bluuebunny/crossref_metadata_2025 huggingface dataset:
Dense cortical input to the rostromedial tegmental nucleus mediates aversive signaling
Authors: Glover Elizabeth J , Starr E Margaret , Gascon Andres , Clayton-Stiglbauer Kacey , Amegashie Christen L , Selchick Alyson H , Vaughan Dylan T , Wayman Wesley N , Woodward John J , Chandler L Judson
Published: September 2021

Abstract

The rostromedial tegmental nucleus (RMTg) encodes negative reward prediction error (RPE) and plays an important role in guiding behavioral responding to aversive stimuli. While initial studies describing the RMTg revealed the presence of cortical afferents, the density and distribution of this input has not been explored in detail. In addition, the functional consequences of cortical modulation of RMTg signaling are only just beginning to be investigated. The current study anatomically and functionally characterizes cortical input to the RMTg in rats. Findings from this work reveal dense input spanning the entire medial prefrontal cortex (PFC) as well as the orbitofrontal cortex and anterior insular cortex. Afferents were most dense in the dorsomedial subregion of the PFC (dmPFC), an area which has also been implicated in both RPE signaling and aversive responding. RMTg-projecting dmPFC neurons originate in layer V and collateralize extensively throughout the brain. In-situ mRNA hybridization further revealed that neurons in this circuit are predominantly D1 receptor-expressing with a high degree of D2 receptor colocalization. Optogenetic stimulation of dmPFC terminals in the RMTg drives avoidance, and cFos expression is enhanced in this neural circuit during exposure to aversive stimuli. Exposure to such aversive stimuli results in significant physiological and structural plasticity suggestive of a loss of top-down modulation of RMTg-mediated signaling. Altogether, these data reveal the presence of a prominent cortico-subcortical projection involved in adaptive behavioral responding and provide a foundation for future work aimed at exploring alterations in circuit function in diseases characterized by deficits in cognitive control over the balance between reward and aversion.
A well conserved archaeal B-family polymerase functions as a mismatch and lesion extender
Authors: Feng Xu , Zhang Baochang , Gao Zhe , Xu Ruyi , Liu Xiaotong , Ishino Sonoko , Feng Mingxia , Shen Yulong , Ishino Yoshizumi , She Qunxin
Published: September 2021

B-family DNA polymerases (PolBs) of different groups are widespread in Archaea and different PolBs often coexist in the same organism. Many of these PolB enzymes remain to be investigated. One of the main groups that are poorly characterized is PolB2 whose members occur in many archaea but are predicted as an inactivated form of DNA polymerase. Herein,Sulfolobus islandicusDNA polymerase 2 (Dpo2), a PolB2 enzyme was expressed in its native host and purified. Characterization of the purified enzyme revealed that the polymerase harbors a robust nucleotide incorporation activity, but devoid of the 3’-5’ exonuclease activity. Enzyme kinetics analyses showed that Dpo2 replicates undamaged DNA templates with high fidelity, which is consistent with its inefficient nucleotide insertion activity opposite different DNA lesions. Strikingly, the polymerase is highly efficient in extending mismatches and mispaired primer termini once a nucleotide is placed opposite a damaged site. Together, these data suggested Dpo2 functions as a mismatch and lesion extender, representing a novel type of PolB that is primarily involved in DNA damage repair in Archaea. Insights were also gained into the functional adaptation of the motif C in the mismatch extension of the B-family DNA polymerases.
Genomic estimation of quantitative genetic parameters in wild admixed populations
Authors: Aase Kenneth , Jensen Henrik , Muff Stefanie
Published: September 2021

Heritable genetic variation among free-living animals or plants is essential for populations to respond to selection and adapt. It is therefore important to be able to estimate additive genetic variance VA, which can be obtained using a generalized linear mixed model known as the animal model. An underlying assumption of the standard animal model is that the study population is genetically unstructured, which is often unrealistic. In fact, admixture might be the norm rather than the exception in the wild, like in geographically structured populations, in the presence of (im)migration, or in re-introduction and conservation contexts. Unfortunately, animal model estimators may be biased in such cases. So-called genetic group animal models that account for genetically differentiated subpopulations have recently become popular, but methodology is currently only available for cases where relatedness among individuals can be estimated from pedigrees.

To ensure that genetic group animal models with heterogeneous VA remain applicable to populations with genomic data but no pedigrees, there is a clear need to generalize these models to the case when exclusively genomic data is available. We therefore introduce such methodology for wild admixed systems by extending methods that were recently suggested in the context of plant breeding. Our extension relaxes the limiting assumptions that currently restrict their use to artificial breeding setups.

We illustrate the usefulness of the extended genomic genetic groups animal model on a wild admixed population of house sparrows resident in an island system in Northern Norway, where genome-wide data on more than 180 000 single nucleotide polymorphisms (SNPs) is available to derive genomic relatedness. We compare our estimates of quantitative genetic parameters to those derived from a corresponding pedigree-based genetic groups animal model. The satisfactory agreement indicates that the new method works as expected.

Our extension of the very popular animal model ensures that the upcoming challenges with increasing availability of genomic data for quantitative genetic studies of wild admixed populations can be handled. To make the method widely available to the scientific community, we offer guidance in the form of a tutorial including step-by-step instructions to facilitate implementation.
MetaCoAG: Binning Metagenomic Contigs via Composition, Coverage and Assembly Graphs
Authors: Mallawaarachchi Vijini , Lin Yu
Published: September 2021

Metagenomics binning has allowed us to study and characterize various genetic material of different species and gain insights into microbial communities. While existing binning tools bin metagenomics de novo assemblies, they do not make use of the assembly graphs that produce such assemblies. Here we propose MetaCoAG, a tool that utilizes assembly graphs with the composition and coverage information to bin metagenomic contigs. MetaCoAG uses single-copy marker genes to estimate the number of initial bins, assigns contigs into bins iteratively and adjusts the number of bins dynamically throughout the binning process. Experimental results on simulated and real datasets demonstrate that MetaCoAG significantly outperforms state-of-the-art binning tools, producing more high-quality bins than the second-best tool, with an average median F1-score of 88.40%. To the best of our knowledge, MetaCoAG is the first stand-alone binning tool to make direct use of the assembly graph information. MetaCoAG is available at https://github.com/Vini2/MetaCoAG.
Optimal strategies to protect a sub-population at risk due to an established epidemic
Authors: Bussell Elliott H. , Cunniffe Nik J.
Published: September 2021

Epidemics can particularly threaten certain sub-populations. For example, for SARS-CoV-2, the elderly are often preferentially protected. For diseases of plants and animals, certain sub-populations can drive mitigation because they are intrinsically more valuable for ecological, economic, socio-cultural or political reasons. Here we use optimal control theory to identify strategies to optimally protect a “high value” sub-population when there is a limited budget and epidemiological uncertainty. We use protection of the Redwood National Park in California in the face of the large ongoing state-wide epidemic of sudden oak death (caused by Phytophthora ramorum) as a case study. We concentrate on whether control should be focused entirely within the National Park itself, or whether treatment of the growing epidemic in the surrounding “buffer region” can instead be more profitable. We find that, depending on rates of infection and the size of the ongoing epidemic, focusing control on the high value region is often optimal. However, priority should sometimes switch from the buffer region to the high value region only as the local outbreak grows. We characterise how the timing of any switch depends on epidemiological and logistic parameters, and test robustness to systematic misspecification of these factors due to imperfect prior knowledge.
Horizontal connectivity in V1 : Prediction of coherence in contour and motion integration
Authors: Le Bec Benoit , Troncoso Xoana G. , Desbois Christophe , Passarelli Yannick , Baudot Pierre , Monier Cyril , Pananceau Marc , Frégnac Yves
Published: September 2021

This study demonstrates the functional importance of the Surround context relayed laterally in V1 by the horizontal connectivity, in controlling the latency and the gain of the cortical response to the feedforward visual drive. We report here four main findings : 1) a centripetal apparent motion sequence results in a shortening of the spiking latency of V1 cells, when the orientation of the local inducer and the global motion axis are both co-aligned with the RF orientation preference; 2) this contextual effects grows with visual flow speed, peaking at 150-250°/s when it matches the propagation speed of horizontal connectivity (0.15-0.25 mm/ms); 3) For this speed range, the axial sensitivity of V1 cells is tilted by 90° to become co-aligned with the orientation preference axis; 4) the strength of modulation by the surround context correlates with the spatiotemporal coherence of the apparent motion flow. Our results suggest an internally-generated binding process, linking local (orientation /position) and global (motion/direction) features as early as V1. This long-range diffusion process constitutes a plausible substrate in V1 of the human psychophysical bias in speed estimation for collinear motion. Since it is demonstrated in the anesthetized cat, this novel form of contextual control of the cortical gain and phase is a built-in property in V1, whose expression does not require behavioral attention and top-down control from higher cortical areas. We propose that horizontal connectivity participates in the propagation of an internal “prediction” wave, shaped by visual experience, which links contour co-alignment and global axial motion at an apparent speed in the range of saccade-like eye-movements.
Clonal evolution and specificity of the human T follicular helper cell response toPlasmodium falciparumcircumsporozoite protein
Authors: Wahl Ilka , Obraztsova Anna , Puchan Julia , Hundsdorfer Rebecca , Chakravarty Sumana , Lee Sim B. Kim , Hoffman Stephen L. , Kremsner Peter G. , Mordmüller Benjamin , Wardemann Hedda
Published: September 2021

T follicular helper (TFH) cells play a crucial role in the development of long-lived, quality-improved B cell responses after infection and vaccination. However, little is known about their clonal evolution. Here we assessed the cell phenotype, clonal dynamics, and TCR specificity of human circulating TFH(cTFH) cells at monoclonal level during successive malaria immunizations with radiation-attenuatedPlasmodium falciparum(Pf) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cTFHresponse with high frequency of cells specific to thePfcircumsporozoite protein (PfCSP), the main surface protein of sporozoites and a validated vaccine target. Repeated immunizations were required to induce detectable PfCSP-reactive cTFHcell responses to a small number of epitopes. HLA-restrictions and differences in TCR generation probability explain the high targeting frequency of the polymorphic Th2R/T* region over the conserved T1 epitope. The vast majority of anti-Th2R/T* TCRs failed to tolerate natural polymorphisms in their target peptide sequence suggesting that parasite diversity limits natural boosting of the cTFHcell response in endemic areas and protection from non-vaccine strains. Among convergent anti-Th2R/T* TCRs with high sequence similarity, subtle differences in CDR3 composition discriminated cross-reactive from non-cross-reactive cTFHcells. Thus, our study provides deep molecular and cellular insights into the kinetics, fine specificity and HLA-restrictions of the anti-cTFHcell response that are of direct relevance for the design of PfCSP-based malaria vaccines by guiding the selection of PfCSP peptides that induce optimal B cell help.
Protein-lipid interaction at low pH induces oligomerisation of the MakA cytotoxin from Vibrio cholerae
Authors: Nadeem Aftab , Berg Alexandra , Pace Hudson , Alam Athar , Toh Eric , Ådén Jörgen , Zlatkov Nikola , Myint Si Lhyam , Persson Karina , Gröbner Gerhard , Sjöstedt Anders , Bally Marta , Barandun Jonas , Uhlin Bernt Eric , Wai Sun Nyunt
Published: September 2021

Many pathogenic bacteria produce protein toxins that target and perturb host cell membranes. The secreted α-pore-forming toxins (α-PFTs) cause membrane damage via pore formation. This study demonstrates a remarkable, hitherto unknown mechanism by an α-PFT protein from Vibrio cholerae. As part of the MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA protein alone induces tube-like structures in the acidic lysosomal host cell compartment. In vitro studies unravel the dynamics of tubular growth, which occur in a pH-, lipid- and concentration-dependent manner. A 3.7-Å cryo-electron microscopy structure of MakA filaments reveals a unique protein-lipid superstructure. In its active α-PFT conformation, MakA embeds its transmembrane helices into a thin annular lipid bilayer and spirals around a central cavity. Our study provides molecular insights into a novel tubulation mechanism of an α-PFT protein, revealing a new mode of action by a secreted bacterial toxin.
Kinase activity profiling identifies putative downstream targets of cGMP/PKG signaling in inherited retinal neurodegeneration
Authors: Roy Akanksha , Tolone Arianna , Hilhorst Riet , Groten John , Tomar Tushar , Durand Francois-Paquet
Published: September 2021

Inherited retinal diseases (IRDs) are a group of neurodegenerative disorders that lead to photoreceptor cell death and eventually blindness. IRDs are characterised by a high genetic heterogeneity, making it imperative to design mutation-independent therapies. Mutations in a number of IRD disease genes have been associated with a rise of cyclic 3’,5’-guanosine monophosphate (cGMP) levels in photoreceptors. Accordingly, the cGMP-dependent protein kinase (PKG) has emerged as a new potential target for the mutation-independent treatment of IRDs. However, the substrates of PKG and the downstream degenerative pathways triggered by its activity have yet to be determined. Here, we performed kinome activity profiling of different murine organotypic retinal explant cultures (diseased rd1 and wild-type controls) using multiplex peptide microarrays to identify proteins whose phosphorylation was significantly altered by PKG activity. In addition, we tested the downstream effect of a known PKG inhibitor CN03 in these organotypic retina cultures. Among the PKG substrates were potassium channels belonging to the Kv1 family (KCNA3, KCNA6), Cyclic AMP-responsive element-binding protein 1 (CREB1), DNA topoisomerase 2-α (TOP2A), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (F263), and the glutamate ionotropic receptor kainate 2 (GRIK2). The retinal expression of these PKG targets was further confirmed by immunofluorescence and could be assigned to various neuronal cell types, including photoreceptors, horizontal cells, and ganglion cells. Taken together, this study confirmed the key role of PKG in photoreceptor cell death and identified new downstream targets of cGMP/PKG signalling that will improve the understanding of the degenerative mechanisms underlying IRDs.
clipplotr - a comparative visualisation and analysis tool for CLIP data
Authors: Chakrabarti Anob M. , Capitanchik Charlotte , Ule Jernej , Luscombe Nicholas M.
Published: September 2021

CLIP technologies are now widely used to study RNA-protein interactions and many datasets are now publicly available. An important first step in CLIP data exploration is the visual inspection and assessment of processed genomic data on selected genes or regions and performing comparisons: either across conditions within a particular project, or incorporating publicly available data. However, the output files produced by data processing pipelines or preprocessed files available to download from data repositories are often not suitable for direct comparison and usually need further processing. Furthermore, to derive biological insight it is usually necessary to visualise CLIP signal alongside other data such as annotations, or orthogonal functional genomic data (e.g. RNA-seq). We have developed a simple, but powerful, command-line tool: clipplotr, which facilitates these visual comparative and integrative analyses with normalisation and smoothing options for CLIP data and the ability to show these alongside reference annotation tracks and functional genomic data. These data can be supplied as input to clipplotr in a range of file formats, which will output a publication quality figure. It is written in R and can both run on a laptop computer independently, or be integrated into computational workflows on a high-performance cluster. Releases, source code and documentation are freely available at: https://github.com/ulelab/clipplotr.
Making Plants Smell Like Moths:Nicotiana benthamianarelease moth pheromone alcohol, aldehyde and acetate upon transient expression of biosynthetic genes of different origin
Authors: Xia Yi-Han , Ding Bao-Jian , Dong Shuang-Lin , Wang Hong-Lei , Hofvander Per , Löfstedt Christer
Published: September 2021

Using genetically modified plants as natural dispensers of insect pheromones may eventually become part of a novel strategy for integrated pest management. In the present study, we first characterized essential functional genes for sex pheromone biosynthesis in the rice stem borerChilo suppressalis(Walker) by heterologous expression inSaccharomyces cerevisiaeandNicotiana benthamiana, including two desaturase genesCsupYPAQandCsupKPSE, and a reductase geneCsupFAR2. Subsequently, we co-expressedCsupYPAQandCsupFAR2together with the previously characterized moth desaturaseAtrΔ11inN. benthamiana. This resulted in the production of (Z)-11-hexadecenol together with (Z)-11-hexadecenal, the major pheromone component ofC. suppressalis. Both compounds were collected from the transformedN. benthamianaheadspace volatiles using solid phase microextraction. We finally added the expression of a yeast acetyltransferase geneATF1and could then confirm also (Z)-11-hexadecenyl acetate release from the plant. Our results pave the way for stable transformation of plants to be used as biological pheromone sources in different pest control strategies.
Working memory performance is tied to stimulus complexity
Authors: Pusch Roland , Packheiser Julian , Azizi Amir Hossein , Sevincik Celil Semih , Rose Jonas , Cheng Sen , Stüttgen Maik C. , Güntürkün Onur
Published: September 2021

1.

Working memory is the cognitive capability to maintain and process information over short periods. Behavioral and computational studies have shown that visual information is associated with working memory performance. However, the underlying neural correlates remain unknown. To identify how visual information affects working memory performance, we conducted behavioral experiments and single unit recordings in the avian prefrontal analog, the nidopallium caudolaterale (NCL). Complex pictures featuring luminance, spatial and color information, were associated with higher working memory performance compared to uniform gray pictures in conjunction with distinct neural coding patterns. For complex pictures, we found a multiplexed neuronal code displaying visual and value-related features that switched to a representation of the upcoming choice during a delay period. When processing gray stimuli, NCL neurons did not multiplex and exclusively represented the choice already during stimulus presentation and throughout the delay period. The prolonged representation possibly resulted in a decay of the memory trace ultimately leading to a decrease in performance. In conclusion, we found that high stimulus complexity is associated with neuronal multiplexing of the working memory representation possibly allowing a facilitated read-out of the neural code resulting in enhancement of working memory performance.
Whole brain mapping of glutamate in adult and old primates at 11.7T
Authors: Garin Clément M. , Nadkarni Nachiket A. , Pépin Jérémy , Flament Julien , Dhenain Marc
Published: September 2021

Glutamate is the amino acid with the highest cerebral concentration. It plays a central role in brain metabolism. It is also the principal excitatory neurotransmitter in the brain and is involved in multiple cognitive functions. Alterations of the glutamatergic system may contribute to the pathophysiology of many neurological disorders. For example, changes of glutamate availability are reported in rodents and humans during Alzheimer’s and Huntington’s diseases, epilepsy as well as during aging.

Most studies evaluating cerebral glutamate have used invasive or spectroscopy approaches focusing on specific brain areas. Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) is a recently developed imaging technique that can map glutamate distribution in the entire brain with higher sensitivity and at higher resolution than previous techniques. It thus has strong potential clinical applications to assess glutamate changes in the brain. High field is a key condition to perform gluCEST images with a meaningful signal to noise ratio. Thus, even if some studies started to evaluate gluCEST in humans, most studies focused on rodent models that can be imaged at high magnetic field.

In particular, systematic characterization of gluCEST contrast distribution throughout the whole brain has never been performed in humans or non-human primates. Here, we characterized for the first time the distribution of the glutamate index in the whole brain and in large-scale networks of mouse lemur primates at 11.7 Tesla. Because of its small size, this primate can be imaged in high magnetic field systems. It is widely studied as a model of cerebral aging or Alzheimer’s disease. We observed high gluCEST contrast in cerebral regions such as the nucleus accumbens, septum, basal forebrain, cortical areas 24 and 25. Age-related alterations of this biomarker were detected in the nucleus accumbens, septum, basal forebrain, globus pallidus, hypophysis, cortical areas 24, 21, 6 and in olfactory bulbs. An age-related gluCEST contrast decrease was also detected in specific neuronal networks, such as fronto-temporal and evaluative limbic networks. These results outline regional differences of gluCEST contrast and strengthen its potential to provide new biomarkers of cerebral function in primates.

Graphical abstract
An in-vivo validation of ESI methods with focal sources
Authors: Pascarella Annalisa , Mikulan Ezequiel , Sciacchitano Federica , Sarasso Simone , Rubino Annalisa , Sartori Ivana , Cardinale Francesco , Zauli Flavia , Avanzini Pietro , Nobili Lino , Pigorini Andrea , Sorrentino Alberto
Published: September 2021

Electrical source imaging (ESI) aims at reconstructing the electrical brain activity from measurements of the electric field on the scalp. Even though the localization of single focal sources should be relatively straightforward, different methods provide diverse solutions due to the different underlying assumptions. Furthermore, their input parameter(s) further affects the solution provided by each method, making localization even more challenging. In addition, validations and comparisons are typically performed either on synthetic data or through post-operative outcomes, in both cases with considerable limitations.

We use an in-vivo high-density EEG dataset recorded during intracranial single pulse electrical stimulation, in which the true sources are substantially dipolar and their locations are known. We compare ten different ESI methods under multiple choices of input parameters, to assess the accuracy of the best reconstruction, as well as the impact of the parameters on the localization performance.

Best reconstructions often fall within 1 cm from the true source, with more accurate methods outperforming less accurate ones by 1 cm, on average. Expectedly, dipolar methods tend to outperform distributed methods. Sensitivity to input parameters varies widely between methods. Depth weighting played no role for three out of six methods implementing it. In terms of regularization parameters, for several distributed methods SNR=1 unexpectedly turned out to be the best choice among the tested ones.

Our data show similar levels of accuracy of ESI techniques when applied to “conventional” (32 channels) and dense (64, 128, 256 channels) EEG recordings.

Overall findings reinforce the importance that ESI may have in the clinical context, especially when applied to identify the surgical target in potential candidates for epilepsy surgery.
Corticothalamic Projections Gate Alpha Rhythms in the Pulvinar
Authors: Cortes Nelson , Farishta Reza Abbas , Ladret Hugo , Casanova Christian
Published: September 2021

Two types of corticothalamic (CT) terminals reach the pulvinar nucleus of the thalamus, and their distribution varies according to the hierarchical level of the cortical area they originate from. While type 2 terminals are more abundant at lower hierarchical levels, terminals from higher cortical areas mostly exhibit type 1 axons. Such terminals also evoke different excitatory postsynaptic potential dynamic profiles, presenting facilitation for type 1 and depression for type 2. As the pulvinar is involved in the oscillatory regulation between intercortical areas, fundamental questions about the role of these different terminal types in the neuronal communication throughout the cortical hierarchy are yielded. Our theoretical results support that the co-action of the two types of terminals produces different oscillatory rhythms in pulvinar neurons. More precisely, terminal types 1 and 2 produce alpha-band oscillations at a specific range of connectivity weights. Such oscillatory activity is generated by an unstable transition of the balanced state network’s properties that it is found between the quiescent state and the stable asynchronous spike response state. While CT projections from areas 17 and 21a are arranged in the model as the empirical proportion of terminals types 1 and 2, the actions of these two cortical connections are antagonistic. As area 17 generates low-band oscillatory activity, cortical area 21a shifts pulvinar responses to stable asynchronous spiking activity and vice-versa when area 17 produces an asynchronous state. To further investigate such oscillatory effects through corticothalamo-cortical projections, the transthalamic pathway, we created a cortical feedforward network of two cortical areas, 17 and 21a, with CT connections to a pulvinar-like network. With this model, the transthalamic pathway propagates alpha waves from the pulvinar to area 21a. This oscillatory transfer ceases when reciprocal connections from area 21a reach the pulvinar, closing the cortico-thalamic loop. Taken together, results of our model suggest that the pulvnar shows a bi-stable spiking activity, oscillatory or regular asynchronous spiking, whose responses are gated by the different activation of cortico-pulvinar projections from lower to higher-order areas such as areas 17 and 21a.
Modelling neural entrainment and its persistence: influence of frequency of stimulation and phase at the stimulus offset
Authors: Otero Mónica , Lea-Carnall Caroline , Prado Pavel , Escobar María-José , El-Deredy Wael
Published: September 2021

The entrainment (synchronization) of brain oscillations to the frequency of sensory stimuli is a key mechanism that shapes perceptual and cognitive processes, such that atypical neural entrainment leads to neuro-psychological deficits.

Objective

We investigated the dynamic of neural entrainment. Particular attention was paid to the oscillatory behavior that succeed the end of the stimulation, since the persistence (reverberation) of neural entrainment may condition future sensory representations based on predictions about stimulus rhythmicity.

Approach

A modified Jansen-Rit neural mass model of coupled cortical columns generated a time series whose frequency spectrum resembled that of the electroencephalogram. We evaluated spectro-temporal features of entrainment, during and after rhythmic stimulation of different frequencies, as a function of the resonance frequency of the neural population and the coupling strength between cortical columns. We tested if the duration of the entrainment persistence depended on the state of the neural network at the time the stimulus ends.

Main Results

The entrainment of the column that received the stimulation was maximum when the frequency of the entrainer was within a narrow range around the resonance frequency of the column. When this occurred, entrainment persisted for several cycles after the stimulus terminated, and the propagation of the entrainment to other columns was facilitated. Propagation depended on the resonance frequency of the second column, and the coupling strength between columns. The duration of the persistence of the entrainment depended on the phase of the neural oscillation at the time the entrainer terminated, such that falling phases (from π/2 to 3π/2 in a sine function) led to longer persistence than rising phases (from 0 to π/2 and 3π/2 to 2π).

Significance

The study bridges between models of neural oscillations and empirical electrophysiology, and provides insights to the use of rhythmic sensory stimulation for neuroenhancement.
Gilda: biomedical entity text normalization with machine-learned disambiguation as a service
Authors: Gyori Benjamin M. , Hoyt Charles Tapley , Steppi Albert
Published: September 2021

Gilda is a software tool and web service which implements a scored string matching algorithm for names and synonyms across entries in biomedical ontologies covering genes, proteins (and their families and complexes), small molecules, biological processes and diseases. Gilda integrates machine-learned disambiguation models to choose between ambiguous strings given relevant surrounding text as context, and supports species-prioritization in case of ambiguity.

Availability

The Gilda web service is available at http://grounding.indra.bio with source code, documentation and tutorials are available via https://github.com/indralab/gilda.

Contact

benjamin_gyori@hms.harvard.edu
Finding a Balance: Characterizing Teaching and Research Anxieties in Biology Graduate Teaching Assistants (GTAs)
Authors: Chen Musgrove Miranda M. , Petrie Kate , Cooley Alyssa , Schussler Elisabeth E.
Published: September 2021

Graduate students in the United States are reporting increased anxiety, affecting their mental health and attrition in graduate programs. Yet we are only beginning to understand what contributes to graduate student anxiety. Biology Graduate Teaching Assistants (GTAs) have simultaneous roles as teachers, researchers, students, and employees, and factors associated with these tasks may contribute to anxieties in graduate school, particularly in relation to teaching and research responsibilities. To explore factors related to GTA teaching and research anxieties, and guided by social cognitive career theory, we interviewed 23 Biology GTAs at a research-intensive southeastern university. Thematic analysis of interview transcripts revealed five major factors related to GTA anxieties: negative impact on self, negative impact on others, lack of self-efficacy, role tension, and personal anxieties. Lack of self-efficacy was most prevalent for research anxieties, compared to teaching anxieties, where the impact on others (e.g. students) was most prevalent. In research contexts, GTAs with academic career aspirations expressed less anxiety about role tensions compared to GTAs with non-academic career goals. By investigating GTA anxieties, this work can inform professional development or mental health interventions for GTAs and encourage greater awareness and dialogue about mental health issues in academia.
Deep-Learning-Based Accelerated and Noise-Suppressed Estimation (DANSE) of quantitative Gradient Recalled Echo (qGRE) MRI metrics associated with Human Brain Neuronal Structure and Hemodynamic Properties
Authors: Kahali Sayan , Kothapalli Satya V.V.N. , Xu Xiaojian , Kamilov Ulugbek S. , Yablonskiy Dmitriy A.
Published: September 2021

Purpose

To introduce a Deep-Learning-Based Accelerated and Noise-Suppressed Estimation (DANSE) method for reconstructing quantitative maps of biological tissue cellular-specific,R2t*and hemodynamic-specific,R2′ from Gradient-Recalled-Echo (GRE) MRI data with multiple gradient-recalled echoes.

Methods

DANSE method adapts supervised learning paradigm to train a convolutional neural network for robust estimation ofR2t*andR2′ maps free from the adverse effects of macroscopic (B0) magnetic field inhomogeneities directly from the GRE magnitude images without utilizing phase images. The corresponding ground-truth maps were generated by means of a voxel-by-voxel fitting of a previously-developed biophysical quantitative GRE (qGRE) model accounting for tissue, hemodynamic andB0-inhomogeneities contributions to GRE signal with multiple gradient echoes using nonlinear least square (NLLS) algorithm.

Results

We show that the DANSE model efficiently estimates the aforementioned brain maps and preserves all features of NLLS approach with significant improvements includingnoise-suppressionandcomputation speed(from many hours to seconds). The noise-suppression feature of DANSE is especially prominent for data with SNR characteristic for typical GRE data (SNR~50), where DANSE-generatedR2t*andR2′ maps had three times smaller errors than that of NLLS method.

Conclusions

DANSE method enables fast reconstruction ofmagnetic-field-inhomogeneity-freeandnoise-suppressedquantitative qGRE brain maps. DANSE method does not require any information about field inhomogeneities during application. It exploits spatial patterns in the qGRE MRI data and previously-gained knowledge from the biophysical model, thus producing clean brain maps even in the environments with high noise levels. These features along with fast computational speed can lead to broad qGRE clinical and research applications.
An integrated view of baseline protein expression in human tissues
Authors: Prakash Ananth , García-Seisdedos David , Wang Shengbo , Kundu Deepti Jaiswal , Collins Andrew , George Nancy , Moreno Pablo , Papatheodorou Irene , Jones Andrew R. , Vizcaíno Juan Antonio
Published: September 2021

The availability of proteomics datasets in the public domain, and in the PRIDE database in particular, has increased dramatically in recent years. This unprecedented large-scale availability of data provides an opportunity for combined analyses of datasets to get organism-wide protein abundance data in a consistent manner. We have reanalysed 24 public proteomics datasets from healthy human individuals, to assess baseline protein abundance in 31 organs. We defined tissue as a distinct functional or structural region within an organ. Overall, the aggregated dataset contains 67 healthy tissues, corresponding to 3,119 mass spectrometry runs covering 498 samples, coming from 489 individuals.

We compared protein abundances between the different organs and studied the distribution of proteins across organs. We also compared the results with data generated in analogous studies. We also performed gene ontology and pathway enrichment analyses to identify organ-specific enriched biological processes and pathways. As a key point, we have integrated the protein abundance results into the resource Expression Atlas, where it can be accessed and visualised either individually or together with gene expression data coming from transcriptomics datasets. We believe this is a good mechanism to make proteomics data more accessible for life scientists.
BINANA 2.0: Characterizing Protein/Ligand Interactions in Python and JavaScript
Authors: Young Jade , Garikipati Neerja , Durrant Jacob D.
Published: September 2021

BINding ANAlyzer (BINANA) is an algorithm for identifying and characterizing protein/ligand interactions and other factors that contribute to binding. We recently updated BINANA to make the algorithm more accessible to a broader audience. We have also ported the Python3 codebase to JavaScript, thus enabling BINANA analysis in the web browser. As proof of principle, we created a web-browser application so students and chemical-biology researchers can quickly visualize receptor/ligand complexes and their unique binding interactions.
BRAIN-DERIVED NEUROTROPHIC FACTOR IN AN ORBITOFRONTAL CORTICAL-DORSOLATERAL STRIATAL CIRCUIT GATES ALCOHOL CONSUMPTION
Authors: Moffat Jeffrey J. , Sakhai Samuel A. , Ehinger Yann , Phamluong Khanhky , Ron Dorit
Published: September 2021

Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) gates alcohol self-administration in rodents. The major source of BDNF in the striatum is the cortex, and we recently found that BDNF-expressing neurons in the ventrolateral orbitofrontal cortex (vlOFC) extend axonal projections to the DLS. We therefore hypothesized that BDNF in the vlOFC to DLS circuit moderates alcohol intake. We show that overexpression of BDNF in the vlOFC, which activates BDNF signaling in the DLS, is sufficient to attenuate voluntary consumption and seeking of 20% alcohol in the home cage using a two-bottle choice paradigm. Overexpressing BDNF in the vlOFC had no effect on the consumption of a sweetened saccharin solution. In addition, BDNF overexpression in the neighboring motor cortex did not alter alcohol intake. Finally, pathway-specific overexpression of BDNF in DLS-projecting vlOFC neurons significantly reduced alcohol intake and preference. Overall, BDNF in the vlOFC, and specifically in a vlOFC-DLS pathway, keeps alcohol drinking in moderation.
High-fat diet feeding reduces the expression of Rab3a, Rab3gap1, and Rab3Gap2 genes that are pivotal to neuronal exocytosis
Authors: Ferreira Luana Assis , Rubatino Fernando Victor Martins , de Freitas Mariana Lacerda , de Oliveira Leonardo Rossi , de Castro Junior Célio Jose , Jehee Fernanda Sarquis , Bosco Adriana Aparecida , Fernandes Karla Silva
Published: September 2021

The Rab3A and Rab3gaps are essential to the Ca+2-dependent neuronal exocytosis in the hypothalamus. The arcuate nucleus of the hypothalamus (ARC) controls food intake and energy expenditure. We have earlier described that the high-fat diet (HFD) feeding induces an obesity phenotype with high leptin production and alteration of proteins related to endosome sorting, and ubiquitination in the ARC of mice. In this study, real-time PCR data analysis revealed that HFD feeding decreases significantly Rab3a, Rab3gap1, and Rab3gap2 transcript levels in the ARC when compared to the group receiving a control diet. The decrease of Rab3gap1/2 transcript levels in the ARC was strongly associated with an increase in plasma leptin. Altogether, our studies demonstrate that HFD feeding could be altering the general network of endosome compartmentalization in the ARC of mice, contributing to a failure in exocytosis and receptor recycling.

Graphical abstract
Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)-mediated plasticity in the paraventricular thalamic nucleus promotes a fundamental adaptation to stress
Authors: Corbett Brian F. , Luz Sandra , Arner Jay , Vigderman Abigail , Urban Kimberly , Bhatnagar Seema
Published: September 2021

BACKGROUND

Habituation is defined as a progressive decline in response to repeated exposure to a familiar and predictable stimulus and is highly conserved across species. Disrupted habituation is a signature of post-traumatic stress disorder (PTSD). In rodents, habituation is observed in neural, neuroendocrine and behavioral responses to repeated exposure to the predictable and moderately intense stress or restraint. We previously demonstrated that lesions to the posterior division of the paraventricular thalamic nucleus (pPVT) impairs habituation. However, the underlying molecular mechanisms and specific neural connections among the pPVT and other brain regions that underlie habituation are unknown.

METHODS

Behavioral and neuroendocrine habituation was assessed in adult male Sprague-Dawley restraints using the repeated restraint paradigm. Pan neuronal and Cre-dependent Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were used to chemogenetically inhibit the pPVT and the subpopulation of pPVT neurons that project to the medial prefrontal cortex (mPFC), respectively. Activity-regulated cytoskeleton-associated protein (Arc) expression was knocked down in the pPVT using siRNA directed towards Arc. Golgi staining was used to assess structural plasticity of pPVT neurons. Local field potential recordings were used to assess coherent neural activity between the pPVT and mPFC. The attentional set-shifting task was used to assess mPFC-dependent behavior.

RESULTS

Here, we show that Arc promotes habituation by increasing stress-induced spinogenesis in the pPVT, increasing coherent neural activity with the mPFC, and improving mPFC-mediated cognitive flexibility.

CONCLUSION

Our results demonstrate that Arc induction in the pPVT regulates habituation to repeated restraint and mPFC function.

One Sentence Summary

We demonstrate that Arc in the posterior division of the paraventricular thalamic nucleus promotes habituation to repeated stress by increasing dendritic spines.
Dopamine biases sensitivity to personal goals and social influence in self-control over everyday desires
Authors: Castrellon Jaime J. , Young Jacob S. , Dang Linh C. , Smith Christopher T. , Cowan Ronald L. , Zald David H. , Samanez-Larkin Gregory R.
Published: September 2021

People regularly give in to daily temptations in spite of conflict with personal goals. To test hypotheses about neuropharmacological influences on self-control, we used positron emission tomography to measure dopamine D2-like receptors (D2R) and experience sampling surveys to naturalistically track daily desires outside the laboratory in everyday life in a sample of 103 adults. Higher D2R availability in the ventral striatum was associated with increased sensitivity to personal goal conflict but not desire strength in deciding whether to attempt to resist a desire. The influence of D2Rs on sensitivity to personal goal conflict depended on whether desires were experienced in a social context. D2R availability in the midbrain (but not the ventral striatum) influenced whether desires were enacted. These findings provide unique evidence that the dopamine system influences decision making and regulatory behavior and provides new insights into how these mechanisms interact with personal goals and social contexts.
Using BERT to identify drug-target interactions from whole PubMed
Authors: Aldahdooh Jehad , Vähä-Koskela Markus , Tang Jing , Tanoli Ziaurrehman
Published: September 2021

Background

Drug-target interactions (DTIs) are critical for drug repurposing and elucidation of drug mechanisms, and they are collected in large databases, such as ChEMBL, BindingDB, DrugBank and DrugTargetCommons. However, the number of studies providing this data (~0.1 million) likely constitutes only a fraction of all studies on PubMed that contain experimental DTI data. Finding such studies and extracting the experimental information is a challenging task, and there is a pressing need for machine learning for the extraction and curation of DTIs. To this end, we developed new text mining document classifiers based on the Bidirectional Encoder Representations from Transformers (BERT) algorithm. Because DTI data intimately depends on the type of assays used to generate it, we also aimed to incorporate functions to predict the assay format.

Results

Our novel method identified and extracted DTIs from 2.1 million studies not previously included in public DTI databases. Using 10-fold cross-validation, we obtained ~99% accuracy for identifying studies containing drug-target pairs. The accuracy for the prediction of assay format is ~90%, which leaves room for improvement in future studies.

Conclusion

The BERT model in this study is robust and the proposed pipeline can be used to identify new and previously overlooked studies containing DTIs and automatically extract the DTI data points. The tabular output facilitates validation of the extracted data and assay format information. Overall, our method provides a significant advancement in machine-assisted DTI extraction and curation. We expect it to be a useful addition to drug mechanism discovery and repurposing.
Estimating movement rates between Eurasian and North American birds that are vectors of avian influenza (AI)
Authors: Spaulding Fern , McLaughlin Jessica F. , Glenn Travis C. , Winker Kevin
Published: September 2021

1.1

Avian influenza (AI) is an emerging zoonotic disease that will likely be involved in future pandemics. Because waterbird movements are difficult to quantify, determining the host-specific risk of Eurasian-origin AI movements into North America is challenging. We estimated relative rates of movements, based on long-term evolutionary averages of gene flow, between Eurasian and North American waterbird populations to obtain bidirectional baseline rates of the intercontinental movements of these AI hosts. We used population genomics and coalescent-based demographic models to obtain these gene-flow-based movement estimates. Inferred rates of movement between these populations varies greatly among species. Within dabbling ducks, gene flow, relative to effective population size, varies from ∼3-24 individuals/generation between Eurasian and American wigeons (Mareca penelope – M. americana) to ∼100-300 individuals/generation between continental populations of northern pintails (Anas acuta). These are evolutionary long-term averages and provide a solid foundation for understanding the relative risks of each of these host species in potential intercontinental AI movements. We scale these values to census size for evaluation in that context. In addition to being AI hosts, many of these species are also important in the subsistence diets of Alaskans, increasing the risk of direct bird-to-human exposure to Eurasian-origin AI virus. We contrast species-specific rates of intercontinental movements with the importance of each species in Alaskan diets to understand the relative risk of these taxa to humans. Greater scaup (Aythya marila), mallard (Anas platyrhynchos), and northern pintail (Anas acuta) were the top three species presenting the highest risks for intercontinental AI movement both within the natural system and through exposure to subsistence hunters. These directly comparable, species-based intercontinental movement rates and relative risk rankings should help in modeling, monitoring, and mitigating the impacts of intercontinental host and AI movements.