bluuebunny/crossref_metadata_2025 huggingface dataset:
Wind drives temporal variation in pollinator visitation in a fragmented tropical forest
Authors: Crall James D. , Brokaw Julia , Gagliardi Susan F. , Mendenhall Chase D. , Pierce Naomi E. , Combes Stacey A.
Published: August 2019

Wind is a critical factor in the ecology of pollinating insects such as bees. However, the role of wind in determining patterns of bee abundance and floral visitation rates across space and time is not well understood. Orchid bees are an important and diverse group of neotropical pollinators that harvest pollen, nectar and resin from plants. In addition, male orchid bees collect volatile scents that they store in special chambers in their hind legs, and for which the wind-based dispersal of odors may play a particularly crucial role. Here we take advantage of this specialized scent foraging behavior to study the effects of wind on orchid bee visitation at scent sources in a fragmented tropical forest ecosystem. We find that temporal changes in wind speed and turbulence are correlated with visitation to scent stations within sites, while local landscape structure is a strong determinant of spatial variation in visitation across nearby sites. These results suggest that the increased dispersal of attractive scents provided by wind and turbulence outweighs any biomechanical or energetic costs that might deter bees from foraging in these conditions. Overall, our results highlight the significance of wind in the ecology of these important pollinators in neotropical forests.
High-throughput analysis of adaptation using barcoded strains ofSaccharomyces cerevisiae
Authors: Fasanello Vincent J. , Liu Ping , Botero Carlos A. , Fay Justin C.
Published: August 2019

Background

Experimental evolution of microbes can be used to empirically address a wide range of questions about evolution and is increasingly employed to study complex phenomena ranging from genetic evolution to evolutionary rescue. Regardless of experimental aims, fitness assays are a central component of this type of research, and low-throughput often limits the scope and complexity of experimental evolution studies. We created an experimental evolution system inSaccharomyces cerevisiaethat utilizes genetic barcoding to overcome this challenge.

Results

We first confirm that barcode insertions do not alter fitness and that barcode sequencing can be used to efficiently detect fitness differences via pooled competition-based fitness assays. Next, we examine the effects of ploidy, chemical stress, and population bottleneck size on the evolutionary dynamics and fitness gains (adaptation) in a total of 76 experimentally evolving, asexual populations by conducting 1,216 fitness assays and analyzing 532 longitudinal-evolutionary samples collected from the evolving populations. In our analysis of these data we describe the strengths of this experimental evolution system and explore sources of error in our measurements of fitness and evolutionary dynamics.

Conclusions

Our experimental treatments generated distinct fitness effects and evolutionary dynamics, respectively quantified via multiplexed fitness assays and barcode lineage tracking. These findings demonstrate the utility of this new resource for designing and improving high-throughput studies of experimental evolution. The approach described here provides a framework for future studies employing experimental designs that require high-throughput multiplexed fitness measurements.
Flux-based hierarchical organization of Escherichia coli’s metabolic network
Authors: Robaina-Estévez Semidán , Nikoloski Zoran
Published: August 2019

Biological networks across scales exhibit hierarchical organization that may constrain network function. Yet, understanding how these hierarchies arise due to the operational constraint of the networks and whether they impose limits to molecular phenotypes remains elusive. Here we show that metabolic networks include a hierarchy of reactions based on a natural flux ordering that holds for every steady state. We find that the hierarchy of reactions is reflected in experimental measurements of transcript, protein and flux levels of Escherichia coli under various growth conditions as well as in the catalytic rate constants of the corresponding enzymes. Our findings point at resource partitioning and a fine-tuning of enzyme levels in E. coli to respect the constraints imposed by the network structure at steady state. Since reactions in upper layers of the hierarchy impose an upper bound on the flux of the reactions downstream, the hierarchical organization of metabolism due to the flux ordering has direct applications in metabolic engineering.
The circulating lipidome is largely defined by sex descriptors in the GOLDN, GeneBank and the ADNI studies
Authors: Barupal Dinesh Kumar , Zhang Ying , Fan Sili , Hazen Stanley L. , Tang W. H. Wilson , Cajka Tomas , Irvin Marguerite R. , Arnett Donna K. , Kind Tobias , Kaddurah-Daouk Rima , Fiehn Oliver
Published: August 2019

Biological sex is one of the major anthropometric factors which influences physiology, metabolism and health status. We have investigated the effect of sexual dimorphism on the blood lipidome profile in three large population level studies - the Alzheimer’s disease neuroimaging initiative - ADNI (n =806), the GeneBank Functional Cardio-Metabolomics cohort (n= 1015) and the Genetics of Lipid lowering Drugs and Diet Network - GOLDN (n=422). In total, 355 unique lipids from 15 lipid classes were detected across all three studies using LC-MS. Sixty percent of these lipids differed between men and women in all three cohorts, and up to 87% of all lipids demonstrated sex differences in at least one cohort. ChemRICH enrichment statistics on lipid classes showed that phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, ceramides, sphingomyelins and cholesterol esters were found at higher levels in female subjects while triacylglycerols and lysophosphatidylcholines were found at higher levels in male participants across the three cohorts. This strong sex effect on the blood lipidome suggests that specific regulatory mechanisms may exist that regulate lipid metabolism in a different manner between men and women. Cohort studies involving blood lipidomics should consider separate analyses for male and female participants instead of combined analyses treating sex as a confounding factor.
Myristate can be used as a carbon and energy source for the asymbiotic growth of arbuscular mycorrhizal fungi
Authors: Sugiura Yuta , Akiyama Rei , Tanaka Sachiko , Yano Koji , Kameoka Hiromu , Marui Shiori , Saito Masanori , Kawaguchi Masayoshi , Akiyama Kohki , Saito Katsuharu
Published: August 2019

Arbuscular mycorrhizal (AM) fungi, forming symbiotic associations with land plants, are obligate symbionts that cannot complete their natural life cycle without a host. Recently, fatty acid auxotrophy of AM fungi is supported by studies showing that lipids synthesized by the host plants are transferred to the fungi and that the latter lack genes encoding cytosolic fatty acid synthases (1-7). Therefore, to establish an asymbiotic cultivation system for AM fungi, we tried to identify the fatty acids that could promote biomass production. To determine whether AM fungi can grow on medium supplied with fatty acids or lipids under asymbiotic conditions, we tested eight saturated or unsaturated fatty acids (C12–C18) and two β-monoacylglycerols. Only myristate (C14:0) led to an increase in biomass ofRhizophagus irregularis, inducing extensive hyphal growth and formation of infection-competent secondary spores. However, such spores were smaller than those generated symbiotically. Furthermore, we demonstrated thatR. irregulariscan take up fatty acids in its branched hyphae and use myristate as a carbon and energy source. Myristate also promoted the growth ofRhizophagus clarusandGigaspora margarita. Finally, mixtures of myristate and palmitate accelerated fungal growth and induced a substantial change in fatty acid composition of triacylglycerol compared with single myristate application, although palmitate was not used as a carbon source for cell wall biosynthesis in this culture system. In conclusion, here we demonstrate that myristate boosts asymbiotic growth of AM fungi and can also serve as a carbon and energy source.

Significance statement

The origins of arbuscular mycorrhizal (AM) fungi, which form symbiotic associations with land plants, date back over 460 million years ago. During evolution, these fungi acquired an obligate symbiotic lifestyle, and thus depend on their host for essential nutrients. In particular, fatty acids are regarded as crucial nutrients for the survival of AM fungi owing to the absence of genes involved inde novofatty acid biosynthesis in the AM fungal genomes that have been sequenced so far. Here, we show that myristate initiates AM fungal growth under asymbiotic conditions. These findings will advance pure culture of AM fungi.
Laccase-mediated catalyzed fluorescent reporter deposition for live cell imaging
Authors: Cisneros Brandon , Devaraj Neal K.
Published: August 2019

Catalyzed reporter deposition (CARD) is a widely established method for labeling biological samples analyzed using microscopy. Horseradish peroxidase, commonly used in CARD to amplify reporter signals, requires the addition of hydrogen peroxide which may perturb samples used in live-cell microscopy. Herein we describe an alternative method of performing CARD using a laccase enzyme, which does not require exogenous hydrogen peroxide. Laccase is an oxidative enzyme which can carry out single-electron oxidations of phenols and related compounds by reducing molecular oxygen. We demonstrate proof-of-concept for this technique through the non-targeted covalent labeling of bovine serum albumin using a fluorescently-labeled ferulic acid derivative as the laccase reporter substrate. We further demonstrate the viability of this approach by performing live-cell CARD with an antibody-conjugated laccase against a surface bound target. CARD using laccase produces an amplified fluorescence signal by labeling cells without the need for exogenous hydrogen peroxide.
Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Biallelic Loss of ENG or ACVRL1
Authors: Snellings Daniel , Gallione Carol , Clark Dewi , Vozoris Nicholas , Faughnan Marie , Marchuk Douglas
Published: August 2019

Hereditary Hemorrhagic Telangiectasia (HHT) is a Mendelian disease characterized by vascular malformations including visceral arteriovenous malformations and mucosal telangiectasia. HHT is caused by loss-of-function mutations in one of 3 genes; ENG, ACVRL1 or SMAD4 and is inherited as an autosomal dominant condition. Intriguingly, the constitutional mutation causing HHT is present throughout the body, yet the multiple vascular malformations in HHT patients occur focally, rather than manifesting as a systemic vascular defect. This disconnect between genotype and phenotype suggests that a local event is necessary for the development of vascular malformations. We investigated the hypothesis that local somatic mutations seed the formation HHT-related telangiectasia in a genetic two-hit mechanism. We identified low-frequency somatic mutations in 9/19 telangiectasia using high depth next-generation sequencing. We established phase for 7 of 9 samples using long-read sequencing, which confirm that the germline and somatic mutations in all 7 samples exist in trans configuration; consistent with a genetic two-hit mechanism. These combined data suggest that biallelic loss of ENG or ACVRL1 may be a required event in the development of telangiectasia, and that rather than haploinsufficiency, vascular malformations in HHT are caused by a Knudsonian two-hit mechanism.
CrowdGO: machine learning and semantic similarity guided consensus Gene Ontology annotation
Authors: Reijnders Maarten J.M.F. , Waterhouse Robert M.
Published: August 2019

Background

Characterising gene function for the ever-increasing number and diversity of species with annotated genomes relies almost entirely on computational prediction methods. These software are also numerous and diverse, each with different strengths and weaknesses as revealed through community benchmarking efforts. Meta-predictors that assess consensus and conflict from individual algorithms should deliver enhanced functional annotations.

Results

To exploit the benefits of meta-approaches, we developed CrowdGO, an open-source consensus-based Gene Ontology (GO) term meta-predictor that employs machine learning models with GO term semantic similarities and information contents. By re-evaluating each gene-term annotation, a consensus dataset is produced with high-scoring confident annotations and low-scoring rejected annotations. Applying CrowdGO to results from a deep learning-based, a sequence similarity-based, and two protein domain-based methods, delivers consensus annotations with improved precision and recall. Furthermore, using standard evaluation measures CrowdGO performance matches that of the community’s best performing individual methods.

Conclusion

CrowdGO offers a model-informed approach to leverage strengths of individual predictors and produce comprehensive and accurate gene functional annotations.

Availability and Implementation

CrowdGO is implemented in Python3, and is freely available from https://gitlab.com/mreijnders/CrowdGO, with a Snakemake workflow and pre-trained models.
A Combinatorial MAP Code Dictates Polarized Microtubule Transport
Authors: Monroy Brigette Y. , Tan Tracy C. , Oclaman Janah May , Han Jisoo S. , Simo Sergi , Nowakowski Dan W. , McKenney Richard J. , Ori-McKenney Kassandra M.
Published: August 2019

Many eukaryotic cells distribute their intracellular components through asymmetrically regulated active transport driven by molecular motors along microtubule tracks. While intrinsic and extrinsic regulation of motor activity exists, what governs the overall distribution of activated motor-cargo complexes within cells remains unclear. Here, we utilize in vitro reconstitution of purified motor proteins and non-enzymatic microtubule-associated proteins (MAPs) to demonstrate that these MAPs exhibit distinct influences on the motility of the three main classes of transport motors: kinesin-1, kinesin-3, and cytoplasmic dynein. Further, we dissect how combinations of MAPs affect motors, and reveal how transient interactions between MAPs and motors may promote these effects. From these data, we propose a general “MAP code” that has the capacity to strongly bias directed movement along microtubules and helps elucidate the intricate intracellular sorting observed in highly polarized cells such as neurons.
Estimates of locus coeruleus function with functional magnetic resonance imaging are influenced by localization approaches and the use of multi-echo data
Authors: Turker Hamid B. , Riley Elizabeth , Luh Wen-Ming , Colcombe Stan J. , Swallow Khena M.
Published: August 2019

The locus coeruleus (LC) plays a central role in regulating human cognition, arousal, and autonomic states. Efforts to characterize the LC’s function in humans using functional magnetic resonance imaging have been hampered by its small size and location near a large source of noise, the fourth ventricle. We tested whether the ability to characterize LC function is improved by employing neuromelanin-T1 weighted images (nmT1) for LC localization and multi-echo functional magnetic resonance imaging (ME-fMRI) for estimating intrinsic functional connectivity (iFC). Analyses indicated that, relative to a probabilistic atlas, utilizing nmT1 images to individually localize the LC increases the specificity of seed time series and clusters in the iFC maps. When combined with independent components analysis (ME-ICA), ME-fMRI data provided significant gains in the temporal signal to noise ratio relative to denoised single-echo (1E) data. The effects of acquiring nmT1 images and ME-fMRI data did not appear to only reflect increases in power: iFC maps for each approach only moderately overlapped. This is consistent with findings that ME-fMRI offers substantial advantages over 1E data acquisition and denoising. It also suggests that individually identifying LC with nmT1 scans is likely to reduce the influence of other nearby brainstem regions on estimates of LC function.

Highlights

Manual tracing of locus coeruleus increased specificity of seed time series

Manual tracing of locus coeruleus increased specificity of intrinsic connectivity

Multi-echo fMRI increased temporal signal-to-noise ratio compared to single-echo fMRI

Connectivity maps across methodologies overlapped only moderately

Measurement of LC function benefits from multi-echo fMRI and tracing ROIs
scDoc: Correcting Drop-out Events in Single-cell RNA-seq Data
Authors: Ran Di , Zhang Shanshan , Lytal Nicholas , An Lingling
Published: August 2019

Single-cell RNA sequencing (scRNA-seq) has become an important tool to unravel cellular heterogeneity, discover new cell types, and understand cell development at single-cell resolution. However, one major challenge to scRNA-seq research is the presence of “drop-out” events, which usually is due to extremely low mRNA input or the stochastic nature of gene expression. In this paper, we present a novel Single-Cell RNA-seq Drop-Out Correction (scDoc) method, imputing drop-out events by borrowing information for the same gene from highly similar cells. scDoc is the first method that involves drop-out information to account for cell-to-cell similarity estimation, which is crucial in scRNA-seq drop-out imputation but has not been appropriately examined. We evaluated the performance of scDoc using both simulated data and real scRNA-seq studies. Results show that scDoc can impute the drop-out events more accurately and robustly; specifically, it outperforms all available imputation methods in reference to data visualization, cell subpopulation identification, and differential expression detection in scRNA-seq data.
DLDG1, the Arabidopsis Homolog of the Cyanobacterial H+-Extrusion Protein, Regulates Non-Photochemical Quenching in Chloroplasts
Authors: Harada Kyohei , Arizono Takatoshi , Sato Ryoichi , Trinh Mai Duy Luu , Hashimoto Akira , Kono Masaru , Tsujii Masaru , Uozumi Nobuyuki , Takaichi Shinichi , Masuda Shinji
Published: August 2019

Plants convert solar energy into chemical energy through photosynthesis, which supports almost all life activities on earth. Because the intensity and quality of sunlight can change dramatically throughout the day, various regulatory mechanisms help plants adjust their photosynthetic output accordingly, including the regulation of light energy accumulation to prevent the generation of damaging reactive oxygen species. Non-photochemical quenching (NPQ) is a regulatory mechanism that dissipates excess light energy, but how it is regulated is not fully elucidated. Herein, we report a new NPQ-regulatory protein named Day-Length-dependent Delayed-Greening1 (DLDG1). The Arabidopsis DLDG1 associates with the chloroplast envelope membrane, and thedldg1mutant had a large NPQ value compared with wild type. The mutant also had a pale-green phenotype in developing leaves but only under continuous light; this phenotype was not observed whendldg1was cultured in the dark for ≥8 h per day. DLDG1 is a homolog of the plasma-membrane-localizing cyanobacterial proton-extrusion-protein A that is required for light-induced H+extrusion, and also shows similarity in its amino-acid sequence to that of Ycf10 encoded in the plastid genome. Arabidopsis DLDG1 enhances the growth-retardation phenotype of theEscherichia coliK+/H+antiporter mutant, and the everted membrane vesicles of theE. coliexpressing DLDG1 show the K+/H+antiport activity. Our findings suggest that DLDG1 functionally interacts with Ycf10 to control H+homeostasis in chloroplasts, which is important for the light-acclimation response, by optimizing the extent of NPQ.
Structural insights into the mechanism of the human soluble guanylate cyclase
Authors: Kang Yunlu , Liu Rui , Wu Jing-Xiang , Chen Lei
Published: August 2019

Soluble guanylate cyclase (sGC) is the primary nitric oxide (NO) sensor. It plays a central role in NO signaling and is implicated in many essential physiological processes and disease conditions. The binding of NO leads to a significant boost in sGC enzymatic activity. However, the mechanism of NO activation remains incompletely understood. Here, we report the cryo-electron microscopy structures of the human sGC α1β1 heterodimer in different functional states. These structures revealed that the transducer module bridges the NO sensor module and the catalytic module. NO binding to the β1 H-NOX domain triggers the structural rearrangement of the sensor module and the bending-straightening conformational switch of the transducer module. The resulting movement of the N-termini of the catalytic domains drives the structural changes within the catalytic module, which in turn boost sGC enzymatic activity. These observations indicate the structural framework for the mechanism of sGC activation induced by NO binding.
PIWI-piRNA pathway-mediated transposable element repression inHydrasomatic stem cells
Authors: Teefy Bryan B. , Siebert Stefan , Cazet Jack F. , Lin Haifan , Juliano Celina E.
Published: August 2019

Transposable elements (TEs) can damage genomes, thus organisms employ a variety of mechanisms to repress TE expression. However, these mechanisms often fail over time leading to de-repression of TEs in aging tissues. The PIWI-piRNA pathway is a small RNA pathway that represses TE expression in the germline of animals. Here we explore the function of the pathway in the epithelial stem cells ofHydra, a long-lived freshwater cnidarian.Hydrahave three stem cell populations; endodermal and ectodermal epithelial stem cells are strictly somatic, whereas the interstitial stem cells retain germline competence. In our previous study, we found that the PIWI proteins are expressed in all threeHydrastem cell types. In this study, we focus on the ectodermal and endodermal epithelial stem cells to understand the somatic function of the pathway. We isolated piRNAs fromHydrathat lack the interstitial lineage and found that these somatic piRNAs map predominantly to TE transcripts and display the conserved sequence signatures typical of germline piRNAs. Three lines of evidence suggest that the PIWI-piRNA pathway represses TEs inHydraepithelial stem cells. First, epithelial knockdown of theHydraPIWI proteinhywiresulted in upregulation of TE expression. Second, degradome sequencing revealed evidence of PIWI-mediated cleavage of TE RNAs in epithelial cells using the ping-pong mechanism. Finally, we demonstrated a direct association between Hywi protein and TE transcripts in epithelial cells using RNA immunoprecipitation. Interestingly, we found that RNAi knockdown ofhywileads to an upregulation of genes involved in innate immunity, which may be in response to TE upregulation; this is consistent with recent studies on TE expression in mammalian cells. Altogether, this study suggests a function for the PIWI-piRNA pathway in maintaining the long-lived somatic cell lineages ofHydraand may point to a broader role for this pathway in protecting somatic tissue from TE-induced damage.
An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis
Authors: Xiang Guanjue , Keller Cheryl A. , Heuston Elisabeth , Giardine Belinda M. , An Lin , Wixom Alexander Q. , Miller Amber , Cockburn April , Sauria Michael E.G. , Weaver Kathryn , Lichtenberg Jens , Göttgens Berthold , Li Qunhua , Bodine David , Mahony Shaun , Taylor James , Blobel Gerd A. , Weiss Mitchell J. , Cheng Yong , Yue Feng , Hughes Jim , Higgs Douglas R. , Zhang Yu , Hardison Ross C.
Published: August 2019

Thousands of epigenomic datasets have been generated in the past decade, but it is difficult for researchers to effectively utilize all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established forValIdatedSystematicIntegratiONof epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By employing IDEAS as ourIntegrative andDiscriminativeEpigenomeAnnotationSystem, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of over 200,000 candidatecis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website (usevision.org) to aid research in genomics and hematopoiesis.
Computational Evidence for Hierarchically-Structured Reinforcement Learning in Humans
Authors: Eckstein Maria K , Collins Anne GE
Published: August 2019

Humans have the fascinating ability to achieve goals in a complex and constantly changing world, still surpassing modern machine learning algorithms in terms of flexibility and learning speed. It is generally accepted that a crucial factor for this ability is the use of abstract, hierarchical representations, which employ structure in the environment to guide learning and decision making. Nevertheless, how we create and use these hierarchical representations is poorly understood. This study presents evidence that human behavior can be characterized as hierarchical reinforcement learning (RL). We designed an experiment to test specific predictions of hierarchical RL using a series of subtasks in the realm of context-based learning, and observed several behavioral markers of hierarchical RL, such as asymmetric switch costs between changes in higher-level versus lower-level features, faster learning in higher-valued compared to lower-valued contexts, and preference for higher-valued compared to lower-valued contexts. We replicated these results across three independent samples. We simulated three models: a classic RL, a hierarchical RL, and a hierar-chical Bayesian model, and compared their behavior to human results. While the flat RL model captured some aspects of participants’ sensitivity to outcome values, and the hierarchical Bayesian model some markers of transfer, only hierarchical RL accounted for all patterns observed in human behavior. This work shows that hierarchical RL, a biologically-inspired and computationally simple algorithm, can capture human behavior in complex, hierarchical environments, and opens the avenue for future research in this field.
Structure-activity relationship studies of three novel 4-aminopyridine K+ channel blockers
Authors: Rodríguez-Rangel Sofia , Bravin Alyssa D. , Ramos-Torres Karla M. , Brugarolas Pedro , Sánchez-Rodríguez Jorge E.
Published: August 2019

4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate three novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) and trifluoromethyl (-CF3) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (pKa and logD) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that all three derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP, whereas the methoxy (3MeO4AP) and trifluoromethyl (3CF34AP) containing compounds were about 3- to 4-fold less potent than 4AP, respectively. These results suggest that these novel derivatives are potential candidates for therapy and imaging.
GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling
Authors: Lex Rachel K. , Ji Zhicheng , Falkenstein Kristin N. , Zhou Weiqiang , Henry Joanna L. , Ji Hongkai , Vokes Steven A.
Published: August 2019

Transcriptional repression needs to be rapidly reversible during embryonic development. This extends to the Hedgehog pathway, which primarily serves to counter GLI repression by processing GLI proteins into transcriptional activators. In investigating the mechanisms underlying GLI repression, we find that a subset of these regions, termed HH-responsive enhancers, specifically loses acetylation in the absence of HH signaling. These regions are highly enriched around HH target genes and primarily drive HH-specific limb activity. They also retain H3K27ac enrichment in limb buds devoid of GLI activator and repressor, indicating that their activity is primarily regulated by GLI repression. The Polycomb repression complex is not active at most of these regions, suggesting it is not a major mechanism of GLI repression. We propose a model for tissue-specific enhancer activity in which an HDAC-associated GLI repression complex regulates target gene expression by altering the acetylation status at enhancers.
Recruitment of mRNAs to P granules by gelation with intrinsically-disordered proteins
Authors: Lee Chih-Yung S. , Putnam Andrea , Lu Tu , He Shuaixin , Ouyang John Paul T. , Seydoux Geraldine
Published: August 2019

Animals with germ plasm assemble cytoplasmic RNA granules (germ granules) that segregate with the embryonic germ lineage. How germ granules assemble and recruit RNA is not well understood. Here we characterize the assembly and RNA composition of the germ (P) granules ofC. elegans. ∼500 maternal mRNAs are recruited into P granules by a sequence independent mechanism that favors mRNAs with low ribosome coverage. Translational activation correlates temporally with P granule exit for two mRNAs that code for germ cell fate regulators. mRNAs are recruited into the granules by MEG-3, an intrinsically disordered protein that condenses with RNA to form nanoscale gels. Our observations reveal parallels between germ granules and stress granules and suggest that cytoplasmic RNA granules are reversible super-assemblies of nanoscale RNA-protein gel condensates.
Improvising at Rest: Differentiating Jazz and Classical Music Training with Resting State Functional Connectivity
Authors: Belden Alexander , Zeng Tima , Przysinda Emily , Anteraper Sheeba Arnold , Whitfield-Gabrieli Susan , Loui Psyche
Published: August 2019

Jazz improvisation offers a model for creative cognition, as it involves the real-time creation of a novel, information-rich product. Previous research has shown that when musicians improvise, they recruit regions in the Default Mode Network (DMN) and Executive Control Network (ECN). Here, we ask whether these findings from task-fMRI studies might extend to intrinsic differences in resting state functional connectivity. We compared Improvising musicians, Classical musicians, and Minimally Musically Trained (MMT) controls in seed-based functional connectivity and network analyses in resting state functional MRI. We also examined the functional correlates of behavioral performance in musical improvisation and divergent thinking. Seed-based analysis consistently showed higher connectivity in ventral DMN (vDMN) and bilateral ECN in both groups of musically trained individuals as compared to MMT controls, with additional group differences in primary visual network, precuneus network, and posterior salience network. In particular, primary visual network connectivity to DMN and ECN was highest in Improvisational musicians, whereas within-network connectivity of vDMN and precuneus network was higher in both Improvisational and Classical musicians than in MMT controls; in contrast, connectivity between posterior salience network and superior parietal lobule was highest in Classical musicians. Furthermore, graph-theoretical analysis indicated heightened betweenness centrality, clustering, and local efficiency in Classical musicians. Taken together, results suggest that heightened functional connectivity among musicians can be explained by higher within-network connectivity (more tight-knit cortical networks) in Classical musicians, as opposed to more disperse, globally-connected cortical networks in Improvisational musicians.

Highlights

Music training is associated with higher resting state connectivity

Higher connectivity in Improvisational musicians from visual network to ECN and DMN

Classical musicians show higher vDMN and Precuneus within-network connectivity

Improvisation and divergent thinking performance correlate with similar connectivity patterns
Unexpected sound omissions are signaled in human posterior superior temporal gyrus: an intracranial study
Authors: Fonken Yvonne M. , Mukerji Arjun , Jimenez Richard , Lin Jack , Brunner Peter , Schalk Gerwin , Knight Robert T.
Published: August 2019

Context modulates sensory neural activations enhancing perceptual and behavioral performance and reducing prediction errors. However, the mechanism of when and where these high-level expectations act on sensory processing is unclear. Here, we isolate the effect of expectation absent any auditory evoked activity by assessing the response to omitted expected sounds. Electrophysiological signals were recorded directly from the superior temporal gyrus (STG) and superior temporal sulcus (STS) in patients with medically refractory epilepsy. Subjects listened to a predictable sequence of syllables, with some infrequently omitted. We found a high frequency band (HFB, 70-150Hz) response to omissions, which overlap with a posterior subset of auditory active electrodes. This response is distinct from omission activations observed in non-auditory selective sites in STG. Heard syllables could be classified reliably from STG, but not the identity of the omitted stimulus. Both omission- and target detection activations were also observed in prefrontal cortex.

We propose that the posterior STG and STS are central for implementing predictions in the auditory environment. HFB omission activations in this region appear to index mismatch-signaling or salience detection processes.
Shrinkage Classification for Overlapping Time Series: An interpretable method for mapping stimulus-differentiated evoked response
Authors: Elliott Peter W. , Boring Matthew J. , Li Yuanning , Richardson R. Mark , Ghuman Avniel Singh , G’Sell Max
Published: August 2019

Multivariate time series from neural electrophysiological recordings are a rich source of information about neural processing systems and require appropriate methods for proper analysis. Current methods for mapping brain function in these data using neural decoding aggregate information across space and time in limited ways, rarely incorporating spatial dependence across recording locations. We propose Shrinkage Classification for Overlapping Time Series (SCOTS), a neural decoding method that maps brain function, while accounting for spatio-temporal dependence, through interpretable dimensionality reduction and classification of multivariate neural time series. SCOTS has two components: first, overlapping clustering from sparse semi-nonnegative matrix factorization gives a data-driven aggregation of neural information across space; second, wavelet-transformed nearest shrunken centroids with sparse group lasso performs multi-class classification with selection of informative clusters and time intervals. We demonstrate use of SCOTS by applying it to human intracranial electrophysiological and MEG data collected while participants viewed visual stimuli from a range of categories. The method reveals the dynamic activation of brain regions with sensitivity to different object categories, giving insight into spatio-temporal contributions of these neural processing systems.
Girdin is a component of the lateral polarity protein network restricting cell dissemination
Authors: Biehler Cornélia , Wang Li-Ting , Sévigny Myriam , Jetté Alexandra , Gamblin Clémence , Catterall Rachel , Houssin Élise , McCaffrey Luke , Laprise Patrick
Published: August 2019

Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show thatDrosophilaGirdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination fromGIRDINknockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration ofGIRDINexpression is associated with a poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.
Human Proteome Project Mass Spectrometry Data Interpretation Guidelines 3.0
Authors: Deutsch Eric W. , Lane Lydie , Overall Christopher M. , Bandeira Nuno , Baker Mark S. , Pineau Charles , Moritz Robert L. , Corrales Fernando , Orchard Sandra , Van Eyk Jennifer E. , Paik Young-Ki , Weintraub Susan T. , Vandenbrouck Yves , Omenn Gilbert S.
Published: August 2019

The Human Proteome Organization’s (HUPO) Human Proteome Project (HPP) developed Mass Spectrometry (MS) Data Interpretation Guidelines that have been applied since 2016. These guidelines have helped ensure that the emerging draft of the complete human proteome is highly accurate and with low numbers of false-positive protein identifications. Here, we describe an update to these guidelines based on consensus-reaching discussions with the wider HPP community over the past year. The revised 3.0 guidelines address several major and minor identified gaps. We have added guidelines for emerging data independent acquisition (DIA) MS workflows and for use of the new Universal Spectrum Identifier (USI) system being developed by the HUPO Proteomics Standards Initiative (PSI). In addition, we discuss updates to the standard HPP pipeline for collecting MS evidence for all proteins in the HPP, including refinements to minimum evidence. We present a new plan for incorporating MassIVE-KB into the HPP pipeline for the next (HPP 2020) cycle in order to obtain more comprehensive coverage of public MS data sets. The main checklist has been reorganized under headings and subitems and related guidelines have been grouped. In sum, Version 2.1 of the HPP MS Data Interpretation Guidelines has served well and this timely update to version 3.0 will aid the HPP as it approaches its goal of collecting and curating MS evidence of translation and expression for all predicted ∼20,000 human proteins encoded by the human genome.

Abstract Figure
Benchmarking machine learning models for the analysis of genetic data using FRESA.CAD Binary Classification Benchmarking
Authors: de Velasco Oriol Javier , Martinez-Torteya Antonio , Trevino Victor , Alanis Israel , Vallejo Edgar E. , Tamez-Pena Jose Gerardo
Published: August 2019

Background

Machine learning models have proven to be useful tools for the analysis of genetic data. However, with the availability of a wide variety of such methods, model selection has become increasingly difficult, both from the human and computational perspective.

Results

We present the R package FRESA.CAD Binary Classification Benchmarking that performs systematic comparisons between a collection of representative machine learning methods for solving binary classification problems on genetic datasets.

Conclusions

FRESA.CAD Binary Benchmarking demonstrates to be a useful tool over a variety of binary classification problems comprising the analysis of genetic data showing both quantitative and qualitative advantages over similar packages.
Statistics of spatial rotations in 3D electron cryo-microscopy by unit quaternion description
Authors: Hu Mingxu , Zhang Qi , Yang Jing , Li Xueming
Published: August 2019

Electron cryo-microscopy (cryoEM) involves the estimation of orientations of projection images or three-dimensional (3D) volumes. However, the lack of statistical tools of rotations in cryoEM fails to answer the growing demands for adopting advanced statistical methods. In this study, we develop a comprehensive statistical tool specialized for cryoEM based on an unit quaternion description of spatial rotations. Some basic properties and definitions of the quaternion, as well as a way to use the unit quaternion to describe and perform rotations, are first recalled. Then, based on the unit quaternion, the distance and geodesic between rotations are designed for cryoEM to enable comparisons and interpolations between rotations, which are prerequisites of statistics of rotations in 3D cryoEM. Further, methods of directional statistics specialized for cryoEM are developed, including calculations of the average rotation, sampling, and inference with uniform and angular central Gaussian (ACG) distribution, as well as an estimation of the rotation precision. Finally, the method of handling molecular symmetry is introduced. Using the unit quaternion system for cryoEM, we provide comprehensive mathematical tools for the analysis of spatial rotations in cryoEM.
Selection for altruistic defense in structured populations
Authors: Jordan Felix , Hutzenthaler Martin , Metzler Dirk
Published: August 2019

We model natural selection for or against an anti-parasite (or anti-predator) defense allele in a host (or prey) population that is structured into many demes. The defense behavior has a fitness cost for the actor compared to non defenders (“cheaters”) in the same deme and locally reduces parasite growth rates. Hutzenthaler et al. (2022) have analytically derived a criterion for fixation or extinction of defenders in the limit of large populations, many demes, weak selection and slow migration. Here, we use both individual-based and diffusion-based simulation approaches to analyze related models. We find that the criterion still leads to accurate predictions for settings with finitely many demes and with various migration patterns.

A key mechanism of providing a benefit of the defense trait is genetic drift due to randomness of reproduction and death events leading to between-deme differences in defense allele frequencies and host population sizes. We discuss an inclusive-fitness interpretation of this mechanism and presentin-silicoevidence that under these conditions a defense trait can be altruistic and still spread in a structured population.
Dissecting genetic and sex-specific host heterogeneity in pathogen transmission potential
Authors: Siva-Jothy Jonathon A. , Vale Pedro F.
Published: August 2019

Heterogeneity in disease transmission is widespread and, when not accounted for, can produce unpredictable outbreaks of infectious disease. Despite this, precisely how different sources of variation in host traits drive heterogeneity in disease transmission is poorly understood. Here we dissected the sources of variation in pathogen transmission usingDrosophila melanogasterandDrosophilaC Virus as a host-pathogen model system. We found that infected lifespan, viral growth, virus shedding, and viral load at death were all significantly influenced by fly genetic background, sex and female mating status. To understand how variation in each of these traits may generate heterogeneity in disease transmission, we estimated individual transmission potential by integrating data on virus shedding and lifespan alongside previously collected data on social aggregation. We found that ∼15% of between-individual heterogeneity in disease transmission was explained by a significant interaction between genetic and sex-specific variation. We also characterised the amount of variation in viral load, virus shedding, and lifespan following infection that could be explained by genetic background and sex. Amongst the determinants of individual variation in disease transmission these sources of host variation play roles of varying importance, with genetic background generally playing the largest role. Our results highlight the importance of characterising sources of variation in multiple host traits when studying disease transmission at the individual-level.
Lecithin:Retinol Acyl Transferase (LRAT) induces the formation of lipid droplets
Authors: Molenaar Martijn R. , Wassenaar Tsjerk A. , Yadav Kamlesh K. , Toulmay Alexandre , Mari Muriel C. , Caillon Lucie , Chorlay Aymeric , Haaker Maya W. , Wubbolts Richard W. , Houweling Martin , Vaandrager A. Bas , Reggiori Fulvio , Thiam Abdou Rachid , Prinz William A. , Helms J. Bernd
Published: August 2019

Lipid droplets are unique and nearly ubiquitous organelles that store neutral lipids in a hydrophobic core, surrounded by a monolayer of phospholipids. The primary neutral lipids are triacylglycerols and steryl esters. It is not known whether other classes of neutral lipids can form lipid droplets by themselves. Here we show that production of retinyl esters by lecithin:retinol acyl transferase (LRAT) in yeast cells, incapable of producing triacylglycerols and steryl esters, causes the formation of lipid droplets. By electron microscopy, these lipid droplets are morphologically indistinguishable from those in wild-type cells.In silicoandin vitroexperiments confirmed the propensity of retinyl esters to segregate from membranes and to form lipid droplets. The hydrophobic N-terminus of LRAT displays preferential interactions with retinyl esters in membranes and promotes the formation of large retinyl ester-containing lipid droplets in mammalian cells. Our combined data indicate that the molecular design of LRAT is optimally suited to allow the formation of characteristic large lipid droplets in retinyl ester-storing cells.
Single nucleus andin situRNA sequencing reveals cell topographies in the human pancreas
Authors: Tosti Luca , Hang Yan , Debnath Olivia , Tiesmeyer Sebastian , Trefzer Timo , Steiger Katja , Ten Foo Wei , Lukassen Sören , Ballke Simone , Kühl Anja A. , Spieckermann Simone , Bottino Rita , Ishaque Naveed , Weichert Wilko , Kim Seung K. , Eils Roland , Conrad Christian
Published: August 2019

Molecular evidence of cellular heterogeneity in the human exocrine pancreas has not been established, due to the local concentration of hydrolytic enzymes that can rapidly degrade cells and RNA upon resection. Here we innovated single-nucleus RNA sequencing protocols, and profiled more than 120,000 cells from adult and neonatal human donors to create the first comprehensive atlas of human pancreas cells, including epithelial and non-epithelial constituents. Adult and neonatal pancreata shared common features, including the presence of previously undetected acinar subtypes, but also showed marked differences in the composition of the endocrine, endothelial, and immune compartments. Spatial cartography, including cell proximity mapping throughin situsequencing, revealed dynamic developmental cell topographies in the endocrine and exocrine pancreas. Our human pancreas cell atlas can be interrogated to understand pancreatic cell biology, and provides a crucial reference set for future comparisons with diseased tissue samples to map the cellular foundations of pancreatic diseases.