses. We first estimated the heritability of dorsal hindwing eyespot number by breeding multiple butterfly families differing in eyespot number, and regressing eyespot number of offspring on mid-parent values. We then estimated the number and identity of independent genetic loci contributing to eyespot number variation by performing a genome-wide association study with restriction site-associated DNA Sequencing (RAD-seq) from multiple individuals varying in number of eyespots sampled across a freely breeding lab population. We found that dorsal hindwing eyespot number has a moderately high heritability of approximately 0.50. In addition, multiple loci near previously identified genes involved in eyespot development display high association with dorsal hindwing eyespot number, suggesting that homolog number variation is likely determined by regulatory changes at multiple loci that build the trait and not by variation at single master regulators or input-output genes.
Elongated cells drive morphogenesis in a surface-wrapped finite element model of germband retraction
Authors: McCleery W. T. , Veldhuis J. , Brodland G. W. , Bennett M. E. , Hutson M. S.
Published: December 2018

DuringDrosophilaembryogenesis, the germband first extends to curl around the posterior end of the embryo, and then retracts back; however, retraction is not simply the reversal of extension. At a tissue level, extension is coincident with ventral furrow formation, and at a cellular level, extension occurs via convergent cell neighbor exchanges in the germband while retraction involves only changes in cell shape. To understand how cell shapes, tissue organization and cellular forces drive germband retraction, we investigate this process using a whole-embryo, surface-wrapped cellular finite element model. This model represents two key epithelial tissues – amnioserosa and germband – as adjacent sheets of 2D cellular finite elements that are wrapped around an ellipsoidal 3D approximation of an embryo. The model reproduces the detailed kinematics ofin vivoretraction by fitting just one free model parameter, the tension along germband cell interfaces; all other cellular forces are constrained to follow ratios inferred from experimental observations. With no additional parameter adjustments, the model also reproduces failures of retraction when amnioserosa cells are removed to mimic U-shaped mutants or laser-microsurgery experiments. Surprisingly, retraction in the model is robust to changes in cellular force values, but is critically dependent on starting from a configuration with highly elongated amnioserosa cells. Their extreme cellular elongation is established during the prior process of germband extension and is then used to drive retraction. The amnioserosa is the one tissue whose cellular morphogenesis is reversed in germband extension and retraction – serving as a store of morphological information that coordinates the forces needed to retract the germband back to its pre-extension position and shape. In this case, and perhaps more generally, cellular force strengths are less important than the carefully established cell shapes that direct them.
Visual delay affects force scaling and weight perception when lifting objects in virtual reality: Supplemental model code
Authors: van Polanen Vonne , Tibold Robert , Nuruki Atsuo , Davare Marco
Published: December 2018

Lifting an object requires precise scaling of fingertip forces based on a prediction of object weight. At object contact, a series of tactile and visual events arise that need to be rapidly processed online to fine-tune the planned motor commands for lifting the object. The brain mechanisms underlying multisensory integration serially at transient sensorimotor events, a general feature of actions requiring hand-object interactions, are not yet understood. Here we tested the relative weighting between haptic and visual signals when they are integrated online into the motor command. We used a new virtual reality setup to desynchronize visual feedback from haptics, which allowed us to probe the relative contribution of haptics and vision in driving participants' movements when they grasped virtual objects simulated by two force-feedback robots. We found that visual delay changed the profile of fingertip force generation and led participants to perceive objects as heavier than when lifts were performed without visual delay. We further modeled the effect of vision on motor output by manipulating the extent to which delayed visual events could bias the force profile, which allowed us to determine the specific weighting the brain assigns to haptics and vision. Our results show for the first time how visuo-haptic integration is processed at discrete sensorimotor events for controlling object lifting dynamics and further highlight the organization of multisensory signals online for controlling action and perception.
From skylight input to behavioural output: a computational model of the insect polarised light compass
Authors: Gkanias Evripidis , Risse Benjamin , Mangan Michael , Webb Barbara
Published: December 2018

Many insects navigate by integrating the distances and directions travelled on an outward path, allowing direct return to the starting point. Fundamental to the reliability of this process is the use of a neural compass based on external celestial cues. Here we examine how such compass information could be reliably computed by the insect brain, given realistic constraints on the sky polarisation pattern and the insect eye sensor array. By processing the degree of polarisation in different directions for different parts of the sky, our model can directly estimate the solar azimuth and also infer the confidence of the estimate. We introduce a method to correct for tilting of the sensor array, as might be caused by travel over uneven terrain. We also show that the confidence can be used to approximate the change in sun position over time, allowing the compass to remain fixed with respect to ‘true north’ during long excursions. We demonstrate that the compass is robust to disturbances and can be effectively used as input to an existing neural model of insect path integration. We discuss the plausibility of our model to be mapped to known neural circuits, and to be implemented for robot navigation.

Author summary

We propose a new hypothesis for how insects process polarised skylight to extract global orientation information that can be used for accurate path integration. Our model solves the problem of solar/anti-solar meridian ambiguity by using a biologically constrained sensor array, and includes methods to deal with tilt and time, providing a complete insect celestial compass output. We analyse the performance of the model using a realistic sky simulation and various forms of disturbances, and compare the results to both engineering approaches and biological data.
Salivary proteins ofPhloeomyzus passerinii, a plant-manipulating aphid, and their impact on early gene responses of susceptible and resistant poplar genotypes
Authors: Lemus Luis Portillo , Tricard Jessy , Duclercq Jérôme , Coulette Quentin , Giron David , Hano Christophe , Huguet Elisabeth , Lamblin Frédéric , Cherqui Anas , Sallé Aurélien
Published: December 2018

Successful plant colonization by parasites requires the circumvention of host defenses, and sometimes a reprogramming of host metabolism, mediated by effector molecules delivered into the host. Using transcriptomic and enzymatic approaches, we characterized salivary glands and saliva ofPhloeomyzus passerinii, an aphid exhibiting an atypical feeding strategy. Plant genes responses to salivary extracts ofP. passeriniiandMyzus persicaewere assessed with poplar protoplasts of a susceptible and a resistant genotype, and in a heterologousArabidopsissystem. We predict thatP. passeriniisecretes a highly peculiar saliva containing effectors potentially interfering with host defenses, biotic stress signaling and plant metabolism, notably phosphatidylinositol phosphate kinases which seemed specific toP. passerinii. Gene expression profiles indicated that salivary extracts ofM. persicaemarkedly affected host defenses and biotic stress signaling, while salivary extracts ofP. passeriniiinduced only weak responses. The effector-triggered susceptibility was characterized by downregulations of genes involved in cytokinin signaling and auxin homeostasis. This suggests thatP. passeriniiinduces an intracellular accumulation of auxin in susceptible host genotypes, which is supported by histochemical assays inArabidopsis. This might in turn affect biotic stress signaling and contribute to host tissue manipulation by the aphid.
Complement C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa
Authors: Silverman Sean M. , Ma Wenxin , Wang Xu , Zhao Lian , Wong Wai T.
Published: December 2018

Complement activation has been implicated as an inflammatory driver of neurodegeneration in retinal and brain pathologies. However, its involvement and influence of photoreceptor degeneration in retinitis pigmentosa (RP), an inherited, largely incurable blinding disease, is unclear. We discover that markedly upregulated retinal expression of multiple complement components coincided spatiotemporally with photoreceptor degeneration in both the rd10 mouse model and in human specimens of RP, with increased complement C3 expression and activation localizing to infiltrating microglia near photoreceptors. Genetic ablation of C3 in the rd10 background resulted in accelerated structural and functional photoreceptor degeneration and altered retinal expression of inflammatory genes. These effects were phenocopied by the genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product C3b, implicating an adaptive microglial-mediation mechanism involving C3-CR3 interaction. Deficiency of either C3 or CR3 resulted in deficient microglial phagocytosis of apoptotic photoreceptors in vivo, as well as increased microglial neurotoxicity to photoreceptors in vitro. These findings demonstrate a novel adaptive role for complement activation in RP that facilitates microglial clearance of apoptotic photoreceptors, without which increased proinflammatory microglial neurotoxicity ensues. These positive contributions of complement via microglial-mediated mechanisms are important in the design of immunomodulatory therapeutic approaches to neurodegeneration.

One Sentence Summary

Complement activation mediates adaptive neuroprotection for photoreceptors by facilitating C3-CR3 dependent microglial clearance of apoptotic cells.
Encoding of wind direction by central neurons inDrosophila
Authors: Suver Marie P. , Matheson Andrew M. M. , Sarkar Sinekdha , Damiata Matthew , Schoppik David , Nagel Katherine I.
Published: December 2018

Wind is a major navigational cue for insects, but how wind direction is decoded by central neurons in the insect brain is unknown. Here, we find that walking flies combine signals from both antennae to orient to wind during olfactory search behavior. Movements of single antennae are ambiguous with respect to wind direction, but the difference between left and right antennal displacements yields a linear code for wind direction in azimuth. Second-order mechanosensory neurons share the ambiguous responses of single antenna and receive input primarily from the ipsilateral antenna. Finally, we identify a novel set of neurons, which we call wedge projection neurons, that integrate signals across the two antennae and receive input from at least three classes of second-order neurons to produce a more linear representation of wind direction. This study establishes how a feature of the sensory environment – the wind direction – is decoded by single neurons that compare information across two sensors.
Network topology of neural systems supporting avalanche dynamics predicts stimulus propagation and recovery
Authors: Ju Harang , Kim Jason Z. , Bassett Danielle S.
Published: December 2018

Many neural systems display avalanche behavior characterized by uninterrupted sequences of neuronal firing whose distributions of size and durations are heavy-tailed. Theoretical models of such systems suggest that these dynamics support optimal information transmission and storage. However, the unknown role of network structure precludes an understanding of how variations in network topology manifest in neural dynamics and either support or impinge upon information processing. Here, using a generalized spiking model, we develop a mechanistic understanding of how network topology supports information processing through network dynamics. First, we show how network topology determines network dynamics by analytically and numerically demonstrating that network topology can be designed to propagate stimulus patterns for long durations. We then identify strongly connected cycles as empirically observable network motifs that are prevalent in such networks. Next, we show that within a network, mathematical intuitions from network control theory are tightly linked with dynamics initiated by node-specific stimulation and can identify stimuli that promote long-lasting cascades. Finally, we use these network-based metrics and control-based stimuli to demonstrate that long-lasting cascade dynamics facilitate delayed recovery of stimulus patterns from network activity, as measured by mutual information. Collectively, our results provide evidence that cortical networks are structured with architectural motifs that support long-lasting propagation and recovery of a few crucial patterns of stimulation, especially those consisting of activity in highly controllable neurons. Broadly, our results imply that avalanching neural networks could contribute to cognitive faculties that require persistent activation of neuronal patterns, such as working memory or attention.
Metagenomic unmapped reads provide important insights into human microbiota and disease associations
Authors: Zhu Zifan , Ren Jie , Michail Sonia , Sun Fengzhu
Published: December 2018

We developed a computational pipeline, MicroPro, for metagenomic data analyses that take into account all the reads from known and unknown microbial organisms and for associating viruses with complex diseases. We utilized MicroPro to analyze metagenomics data related to three diseases: colorectal cancer, type-2 diabetes and liver cirrhosis, and showed that including reads from unknown organisms will markedly increase the prediction accuracy of the disease status based on metagenomics data. We identified new microbial organisms associated with these diseases. Viruses were shown to play important roles in colorectal cancer and liver cirrhosis, but not in type-2 diabetes. MicroPro is available at https://github.com/zifanzhu/MicroPro.