bluuebunny/crossref_metadata_2025 huggingface dataset:
Pain-related fear – Dissociable neural sources of different fear constructs
Authors: Meier Michael Lukas , Vrana Andrea , Humphreys Barry Kim , Seifritz Erich , Stämpfli Philipp , Schweinhardt Petra
Published: January 2018

Fear of pain demonstrates significant prognostic value regarding the development of persistent musculoskeletal pain and disability. Its assessment often relies on self-report measures of pain-related fear by a variety of questionnaires. However, based either on “fear of movement/(re)injury/kinesiophobia”, “fear avoidance beliefs” or “pain anxiety”, pain-related fear constructs seemingly differ while the potential overlap of the questionnaires is unclear. Furthermore, the relationship to other anxiety measures such as state or trait anxiety remains ambiguous. Because the neural bases of fearful and anxious states are well described, advances in neuroimaging such as machine learning on brain activity patterns recorded by functional magnetic resonance imaging might help to dissect commonalities or differences across pain-related fear constructs. We applied a pattern regression approach in 20 non-specific chronic low back pain patients to reveal predictive relationships between fear-related neural information and different pain-related fear questionnaires. More specifically, the applied Multiple Kernel Learning approach allowed generating models to predict the questionnaire scores based on a hierarchical ranking of fear-related neural patterns induced by viewing videos of potentially harmful activities for the back. We sought to find evidence for or against overlapping pain-related fear constructs by comparing the questionnaire prediction models according to their predictive abilities and associated neural contributors. The results underpin the diversity of pain-related fear constructs by demonstrating evidence of non-overlapping neural predictors within fear processing regions. This neuroscientific approach might ultimately help to further understand and dissect psychological pain-related fear constructs.

Significance

Pain-related fear, often assessed through self-reports such as questionnaires, has shown prognostic value and clinical utility for a variety of musculoskeletal pain disorders. However, it remains difficult to determine a common underlying construct of pain-related fear due to several proposed constructs among questionnaires. The current study describes a novel neuroscientific approach using machine learning of neural patterns within the fear circuit of chronic low back pain patients that has the potential to identify neural commonalities or differences among the various pain-related fear constructs. Ultimately, this approach might afford a deeper understanding of the suggested constructs and might be also applied to other domains where ambiguity exists between different psychological constructs.
A compact head-mounted endoscope for in vivo calcium imaging in freely-behaving mice
Authors: Jacob Alexander D. , Ramsaran Adam I. , Mocle Andrew J. , Tran Lina M. , Yan Chen , Frankland Paul W. , Josselyn Sheena A
Published: January 2018

Miniaturized fluorescence microscopes for imaging calcium transients are a promising tool for investigating the relationship between behaviour and population-level neuronal activity in rodents. However, commercially available miniature microscopes may be costly, and, because they are closed-source, may not be easily modified based on particular experimental requirements. Here, we describe how to build and use a low-cost compact head-mounted endoscope (CHEndoscope) system for in vivo calcium imaging. The CHEndoscope uses an implanted gradient index (GRIN) lens along with the genetically encoded calcium indicator GCaMP6 to image calcium transients from hundreds of neurons simultaneously in awake behaving mice. This system is affordable, open-source, and flexible, permitting modification depending on the particular experiment. This Unit describes in detail the assembly, surgical implantation, data collection, and processing of calcium signals using the CHEndoscope system. The aim of this open framework model is to provide an accessible set of miniaturized calcium imaging tools for the neuroscience research community.

Significance Statement

The ability to image calcium transients in awake, behaving rodents using miniature microscopes opens exciting and novel avenues for gaining insights into how information is encoded in neural circuits. The development of this tool has already had a significant impact on neuroscience research. The cost of commercial systems, however, may be prohibitive for many laboratories. Here, we describe an affordable, open-source compact head-mounted endoscope (CHEndoscope) system for performing in vivo calcium imaging in freely-behaving mice. CHEndoscopes may be manufactured by individual laboratories at relatively minor cost. Our hope is that greater availability of affordable, open-source tools (such as the one presented here) will accelerate the pace of discoveries in systems neuroscience.
Prediction and information integration determine subtle anticipatory fixation biases
Authors: Notaro Giuseppe , van Zoest Wieske , Melcher David , Hasson Uri
Published: January 2018

A core question underlying neurobiological and computational models of behavior is how individuals learn environmental statistics and use them for making predictions. Treatment of this issue largely relies on reactive paradigms, where inferences about predictive processes are derived by modeling responses to stimuli that vary in likelihood. Here we deployed a novel proactive oculomotor metric to determine how input statistics impact anticipatory behavior, decoupled from stimulus-response. We implemented transition constraints between target locations, and quantified a subtle fixation bias (FB) discernible while individuals fixated a screen center awaiting target presentation. We show that FB is informative with respect the input statistics, reflects learning at different temporal scales, predicts saccade latencies on a trial level, and can be linked to fundamental oculomotor metrics. We also present an extension of this approach to a more complex paradigm. Our work demonstrates how learning impacts strictly predictive processes and presents a novel direction for studying learning and prediction.
WEADE: A Workflow for Enrichment Analysis and Data Exploration
Authors: Trost Nils , Rempel Eugen , Ermakova Olga , Tamirisa Srividya , Pârcălăbescu Letiția , Boutros Michael , Lohmann Jan U. , Lohmann Ingrid
Published: January 2018

Data analysis based on enrichment of Gene Ontology terms has become an important step in exploring large gene or protein expression datasets and several stand-alone or web tools exist for that purpose. However, a comprehensive and consistent analysis downstream of the enrichment calculation is missing so far. With WEADE we present a free web application that offers an integrated workflow for the exploration of genomic data combining enrichment analysis with a versatile set of tools to directly compare and intersect experiments or candidate gene lists of any size or origin including cross-species data. Lastly, WEADE supports the graphical representation of output data in the form of functional interaction networks based on prior knowledge, allowing users to go from plain expression data to functionally relevant candidate sub-lists in an interactive and consistent manner.
Large-scale two-photon imaging revealed super-sparse population codes in V1 superficial layer of awake monkeys
Authors: Tang Shiming , Zhang Yimeng , Li Zhihao , Li Ming , Liu Fang , Jiang Hongfei , Lee Tai Sing
Published: January 2018

Efficient coding has been proposed as a general principle for the sensory systems. The efficient coding hypothesis predicts that neuronal population responses should be sparse, but limited by the measurement techniques, the precise estimates of the population sparseness of visual cortical neurons are still uncertain. Here, we employed large-scale two-photon calcium imaging to examine the neuronal population activities in V1 superficial layers of awake macaques in response to a large set of natural images. We found that only 0.5% of these neurons on average responded strongly to any given natural image with response strength above half of their individual peak responses, which is more than tenfold sparse over those reported by early studies. We further showed that these sparse population activities contain sufficient information for discriminating images with high accuracy. This study provided the first accurate measure of sparseness in V1 neuronal population responses, which support super-sparse neural codes in primates.
In Vivo Measurements of the Frequency-Dependent Impedance of the Spinal Cord
Authors: Utz Marcel , Miller John W. , Reddy Chandan G. , Wilson Saul , Abode-Iyamah Kingsley O. , Fredericks Douglas C. , Gillies George T. , Howard Matthew A.
Published: January 2018

Improved knowledge of the electrode-tissue impedance will be useful in optimizing the clinical protocols and resulting efficacy of the existing and emerging approaches to spinal cord stimulation. Toward that end, the complex impedance (amplitude and phase) of in vivo ovine spinal cord tissue was measured at the electrode-pial subdural surface interface from 5 Hz to 1 MHz, and with the bi-polar electrodes oriented both parallel and perpendicular to the rostral-caudal axis of the spinal cord. At stimulation frequencies above 10 kHz, most of the impedance then becomes resistive in nature and the phase diference between the stimulation signal and the resulting current drops to ≈ 10˚, thus maximizing power transfer to the tissues. Also, at these higher frequencies, the current pulse maintains significantly greater fidelity to the shape of the stimulation signal applied across the electrodes. Lastly, there were lower impedances associated with parallel as opposed to perpendicular orientation of the electrodes, thus reflecting the effects of fiber orientation within the spinal cord. Impedance differences of this kind have not been reported with epidural stimulation because of the electrical shunting effects of the intervening layer of relatively high conductivity cerebrospinal fluid. These observations provide a quantitative basis for improved models of spinal cord stimulation and suggest certain advantages for direct intradural stimulation relative to the standard epidural approaches. (Some figures in this article are in colour only in the electronic version)
Dendritic spikes in hippocampal granule cells are necessary for long-term potentiation at the perforant path synapse
Authors: Kim Sooyun , Kim Yoonsub , Lee Suk-Ho , Ho Won-Kyung
Published: January 2018

Long-term potentiation (LTP) of synaptic responses is essential for hippocampal memory function. Perforant-path (PP) synapses on hippocampal granule cells (GCs) contribute to the formation of associative memories, which are considered the cellular correlates of memory engrams. However, the mechanisms of LTP at these synapses are not well understood. Due to sparse firing activity and the voltage attenuation in their dendrites, it remains unclear how associative LTP at distal synapses occurs. Here we show that NMDA receptor-dependent LTP can be induced at PP-GC synapses without backpropagating action potentials (bAPs) in acute rat brain slices. Dendritic recordings reveal substantial attenuation of bAPs as well as local dendritic Na + ‐spike generation during PP-GC input. Inhibition of Na+ ‐spikes impairs LTP suggesting that LTP at PP-GC synapse requires local Na + ‐spikes. Thus, dendritic spikes are essential for LTP induction at PP-GC synapse and may constitute a key cellular mechanism for memory formation in the dentate gyrus.
Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems
Authors: V. Lombardo Michael , Auyeung Bonnie , Pramparo Tiziano , Quartier Angélique , Courraud Jérémie , J. Holt Rosemary , Waldman Jack , N. V. Ruigrok Amber , Mooney Natasha , Lai Meng-Chuan , Kundu Prantik , T. Bullmore Edward , Mandel Jean-Louis , Piton Amélie , Baron-Cohen Simon
Published: January 2018

Many early-onset neurodevelopmental conditions such as autism affect males more frequently than females and affect corresponding domains such as social cognition, social-communication, language, emotion, and reward. Testosterone is well-known for its role as a sex-related biological mechanism and affects these conditions and domains of functioning. Developmentally, testosterone may sex-differentially impact early fetal brain development by influencing early neuronal development and synaptic mechanisms behind cortical circuit formation, particularly for circuits that later develop specialized roles in such cognitive domains. Here we find that variation in fetal testosterone (FT) exerts sex-specific effects on later adolescent functional connectivity between social brain default mode network (DMN) subsystems. Increased FT is associated with dampening of functional connectivity between DMN subsystems in adolescent males, but has no effect in females. To isolate specific prenatal neurobiological mechanisms behind this effect, we examined changes in gene expression identified following a treatment with a potent androgen, dihydrotestosterone (DHT) in an in-vitro model of human neural stem cell (hNSC). We previously showed that DHT-dysregulates genes enriched with known syndromic causes for autism and intellectual disability. DHT dysregulates genes in hNSCs involved in early neurodevelopmental processes such as neurogenesis, cell differentiation, regionalization, and pattern specification. A significant number of these DHT-dysregulated genes shows spatial expression patterns in the adult brain that highly correspond to the spatial layout of the cortical midline DMN subsystem. These DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation/inhibition imbalance. Focusing on MEF2C, we find replicable upregulation of expression after DHT treatment as well as dysregulated expression in induced pluripotent stem cells and neurons of individuals with autism. This work highlights sex-specific prenatal androgen influence on social brain DMN circuitry and autism-related mechanisms and suggests that such influence may impact early neurodevelopmental processes (e.g., neurogenesis, cell differentiation) and later developing synaptic processes.
Neural spiking for causal inference
Authors: Lansdell Benjamin James , Kording Konrad Paul
Published: January 2018

When a neuron is driven beyond its threshold it spikes, and the fact that it does not communicate its continuous membrane potential is usually seen as a computational liability. Here we show that this spiking mechanism allows neurons to produce an unbiased estimate of their causal influence, and a way of approximating gradient descent learning. Importantly, neither activity of upstream neurons, which act as confounders, nor downstream non-linearities bias the results. By introducing a local discontinuity with respect to their input drive, we show how spiking enables neurons to solve causal estimation and learning problems.
Fast Memory Integration Facilitated by Schema Consistency
Authors: Zhang Qiong , Popov Vencislav , Koch Griffin E. , Calloway Regina C. , Coutanche Marc N.
Published: January 2018

Many of our everyday decisions are based not only on memories of direct experiences, but on memories that are integrated across multiple distinct experiences. Sometimes memory integration between existing memories and newly learnt information occurs rapidly, without requiring inference at the time of a decision. Such fast memory integration is known to be supported by the hippocampus but not the neocortex. In this study, we explore an alternative mechanism of fast memory integration, through related prior knowledge (i.e., schema), which is associated with neocortical learning. Paired associates were selected to be schema consistent or inconsistent, and confirmed with a latent semantic analysis of text corpora. We observed that after enabling fast learning by using material that is consistent with a schema, faster memory integration can occur. This result suggests that the hippocampus-mediated integration of new information is not the only available mechanism that supports fast memory integration.
Quality control-based signal drift correction and interpretations of metabolomics/proteomics data using random forest regression
Authors: Luan Hemi , Ji Fenfen , Chen Yu , Cai Zongwei
Published: January 2018

Large-scale mass spectrometry-based metabolomics and proteomics study requires the long-term analysis of multiple batches of biological samples, which often accompanied with significant signal drift and various inter‐ and intra‐ batch variations. The unwanted variations can lead to poor inter‐ and intra-day reproducibility, which is a hindrance to discover real significance. We developed a novel quality control-based random forest signal correction algorithm, being ensemble learning approach to remove inter‐ and intra‐ batches of unwanted variations at feature-level. Our evaluation based on real samples showed the developed algorithm improved the data precision and statistical accuracy for metabolomics and proteomics, which was superior to other common correction methods. We have been able to improve its performance for interpretations of large-scale metabolomics and proteomics data, and to allow the improvement of the data precision for uncovering the real biologically differences.
Valproic acid attenuates hyperglycemia-induced complement and coagulation cascade gene expression
Authors: Felisbino Marina Barreto , Ziemann Mark , Khurana Ishant , de Oliveira Camila Borges Martins , Mello Maria Luiza S. , El-Osta Assam
Published: January 2018

Atherothrombosis remains the leading cause of morbidity and mortality in patients diagnosed with diabetes mellitus, but the molecular mechanisms underpinning this remain unresolved. As the liver plays a major role in metabolic homeostasis and secretion of clotting factors and inflammatory innate immune proteins, there is an interest in understanding the mechanisms of hepatic cell activation under hyperglycemia and whether this can be attenuated pharmacologically. We have previously shown that hyperglycemia stimulates major changes in chromatin organisation and metabolism in hepatocytes, and that the histone deacetylase inhibitor valproic acid (VPA; IUPAC: 2-propylpentanoic acid) is able to reverse some of these metabolic changes. In this study, we used deep transcriptome sequencing to show that VPA attenuates hyperglycemia-induced activation of complement and coagulation cascade genes. These findings reveal a novel mechanism of VPA protection against hyperglycemia, which might improve the therapeutic approaches for diabetes.
Monitoring the 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) modification in eukaryotic tRNAs via the gamma-toxin endonuclease
Authors: Lentini Jenna M. , Ramos Jillian , Fu Dragony
Published: January 2018

The post-transcriptional modification of tRNA at the wobble position is a universal process occurring in all domains of life. In eukaryotes, the wobble uridine of particular tRNAs is transformed to the 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) modification which is critical for proper mRNA decoding and protein translation. However, current methods to detect mcm5s2U are technically challenging and/or require specialized instrumental expertise. Here, we show that gamma-toxin endonuclease from the yeastKluyveromyces lactiscan be used as a probe for assaying mcm5s2U status in the tRNA of diverse eukaryotic organisms ranging from protozoans to mammalian cells. The assay couples the mcm5s2U-dependent cleavage of tRNA by gamma-toxin with standard molecular biology techniques such as Northern blot analysis or quantitative PCR to monitor mcm5s2U levels in multiple tRNA isoacceptors. The results gained from the gamma-toxin assay reveals the evolutionary conservation of the mcm5s2U modification across eukaryotic species. Moreover, we have employed the gamma-toxin assay to verify uncharacterized eukaryotic Trm9 and Trm112 homologs that catalyze the formation of mcm5s2U. These findings demonstrate the use of gamma-toxin as a detection method to monitor mcm5s2U status in diverse eukaryotic cell types for cellular, genetic and biochemical studies.
High-throughput microcolony growth analysis from suboptimal low-magnification micrographs
Authors: Plavskin Yevgeniy , Li Shuang , Jung Hyun , Sartori Federica M. O. , Buzby Cassandra , Müller Heiko , Ziv Naomi , Levy Sasha F. , Siegal Mark L.
Published: January 2018

New technological advances have enabled high-throughput phenotyping at the single-cell level, yet analyzing the large amount of data generated by high throughput phenotyping experiments automatically and accurately is a considerable challenge. Here we introduce Processing Images Easily (PIE), software that automatically tracks growth of microbial colonies in low-magnification brightfield images by combining adaptive object-center recognition with gradient-based object-outline recognition. PIE recognizes colony outlines very robustly and accurately across a wide range of image brightnesses, focal depths, and organisms. Beyond accurate colony recognition, PIE is designed to easily integrate with complex experiments, allowing colony tracking across multiple experimental phases and classification based on fluorescence intensity. We show that PIE can be used to accurately measure the growth rates of large numbers (>90,000) of bacterial or yeast microcolonies in a single-time-lapse experiment, allowing calculation of population-wide growth properties. Finally, PIE is able to track individual colonies across multiple experimental phases, measuring both growth and fluorescence properties of the microcolonies.

Author Summary

High-throughput microscopy has enabled automated collection of large amounts of growth and gene-expression data in microbes. Computational methods that can precisely recognize and track organisms in images are essential to performing measurements at scale using automated microscopy. We have developed PIE, software that automatically recognizes microbial colonies in microscopy images, tracks them in imaging time-series, and performs measurements of growth and, potentially, gene expression. PIE is highly effective on low-resolution images, outperforming current state-of-the-art approaches in both speed and accuracy, and works well in microbes of varying shapes and sizes. In addition, PIE allows tracking microcolonies across arbitrary sequences of experimental phases, each collecting data in different modalities. We show that PIE allows measurement of growth and fluorescence properties in tens of thousands of microbial colonies in a single experiment, and that in turn the scale of these measurements can lead to important insights about interindividual differences in growth and stress response. PIE is available as a Python package (https://doi.org/10.5281/zenodo.4987127) with documentation currently at https://pie-image.readthedocs.io/; users can also run analysis on individual images or time-series without the need to install PIE by using our web application, currently available at http://pie.hpc.nyu.edu/.
Efficient lentiviral transduction of different human and mouse cells
Authors: Zhang Gang , Wang Taihua
Published: January 2018

Background

Lentiviral vectors (LVs) allowing efficient establishment of stable transgene overexpression mammalian and human cell lines are invaluable tools for genetic research. Currently, although LV transductions are broadly adopted, they are often limited due to their low titers for efficient transduction.

Results

Here, we described a set of optimized, efficient techniques, which could produce sufficiently high LV titers, and, provide efficient transduction of cells. According to these optimizations, most of the mammalian and human cells, both primary cells and cell lines, could be transduced successfully with high levels of transgene stable expression, including both constitutive and induced expressions.

Conclusions

Our data demonstrated the highly usefulness of our optimized methods. Therefore, this study provided an efficient method for most of LV transduction experiments in vitro.
A molecular network for functional versatility ofHECATEtranscription factors
Authors: Gaillochet Christophe , Jamge Suraj , van der Wal Froukje , Angenent Gerco , Immink Richard , Lohmann Jan U.
Published: January 2018

During the plant life cycle, diverse signalling inputs are continuously integrated and engage specific genetic programs depending on the cellular or developmental context. Consistent with an important role in this process, HECATE (HEC) bHLH transcription factors display diverse functions, from photomorphogenesis to the control of shoot meristem dynamics and gynoecium patterning. However, the molecular mechanisms underlying their functional versatility and the deployment of specific HEC sub-programs still remain elusive.

To address this issue, we systematically identified proteins with the capacity to interact with HEC1, the best characterized member of the family, and integrated this information with our data set of direct HEC1 target genes. The resulting core genetic modules were consistent with specific developmental functions of HEC1, including its described activities in light signalling, gynoecium development and auxin homeostasis. Importantly, we found that in addition,HECgenes play a role in the modulation of flowering time and uncovered that their role in gynoecium development may involve the direct transcriptional regulation ofNGATHA1 (NGA1)andNGA2genes. NGA factors were previously shown to contribute to fruit development, but our data now show that they also modulate stem cell homeostasis in the SAM.

Taken together, our results suggest a molecular network underlying the functional versatility of HEC transcription factors. Our analyses have not only allowed us to identify relevant target genes controlling shoot stem cell activity and a so far undescribed biological function of HEC1, but also provide a rich resource for the mechanistic elucidation of further context dependent HEC activities.

Significance statement

Although many transcription factors display diverse regulatory functions during plant development, our understanding of the underlying mechanisms remains poor. Here, by reconstructing the regulatory modules orchestrated by the bHLH transcription factor HECATE1 (HEC1), we defined its regulatory signatures and delineated a regulatory network that provides a molecular basis for its functional versatility. In addition, we uncovered a function forHECgenes in modulating flowering time and further identified downstream signalling components balancing shoot stem cell activity.
OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development
Authors: Hrit Joel , Li Cheng , Martin Elizabeth Allene , Simental Eric , Goll Mary , Panning Barbara
Published: January 2018

TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with and are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism and the epigenome. Here, we show for the first time that modification by OGT enhances TET1 activityin vitro.We identify a domain of TET1 responsible for binding to OGT and report a point mutation that disrupts the TET1-OGT interaction. We show that the TET1-OGT interaction is necessary for TET1 to rescue hematopoetic stem cell production in tet mutant zebrafish embryos, suggesting that OGT promotes TET1’s function during development. Finally, we show that disrupting the TET1-OGT interaction in mouse embryonic stem cells changes the abundance of TET-containing high molecular weight complexes and causes widespread gene expression changes. These results link metabolism and epigenetic control, which may be relevant to the developmental and disease processes regulated by these two enzymes.
Dawn and photoperiod sensing by phytochrome A
Authors: Seaton Daniel D , Toledo-Ortiz Gabriela , Kubota Akane , Ganpudi Ashwin , Imaizumi Takato , Halliday Karen J
Published: January 2018

In plants, light receptors play a pivotal role in photoperiod sensing, enabling them to track seasonal progression. Photoperiod sensing arises from an interaction between the plant’s endogenous circadian oscillator and external light cues. Here, we characterise the role of phytochrome A (phyA) in photoperiod sensing. Our meta-analysis of functional genomic datasets identified phyA as a principal transcriptional regulator of morning-activated genes, specifically in short photoperiods. We demonstrate that PHYA expression is under the direct control of the PHYTOCHROME INTERACTING FACTOR transcription factors, PIF4 and PIF5. As a result, phyA protein accumulates during the night, especially in short photoperiods. At dawn phyA activation by light results in a burst of gene expression, with consequences for anthocyanin accumulation. The combination of complex regulation of PHYA transcript and the unique molecular properties of phyA protein make this pathway a sensitive detector of both dawn and photoperiod.

Significance statement

The changing seasons subject plants to a variety of challenging environments. In order to deal with this, many plants have mechanisms for inferring the season by measuring the duration of daylight in a day. A number of well-known seasonal responses such as flowering are responsive to daylength or photoperiod. Here, we describe how the photoreceptor protein phytochrome A senses short photoperiods. This arises from its accumulation during long nights, as happens during winter, and subsequent activation by light at dawn. As a result of this response, the abundance of red anthocyanin pigments is increased in short photoperiods. Thus, we describe a mechanism underlying a novel seasonal phenotype in an important model plant species.
Individual repeatability and heritability of divorce in a wild population
Authors: Germain Ryan R. , Wolak Matthew E. , Reid Jane M.
Published: January 2018

Understanding micro-evolutionary responses of mating systems to contemporary selection requires estimating sex-specific additive genetic variances and cross-sex genetic covariances in key reproductive strategy traits. One key trait comprises the occurrence of divorce versus mate-fidelity across sequential reproductive attempts. If divorce represents an evolving behavioural strategy it must have non-zero individual repeatability and heritability, but quantitative estimates from wild populations are scarce. We used 39 years of individual breeding records and pedigree data from free-living song sparrows (Melospiza melodia) to quantify sex-specific permanent individual and additive genetic variances, and hence estimate repeatability and heritability, in liability for divorce. We estimated moderate repeatability in females, but little repeatability in males. Estimates of additive genetic variance were small in both sexes, and the cross-sex genetic covariance was close to zero. However, the total heritability was likely non-zero but small, indicating low potential for micro-evolutionary response to selection. Rapid micro-evolution of divorce rate therefore appears unlikely, even if there were substantial fitness benefits of divorce and resulting selection.
Exposure to the oral host niche yields rapid phenotypic and genotypic diversification in Candida albicans
Authors: Forche A. , Cromie G. , Gerstein A.C. , Solis N. V. , Pisithkul Z. , Srifa W. , Jeffery E. , Filler S.G. , Dudley A.M. , Berman J.
Published: January 2018

In vitro studies suggest that stress may generate random standing variation, and that different cellular and ploidy states may evolve more rapidly under stress. Yet this idea has not been tested with pathogenic fungi growing within their host niche in vivo. Here, we analyzed the generation of both genotypic and phenotypic diversity during exposure of Candida albicans to the mouse oral cavity. Ploidy, aneuploidy, loss of heterozygosity (LOH) and recombination were determined using flow cytometry and ddRADseq. Colony phenotypic changes (CPs) in size and filamentous growth were evident without selection, and were enriched among colonies selected for LOH of the GAL1 marker. Aneuploidy and LOH occurred on all chromosomes (Chrs), with aneuploidy more frequent for smaller Chrs and whole Chr LOH more frequent for larger Chrs. Large genome shifts in ploidy to haploidy often maintained one or more heterozygous disomic Chrs, consistent with random Chr missegregation events. Most isolates displayed several different types of genomic changes, suggesting that the oral environment rapidly generates diversity de novo. In sharp contrast, following in vitro propagation isolates were not enriched for multiple LOH events, except in those that underwent haploidization and/or had high levels of Chr loss. The frequency of events was overall 100 times higher for C. albicans populations following in vivo passage compared to in vitro. These hyperdiverse in vivo isolates likely provide C. albicans with the ability to adapt rapidly to the diversity of stress environments it encounters inside the host.

Author summary

Adaption is a continuous dynamic process that requires genotypic and phenotypic variation. Here we studied the effects of a single passage in a mouse oropharyngeal model of infection on the appearance of diversity in C. albicans, a common commensal of the human oral cavity and GI tract. We found that variation could be rapidly detected following oral colonization, with the frequency of genome change being considerably higher with pre-selection for recombination and colony phenotypic changes. Importantly, one third of all isolates had multiple genome changes, significantly higher than expected by chance alone. We suggest that some cells in the population are naturally hypervariable and that they are a major source of diversity upon which selection can act in stressful conditions in vivo and in vitro.
Genetics behind the biosynthesis of nonulosonic acid containing lipooligosaccharides inCampylobacter coli
Authors: Kolehmainen Alejandra , Rossi Mirko , Stupak Jacek , Li Jianjun , Gilbert Michel , Wakarchuk Warren
Published: January 2018

Campylobacter jejuniandCampylobacter coliare the most common cause of bacterial gastroenteritis in the world. Ganglioside mimicry byC. jejunilipooligosaccharide (LOS) is the triggering factor of Guillain-Barré syndrome (GBS), an acute polyneuropathy. Sialyltransferases from the glycosyltransferase (GT) family 42 are essential for the expression of ganglioside mimics inC. jejuni. Recently, two novel GT-42 genes,cstIVandcstV, have been identified inC. coli.Despite being present in ∼11% of currently availableC. coligenomes, the biological role ofcstIVandcstVis unknown. In the present study, mutation studies in two strains expressing eithercstIVorcstVwere performed and mass spectrometry was used to investigate differences in the chemical composition of LOS. Attempts were made to identify donor and acceptor molecules usingin vitroactivity tests with recombinant GT-42 enzymes. Here, we show that CstIV and CstV are involved inC. coliLOS biosynthesis. In particular,cstVis associated with LOS sialylation, whilecstIVis linked to the addition of a diacetylated nonulosonic acid residue.

IMPORTANCE

Despite being a major foodborne pathogen,Campylobacter coliglycobiology has been largely neglected. The genetic makeup of theC. colilipooligosaccharide biosynthesis locus was largely unknown until recently.C. coliharbour a large set of genes associated to lipooligosaccharide biosynthesis, including several putative glycosyltransferases involved in the synthesis of sialylated lipooligosaccharide inCampylobacter jejuni. In the present study,C. coliwas found to express lipooligosaccharide structures containing sialic acid and other nonulosonate acids. These findings have a strong impact in understandingC. coliecology, host-pathogen interaction, and pathogenesis.
Acute antidepressant effect of ayahuasca in juvenile non-human primate model of depression
Authors: Santos da Silva Flávia , Silva Erick Allan dos Santos , de Sousa Junior Geovan Menezes , Maia-de-Oliveira Joao Paulo , Rachetti Vanessa de Paula Soares , Barros de Araujo Draulio , Cordeiro de Sousa Maria Bernardete , Lobão Soares Bruno , Leite Galvão-Coelho Nicole
Published: January 2018

The incidence of major depression in adolescents, aged between 15 to 18 years, reaches approximately 14%. Usually, this disorder presents a recurrent way, without remission of symptoms even after several pharmacological treatments, persisting through adult life. Due to the relatively low efficacy of commercially available antidepressant, new pharmacological therapies are under continuous exploration. Recent evidence suggests that classic psychedelics, such as ayahuasca, produce rapid and robust antidepressant effects in treatment-resistant depression patients. In this study, we evaluated the potential of antidepressant effects of ayahuasca in a juvenile model of depression in a non-human primate, common marmoset (Callithrix jacchus). The model induces depressive-like symptoms by chronic social isolation (60 days) and antidepressant effects monitoring included fecal cortisol, body weight, and behavioral parameters. The animals presented hypocortisolemia and the recovery of cortisol to baseline levels started already at 24h after the ingestion of ayahuasca, but not the vehicle. Moreover, in males, ayahuasca, and not the vehicle, reduced the scratching, a stereotypic behavior, and increased the feeding. Ayahuasca also improving body weight to baseline levels in male and female common marmosets. The behavioral response induced by ayahuasca shows long effect, lasting 14 days. Therefore, for this translational animal model of juvenile depression, it could be proposed that ayahuasca treatment presented more notable antidepressant effects than tricyclic antidepressant nortriptyline, investigated by our group, using this same protocol in an anterior study. Ayahuasca produced faster and more durable effect on reversion of physiological changes and depressive-like symptoms. Therefore, the results found for ayahuasca treatment corroborates in the validation of this substance as an effective antidepressant drug and encourages the return of studies with psychedelic drugs in the treatment of humor disorders, including adolescents with early-age depression.
Functional Gradients of the Cerebellum: A Fundamental Movement-To-Thought Principle
Authors: Guell Xavier , Schmahmann Jeremy D. , Gabrieli John D.E. , Ghosh Satrajit S.
Published: January 2018

A central principle for understanding the cerebral cortex is that macroscale anatomy reflects a functional hierarchy from primary to transmodal processing. In contrast, the central axis of motor and nonmotor macroscale organization in the cerebellum remains unknown. Here we applied diffusion map embedding to resting-state data from the Human Connectome Project dataset (n=1003), and show for the first time that cerebellar functional regions follow a gradual organization which progresses from primary (motor) to transmodal (DMN, task-unfocused) regions. A secondary axis extends from task-unfocused to task-focused processing. Further, these two principal gradients reveal functional properties of the well-established cerebellar double motor representation, and its relationship with the recently described triple nonmotor representation. These interpretations are further supported by data-driven clustering and cerebello-cerebral functional connectivity analyses. Importantly, these descriptions remain observable at the individual subject level. These findings, from an exceptionally large and high-quality dataset, provide new and fundamental insights into the functional organization of the human cerebellum, unmask new testable hypotheses for future studies, and yield an unprecedented tool for the topographical, macroscale interpretation of cerebellar findings.
Predicting protein targets for drug-like compounds using transcriptomics
Authors: Pabon Nicolas A. , Xia Yan , Estabrooks Samuel K. , Ye Zhaofeng , Herbrand Amanda K. , Süß Evelyn , Biondi Ricardo M. , Assimon Victoria A. , Gestwicki Jason E. , Brodsky Jeffrey L. , Camacho Carlos J. , Bar-Joseph Ziv
Published: January 2018

The development of an expanded chemical space for screening is an essential step in the challenge of identifying chemical probes for new, genomic-era protein targets. However, the difficulty of identifying targets for novel compounds leads to the prioritization of synthesis linked to known active scaffolds that bind familiar protein families, slowing the exploration of available chemical space. To change this paradigm, we validated a new pipeline capable of identifying compound-protein interactions even for compounds with no similarity to known drugs. Based on differential mRNA profiles from drug treatments and gene knockdowns across multiple cell types, we show that drugs cause gene regulatory network effects that correlate with those produced by silencing their target protein-coding gene. Applying supervised machine learning to exploit compound-knockdown signature correlations and enriching our predictions using an orthogonal structure-based screen, we achieved top-10/top-100 target prediction accuracies of 26%/41%, respectively, on a validation set 152 FDA-approved drugs and 3104 potential targets. We further predicted targets for 1680 compounds and validated a total of seven novel interactions with four difficult targets, including non-covalent modulators of HRAS and KRAS. We found that drug-target interactions manifest as gene expression correlations between drug treatment and both target gene knockdown and up/down-stream knockdowns. These correlations provide biologically relevant insight on the cell-level impact of disrupting protein interactions, highlighting the complex genetic phenotypes of drug treatments. Our pipeline can accelerate the identification and development of novel chemistries with potential to become drugs by screening for compound-target interactions in the full human interactome.
Study of the critical success factors of emblematic hotels through the analysis of content of online opinions
Authors: Fuentes-Medina M. Lilibeth , Hernández-Estárico Estefanía , Morini-Marrero Sandra
Published: January 2018

Purpose

The purpose of this paper is to identify the critical success factors of emblematic hotels from the perspective of the guest, by analysing the direct activities that make up the value chain of these types of establishments.

Design/methodology/approach

The authors use the case study methodology to derive conclusions that contribute to the development of a theory about the success factors of emblematic hotels. The case selected is the Spanish Tourist Parador chain. The authors carried out over a period of two years a data mining analysis of the online comments posted by its guests.

Findings

The results indicate that the attributes of location and facilities are critical success factors expected a priori given the nature of the business of such establishments, based on the singular nature of the buildings. Another critical success factor is personnel, which seems to indicate that the Paradors support their business model by employing highly qualified staff, but give less attention to restaurant services or the room, according to guest perceptions.

Originality/value

The paper provides required evidence on the critical success factors of emblematic hotels adapting Porter’s value chain, for the tourism accommodation sector, through the analysis of direct value chain activities. In addition, the existing literature is broadened by taking a perspective scarcely studied, the guest perception of hotel establishments, online content posted by the user on the establishment’s website, rather than simply considering the traditional views of the experts/managers, through structures questionnaires. Besides, the results provide practical and useful implications for the managements of the emblematic hotels under study.
Unveiling the factors affecting final electricity consumption: does the regional component matter?
Authors: Borozan Djula , Pekanov Starcevic Dubravka
Published: January 2018

Purpose

The purpose of this paper is to explore the developments in final electricity consumption, estimate the portions of changes that can be attributed to national, sectoral or regional factors, and to investigate determinants of the regional component (RC) in Croatia at the subnational level in the period 2001-2013.

Design/methodology/approach

In the first stage, the dynamic shift-share method is used to decompose final electricity consumption, and then, in the second stage, the panel population-averaged logit model is conducted to find the main determinants of the extracted RC.

Findings

The results show that both the sectoral factor and the regional factor are responsible for an increase in electricity consumption over the period considered, whereby the regional specificities had a larger impact in general. Thereby, the most developed regions, including the tourism-oriented ones, exhibited the largest average increase in electricity consumption mainly due to positive effects of the regional-specific factors, while the negative effects of these factors were mainly responsible for low average rates of changes in electricity consumption in less developed regions.

Practical implications

The results suggest that regional-specific energy conservation programs might be more effective in improving energy efficiency than the sector-oriented ones, as well as that socio-economic and contextual determinants matter when it comes to the probability of having a positive regional effect on the electricity consumption rate.

Originality/value

The paper investigated the determinants of the extracted RC which has not yet been addressed in the energy economics literature.