bluuebunny/crossref_metadata_2025 huggingface dataset:
No behavioral evidence for rhythmic facilitation of perceptual discrimination
Authors: Lin Wy Ming , Oetringer Djamari A. , Bakker-Marshall Iske , Emmerzaal Jill , Wilsch Anna , ElShafei Hesham A. , Rassi Elie , Haegens Saskia
Published: December 2020

It has been hypothesized that internal oscillations can synchronize (i.e., entrain) to external environmental rhythms, thereby facilitating perception and behavior. To date, evidence for the link between the phase of neural oscillations and behavior has been scarce and contradictory; moreover, it remains an open question whether the brain can use this tentative mechanism for active temporal prediction. In our present study, we conducted a series of auditory pitch discrimination tasks with 181 healthy participants in an effort to shed light on the proposed behavioral benefits of rhythmic cueing and entrainment. In the three versions of our task, we observed no perceptual benefit of purported entrainment: targets occurring in-phase with a rhythmic cue provided no perceptual benefits in terms of discrimination accuracy or reaction time when compared with targets occurring out-of-phase or targets occurring randomly, nor did we find performance differences for targets preceded by rhythmic vs. random cues. However, we found a surprising effect of cueing frequency on reaction time, in which participants showed faster responses to cue rhythms presented at higher frequencies. We therefore provide no evidence of entrainment, but instead a tentative effect of covert active sensing in which a faster external rhythm leads to a faster communication rate between motor and sensory cortices, allowing for sensory inputs to be sampled earlier in time.
The gut microbiome facilitates ecological adaptation in an invasive vertebrate
Authors: Wagener Carla , Mohanty Nitya Prakash , Measey John
Published: December 2020

Gut microbial communities regulate host physiology and health of humans and laboratory animals. The functional significance of these collective bacterial genomes (i.e. the microbiome) to the adaptive potential of wildlife hosts is still unknown. Studies demonstrating convincing examples of microbial flexibility to environmental change so far lack the experimental approaches to demonstrate the effect on host physiology. Invasive species provide natural experiments to tease apart these host-microbe relationships. However, no studies have investigated how microbial symbionts might mediate responses of invasive hosts’ physiology to environmental change. In this study, we examine whether invasive gut microbiomes have significantly diverged in their ability to respond to novel environmental change (i.e. a dietary challenge) compared to native gut microbiomes by performing reciprocal faecal microbial transplant (FMT) experiments in native and invasive guttural toad (Sclerophrys gutturalis) populations. Subsequently, we determine how the microbiome regulates host physiological changes in response to a dietary challenge. We show that invasive gut microbiomes exhibit higher microbial compositional and predicted functional flexibility to novel dietary change, compared to native gut microbiomes. This increased microbial flexibility is coupled with significant flexibility in energy harvesting. Furthermore, our results indicate that overall invasive gut microbiomes significantly upregulate energy harvesting and physiological performance of hosts, compared to native microbiomes. Our study is the first identifying gut microbiota as the sole factor contributing to the adaptive physiology of a vertebrate using a unique study design. These findings provide novel insights into the key role of gut microbial symbionts in increasing the invasive potential of its vertebrate host.
Human liver microbiota modeling strategy at the early onset of fibrosis
Authors: Champion Camille , Neagoe Radu M. , Effernberger Maria , Sala Daniela T. , Servant Florence , Christensen Jeffrey E. , Arnoriaga-Rodriguez Maria , Amar Jacques , Lelouvier Benjamin , Gamboa Fabrice , Tilg Herbert , Federici Massimo , Fernández-Real Jose-Manuel , Loubes Jean Michel , Burcelin Rémy
Published: December 2020

To understand the pathophysiological impact of liver microbiota on the early stages of fibrosis we identified the corresponding microbiota sequences and overcome the impact of different group size and patient origins with adapted statistical approaches. Liver samples with low liver fibrosis scores (F0, F1, F2) were collected from Romania(n=36), Austria(n=10), Italy(n=19), and Spain(n=17). The 16SrDNA gene was sequenced. We considered the frequency, sparsity, unbalanced sample size between cohorts to identify taxonomic profiles and statistical differences. Multivariate analyses, including adapted spectral clustering with L1-penalty fair-discriminant strategies, and predicted metagenomics were used to identify that 50 % of liver taxa were Enterobacteriaceae and Pseudomonadaceae. The Caulobacteraceae, Flavobacteriaceae and Propionibacteriaceae discriminated between F0 and F1. The preQ0 biosynthesis and pathways involving glucoryranose and glycogen degradation were negatively associated with liver fibrosis F1-F2 vs F0. Altogether, our results suggest a role of bacterial translocation to the liver in the progression of fibrosis. This statistical approach can identify microbial signatures and overcome issues regarding sample size differences, the impact of environment, and sets of analyses.
Revisiting the Out of Africa event with a novel Deep Learning approach
Authors: Montinaro Francesco , Pankratov Vasili , Yelmen Burak , Pagani Luca , Mondal Mayukh
Published: December 2020

Anatomically modern humans evolved around 300 thousand years ago in Africa1. Modern humans started to appear in the fossil record outside of Africa about 100 thousand years ago though other hominins existed throughout Eurasia much earlier2–4. Recently, several researchers argued in favour of a single out of Africa event for modern humans based on whole-genome sequences analyses5–7. However, the single out of Africa model is in contrast with some of the findings from fossil records, which supports two out of Africa8,9, and uniparental data, which proposes back to Africa movement10,11. Here, we used a novel deep learning approach coupled with Approximate Bayesian Computation and Sequential Monte Carlo to revisit these hypotheses from the whole genome sequence perspective. Our results support the back to Africa model over other alternatives. We estimated that there are two successive splits between Africa and out of African populations happening around 60-80 thousand years ago and separated by 12-13 thousand years. One of the populations resulting from the more recent split has to a large extent replaced the older West African population while the other one has founded the out of Africa populations.
A new Petri Net Model of Working Memory to Predict the Root Causes of Attention Deficit Disorder Symptoms
Authors: Baghdadi Golnaz , Doustmohammadi Ali , Jamshidi Ainaz , Towhidkhah Farzad
Published: December 2020

Working memory is a system that helps us to store, retrieve, and manipulate information for a short period. The improper function of working memory is highly reported in people with attention deficit disorder. Attention deficit disorder is one of the most common disruptive behavioral disorders in children. Finding the actual reasons that may lead to inattentive symptoms is still an enigma for scientists. In this study, a model was proposed to show the flow of information through sensory, long-term, and working memory based on the Petri net approach. A new “selective updating” mechanism is also suggested. It is speculated that the central executive part of working memory uses this mechanism for updating the less important content with new incoming essential inputs. The analysis of the proposed model shows how an abnormality in the time setting or unexpected delays in information transmission may lead to some symptoms of inattention. These predictions about the possible causes of inattentive symptoms would be valuable for psychologists to find new possible treatments. This study also illustrates the great potential of Petri net approach for modeling and analysis of biological systems.
Zebrafish skeletal muscle cell cultures: Monolayer to three-dimensional tissue engineered collagen constructs
Authors: Vishnolia K.K , Martin N.R.W , Player D.J , Spikings E , Lewis M.P
Published: December 2020

Zebrafish (Danio rerio) are a commonly used model organism to study human muscular myopathies and dystrophies. To date, much of the work has been conductedin vivodue to limitations surrounding the consistent isolation and culture of zebrafish muscle progenitor cells (MPCs)in vitroand the lack of physiologically relevant models.

Here we report a robust, repeatable, and cost-effective protocol for the isolation and culture of zebrafish MPCs in conventional monolayer (2D) and have successfully transferred these cells to 3D culture in collagen based three-dimensional (3D) tissue-engineered constructs. Zebrafish MPC’s cultured in 2D were consistently reported to be Desmin positive reflecting their muscle specificity, with those demonstrating Desmin positivity in the 3D cultures. In addition, mRNA expression of muscle markers specific for proliferation, differentiation and maturation measured from both monolayer and 3D cultures at appropriate developmental stages were found consistent with previously published from other speciesin vitro and in vivomuscle data.

Collagen constructs seeded with zebrafish MPC’s were initially characterised for optimal seeding density, followed by macroscopic characterisation (three-fold contraction) of the matrix. Direct comparison between the morphological characteristics (proportion of cells) and gene expression profiles of cells cultured in collagen constructs revealed higher maturation and differentiation compared to monolayer cultures. In this regard, cells embedded in 3D collagen constructs revealed higher fusion index, Desmin positivity, hypertrophic growth, myotube maturity and myogenic mRNA expression when compared to in monolayer.

In conclusion, these methods and models developed herein will facilitatein vitroexperiments, which would complementin vivozebrafish studies used to investigate the basic developmental, myopathies and dystrophies in skeletal muscle cells.
Resonating neurons stabilize heterogeneous grid-cell networks
Authors: Mittal Divyansh , Narayanan Rishikesh
Published: December 2020

A central theme that governs the functional design of biological networks is their ability to sustain stable function despite widespread parametric variability. Here, we investigated the impact of distinct forms of biological heterogeneities on the stability of a two-dimensional continuous attractor network (CAN) implicated in grid-patterned activity generation. We show that increasing degrees of biological heterogeneities progressively disrupted the emergence of grid- patterned activity and resulted in progressively large perturbations in low-frequency neural activity. We postulated that targeted suppression of low-frequency perturbations could ameliorate heterogeneity-induced disruptions of grid-patterned activity. To test this, we introduced intrinsic resonance, a physiological mechanism to suppress low-frequency activity, either by adding an additional high-pass filter (phenomenological) or by incorporating a slow negative feedback loop (mechanistic) into our model neurons. Strikingly, CAN models with resonating neurons were resilient to the incorporation of heterogeneities and exhibited stable grid-patterned firing. We found CAN networks with mechanistic resonators to be more effective in targeted suppression of low-frequency activity, with the slow kinetics of the negative feedback loop essential in stabilizing these networks. As low-frequency perturbations (1/fnoise) are pervasive across biological systems, our analyses suggest a universal role for mechanisms that suppress low- frequency activity in stabilizing heterogeneous biological networks.
Differences in neuronal numbers, morphology and developmental apoptosis in mice nigra provide experimental evidence of ontogenic origin of vulnerability to Parkinson’s disease
Authors: Vidyadhara D J , Yarreiphang Haorei , Raju Trichur R , Alladi Phalguni Anand
Published: December 2020

Parkinson disease (PD) prevalence varies by ethnicity. In an earlier study we replicated the reduced vulnerability to PD in an admixed population, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-susceptible C57BL/6J, MPTP-resistant CD-1 and their F1 crossbreds. In the present study we investigated if the differences have a developmental origin. Substantia nigra was evaluated at postnatal days 2 (P2), P6, P10, P14, P18, and P22. C57BL/6J mice had smaller nigra and fewer dopaminergic neurons than the CD-1 and crossbreds at P2, which persisted through development. A significant increase in numbers and nigral volume was observed across strains till P14. A drastic decline thereafter was specific to C57BL/6J. CD-1 and crossbreds retained their numbers from P14 to stabilize with supernumerary neurons at adulthood. The neuronal size increased gradually to attain adult morphology at P10 in the resistant strains, vis-à-vis at P22 in C57BL/6J. Accordingly, in comparison to C57BL/6J, the nigra of CD-1 and reciprocal crossbreds possessed cyto-morphological features of resilience, since birth. The considerably lesser dopaminergic neuronal loss in the CD-1 and crossbreds seen at P2, P14 and thereafter was complemented by attenuated developmental cell death. The differences in programmed cell death were confirmed by reduced TUNEL labelling, AIF and caspase-3 expression. GDNF expression aligned with the cell death pattern at P2 and P14 in both nigra and striatum. Earlier maturity of nigra and its neurons appear to be better features that reflect as MPTP-resistance at adulthood. Thus variable MPTP-vulnerability in mice and also differential susceptibility to PD in humans may arise early during nigral development.
Generation of a new Tbx6-inducible reporter mouse line to trace presomitic mesoderm derivatives throughout development and in adults
Authors: Yvernogeau Laurent , Klaus Anna , van Rooijen Carina , Robin Catherine
Published: December 2020

The presomitic mesoderm (PSM) is initially an unsegmented structure localized on each side of the neural tube of the developing embryo, which progressively segments to form the somites. The somites will segregate and partition to generate the dorsal dermomyotome and the ventral sclerotome. Endothelial and myogenic cells of both the trunk and limbs are derived from the somites. There is a lack of efficient reporter mouse models to label and trace the PSM derivatives, despite their crucial contribution to many developmental processes. In this study, we generated a tamoxifen inducible transgenic Tbx6 mouse line, Tg(Tbx6_Cre/ERT2)/ROSA-eYFP, to tag and follow PSM-derivatives from early embryonic stages until adulthood. After induction, endothelial and myogenic cells can be easily identified within the trunk and limbs with proper expression patterns. Since our Tg(Tbx6_Cre/ERT2)/ROSA-eYFP model allows to permanently label the PSM-derived cells, their progeny can be studied at long-term, opening the possibility to perform lineage tracing of stem cells upon aging.
Improved estimation of phenotypic correlations using summary association statistics
Authors: Li Ting , Ning Zheng , Shen Xia
Published: December 2020

Estimating the phenotypic correlations between complex traits and diseases based on their genome-wide association summary statistics has been a useful technique in genetic epidemiology and statistical genetics inference. Two state-of-the-art strategies, Z-score correlation across null-effect SNPs and LD score regression intercept, were widely applied to estimate phenotypic correlations. Here, we propose an improved Z-score correlation strategy based on SNPs with low minor allele frequencies (MAFs), and show how this simple strategy can correct the bias generated by the current methods. Comparing to LDSC, the low-MAF estimator improves phenotypic correlation estimation thus is beneficial for methods and applications using phenotypic correlations inferred from summary association statistics.
DNA methylation and survival differences associated with the type of IDH mutation in 1p/19q non-codeleted astrocytomas
Authors: Tesileanu C Mircea S , Vallentgoed Wies R , Sanson Marc , Taal Walter , Clement Paul M , Wick Wolfgang , Brandes Alba Ariela , Baurain Jean Francais , Chinot Olivier L , Wheeler Helen , Gill Sanjeev , Griffin Matthew , Rogers Leland , Rudà Roberta , Weller Michael , McBain Catherine , Reijneveld Jaap , Enting Roelien H , Caparrotti Francesca , Lesimple Thierry , Clenton Susan , Gijtenbeek Anja , Lim Elisabeth , de Vos Filip , Mulholland Paul J , Taphoorn Martin J B , de Heer Iris , Hoogstrate Youri , de Wit Maurice , Boggiani Lorenzo , Venneker Sanne , Oosting Jan , Bovée Judith VMG , Erridge Sara , Vogelbaum Michael A , Nowak Anna K , Mason Warren P , Kros Johan M , Wesseling Pieter , Aldape Ken , Jenkins Robert B , Dubbink Hendrikus J , Baumert Brigitta , Golfinopoulos Vassilis , Gorlia Thierry , van den Bent Martin , French Pim J
Published: December 2020

Somatic mutations in the isocitrate dehydrogenase genesIDH1andIDH2occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132Hmutations. This high prevalence is important as IDH1R132His presumed to be relatively poor at producing D-2-hydroxyglutarate (D-2HG) whereas high concentrations of this oncometabolite are required to inhibit TET2 DNA demethylating enzymes. Indeed, patients harbouring IDH1R132Hmutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of site of origin. For 1p/19q non-codeleted glioma patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring non-R132H mutated tumours have better outcome (HR 0.41, 95% CI [0.24, 0.71], p=0.0013). Non-R132H mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p<0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H mutated 1p/19q non-codeleted gliomas have a more favourable prognosis than their IDH1R132Hmutated counterpart is clinically relevant and should be taken into account for patient prognostication.

Single sentence summary

Astrocytoma patients with tumours harbouring IDH mutations other than p.R132H have increased DNA methylation levels and longer survival
Chill coma onset and recovery fail to reveal true variation in thermal performance among populations ofDrosophila melanogaster
Authors: Davis Hannah E. , Cheslock Alexandra , MacMillan Heath A.
Published: December 2020

Species from colder climates tend to be more chill tolerant regardless of the chill tolerance trait measured, but forDrosophila melanogaster, population-level differences in chill tolerance among populations are not always found when a single trait is measured in the laboratory.

We measured chill coma onset temperature, chill coma recovery time, and survival after chronic cold exposure in replicate lines derived from multiple paired African and EuropeanD. melanogasterpopulations. The populations in our study were previously found to differ in chronic cold survival ability, which is believed to have evolved independently in each population pair.

To our surprise, the populations did not differ in chill coma onset temperature and chill coma recovery time in a manner that reflected their geographic origins, even though these traits are known to vary with origin latitude amongDrosophilaspecies and among the most common metrics of thermal tolerance in insects. The populations did, however, still differ in their ability to survive chronic cold exposure.

While it is common practice to measure only one chill tolerance trait when comparing chill tolerance among insect populations, our results emphasise the importance of measuring more than one thermal tolerance trait to minimize the risk of missing real adaptive variation in insect thermal tolerance.
A 4-lineage statistical suite to evaluate the support of large-scale retrotransposon insertion data to reconstruct evolutionary trees
Authors: Churakov G , Kuritzin A , Chukharev K , Zhang F , Wünnemann F , Ulyantsev V , Schmitz J
Published: December 2020

Retrophylogenomics makes use of genome-wide retrotransposon presence/absence insertion patterns to resolve questions in phylogeny and population genetics. In the genomics era, evaluating high-throughput data requires the associated development of appropriately powerful statistical tools. The currently used KKSC 3-lineage statistical test for estimating the significance of retrophylogenomic data is limited by the number of possible tree topologies it can assess in one step. To improve on this, we have extended the analysis to simultaneously compare 4-lineages, enabling us to evaluate ten distinct presence/absence insertion patterns for 26 possible tree topologies plus 129 trees with different incidences of hybridization or introgression. The new tool provides statistics for cases involving multiple ancestral hybridizations/introgressions, ancestral incomplete lineage sorting, bifurcation, and polytomy. The test is embedded in a user-friendly web R-application (http://retrogenomics.uni-muenster.de:3838/hammlet/) and is available for use by the scientific community.
Novelty at second glance: A critical appraisal of the novel-object paradigm based on meta-analysis
Authors: Takola E. , Krause E. T. , Müller C. , Schielzeth H.
Published: December 2020

The study of consistent individual differences in behaviour has become an important focus in research on animal behaviour. Behavioural phenotypes are typically measured through standardized testing paradigms and one frequently used paradigm is the novel object test. In novel object tests, animals are exposed to new (unknown) objects and their reaction is quantified. When repeating trials to assess the temporal consistency of individual differences, researchers face the dilemma of whether to use the same or different ‘novel’ objects, since the same stimulus can result in habituation, while exposure to different objects can result in context-dependent responses. We performed a quantitative assessment of 254 effect sizes from 113 studies on novel-object trials to evaluate the properties of this testing paradigm, in particular the effect of object novelty and time interval between novel-object trials on estimates of individual consistency. We found an increase of sample sizes and an increase of estimates of repeatabilities with time. The vast majority of short-term studies (one month) used either the same or different novel objects about equally often. The average estimate for individual consistency was r = 0.47 (short-term r = 0.52, long-term r = 0.44). Novelty, time interval between trials and their interaction together explained only 3% of the total heterogeneity. Overall, novelobject trials reliably estimate individual differences in behaviour, but results were very heterogeneous even within the same study species, suggesting susceptibility to unknown details in testing conditions. Most studies that measure novel-object responses in association with food label the trait as neophobia, while novel-object trials in a neutral context are labelled variously as boldness/shyness, exploratory behaviour or neophobia/neophilia. Neophobia/neophilia is also the term most specific to novel object presentations. To avoid ambiguity, we suggest object neophobia/neophilia as the most specific label for novel-object responses.
Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons
Authors: Tereshko Lauren R. , Gao Ya , Cary Brian A. , Turrigiano Gina G. , Sengupta Piali
Published: December 2020

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.
Aiming off the target: studying repetitive DNA using target capture sequencing reads
Authors: Costa Lucas , Marques André , Buddenhagen Chris , Thomas William Wayt , Huettel Bruno , Schubert Veit , Dodsworth Steven , Houben Andreas , Souza Gustavo , Pedrosa-Harand Andrea
Published: December 2020

With the advance of high-throughput sequencing (HTS), reduced-representation methods such as target capture sequencing (TCS) emerged as cost-efficient ways of gathering genomic information. As the off-target reads from such sequencing are expected to be similar to genome skims (GS), we assessed the quality of repeat characterization using this data.

For this, repeat composition from TCS datasets of fiveRhynchospora(Cyperaceae) species were compared with GS data from the same taxa.

All the major repetitive DNA families were identified in TCS, including repeats that showed abundances as low as 0.01% in the GS data. Rank correlation between GS and TCS repeat abundances were moderately high (r= 0.58-0.85), increasing after filtering out the targeted loci from the raw TCS reads (r= 0.66-0.92). Repeat data obtained by TCS was also reliable to develop a cytogenetic probe and solve phylogenetic relationships ofRhynchosporaspecies with high support.

In light of our results, TCS data can be effectively used for cyto- and phylogenomic investigations of repetitive DNA. Given the growing availability of HTS reads, driven by global phylogenomic projects, our strategy represents a way to recycle genomic data and contribute to a better characterization of plant biodiversity.
Signal processing capacity of the cellular sensory machinery regulates the accuracy of chemotaxis under complex cues
Authors: Moon Hye-ran , Saha Soutick , Mugler Andrew , Han Bumsoo
Published: December 2020

Chemotaxis is ubiquitous in many biological processes, but it still remains elusive how cells sense and decipher multiple chemical cues. In this study, we postulate a hypothesis that the chemotactic performance of cells under complex cues is regulated by the signal processing capacity of the cellular sensory machinery. The underlying rationale is that cellsin vivoshould be able to sense and process multiple chemical cues, whose magnitude and compositions are entangled, to determine their migration direction. We experimentally show that the combination of TGF-β and EGF suppresses the chemotactic performance of cancer cells using independent receptors to sense the two cues. Based on this observation, we develop a biophysical framework suggesting that the antagonism is caused by the saturation of the signal processing capacity, but not by the mutual repression. Our framework suggests the significance of the signal processing capacity in the cellular sensory machinery.
Coiled coil control of growth factor and inhibitor-dependent EGFR trafficking and degradation
Authors: Mozumdar Deepto , Chang Sol Hsun-Hui , Quach Kim , Doerner Amy , Schepartz Alanna
Published: December 2020

EGFR exhibits biased signaling, whereby growth factor or mutation-dependent changes in receptor conformation and/or dynamics elicit distinct intracellular outcomes. We report that many outcomes associated with activated EGFR are controlled by a two-state coiled coil switch located within the juxtamembrane segment (JM), an essential component of the cytosolic dimer interface. The position of this switch defines the path of endocytic trafficking and whether or not EGFR is degraded within lysosomes. JM coiled coil identity also predicts kinase-independent effects of oncogenic EGFR mutations and clinically relevant tyrosine kinase inhibitors (TKIs) that promote efficient, lysosome-based EGFR degradation. These findings provide a model for biased EGFR signaling, insights into kinase-independent activities of EGFR and clinically relevant TKIs, and identify new strategies for modulating protein lifetime.
Regions of Highly Recurrent Electrogram Morphology at Sites of Low Cycle Length Accurately Reflect Arrhythmogenic Substrate for Atrial Fibrillation – Implications For a New, Mechanism Guided Therapeutic Approach for Atrial Fibrillation
Authors: Yoo Shin , Rottmann Markus , Ng Jason , Johnson David , Shanab Bassel , Pfenniger Anna , Geist Gail Elizabeth , Mandawa Suman , Burrell Amy , Zhang Wenwei , Wasserstrom J Andy , Knight Bradley P , Passman Rod , Goldberger Jeffrey J , Arora Rishi
Published: December 2020

Background

Although atrial electrograms (EGMs) are thought to reflect pathophysiological substrate for atrial fibrillation (AF), it is not known which electrograms are suitable targets during AF ablation. We hypothesized that electrogram morphology recurrence (EMR) better reflects arrhythmogenic AF substrate than traditional frequency and complexity measures of AF. In a canine rapid atrial pacing (RAP) model of AF, we assessed the relationship between EMR and traditional AF electrogram measures, rotational activity in the atria, fibrosis, myofiber orientation and parasympathetic innervation.

Methods

Persistent AF was induced in 13 dogs by RAP for 6-8 weeks. High-density epicardial mapping (117 electrodes) was performed in six atrial sub-regions. EMR measures Recurrence percentage (Rec%) and cycle length of the most frequent electrogram morphology (CLR), Fractionated Interval (FI), Organization Index (OI), Dominant Frequency (DF) and Shannon’s Entropy (ShEn) were analyzed before and after atropine administration. Myocyte fiber orientation, amount of fibrosis and spatial distribution of parasympathetic nerve fibers were quantified.

Results

Rec% was greatest in the appendages, and CLRwas lowest in the posterior left atrium. Rec%/CLRcorrelated with FI, OI and the complexity measure ShEn, but not with DF. All electrogram measures were poorly correlated with fibrosis and myofiber anisotropy. Rec% correlated closely with stability of rotational activity. Unlike other measures, Rec% correlated closely with spatial heterogeneity of parasympathetic nerve fibers; this was reflected in CLRresponse to atropine.

Conclusion

EMR correlates closely with stability of rotational activity and with the pattern of atrial parasympathetic innervation. CLRmay therefore be a viable therapeutic target in persistent AF.
AIM: A Network Model of Attention in Auditory Cortex
Authors: Chou Kenny F. , Sen Kamal
Published: December 2020

Attentional modulation of cortical networks is critical for the cognitive flexibility required to process complex scenes. Current theoretical frameworks for attention are based almost exclusively on studies in visual cortex, where attentional effects are typically modest and excitatory. In contrast, attentional effects in auditory cortex can be large and suppressive. A theoretical framework for explaining attentional effects in auditory cortex is lacking, preventing a broader understanding of cortical mechanisms underlying attention. Here, we present a cortical network model of attention in primary auditory cortex (A1). A key mechanism in our network is attentional inhibitory modulation (AIM) of cortical inhibitory neurons. In this mechanism, top-down inhibitory neurons disinhibit bottom-up cortical circuits, a prominent circuit motif observed in sensory cortex. Our results reveal that the same underlying mechanisms in the AIM network can explain diverse attentional effects on both spatial and frequency tuning in A1. We find that a dominant effect of disinhibition on cortical tuning is suppressive, consistent with experimental observations. Functionally, the AIM network may play a key role in solving the cocktail party problem. We demonstrate how attention can guide the AIM network to monitor an acoustic scene, select a specific target, or switch to a different target, providing flexible outputs for solving the cocktail party problem.
The RNA binding protein Nab2 regulates the proteome of the developingDrosophilabrain
Authors: Corgiat Edwin B. , List Sara M. , Rounds J. Christopher , Corbett Anita H. , Moberg Kenneth H.
Published: December 2020

The humanZC3H14gene, which encodes a ubiquitously expressed polyadenosine zinc finger RNA binding protein, is mutated in an inherited form of autosomal recessive, non-syndromic intellectual disability. To gain insight into ZC3H14 neurological functions, we previously developed aDrosophila melanogastermodel of ZC3H14 loss by deleting the fly ortholog, Nab2. Studies in this invertebrate model reveal that Nab2 controls final patterns of neuron projection within fully developed adult brains. Here, we examine earlier pupal stages and define roles for Nab2 in controlling the dynamic growth of axons into the developing brain mushroom bodies (MBs), which support olfactory learning and memory, and in regulating abundance of a small fraction of the total brain proteome, a portion of which is rescued by overexpression ofNab2specifically in brain neurons. The group of Nab2-regulated brain proteins, identified by quantitative proteomic analysis, includes the microtubule binding protein Futsch, the neuronal Ig-family transmembrane protein Turtle, the glial:neuron adhesion protein Contactin, the RacGAP Tumbleweed, and the planar cell polarity factor Van Gogh, which collectively link Nab2 to a the processes of brain morphogenesis, neuroblast proliferation, circadian sleep/wake cycles, and synaptic development. Overall, these data indicate that Nab2 controls abundance of a subset of brain proteins during the active process of wiring the pupal brain mushroom body, and thus provide a window into potentially conserved functions of the Nab2/ZC3H14 RNA binding proteins in neurodevelopment and function.
The Laplacian eigenmaps dimensionality reduction of fMRI data for discovering stimulus-induced changes in the resting-state brain activity
Authors: Pospelov Nikita , Tetereva Alina , Martynova Olga , Anokhin Konstantin
Published: December 2020

The resting brain at wakefulness is active even in the absence of goal-directed behavior or salient stimuli. However, patterns of this resting-state (RS) activity can undergo alterations following exposure to meaningful stimuli. This study aimed to develop an unbiased method to detect such changes in the RS activity after exposure to emotionally meaningful stimuli. For this purpose, we used functional magnetic resonance imaging (fMRI) of RS brain activity before and after the acquisition and extinction of experimental conditioned fear. A group of healthy volunteers participated in three fMRI sessions: a RS before fear conditioning, a fear extinction session, and a RS immediately after fear extinction. The fear-conditioning paradigm consisted of three neutral visual stimuli paired with a partial reinforcement by a mild electric current. We used both linear and non-linear dimensionality reduction approaches to distinguish between the initial RS and the RS after stimuli exposure. The principal component analysis (PCA) as a linear dimensionality reduction method did not differentiate these states. Using the non-linear Laplacian eigenmaps manifold learning method, we were able to show significant differences between the two RSs at the level of individual participants. This detection was further improved by smoothing the BOLD signal with the wavelet multiresolution analysis. The developed method can improve the discrimination of functional states collected in longitudinal fMRI studies.
Alzheimer’s Aβ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway
Authors: Sasahara Tomoya , Satomura Kaori , Tada Mari , Kakita Akiyoshi , Hoshi Minako
Published: December 2020

Amyloid β-protein (Aβ) may contribute to worsening of Alzheimer’s disease (AD) through vascular dysfunction, but the actual molecular mechanisms remain controversial. Usingex-vivoblood vessels and primary endothelial cells derived from human brain microvessels, we revealed that patient-derived Aβ assemblies, termed amylospheroids (ASPD), exist on the microvascular surface in patient brains and inhibit vasorelaxation through binding to the α3 subunit of sodium, potassium-ATPase (NAKα3) on endothelial cells. Interestingly, NAKα3 also serves as the toxic target of ASPD in neurons. ASPD elicit neurodegeneration through calcium overload, while ASPD suppress vasorelaxation by inhibiting nitric oxide (NO) production. ASPD-NAKα3 interaction on cerebrovascular endothelial cells disturbs the NO release by inactivating endothelial NO synthase through mitochondrial reactive oxygen species and protein kinase C. The findings suggest that ASPD may dually contribute to neuronal and vascular pathologies through binding to NAKα3. Thus, blocking the ASPD-NAKα3 interaction may be a useful target for AD therapy.
Fate mapping analysis reveals a novel dermal migratory Langerhans-like cell population
Authors: Sheng Jianpeng , Qi Chen , Wen Dong Yu , Xiaoting Wu , Mayer Johannes , Lin Wang , Xueli Bai , Tingbo Liang , Ho Sung Yang , Goh Wilson Wen Bin , Ronchese Franca , Ruedl Christiane
Published: December 2020

Dendritic cells residing in the skin represent a large family of antigen presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single cell RNA sequencing we have identified a novel separate population of LC-independent CD207+CD326+LClikecells in the dermis that homed at a slow rate to the LNs. These LClikecells were long-lived and radioresistant but, unlike LCs, they were gradually replenished by bone-marrow-derived precursors under steady state. LClikecells together with cDC1s were the main migratory CD207+CD326+cell fractions present in the LN and not, as currently assumed, LCs, which were barely detectable, if at all. These findings bring new insights into the dynamism of cutaneous dendritic cells and opens novel avenues in the development of treatments to cure inflammatory skin disorders.
Joint modeling of zero-inflated longitudinal proportions and time-to-event data with application to a gut microbiome study
Authors: Hu Jiyuan , Wang Chan , Blaser Martin J. , Li Huilin
Published: December 2020

Recent studies have suggested that the temporal dynamics of the human microbiome may have associations with human health and disease. An increasing number of longitudinal microbiome studies, which record time to disease onset, aim to identify candidate microbes as biomarkers for prognosis. Owing to the ultra-skewness and sparsity of microbiome proportion (relative abundance) data, directly applying traditional statistical methods may result in substantial power loss or spurious inferences. We propose a novel joint modeling framework [JointMM], which is comprised of two sub-models: a longitudinal sub-model called zero-inflated scaled-Beta generalized linear mixed-effects regression to depict the temporal structure of microbial proportions among subjects; and a survival sub-model to characterize the occurrence of an event and its relationship with the longitudinal microbiome proportions. JointMM is specifically designed to handle the zero-inflated and highly skewed longitudinal microbial proportion data and examine whether the temporal pattern of microbial presence and/or the non-zero microbial proportions are associated with differences in the time to an event. The longitudinal sub-model of JointMM also provides the capacity to investigate how the (time-varying) covariates are related to the temporal microbial presence/absence patterns and/or the changing trend in non-zero proportions. Comprehensive simulations and real data analyses are used to assess the statistical efficiency and interpretability of JointMM.
Concurrent assessment of gait kinematics using marker-based and markerless motion capture
Authors: Kanko Robert , Laende Elise K. , Davis Elysia M. , Selbie W. Scott , Deluzio Kevin J.
Published: December 2020

Kinematic analysis is a useful and widespread tool used in research and clinical biomechanics for the estimation of human pose and the quantification of human movement. Common marker-based optical motion capture systems are expensive, time intensive, and require highly trained operators to obtain kinematic data. Markerless motion capture systems offer an alternative method for the measurement of kinematic data with several practical benefits. This work compared the kinematics of human gait measured using a deep learning algorithm-based markerless motion capture system to those of a common marker-based motion capture system. Thirty healthy adult participants walked on a treadmill while data were simultaneously recorded using eight video cameras (markerless) and seven infrared optical motion capture cameras (marker-based). Video data were processed using markerless motion capture software, marker-based data were processed using marker-based capture software, and both sets of data were compared. The average root mean square distance (RMSD) between corresponding joints was less than 2.5 cm for all joints except the hip, which was 3.6 cm. Lower limb segment angles indicated pose estimates from both systems were very similar, with RMSD of less than 5.5° for all segment angles except those that represent rotations about the long axis of the segment. Lower limb joint angles captured similar patterns for flexion/extension at all joints, ab/adduction at the knee and hip, and toe-in/toe-out at the ankle. These findings demonstrate markerless motion capture can measure similar 3D kinematics to those from marker-based systems.
Single-trial neural dynamics influence auditory category learning
Authors: Mankel Kelsey , Pavlik Philip I. , Bidelman Gavin M.
Published: December 2020

Percepts are naturally grouped into meaningful categories to process continuous stimulus variations in the environment. Theories of category acquisition have existed for decades, but how they arise in the brain due to learning is not well understood. Here, advanced computational modeling techniques borrowed from educational data mining and cognitive psychology were used to trace the development of auditory categories within a short-term training session. Nonmusicians were rapidly trained for 20 min on musical interval identification (i.e., minor and major 3rdinterval dyads) while their brain activity was recorded via EEG. Categorization performance and neural responses were then assessed for the trained (3rds) and novel untrained (major/minor 6ths) continua. Computational modeling was used to predict behavioral identification responses and whether the inclusion of single-trial features of the neural data could predict successful learning performance. Model results revealed meaningful brain-behavior relationships in auditory category learning detectible on the single-trial level; smaller P2 amplitudes were associated with a greater probability of correct interval categorization after learning. These findings highlight the nuanced dynamics of brain-behavior coupling that help explain the temporal emergence of auditory categorical learning in the brain.
Molecular evolutionary trends and biosynthesis pathways in the Oribatida revealed by the genome ofArchegozetes longisetosus
Authors: Brückner Adrian , Barnett Austen A. , Antoshechkin Igor A. , Kitchen Sheila A.
Published: December 2020

Oribatid mites are a specious order of microarthropods within the subphylum Chelicerata, compromising about 11,000 described species. They are ubiquitously distributed across different microhabitats in all terrestrial ecosystems around the world and were among the first animals colonizing terrestrial habitats as decomposers and scavengers. Despite their species richness and ecological importance genomic resources are lacking for oribatids. Here, we present a 190-Mb genome assembly of the clonal, all-female oribatid mite speciesArchegozetes longisetosusAoki, a model species used by numerous laboratories for the past 30 years. Comparative genomic and transcriptional analyses revealed patterns of reduced body segmentation and loss of segmental identity geneabd-Awithin Acariformes, and unexpected expression of key eye development genes in these eyeless mites across developmental stages. Consistent with their soil dwelling lifestyle, investigation of the sensory genes revealed a species-specific expansion of gustatory receptors, the largest chemoreceptor family in the genome used in olfaction, and evidence of horizontally transferred enzymes used in cell wall degradation of plant and fungal matter, both components of theA. longisetosusdiet. Oribatid mites are also noted for their biosynthesis capacities and biochemical diversity. Using biochemical and genomic data, we were able to delineate the backbone biosynthesis of monoterpenes, an important class of compounds found in the major exocrine gland system of Oribatida – the oil glands. Given the mite’s strength as an experimental model, the new high-quality resources provided here will serve as the foundation for molecular research in Oribatida and will enable a broader understanding of chelicerate evolution.