bluuebunny/crossref_metadata_2025 huggingface dataset:
pysradb: A Python package to query next-generation sequencing metadata and data from NCBI Sequence Read Archive
Authors: Choudhary Saket
Published: March 2019

NCBIs Sequence Read Archive (SRA) is the primary archive of next-generation sequencing datasets. SRA makes metadata and raw sequencing data available to the research community to encourage reproducibility, and to provide avenues for testing novel hypotheses on publicly available data. However, existing methods to programmatically access these data are limited. We introduce a Python packagepysradbthat provides a collection of command line methods to query and download metadata and data from SRA utilizing the curated metadata database available through the SRAdb project. We demonstrate the utility ofpysradbon multiple use cases for searching and downloading SRA datasets. It is available freely athttps://github.com/saketkc/pysradb.
Exploring the limitations of event-related potential measures in moving subjects. Case studies of four different technical modifications in ergometer rowing
Authors: Hill Holger
Published: March 2019

Measuring brain activity outside the laboratory is of great importance for investigating human behavior under naturalistic conditions (e.g., in cognition and movement research, application of brain-computer interfaces). To measure neuronal activity in moving subjects, only modified NIRS and EEG systems are applicable. Because conventional EEG systems are too sensitive to movement artifacts, artifact sources should be eliminated beforehand to improve signal quality. Four different approaches for EEG/ERP measures with moving subjects were tested in case studies: (i) a purpose-built head-mounted preamplifier, (ii) a laboratory system with active electrodes, (iii)+(iv) a wireless headset combined with (iii) passive or (iv) active electrodes. A standard visual oddball task was applied during rest (without movement) and during ergometer rowing. All 14 measures revealed very similiar (within subjects) visual evoked potentials for rowing and rest. The small intraindividual differences between rowing and rest, in comparison to the typically larger interindividual differences in the ERP waveforms revealed that ERPs can be measured reliably even in an athletic movement like rowing. The expected modulation of the motor-related activity by force output, on the other hand, was largely affected by movement artifacts. Therefore, for a successful application of ERP measures in movement research, further developments to differentiate between movement-related neuronal activity and movement-related artifacts are required. However, it cannot be excluded that activities with small magnitudes related to motor learning and motor control cannot be detected because they are superimposed by the very large motor potential which increases with force output.
Constrained sampling from deep generative image models reveals mechanisms of human target detection
Authors: Fruend Ingo
Published: March 2019

The first steps of visual processing are often described as a bank of oriented filters followed by divisive normalization. This approach has been tremendously successful at predicting contrast thresholds in simple visual displays. However, it is unclear to what extent this kind of architecture also supports processing in more complex visual tasks performed in naturally looking images.

We used a deep generative image model to embed arc segments with different curvatures in naturalistic images. These images contain the target as part of the image scene, resulting in considerable appearance variation of target as well as background. Three observers localized arc targets in these images, achieving an accuracy of 74.7% correct responses on average. Data were fit by several biologically inspired models, 4 standard deep convolutional neural networks (CNN) from the computer vision literature, and by a 5-layer CNN specifically trained for this task. Four models were particularly good at predicting observer responses, (i) a bank of oriented filters, similar to complex cells in primate area V1, (ii) a bank of oriented filters followed by tuned gain control, incorporating knowledge about cortical surround interactions, (iii) a bank of oriented filters followed by local normalization, (iv) the 5-layer specifically trained CNN. A control experiment with optimized stimuli based on these four models showed that the observers’ data were best explained by model (ii) with tuned gain control.

These data suggest that standard models of early vision provide good descriptions of performance in much more complex tasks than what they were designed for, while general purpose non-linear models such as convolutional neural networks do not.
Flexible representation of higher-dimensional cognitive variables with grid cells
Authors: Klukas Mirko , Lewis Marcus , Fiete Ila
Published: March 2019

We shed light on the theoretical capabilities of entorhinal grid cells to encode variables of dimension greater than two. Our model constructs representations of high-dimensional inputs through a combination of low-dimensional random projections and “classical” low-dimensional hexagonal grid cell responses. Without reconfiguration of the recurrent circuit, the same system can flexibly encode multiple variables of different dimensions while maximizing the coding range (per dimension) by automatically trading-off dimension with an exponentially large coding range. In contrast to previously proposed schemes, the model does not require the formation of higher-dimensional grid responses, a cell-inefficient and rigid mechanism. The firing fields observed in flying bats or climbing rats can be generated by neurons that combine activity from multiple grid modules, each representing higher-dimensional spaces according to our model. The idea expands our understanding of grid cells, suggesting that they could implement a general circuit that generates on-demand coding and memory states for variables in high-dimensional vector spaces.
Pervasive convergent evolution and extreme phenotypes define chaperone requirements of protein homeostasis
Authors: Draceni Yasmine , Pechmann Sebastian
Published: March 2019

Maintaining protein homeostasis is an essential requirement for cell and organismal viability. An elaborate regulatory system within cells, the protein homeostasis network, safeguards that proteins are correctly folded and functional. At the heart of this regulatory system lies a class of specialized protein quality control enzymes called chaperones that are tasked with assisting proteins in their folding, avoiding aggregation, and degradation. Failure and decline of protein homeostasis are directly associated with conditions of aging and aging-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s. However, it is not clear what tips the balance of protein homeostasis and leads to onset of aging and diseases. Here, we present a comparative genomics analysis of protein homeostasis in eukaryotes and report general principles of maintaining protein homeostasis across the eukaryotic tree of life. Expanding a previous analysis of 16 eukaryotes to 216 eukaryotic genomes, we find a strong correlation between the size of eukaryotic chaperone networks and size of the genomes that is distinct for different species kingdoms. Importantly, organisms with pronounced phenotypes clearly buck this trend.Northobranchius furzeri, the shortest-lived vertebrate and widely used model for fragile protein homeostasis is found to be chaperone limited.Heterocephalus glaberas the longest-lived rodent thus especially robust organism is characterized by above average numbers of chaperones. Our work thus indicates that the balance in protein homeostasis may be a key variable in explaining organismal robustness. Finally, our work provides an elegant example of harnessing the power of evolution and comparative genomics to address fundamental open questions in biology with direct relevance to human diseases.
Genomic signatures of extreme body size divergence in baboons
Authors: Chiou Kenneth L. , Bergey Christina M. , Burrell Andrew S. , Disotell Todd R. , Rogers Jeffrey , Jolly Clifford J. , Phillips-Conroy Jane E.
Published: March 2019

Kinda and gray-footed chacma baboons occupy opposite extremes of the body size distribution in extant baboons (genusPapio). In order to detect signatures of natural selection in these two species, we genotyped 24,790 genome-wide autosomal SNPs from populations of Zambian baboons using double digest RADseq. We scanned the genome for evidence of selection by identifying regions with extreme differentiation between populations. We find evidence of selection on body size influencing multiple genes in one or both species, includingFGF1, ATXN2, andPRKCE. We also find an enriched signal of selection associated with biological processes involved in multicellular organism growth and development, cell proliferation and cell growth, nutrient metabolism, and chondrocyte differentiation. Finally, we find that selection has impacted components of the CCKR signaling pathway, which regulates food intake and metabolism, and the JAK/STAT signaling pathway, which mediates the effect of cytokine signals on processes including epiphyseal chondrocyte proliferation essential for longitudinal bone growth. Our findings highlight promising avenues for future studies disentangling the genetic architecture of body size in primates including humans.
fuNTRp: Identifying protein positions for variation driven functional tuning
Authors: Miller Maximilian , Vitale Daniel , Kahn Peter , Rost Burkhard , Bromberg Yana
Published: March 2019

Evaluating the impact of non-synonymous genetic variants is essential for uncovering disease associations and mechanisms of evolution. Understanding corresponding sequence changes is also fundamental for synthetic protein design and stability assessments. However, the performance gain of variant effect predictors observed in recent years is not in line with the increased complexity of new methods. One likely reason for this might be that most approaches use similar sets of gene/protein features for modeling variant effect, often emphasizing sequence conservation. While high levels of conservation highlight residues essential for protein activity, much of the in vivo observable variation is arguably weaker in its impact and, thus, requires evaluation at a higher level of resolution. Here we describe function Neutral/Toggle/Rheostat predictor (funtrp), a novel computational method that categorizes protein positions based on the position-specific expected range of mutational impacts: Neutral (weak/no effects), Rheostat (function-tuning positions), or Toggle (on/off switches). We show that position types do not correlate strongly with familiar protein features such as conservation or protein disorder. We also find that position type distribution varies across different protein functions. Finally, we demonstrate that position types reflect experimentally determined functional effects and can thus improve performance of existing variant effect predictors and suggest a way forward for the development of new ones.
Genome-wide ancestry and introgression in a Zambian baboon hybrid zone
Authors: Chiou Kenneth L , Bergey Christina M , Burrell Andrew S , Disotell Todd R , Rogers Jeffrey , Jolly Clifford J , Phillips-Conroy Jane E
Published: March 2019

Hybridization in nature offers unique insights into the process of natural selection in incipient species and their hybrids. In order to evaluate the patterns and targets of selection, we examine a recently discovered baboon hybrid zone in the Kafue River valley of Zambia, where Kinda baboons (Papio kindae) and gray-footed chacma baboons (P. ursinus griseipes) coexist with hybridization. We genotyped baboons at 14,962 variable genome-wide autosomal markers using double-digest RADseq. We compare ancestry patterns from this genome-wide dataset to previously reported ancestry from mitochondrial-DNA and Y-chromosome sources. We also fit a Bayesian genomic cline model to scan for genes with extreme patterns of introgression. We show that the Kinda baboon Y chromosome has penetrated the species boundary to a greater extent than either mitochondrial DNA or the autosomal chromosomes. We also find evidence for overall restricted introgression in the JAK/STAT signaling pathway. Echoing results in other species including humans, we find evidence for enhanced and/or directional introgression of immune-related genes or pathways including the toll-like receptor pathway, the blood coagulation pathway, and the LY96 gene. Finally we show enhanced introgression and excess chacma baboon ancestry in the sperm tail gene ODF2. Together, our results elucidate the dynamics of introgressive hybridization in a primate system while highlighting genes and pathways under selection.
Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex
Authors: Dickinson Abigail , Varcin Kandice J. , Sahin Mustafa , Nelson Charles A. , Jeste Shafali S.
Published: March 2019

Lay Abstract

Around half of infants with tuberous sclerosis complex (TSC) develop autism. Here, using EEG, we find that there is a reduction in communication between brain regions during infancy in TSC, and that the infants who show the largest reductions are those who later develop autism. Being able to identify infants who show early signs of disrupted brain development may improve the timing of early prediction and interventions in TSC, and also help us to understand how early brain changes lead to autism.

Tuberous sclerosis complex (TSC) is a rare genetic disorder that confers a high risk for autism spectrum disorders (ASD), with behavioral predictors of ASD emerging early in life. Deviations in structural and functional neuronal connectivity are highly implicated in both TSC and ASD.

For the first time, we explore whether electroencephalographic (EEG) measures of network function precede or predict the emergence of ASD in TSC. We determine whether altered brain function (1) is present in infancy in TSC, (2) differentiates infants with TSC based on ASD diagnostic status, and (3) is associated with later cognitive function.

We studied 35 infants with TSC (N=35), and a group of typically developing infants (n=20) at 12 and 24 months of age. Infants with TSC were later subdivided into ASD and non-ASD groups based on clinical evaluation. We measured features of spontaneous alpha oscillations (6-12Hz) that are closely associated with neural network development: alpha power, alpha phase coherence (APC) and peak alpha frequency (PAF).

Infants with TSC demonstrated reduced interhemispheric APC compared to controls at 12 months of age, and these differences were found to be most pronounced at 24 months in the infants who later developed ASD. Across all infants, PAF at 24 months was associated with verbal and non-verbal cognition at 36 months.

Associations between early network function and later neurodevelopmental and cognitive outcomes highlight the potential utility of early scalable EEG markers to identify infants with TSC requiring additional targeted intervention initiated very early in life.
Rapid light-dependent degradation of fluorescent dyes in formulated serum-free media
Authors: Morawski Peter A. , Motley Samantha J. , Campbell Daniel J.
Published: March 2019

Chemically defined serum-free media is increasingly used as a tool to help standardize experiments by eliminating the potential variability contributed by pooled serum. These media are formulated for the culture and expansion of specific cell types, maintaining cell viability without the need for exogenous animal proteins. Formulated serum-free media could thus help improve viability and reduce variability during sample preparation for flow cytometry, yet a thorough analysis of how such media impact fluorochrome-antibody conjugates has not been performed. In this study, we expose fluorescent antibody-labeled cells or antibody capture beads to white light in the presence of various hematopoietic cell culture media and provide evidence that formulated serum-free media permit rapid light-initiated fluorescent dye degradation in a cell-independent manner. We observed fluorescence signal loss of several dyes, which included fluorescence spillover into adjacent detectors. Finally, photostability of antibody-fluorochrome conjugates in formulated serum-free media is partially restored in the presence of either serum or vitamin C, implicating reactive oxygen species in the observed signal loss. Thus, our data indicate that formulated serum-free media designed to standardize cell culture are not currently optimized for use with fluorochrome-antibody conjugates, and thus extreme caution should be exercised when using these media in cytometric experiments.
Analysis of patient derived xenograft studies in Oncology drug development: impact on design and interpretation of future studies
Authors: Dickinson Jake , de Matas Marcel , Dickinson Paul A , Mistry Hitesh
Published: March 2019

Background

Preclinical Oncology drug development is heavily reliant on xenograft studies to assess the anti-tumour effect of new compounds. Patient derived xenograft (PDX) have become popular as they may better represent the clinical disease, however variability is greater than in cell-line derived xenografts. The typical approach of analysing these studies involves performing an un-paired t-test on the mean tumour volumes between the treated and control group at the end of the study. This approach ignores the time-series and may result in false conclusions, especially when considering the increased variability of PDX studies.

Aim

To test the hypothesis that a model-based analysis provides increased power than analysis of final day volumes and to provide insights into more efficient PDX study designs.

Methods

Data was extracted from tumour xenograft time-series data from a large publicly available PDX drug treatment database released by Novartis. For all 2-arm studies the percent tumour growth inhibition (TGI) at two time-points, day 10 and day 14 was calculated. For each study, the effect of treatment was calculated using an un-paired t-test and also a model-based analysis using the likelihood ratio-test. In addition a simulation study was also performed to assess the difference in power between the two data-analysis approaches for different levels of TGI for PDX or standard cell-line derived xenografts (CDX).

Results

The model-based analysis had greater statistical power than the un-paired t-test approach within the PDX data-set. The model-based approach was able to detect TGI values as low as 25 percent whereas the un-paired t-test approach required at least 50 percent TGI. These findings were confirmed within the simulation study performed which also highlighted that CDX studies require less animals than PDX studies which show the equivalent level of TGI.

Conclusion

The analysis of 59 2-arm PDX studies highlighted that taking a model-based approach gave increased statistical power over simply performing an un-paired t-test on the final study day. Importantly the model-based approach was able to detect smaller size of effect compared to the un-paired t-test approach is which maybe common of such studies. These findings were confirmed within simulated studies which also highlighted the same sample size used for CDX studies would lead to inadequately powered PDX studies. Application of a model-based analysis should allow studies to use less animals and run experiments for a shorter period thus providing effective insight into compound anti-tumour activity
Contribution of private gardens to habitat availability, connectivity and conservation of the common pipistrelle in Paris
Authors: Mimet Anne , Kerbiriou Christian , Simon Laurent , Julien Jean-François , Raymond Richard
Published: March 2019

Urban sprawl is one of the greatest global changes with major negative impacts on biodiversity and human well-being. Recent policies have acknowledged the value of urban green areas in counterbalancing such impacts. These policies aim to increase the ecological value of green areas, making cities more permeable to natural populations. However, they are largely focused on the role and management of public green areas, ignoring the role and potential of private green areas for urban ecological value.

This study aims to evaluate the benefits of considering private green areas for conservation efforts in cities. Using data on bat activity and information on vegetation and building height, we quantify the respective role of public and private green areas in habitat availability and connectivity for the common pipistrelle in the city of Paris, France. Our results show that despite the low proportion of private green areas in Paris (36% of the total green areas), they still contributed up to 47.9% of bat habitat availability and decrease the resistance of the city matrix by 88%. The distribution in the city matrix and vegetation composition of those areas appeared especially beneficial for bat habitat availability and connectivity. The study demonstrates the importance of private green areas in the ecological value of cities in complementing the role of public green areas. Our results confirm the need to develop more inclusive urban conservation strategies that include both public and private stakeholders.

Highlights

The urban ecological value of private gardens outweighs that of public gardens

This is true for both habitat availability and connectivity

Biodiversity policies in cities should also focus on private green areas

Inclusive conservation strategies are also needed in cities
Lithium treatment reverses irradiation-induced changes in rodent neural progenitors
Authors: Giulia Zanni , Shinobu Goto , Giulia Gaudenzi , Vinogran Naidoo , Gabriel Levy , Elena Di Martino , Olga Dethlefsen , Angel Cedazo-Minguez , Paula Merino-Serrais , Ola Hermanson , Klas Blomgren
Published: March 2019

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context, and we previously showed that voluntary running introduced long after irradiation rescued hippocampal neurogenesis in young mice (Naylor et al. 2008a). Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as anti-tumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation, analogous to the voluntary running study. Female mice received a single 4 Gy whole-brain irradiation dose at postnatal day (PND) 21 and were randomized to 0.24% Li2CO3chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed at PND 77, 91 and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors and promoted neuronal integration upon its discontinuation. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with proliferation, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced impairment of hippocampal neurogenesis even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.
The complete, functional and dynamic cycle of the bacterial Initiation Factor 3
Authors: Nakamoto Jose A. , Spurio Roberto , Konevega Andrey L. , Fabbretti Attilio , Milón Pohl
Published: March 2019

Initiation factor 3 (IF3) is an essential protein that enhances the fidelity and speed of bacterial initiation of mRNA translation. The dynamic interplay between the two independent IF3 domains, their alternative binding sites, and the mechanism that ensures translation initiation fidelity remains elusive. Here, we show that the functional positioning of IF3 domains occurs at velocities ranging over two orders of magnitude, driven by each 30S initiation ligand. IF1 and IF2 rapidly promote the accommodation of IF3 on the 30S platform with the C-terminal domain moving towards the P site. Reversion of this movement is triggered by decoding the mRNA start codon and rate limits translation initiation. Binding of the tRNA results in the concomitant accommodation of the N-terminal domain of IF3, largely dependent on the mRNA and initiator tRNA. 70S initiation complex formation promotes the closing and dissociation of IF3, recycling the factor for a new round of translation initiation. Altogether our results unveil the kinetic spectrum of IF3 conformations and highlight fundamental movements of the factor that ensure accurate translation initiation.
The multicellular incoherent feedforward loop motif generates spatial patterns
Authors: Rodríguez Regueira Marcos , García Jesús Daza , Rodríguez-Patón Aradas Alfonso
Published: March 2019

The multicellular incoherent feedforward loop (mIFFL) is an extension of the traditional intracellular IFFL gene motif where the interacting nodes no longer need to be genes inside the same cell but can be spatially distributed in different cells. We studied for the first time the spatial computing abilities of these mIFFL through in silico simulations done with individual-based models (run in Morpheus and GRO software). We observed that: 1) a genetic circuit working as a mIFFL can behaves as an edge detector of the border of an infection, and 2) a mIFFL can be the inner mechanism generating the complex 7 stripe pattern of eve in D. melanogaster embryogenesis. So, in this work, we show that multicellular IFFL architectures can produce spatial patterns and are a promising spatial computing motif that deserves to be incorporated into the toolbox of pattern generation and multicellular coordination mechanisms. This study opens several future lines of research: multi-agent IFFL applied in ecology as a tool to predict spatial position of interacting animals or in distributed robotics.
The speed of human social interaction perception
Authors: Isik Leyla , Mynick Anna , Pantazis Dimitrios , Kanwisher Nancy
Published: March 2019

The ability to detect and understand other people’s social interactions is a fundamental part of the human visual experience that develops early in infancy and is shared with other primates. However, the neural computations underlying this ability remain largely unknown. Is the detection of social interactions a rapid perceptual process, or a slower post-perceptual inference? Here we used magnetoencephalography (MEG) decoding and computational modeling to ask whether social interactions can be detected via fast, feedforward processing. Subjects in the MEG viewed snapshots of visually matched real-world scenes containing a pair of people who were either engaged in a social interaction or acting independently. The presence versus absence of a social interaction could be read out from subjects’ MEG data spontaneously, even while subjects performed an orthogonal task. This readout generalized across different scenes, revealing abstract representations of social interactions in the human brain. These representations, however, did not come online until quite late, at 300 ms after image onset, well after the time period of feedforward visual processes. In a second experiment, we found that social interaction readout occurred at this same latency even when subjects performed an explicit task detecting social interactions. Consistent with these latency results, a standard feedforward deep neural network did not contain an abstract representation of social interactions at any model layer. We further showed that MEG responses distinguished between different types of social interactions (mutual gaze vs joint attention) even later, around 500 ms after image onset. Taken together, these results suggest that the human brain spontaneously extracts the presence and type of others’ social interactions, but does so slowly, likely relying on iterative top-down computations.
Eye in a Disk: eyeIntegration human pan-eye and body transcriptome database version 1.0
Authors: Swamy Vinay , McGaughey David
Published: March 2019

PURPOSE

To develop an accessible and reliable RNA-seq transcriptome database of healthy human eye tissues and a matching reactive web application to query gene expression in eye and body tissues. METHODS: We downloaded the raw sequnce data for 1375 RNA-seq samples across 54 tissues in the GTEx project as a non-eye reference set.

We then queried several public repositories to find all healthy, non-perturbed, human eye-related tissue RNA-seq samples. The 916 eye and 1375 GTEx samples were sent into a Snakemake-based reproducible pipeline we wrote to quantify all known transcripts and genes, removes samples with poor sequence quality and mislabels, normalizes expression values across each tissue, performs 882 differential expression tests, calculates GO term enrichment, and outputs all as a single SQLite database file: the Eye in a Disk (EiaD) dataset. Furthermore, we rewrote the web application eyeIntegration (https://eyeIntegration.nei.nih.gov) to display EiaD.

RESULTS

The new eyeIntegration portal provides quick visualization of human eye-related transcriptomes published to date by database version, gene/transcript, 19 eye tissues, and 54 body tissues. As a test of the value of this unified pan-eye dataset, we showed that fetal and organoid retina are highly similar at a pan-transcriptome level but display distinct differences in certain pathways and gene families like protocadherin and HOXB family members.

CONCLUSION

The eyeIntegration v1.0 web app serves the pan-human eye and body transcriptome dataset, EiaD. This offers the eye community a powerful and quick means to test hypotheses on human gene and transcript expression across 54 body and 19 eye tissues.
Constitutive differences in glucocorticoid responsiveness are related to divergent spatial information processing abilities
Authors: Huzard Damien , Vouros Avgoustinos , Monari Silvia , Astori Simone , Vasilaki Eleni , Sandi Carmen
Published: March 2019

The stress response facilitates survival through adaptation and is intimately related to cognitive processes. The Morris water maze task probes spatial learning and memory in rodents and glucocorticoids (i.e. corticosterone in rats) have been suggested to elicit a facilitating action on memory formation. Moreover, the early aging period (around 16-18 months of age) is susceptible to stress- and glucocorticoid-mediated acceleration of cognitive decline. In this study, we tested three lines of rats selectively bred according to their individual differences in corticosterone responsiveness to repeated stress exposure during juvenility. We investigated whether endogenous differences in glucocorticoid responses influenced spatial learning, long-term memory and reversal learning abilities in a Morris water maze task at early aging. Additionally, we assessed the quality of the different swimming strategies of the rats. Our results indicate that rats with differential corticosterone responsiveness exhibit similar spatial learning abilities but different long-term memory retention and reversal learning. Specifically, the high corticosterone responding line had a better long-term spatial memory, while the low corticosterone responding line was impaired for both long-term retention and reversal learning. Our modeling analysis of performance strategies revealed further important line-related differences. Therefore, our findings support the view that individuals with high corticosterone responsiveness would form stronger long-term memories to navigate in stressful environments. Conversely, individuals with low corticosterone responsiveness would be impaired at different phases of spatial learning and memory.
How phenotypic convergence arises in experimental evolution
Authors: Simões Pedro , Fragata Inês , Santos Josiane , Santos Marta A. , Santos Mauro , Rose Michael R. , Matos Margarida
Published: March 2019

Evolutionary convergence is a core issue in the study of adaptive evolution, as well as a highly debated topic at present. Few studies have analyzed this issue using a “real-time” or evolutionary trajectory approach. Do populations that are initially differentiated converge to a similar adaptive state when experiencing a common novel environment?Drosophila subobscurapopulations founded from different locations and years showed initial differences and variation in evolutionary rates in several traits during short-term (∼20 generations) laboratory adaptation. Here we extend that analysis to 40 more generations to analyze (1) how differences in evolutionary dynamics between populations change between shorter and longer time spans, and (2) whether evolutionary convergence occurs after sixty generations of evolution in a common environment. We found substantial variation in longer-term evolutionary trajectories and differences between short and longer-term evolutionary dynamics. Though we observed pervasive patterns of convergence towards the character values of long-established populations, populations still remain differentiated for several traits at the final generations analyzed. This pattern might involve transient divergence, as we report in some cases, indicating that more generations should lead to final convergence. These findings highlight the importance of longer-term studies for understanding convergent evolution.
Pupillometry as an objective measure of sustained attention in young and older listeners
Authors: Zhao Sijia , Bury Gabriela , Milne Alice , Chait Maria
Published: March 2019

The ability to sustain attention on a task-relevant sound-source whilst avoiding distraction from other concurrent sounds is fundamental to listening in crowded environments. To isolate this aspect of hearing we designed a paradigm that continuously measured behavioural and pupillometry responses during 25-second-long trials in young (18-35 yo) and older (63-79 yo) participants. The auditory stimuli consisted of a number (1, 2 or 3) of concurrent, spectrally distinct tone streams. On each trial, participants detected brief silent gaps in one of the streams whilst resisting distraction from the others. Behavioural performance demonstrated increasing difficulty with time-on-task and with number/proximity of distractor streams. In young listeners (N=20), pupillometry revealed that pupil diameter (on the group and individual level) was dynamically modulated by instantaneous task difficulty such that periods where behavioural performance revealed a strain on sustained attention, were also accompanied by increased pupil diameter. Only trials on which participants performed successfully were included in the pupillometry analysis. Therefore, the observed effects reflect consequences of task demands as opposed to failure to attend.

In line with existing reports, we observed global changes to pupil dynamics in the older group, including decreased pupil diameter, a limited dilation range, and reduced temporal variability. However, despite these changes, the older group showed similar effects of attentive tracking to those observed in the younger listeners. Overall, our results demonstrate that pupillometry can be a reliable and time-sensitive measure of the effort associated with attentive tracking over long durations in both young and (with some caveats) older listeners.
Identification of a novel gammaherpesvirus in Canada lynx (Lynx canadensis)
Authors: Hendrikse Liam D. , Kambli Ankita , Kayko Caroline , Canuti Marta , Rodrigues Bruce , Stevens Brian , Vashon Jennifer , Lang Andrew S. , Needle David B. , Troyer Ryan M.
Published: March 2019

Gammaherpesviruses (GHVs) infect many animal species and are associated with lymphoproliferative disorders in some. Previously, we identified several novel GHVs in North American felids, however a GHV had never been identified in Canada lynx (Lynx canadensis). We therefore hypothesized the existence of an unidentified GHV in lynx. Using degenerate nested and subsequently virus-specific PCR, we amplified and sequenced 3.4 kb of DNA from a novel GHV in lynx, which we namedLynx canadensisgammaherpesvirus 1 (LcaGHV1). We then estimated the prevalence of LcaGHV1 in lynx by developing a PCR-based assay and detected LcaGHV1 DNA in 36% (95% CI: 22-53%) of lynx spleen DNA samples from Maine, USA and 17% (95% CI: 8-31%) from Newfoundland, Canada. Phylogenetic analysis determined that LcaGHV1 is a distinct GHV species belonging to the genusPercavirus. The potential ecologic and pathologic consequences of this novel virus for Canada lynx populations warrant further study.
Phase-specific manipulation of neural oscillatory activity by transcranial alternating current stimulation
Authors: Fiene Marina , Schwab Bettina C. , Misselhorn Jonas , Herrmann Christoph S. , Schneider Till R. , Engel Andreas K.
Published: March 2019

Background

Oscillatory phase has been proposed as a key parameter defining the spatiotemporal structure of neural activity. To enhance our understanding of brain rhythms and improve clinical outcomes in pathological conditions, phase-specific modulation of oscillations by transcranial alternating current stimulation (tACS) emerged as a promising approach. However, the effectiveness of tACS in humans is still critically debated.

Objective

Here, we investigated the phase-specificity of tACS effects on visually evoked steady state responses (SSRs) in 24 healthy human participants of either sex.

Methods

To this end, we used an intermittent electrical stimulation protocol and assessed the influence of tACS on SSR amplitude in the interval immediately following tACS.

Results

We observed that the phase shift between flicker and tACS modulates evoked SSR amplitudes. The tACS effect size was dependent on the strength of flicker-evoked oscillatory activity, with larger effects in participants showing weaker locking of neural responses to flicker phase. Neural sources of phase-specific effects were localized in the parieto-occipital cortex within flicker-entrained regions. Importantly, the optimal phase shift between flicker and tACS associated with strongest SSRs was correlated with cortical SSR onset delays over the visual cortex.

Conclusions

Overall, our data provide electrophysiological evidence for phase-specific modulations of oscillatory activity by tACS in humans. As the optimal timing of tACS application was dependent on neural conduction times as measured by SSR onset delays, data suggest that the interaction between tACS effect and SSR was cortical in nature. These findings corroborate the physiological efficacy of tACS and highlight its potential for controlled modulations of brain signals.
A Musashi-Related Protein is Essential for Gametogenesis in Arabidopsis
Authors: Moody Laura A. , Rabbinowitsch Ester , Dickinson Hugh G. , Clayton Roxaana , Emms David M. , Langdale Jane A.
Published: March 2019

Musashi (Msi) proteins are an evolutionarily conserved group of RNA-binding proteins, required for targeted control of mRNA translation during many important developmental processes in animals. Most notably, Msi proteins play important roles during both spermatogenesis and oogenesis. Msi proteins also exist in plants but these are largely uncharacterized. Here we report the functional characterization of an Arabidopsis Msi orthologABORTED GAMETOPHYTE 2(AOG2), which encodes a protein containing two RNA recognition motifs and an ER-targeting signal. AOG2-GFP translational fusions were localized to the ER in transient assays, suggesting that AOG2 most likely binds to ER-targeted mRNAs. We show that disruptedAOG2function leads to a high rate of both ovule and seed abortion, and that homozygous loss of function mutants are embryo lethal. Furthermore, we demonstrate thatAOG2is required to establish asymmetry during pollen mitosis I, and that loss ofAOG2function leads to loss of pollen viability. Collectively the results reveal that AOG2 is required for the establishment of polarity and/or the progression of mitosis during gametophyte development in Arabidopsis, and thus Msi-related proteins have an evolutionarily conserved role in gametogenesis in both animals and plants.

SIGNIFICANCE STATEMENT

ABORTED GAMETOPHYTE 2(AOG2) encodes a Musashi-related RNA-binding protein that is required for gametogenesis and embryogenesis in Arabidopsis.AOG2is required for the establishment of polarity and/or the progression of mitosis during gametophyte development in Arabidopsis, and thus Musashi-related proteins have an evolutionarily conserved role in gametogenesis in both animals and plants.
LSO:Ce Inorganic Scintillators are Biocompatible with Neuronal and Circuit Function
Authors: Bartley Aundrea F. , Abiraman Kavitha , Stewart Luke T. , Hossain Mohammed Iqbal , Gahan David M , Kamath Abhishek V. , Burdette Mary K. , Andrabe Shaida , Foulger Stephen H. , McMahon Lori L. , Dobrunz Lynn E.
Published: March 2019

Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or UV stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 μm LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acutely prepared hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs), indicating UV activation of ChR2 and excitation of neurons. Importantly, we found that LSO:Ce particles have no effect on survival of primary mouse cortical neurons, even after 24 hours of exposure. In extracellular dendritic field potential recordings, we observed no change in strength of basal glutamatergic transmission up to 3 hours of exposure to LSO:Ce microparticles. However, there was a slight decrease in the frequency of spontaneous EPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. No changes in the amplitude or frequency of spontaneous inhibitory postsynaptic currents (IPSCs) were observed. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.
Transverse sinus injections: A novel method for whole-brain vector-driven gene delivery
Authors: Hamodi Ali S. , Sabino Aude Martinez , Fitzgerald N. Dalton , Crair Michael C.
Published: March 2019

A major challenge in neuroscience is convenient whole-brain delivery of transgenes, especially early in postnatal development. Recent advances demonstrate whole-brain gene delivery by retro-orbital injection of virus, but slow and sparse expression, and the large injection volumes required, precludes early developmental studies. We developed a novel method for simple, fast and efficient gene delivery across the central nervous system in neonates as early as P4 and persisting into adulthood. The method employs transverse sinus injections of 2-4μL of AAV9 at P0. Here, we describe how to use this method to label and/or genetically manipulate cells in the neonatal rat and mouse brain. This protocol is fast, easy, can be readily adopted by any laboratory, and utilizes the widely available AAV9 capsid. The procedure outlined here is adaptable for diverse experimental applications ranging from biochemistry, anatomical and functional mapping, to gene expression, silencing, and editing.
Systematic and comprehensive benchmarking of an exome sequencing based germline copy-number analysis pipeline to detect clinically relevant CNVs
Authors: Rajagopalan Ramakrishnan , Murrell Jill , Luo Minjie , Conlin Laura K.
Published: March 2019

Purpose

Detecting germline copy-number variants (CNVs) from exome sequencing (ES) is not a standard practice in clinical settings owing to several reasons concerning performance. We comprehensively characterized an ES-based CNV pipeline and developed frameworks for minimizing false-positives and assess the reproducibility.

Methods

We used a cohort of 387 individuals with both clinical chromosomal microarray (CMA) and ES data available to estimate the initial performance by comparing CNVs from both platforms. A modification of the default workflow was performed to reduce the number of false positives and the reproducibility of the CNVs was assessed using an iterative variant calling process.

Results

The default pipeline was 93% sensitive with a high false-discovery rate of 44%. The modified workflow had a higher sensitivity of 96% while reducing the total number of CNVs identified and improving the false-discovery rate to 11.4%. With the modified workflow, we demonstrated a 100% validation rate for the CNVs identified in theSTRC, a challenging gene to ascertain by short-read NGS. The exome-based pipeline was 100% sensitive for clinically-relevant, rare variants (including single exon deletions), and was reproducible.

Conclusion

We demonstrate with our modified workflow and the benchmarking data that an exome-based CNV detection pipeline can be reliably used to detect clinically-relevant CNVs.
Relative Concentration of Brain Iron (rcFe) Derived from Standard Functional MRI
Authors: Colcombe Stan J. , Milham Michael P. , MacKay-Brandt Anna , Franco Alex , Castellanos F. Xavier , Craddock R. Cameron , Cloud Jessica
Published: March 2019

Brain iron plays key roles in catecholaminergic neurotransmitter synthesis and early life brain development. It is also central to cellular energetics and neurotransmitter metabolism throughout the lifespan. Disturbances in brain iron have been implicated in a growing number of psychiatric and late-life neurodegenerative disorders. Additionally, brain iron accumulations are thought to play a deleterious role in neuroinflammatory processes in later life. Despite its importance, the role of brain iron in development, aging, and psychiatric disorders remains comparatively understudied. This is partly due to technical challenges inherent in implementation and analysis of formal iron imaging protocols and practical constraints on scan session durations. Here, we introduce a method to estimate relative brain iron concentrations that is 1) computationally simple, 2) shows excellent correspondence with formal iron imaging in-vivo, 3) replicates clinically-relevant findings from formal iron imaging, 4) yields novel insights into brain iron and cognition across the lifespan, and 5) leverages a widely available and frequently shared brain imaging modality: functional MRI. The computationally simple nature of the measure, coupled with the availability of fMRI datasets across the lifespan and disorders, has the potential to transform our understanding of the complex and critical relationship between iron and brain health.