bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating spatiotemporal integration of shape cues
Authors: Burchfield Taylor , Greene Ernest
Published: October 2019

Prior work has shown that humans can successfully identify letters that are constructed with a sparse array of dots, wherein the dot pattern reflects the strokes that would normally be used to fashion a given letter. In the present work the dots were briefly displayed, one at a time in sequence, varying the spatial order in which they were shown. A forward sequence was spatially ordered as though one were passing a stroke across the dots to connect them. Experiments compared this baseline condition to the following three conditions: a) the dot sequence was spatially ordered, but in the reverse direction from how letter strokes might normally be written; b) the dots in each stroke of the letter were displayed in a random order; c) the sequence of displayed dots were chosen for display from any location in the letter. Significant differences were found between the baseline condition and all three of the comparison conditions, with letter recognition being far worse for the random conditions than for conditions that provided consistent spatial ordering of dot sequences. These findings show that spatial order is critical for integration of shape cues that have been sequentially displayed.
Temporal signatures of criticality in human cortical excitability as probed by early somatosensory responses
Authors: Stephani T. , Waterstraat G. , Haufe S. , Curio G. , Villringer A. , Nikulin V. V.
Published: October 2019

Brain responses vary considerably from moment to moment, even to identical sensory stimuli. This has been attributed to changes in instantaneous neuronal states determining the system’s excitability. Yet the spatio-temporal organization of these dynamics remains poorly understood. Here we test whether variability in stimulus-evoked activity can be interpreted within the framework of criticality, which postulates dynamics of neural systems to be tuned towards the phase transition between stability and instability as is reflected in scale-free fluctuations in spontaneous neural activity. Using a novel non-invasive approach in 33 male participants, we tracked instantaneous cortical excitability by inferring the magnitude of excitatory post-synaptic currents from the N20 component of the somatosensory evoked potential. Fluctuations of cortical excitability demonstrated long-range temporal dependencies decaying according to a power law across trials – a hallmark of systems at critical states. As these dynamics covaried with changes in pre-stimulus oscillatory activity in the alpha band (8–13 Hz), we establish a mechanistic link between ongoing and evoked activity through cortical excitability and argue that the co-emergence of common temporal power laws may indeed originate from neural networks poised close to a critical state. In contrast, no signatures of criticality were found in subcortical or peripheral nerve activity. Thus, criticality may represent a parsimonious organizing principle of variability in stimulus-related brain processes on a cortical level, possibly reflecting a delicate equilibrium between robustness and flexibility of neural responses to external stimuli.

Significance Statement

Variability of neural responses in primary sensory areas is puzzling, as it is detrimental to the exact mapping between stimulus features and neural activity. However, such variability can be beneficial for information processing in neural networks if it is of a specific nature, namely if dynamics are poised at a so-called critical state characterized by a scale-free spatio-temporal structure. Here, we demonstrate the existence of a link between signatures of criticality in ongoing and evoked activity through cortical excitability, which fills the long-standing gap between two major directions of research on neural variability: The impact of instantaneous brain states on stimulus processing on the one hand and the scale-free organization of spatio-temporal network dynamics of spontaneous activity on the other.
A Wirelessly Powered Implantable CMOS Neural Recording Sensor Array using Pulse-based Neural Amplifier
Authors: Mulberry Geoffrey , White Kevin A. , Kim Brian N.
Published: October 2019

The most important organ in the human body is unquestionably the brain. Yet, despite its importance, it is one of the least well understood organs. One reason for this lack of understanding of the brain is the lack of data available to researchers from in vivo studies. Historically, collecting measurements from the brain has been difficult due to the high risk to the patient. Recently technology has been developed to allow electrical measurements to be taken from the brain directly, however most systems involve non-permanent sensors because of the requirement for transcranial wiring for power and data. Developments in the field of CMOS circuit design, wireless power transmission, and wireless data transmission have enabled the creation of implantable neural recording devices as a combination of these technologies. The implant designed in this paper is ∼15 mm in diameter and 2 mm at its thickest point on a flexible polyamide PCB. The flexible nature of the implant allows for the implant to conform to the surface of the brain. The implant requires no transcranial orifice since it is powered wirelessly and transmits data wirelessly via Bluetooth low energy. The CMOS neural amplifier chip on the implant utilizes an enhanced form of delta modulation to remove the requirement for large ADCs to be present on the die, saving space and enabling 1024 amplifiers and electrodes to be present on the chip. The implant is capable of measuring, modulating, and wirelessly transmitting a millivolt order signal to a PC for demodulation and analysis.
Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids
Authors: Dunbar Karen , Valanciute Asta , Rajasekaran Vidya , Jamieson Thomas , Vinuela Paz Freile , Lima Ana , Blackmur James , Ochocka-Fox Anna-Maria , Arends Mark J. , Sansom Owen J. , Myant Kevin B , Farrington Susan M. , Dunlop Malcolm G. , Din Farhat V.N.
Published: October 2019

Aspirin reduces the incidence and mortality of colorectal cancer (CRC). Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we investigated whether aspirin can rescue these pro-invasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+mice is associated with EMT inhibition and decreased cell migration, invasion and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 (DKK-1) in CRC cells and organoids derived from FAP patients. We provide evidence of phenotypic biomarkers of aspirin response with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1. Thus we highlight a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.
Sample size evolution in neuroimaging research: an evaluation of highly-cited studies (1990-2012) and of latest practices (2017-2018) in high-impact journals
Authors: Szucs Denes , Ioannidis John PA
Published: October 2019

We evaluated 1038 of the most cited structural and functional (fMRI) magnetic resonance brain imaging papers (1161 studies) published during 1990-2012 and 273 papers (302 studies) published in top neuroimaging journals in 2017 and 2018. 96% of highly cited experimental fMRI studies had a single group of participants and these studies had median sample size of 12, highly cited clinical fMRI studies (with patient participants) had median sample size of 14.5, and clinical structural MRI studies had median sample size of 50. The sample size of highly cited experimental fMRI studies increased at a rate of 0.74 participant/year and this rate of increase was commensurate with the median sample sizes of neuroimaging studies published in top neuroimaging journals in 2017 (23 participants) and 2018 (24 participants). Only 4 of 131 papers in 2017 and 5 of 142 papers in 2018 had pre-study power calculations, most for single t-tests and correlations. Only 14% of highly cited papers reported the number of excluded participants whereas about 45% of papers in 2017 and 2018 reported excluded participants. Targeted interventions from publishers and funders could facilitate increase in sample sizes and adherence to better standards.
Epistasis, inbreeding depression and the evolution of self-fertilization
Authors: Awad Diala Abu , Roze Denis
Published: October 2019

Inbreeding depression resulting from partially recessive deleterious alleles is thought to be the main genetic factor preventing self-fertilizing mutants from spreading in outcrossing hermaphroditic populations. However, deleterious alleles may also generate an advantage to selfers in terms of more efficient purging, while the effects of epistasis among those alleles on inbreeding depression and mating system evolution remain little explored. In this paper, we use a general model of selection to disentangle the effects of different forms of epistasis (additive-by-additive, additive-by-dominance and dominance-by-dominance) on inbreeding depression and on the strength of selection for selfing. Models with fixed epistasis across loci, and models of stabilizing selection acting on quantitative traits (generating distributions of epistasis) are considered as special cases. Besides its effects on inbreeding depression, epistasis may increase the purging advantage associated with selfing (when it is negative on average), while the variance in epistasis favors selfing through the generation of linkage disequilibria that increase mean fitness. Approximations for the strengths of these effects are derived, and compared with individual-based simulation results.
Age-related Structural and Functional Variations in 5967 Individuals across the Adult Lifespan
Authors: Luo Na , Sui Jing , Abrol Anees , Lin Dongdong , Chen Jiayu , Vergara Victor M. , Fu Zening , Du Yuhui , Damaraju Eswar , Xu Yong , Turner Jessica A. , Calhoun Vince D.
Published: October 2019

Exploring brain changes across the human lifespan is becoming an important topic in neuroscience. Though there are multiple studies which investigated the relationship between age and brain imaging data, the results are heterogeneous due to small sample sizes and relatively narrow age ranges. Here, based on year-wise estimation of 5967 subjects from 13 to 72 years old, we aimed to provide a more precise description of adult lifespan variation trajectories of gray matter volume (GMV), structural network correlation (SNC) and functional network connectivity (FNC) using independent component analysis and multivariate linear regression model. Our results revealed the following relationships: 1)GMV linearly declined with age in most regions, while parahippocampus showed an inverted U-shape quadratic relationship with age; SNC presented a U-shape quadratic relationship with age within cerebellum, and inverted U-shape relationship primarily in the default mode network (DMN) and frontoparietal (FP) related correlation. 2) FNC tended to linearly decrease within resting-state networks (RSNs), especially in visual network and DMN. Early increase was revealed between RSNs, primarily in FP and DMN, which experienced decrease at older ages. U-shape relationship was also revealed to compensate for the cognition deficit in attention and subcortical related connectivity at late years. 3) The link between middle occipital gyrus and insula, as well as precuneus and cerebellum, exhibited similar changing trends between SNC and FNC across the adult lifespan. Collectively, these results highlight the benefit of lifespan study and provide a precise description of age-related regional variation and SNC/FNC changes based on a large dataset.
Revealing α oscillatory activity using voltage-sensitive dye imaging in monkey V1
Authors: Chemla Sandrine , Roux Sebastien , Reynaud Alexandre , Chavane Frédéric , VanRullen Rufin
Published: October 2019

The relevance of α oscillations (7-12Hz) in neural processing, although recognized long ago, remains a major research question in the field. While intensively studied in humans, α oscillations appear much less often investigated (and observed) in monkeys. Here we wish to provide data from non-human primates on stimulus-related α rhythm. Indeed, in humans, EEG α is enhanced in response to non-periodic dynamic visual stimulation (“perceptual echoes” or to a static stimulus (“flickering wheel illusion”). Do the same visual patterns induce an oscillatory response in monkey V1? We record voltage-sensitive dye signals from three anesthetized monkeys to investigate the population-based oscillatory neural response that is not resulting from attention-related feedback signals. We revealed α oscillations in monkey V1 which, when they occur, react in a manner comparable to human studies.
Monitoring of group mates in relation to their activity in mandrills
Authors: Schino Gabriele , Scerbo Martina
Published: October 2019

Primates are known to have considerable knowledge about the social relationships that link their group mates, and are likely to derive this information from observing the social interactions that occur in their social group. They may therefore be hypothesized to pay particular attention to the social interactions involving group mates. In this study, we evaluated how the attention captive mandrills (Mandrillus sphinx) devote to their group mates was modulated by the behavior of the latter. Mandrills looked most frequently at foraging individuals and least frequently at sleeping invividuals. Mandrills also looked at grooming individuals more than at individuals that were simply sitting in contact. Grooming dyads were looked at regardless of the social rank and kinship of the individuals involved. These results contribute to our understanding of how primates obtain their social knowledge.
Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle
Authors: Dhuppar Shivnarayan , Mazumder Aprotim
Published: October 2019

Nuclear architecture is the organization of the genome within a cell nucleus with respect to different nuclear landmarks such as nuclear lamina, matrix or nucleoli. Lately it has emerged as a major regulator of gene expression in mammalian cells. The studies connecting nuclear architecture with gene expression are largely population-averaged and do not report on the heterogeneity in genome organization or in gene expression within a population. In this report we present a method for combining 3D DNA Fluorescencein situHybridization (FISH) with single molecule RNA FISH (smFISH) and immunofluorescence to study nuclear architecture-dependent gene regulation on a cell-by-cell basis. We further combine it with an imaging-based cell cycle staging to correlate nuclear architecture with gene expression across the cell cycle. We present this in the context ofCyclin A2 (CCNA2)gene for its known cell cycle-dependent expression. We show that, across the cell cycle, the expression of aCCNA2gene copy is stochastic and depends neither on its sub-nuclear position—which usually lies close to nuclear lamina—nor on the expression from the other copies.
Experimental and field data support habitat expansion of the allopolyploidArabidopsis kamchaticaowing to parental legacy of heavy metal hyperaccumulation
Authors: Paape Timothy , Akiyma Reiko , Cereghetti Teo , Onda Yoshihiko , Hirao Akira , Kenta Tanaka , Shimizu Kentaro K.
Published: October 2019

Little empirical evidence is available whether allopolyploid species combine or merge adaptations of parental species. The allopolyploid speciesArabidopsis kamchaticais a natural hybrid of the diploid parentsA. halleri, a heavy metal hyperaccumulator, andA. lyrata, a non-hyperaccumulating species. Zinc and cadmium were measured in native soils and leaf tissues in natural populations, and in hydroponic cultures ofA. kamchaticaandA. halleri. Pyrosequencing was used to estimate homeolog expression ratios. Soils from human modified sites showed significantly higher Zn concentrations than non-modified sites. Leaf samples ofA. kamchaticacollected from 40 field localities had > 1,000 µg g-1Zn in over half of the populations, with significantly higher amounts of Zn concentrations in plants from human modified sites. In addition, serpentine soils were found in two populations. Most genotypes accumulated >3000 µg g-1of Zn in hydroponic culture with high variability among them. Genes involved in hyperaccumulation showed a bias in thehalleri-derived homeolog.A. kamchaticahas retained constitutive hyperaccumulation ability inherited fromA. halleri. Our field and experimental data provides a compelling example in which the inheritance of genetic toolkits for soil adaptations likely contributed to the habitat expansion of an allopolyploid species.
Joint phylogenetic estimation of geographic movements and biome shifts during the global diversification ofViburnum
Authors: Landis Michael J. , Eaton Deren A. R. , Clement Wendy L. , Park Brian , Spriggs Elizabeth L. , Sweeney Patrick W. , Edwards Erika J. , Donoghue Michael J.
Published: October 2019

Phylogeny, fossils, biogeography, and biome occupancy provide evidence that reflects the singular evolutionary history of a clade. Despite the connections that bind them together, these lines of evidence are most often studied separately, by first inferring a fossil-dated molecular phylogeny, then mapping on ancestral ranges and biomes inferred from extant species. Here we jointly model the evolution of biogeographic ranges, biome affinities, and molecular sequences, incorporating fossils to estimate a dated phylogeny for all of the 163 extant species of the woody plant cladeViburnum(Adoxaceae) that we currently recognize. Our analyses indicate that while the majorViburnumlineages evolved in the Eocene, the majority of extant species originated since the Miocene.Viburnumradiated first in Asia, in warm, broad-leaved evergreen (lucidophyllous) forests. Within Asia we infer several early shifts into more tropical forests, and multiple shifts into forests that experience prolonged freezing. From Asia we infer two early movements into the New World. These two lineages probably first occupied warm temperate forests and adapted later to spreading cold climates. One of these lineages (Porphyrotinus) occupied cloud forests and moved south through the mountains of the Neotropics. Several other movements into North America took place more recently, facilitated by prior adaptations to freezing in the Old World. We also infer four disjunctions between Asia and Europe: theTinuslineage is the oldest and probably occupied warm forests when it spread, while the other three were more recent and in cold-adapted lineages. These results variously contradict published accounts, especially the view thatViburnumradiated initially in cold forests and, accordingly, maintained vessel elements with scalariform perforations. We explored how the location and biome assignments of fossils affected our inference of ancestral areas and biome states. Our results are sensitive to, but not entirely dependent upon, the inclusion of fossil biome data. We argue that it will be critical to take advantage of all available lines of evidence to decipher events in the distant past, and the joint estimation approach developed here provides cautious hope even when fossil evidence is limited.
In vitro Efficacy of Novel Glucan Synthase Inhibitor, Ibrexafungerp (SCY-078), Against Multidrug- and Pan-resistant Candida auris Isolates from the Outbreak in New York
Authors: Zhu Yan Chun , Barat Stephen A. , Borroto-Esoda Katyna , Angulo David , Chaturvedi Sudha , Chaturvedi Vishnu
Published: October 2019

We report low MIC50 of Ibrexafungerp (SCY-078) for 102 Candida auris clinical and surveillance isolates from outbreak in New York. The group included C. auris with a variable resistance to antifungal drugs. Five pan-resistant C. auris isolates were susceptible to Ibrexafungerp with low MIC50 range of 0.12-1 µg/ml.
Lost in Translation: population genomics and long-read sequencing reveals relaxation of concerted evolution of the ribosomal DNA cistron
Authors: Tremble Keaton , Suz Laura M. , Dentinger Bryn T.M.
Published: October 2019

Concerted evolution of the ribosomal DNA array has been studied in numerous eukaryotic taxa, yet is still poorly understood. rDNA genes are repeated dozens to hundreds of times in the eukaryotic genome [1] and it is believed that these arrays are homogenized through concerted evolution [2, 3] preventing the accumulation of intragenomic, and intraspecific, variation. However, numerous studies have reported rampant intragenomic and intraspecific variation in the rDNA array [4–10], contradicting our current understanding of concerted evolution. The internal transcribed spacers (ITS) of the rDNA cistron are the most commonly used DNA barcoding region inFungi[11], and rely on concerted evolution to homogenize the rDNA array leading to a “barcode gap” [12]. Here we show that inBoletus edulisBull., ITS intragenomic variation persists at low allele frequencies throughout the rDNA array, this variation does not correlate with genomic relatedness between populations, and rDNA genes may not evolve in a strictly concerted fashion despite the presence of unequal recombination and gene conversion. Under normal assumptions, heterozygous positions found in ITS sequences represent hybridization between populations, yet through allelic mapping of the rDNA array we found numerous heterozygous alleles to be stochastically introgressed throughout, presenting a dishonest signal of gene flow. Moreover, despite the signal of gene flow in ITS, our organisms were highly inbred, indicating a disconnect between true gene flow and barcoding signals. In addition, we show that while the mechanisms of concerted evolution are ongoing in pseudo-heterozygous individuals, they are not fully homogenizing the ITS array. Concerted evolution of the rDNA array may insufficiently homogenize the ITS gene, allowing for misleading signals of gene flow to persist, vastly complicating the use of the ITS locus for DNA barcoding inFungi.
Identifying density-dependent interactions in collective cell behaviour
Authors: Browning Alexander P , Jin Wang , Plank Michael J , Simpson Matthew J
Published: October 2019

Scratch assays are routinely used to study collective cell behaviour in vitro. Typical experimental protocols do not vary the initial density of cells, and typical mathematical modelling approaches describe cell motility and proliferation based on assumptions of linear diffusion and logistic growth. Jin et al. (2016) find that the behaviour of cells in scratch assays is density-dependent, and show that standard modelling approaches cannot simultaneously describe data initiated across a range of initial densities. To address this limitation, we calibrate an individual based model to scratch assay data across a large range of initial densities. Our model allows proliferation, motility, and a direction bias to depend on interactions between neighbouring cells. By considering a hierarchy of models where we systematically and sequentially remove interactions, we perform model selection analysis to identify the minimum interactions required for the model to simultaneously describe data across all initial densities. The calibrated model is able to match the experimental data across all densities using a single parameter distribution, and captures details about the spatial structure of cells. Our results provide strong evidence to suggest that motility is density-dependent in these experiments. On the other hand, we do not see the effect of crowding on proliferation in these experiments. These results are significant as they are precisely the opposite of the assumptions in standard continuum models, such as the Fisher-Kolmogorov equation and its generalisations.
Heterogeneous synaptic weighting improves neural coding in the presence of common noise
Authors: Sachdeva Pratik S. , Livezey Jesse A. , DeWeese Michael R.
Published: October 2019

Simultaneous recordings from the cortex have revealed that neural activity is highly variable, and that some variability is shared across neurons in a population. Further experimental work has demonstrated that the shared component of a neuronal population’s variability is typically comparable to or larger than its private component. Meanwhile, an abundance of theoretical work has assessed the impact shared variability has upon a population code. For example, shared input noise is understood to have a detrimental impact on a neural population’s coding fidelity. However, other contributions to variability, such as common noise, can also play a role in shaping correlated variability. We present a network of linear-nonlinear neurons in which we introduce a common noise input to model, for instance, variability resulting from upstream action potentials that are irrelevant for the task at hand. We show that by applying a heterogeneous set of synaptic weights to the neural inputs carrying the common noise, the network can improve its coding ability as measured by both Fisher information and Shannon mutual information, even in cases where this results in amplification of the common noise. With a broad and heterogeneous distribution of synaptic weights, a population of neurons can remove the harmful effects imposed by afferents that are uninformative about a stimulus. We demonstrate that some nonlinear networks benefit from weight diversification up to a certain population size, above which the drawbacks from amplified noise dominate over the benefits of diversification. We further characterize these benefits in terms of the relative strength of shared and private variability sources. Finally, we studied the asymptotic behavior of the mutual information and Fisher information analytically in our various networks as a function of population size. We find some surprising qualitative changes in the asymptotic behavior as we make seemingly minor changes in the synaptic weight distributions.
Dynamic encoding of social threat and spatial context in the hypothalamus
Authors: Krzywkowski Piotr , Penna Beatrice , Gross Cornelius T.
Published: October 2019

Territorial animals must be able to express social aggression or avoidance in a manner appropriate to spatial context and dominance status. Recent studies indicate that the ventromedial hypothalamus controls both innate aggression and avoidance, suggesting that it may encode an internal state of threat common to both behaviors. Here we used single unit in vivo calcium microendoscopy to identify neurons in the mouse ventromedial hypothalamus encoding social threat. Threat neurons were activated during social defeat as well as when the animal performed risk assessment. Unexpectedly, threat neurons were also activate in the chamber where the animal had been previously defeated and a distinct set of neurons emerged that were active in its home chamber, demonstrating the dynamic encoding of spatial context in the hypothalamus. Ensemble analysis of neural activity showed that social defeat induced a change in the encoding of social information and optogenetic activation of ventromedial hypothalamus neurons was able to elicit avoidance after, but not before social defeat, demonstrating a functional reorganization of the pathway by social experience. These findings reveal how instinctive behavior circuits in the hypothalamus dynamically encode spatial and sensory cues to drive adaptive social behaviors.
Directed evolution improves the catalytic efficiency of TEV protease
Authors: Sanchez Mateo I , Ting Alice Y
Published: October 2019

Tobacco etch virus protease (TEV) is one of the most widely-used proteases in biotechnology because of its exquisite sequence-specificity. A limitation, however, is its slow catalytic rate. We developed a generalizable yeast-based platform for directed evolution of protease catalytic properties. Protease activity is read out via proteolytic release of a membrane-anchored transcription factor, and we temporally regulate access to TEV’s cleavage substrate using a photosensory LOV domain. By gradually decreasing light exposure time, we enriched faster variants of TEV over multiple rounds of selection. Our S153N mutant (uTEV1Δ), when incorporated into the calcium integrator FLARE, improved the signal/background ratio by 27-fold, and enabled recording of neuronal activity in culture with 60-second temporal resolution. Given the widespread use of TEV in biotechnology, both our evolved TEV mutants and the directed evolution platform used to generate them, could be beneficial across a wide range of applications.
The genetic architecture of human brainstem structures and their involvement in common brain disorders
Authors: Elvsåshagen Torbjørn , Bahrami Shahram , van der Meer Dennis , Agartz Ingrid , Alnæs Dag , Barch Deanna M. , Baur-Streubel Ramona , Bertolino Alessandro , Beyer Mona K. , Blasi Giuseppe , Borgwardt Stefan , Boye Birgitte , Buitelaar Jan , Bøen Erlend , Celius Elisabeth Gulowsen , Cervenka Simon , Conzelmann Annette , Coynel David , Carlo Pasquale Di , Djurovic Srdjan , Eisenacher Sarah , Espeseth Thomas , Fatouros-Bergman Helena , Flyckt Lena , Franke Barbara , Frei Oleksandr , Gelao Barbara , Harbo Hanne Flinstad , Hartman Catharina A. , Håberg Asta , Heslenfeld Dirk , Hoekstra Pieter , Høgestøl Einar A. , Jonassen Rune , Jönsson Erik G. ,   Karolinska Schizophrenia Project (KaSP) consortium, Kirsch Peter , Kłoszewska Iwona , Lagerberg Trine Vik , Landrø Nils Inge , Hellard Stephanie Le , Lesch Klaus-Peter , Maglanoc Luigi A. , Malt Ulrik F. , Mecocci Patrizia , Melle Ingrid , Meyer-Lindenberg Andreas , Moberget Torgeir , Nordvik Jan Egil , Nyberg Lars , O’Connell Kevin S. , Oosterlaan Jaap , Papalino Marco , Papassotiropoulos Andreas , Pauli Paul , Pergola Giulio , Persson Karin , de Quervain Dominique , Reif Andreas , Rokicki Jarek , van Rooij Daan , Shadrin Alexey A. , Schmidt André , Schwarz Emanuel , Selbæk Geir , Soininen Hilkka , Sowa Piotr , Steen Vidar M. , Tsolaki Magda , Vellas Bruno , Wang Lei , Westman Eric , Ziegler Georg , Zink Mathias , Andreassen Ole A. , Westlye Lars T. , Kaufmann Tobias
Published: October 2019

Brainstem regions support critical bodily functions, yet their genetic architectures and involvement in brain disorders remain understudied. Here, we examined volumes of brainstem structures using magnetic resonance imaging in 43,353 individuals. In 27,034 genotyped healthy participants, we identified 16 genetic loci associated with whole brainstem volume and 10, 23, 3, and 9 loci associated with volumes of the midbrain, pons, superior cerebellar peduncle, and medulla oblongata, respectively. These loci were mapped to 305 genes, including genes linked to brainstem development and common brain disorders. We detected genetic overlap between the brainstem volumes and eight psychiatric and neurological disorders. Using imaging data from 16,319 additional individuals, we observed differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease. Together, our results provide new insights into the genetic underpinnings of brainstem structures and support their involvement in common brain disorders.
Genome Report: De novo assembly of a high-quality reference genome for the Horned Lark (Eremophila alpestris)
Authors: Mason Nicholas A. , Pulgarin Paulo , Cadena Carlos Daniel , Lovette Irby J.
Published: October 2019

The Horned Lark (Eremophila alpestris) is a species of small songbird that exhibits remarkable geographic variation in appearance and habitat across an expansive distribution. While E. alpestris and related species have been the focus of many ecological and evolutionary studies, we still lack a highly contiguous genome assembly for horned larks and related taxa (Alaudidae). Here, we present CLO_EAlp_1.0, a highly contiguous assembly for horned larks generated from blood samples of a wild, male bird captured in the Altiplano Cundiboyacense of Colombia. By combining short-insert and mate-pair libraries with the ALLPATHS-LG genome assembly pipeline, we generated a 1.04 Gb assembly comprised of 2708 contigs with an N50 of 10.58 Mb and a L50 of 29. After polishing the genome, we were able to identify 94.5% of single-copy gene orthologs from an Aves data set and 97.7% of single-copy gene orthologs from a vertebrata data set, indicating that our de novo assembly is near complete. We anticipate that this genomic resource will be useful to the broader ornithological community and those interested in studying the evolutionary history and ecological interactions of a widespread, yet understudied lineage of songbirds.
Fully-automated and ultra-fast cell-type identification using specific marker combinations from single-cell transcriptomic data
Authors: Ianevski Aleksandr , Giri Anil K , Aittokallio Tero
Published: October 2019

Single-cell transcriptomics enables systematic charting of cellular composition of complex tissues. Identification of cell populations often relies on unsupervised clustering of cells based on the similarity of their scRNA-seq profiles, followed by manual annotation of cell clusters using established marker genes. However, manual selection of marker genes is a time-consuming process that may lead to sub-optimal annotation results as the selected markers must be informative of both the individual cell clusters and various cell types present in the complex samples. Here, we developed a computational platform, termed ScType, which enables data-driven, fully-automated and ultra-fast cell-type identification based solely on given scRNA-seq data, combined with our comprehensive cell marker database as background information. Using a compendium of six scRNA-seq datasets from various human and mouse tissues, we show how ScType provides an unbiased and accurate cell-type annotation by guaranteeing the specificity of positive and negative marker genes both across cell clusters and cell types. We also demonstrate how ScType enables distinguishing between healthy and malignant cell populations, based on single-cell calling of single-nucleotide variants, making it a versatile tool for exploration and use of single-cell transcriptomic data for anticancer applications. The widely-applicable method is deployed both as an interactive web-tool (https://sctype.app), and as an open-source R-package, connected with a comprehensive ScType database of specific markers.
Lineage-Specific Epigenomic and Genomic Activation of the Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas
Authors: Pan Jian , Silva Tiago C. , Gull Nicole , Yang Qian , Plummer Jasmine , Chen Stephanie , Daigo Kenji , Hamakubo Takao , Gery Sigal , Ding Ling-Wen , Jiang Yan-Yi , Hu Shao-Yan , Xu Li-Yan , Li En-Min , Ding Yanbing , Klempner Samuel J. , Berman Benjamin P. , Phillip Koeffler H. , Lin De-Chen
Published: October 2019

Backgrounds

Gastrointestinal adenocarcinomas (GIACs) of the tubular GI tract including esophagus, stomach, colon and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIACs are less well-characterized.We applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks using 907 GIAC samples from The Cancer Genome Atlas (TCGA). Complementary epigenomic technologies were performed to investigate HNF4A activation, including Circularized Chromosome Conformation Capture (4C), Chromatin immunoprecipitation (ChIP) sequencing, Whole Genome Bisulfite Sequencing (WGBS), and Assay for Transposase-Accessible Chromatin (ATAC) sequencing. In vitro and in vivo cellular phenotypical assays were conducted to study HNF4A functions.

Results

We identified a list of functionally hyperactive master regulator (MR)TFs shared across different GIACs. As the top candidate, HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. We further characterized a complex interplay between HNF4A promoter and three distal enhancer elements, which was coordinated by GIAC-specific MRTFs including ELF3, GATA4, GATA6 and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptionally activating many downstream targets including HNF1A and factors of Interleukin signaling in a lineage-specific manner.

Conclusion

We use a large cohort of patient samples and an unbiased mathematical approach to highlight lineage-specific oncogenic MRTFs, which provide new insights into the GIAC-specific gene regulatory networks, and identify potential therapeutic strategies against these common cancers.
Juvenile rank acquisition influences fitness independent of adult rank
Authors: Strauss Eli D , Shizuka Daizaburo , Holekamp Kay E
Published: October 2019

Social rank has been identified as a significant determinant of fitness in a variety of species. The importance of social rank suggests that the process by which juveniles come to establish their position in the social hierarchy is a critical component of social development. Here, we use the highly predictable process of rank acquisition in spotted hyenas to study the consequences of variation in rank acquisition in early life. In spotted hyenas, rank is ‘inherited’ through a learning process called ‘maternal rank inheritance.’ This pattern is highly predictable: ~80% of juveniles acquire the exact rank predicted by the rules of maternal rank inheritance. This predictable nature of rank acquisition in these societies allows the process of rank acquisition to be studied independently from the ultimate rank that each juvenile attains. In this study, we use a novel application of the Elo-rating method to calculate each juvenile’s deviation from expected pattern of maternal rank inheritance during development. Despite variability in rank acquisition in juveniles, most of these juveniles come to attain the exact rank expected of them according to the rules of maternal rank inheritance. Nevertheless, we find that transient variation in rank acquisition in early life predicts long term fitness consequences for these individuals: juveniles ‘underperforming’ their expected ranks show reduced survival and lower lifetime reproductive success than better-performing peers. Finally, we present evidence that this variability in rank acquisition in early life represents a source of early life adversity, and that multiple sources of early life adversity have cumulative, but not compounding, effects on fitness.
Mechanotransduction activity facilitates hair cell toxicity caused by the heavy metal cadmium
Authors: Schmid Caleigh , Alampi Isabella , Briggs Jay , Tarcza Kelly , Stawicki Tamara M
Published: October 2019

Hair cells are sensitive to many insults including environmental toxins such as heavy metals. We show here that cadmium can consistently kill hair cells of the zebrafish lateral line. Disrupting hair cell mechanotransduction genetically or pharmacologically significantly reduces the amount of hair cell death seen in response to cadmium, suggesting a role for mechanotransduction in this cell death process, possibly as a means for cadmium uptake into the cells. Likewise, when looking at multiple cilia-associated gene mutants that have previously been shown to be resistant to aminoglycoside-induced hair cell death, resistance to cadmium-induced hair cell death is only seen in those with mechanotransduction defects. In contrast to what was seen with mechanotransduction, significant protection was not consistently seen from other ions previously shown to compete for cadmium uptake into cells or tissue including zinc and copper. These results show that functional mechanotransduction activity is playing a significant role in cadmium-induced hair cell death.
Single Cell Transcriptional Profiling of Phox2b-Expressing Geniculate Ganglion Neurons
Authors: Anderson Catherine B. , Larson Eric D.
Published: October 2019

The sense of taste is fundamental for survival as harmful substances can be discriminated and prevented from entering the body. Taste buds act as chemosensory sentinels and detect bitter, salty, sweet, sour, and umami substances and transmit signals to afferent nerve fibers. Whether a single gustatory nerve fiber selectively is responsive to a single taste modality (through taste receptor cell activation) is a point of contention in the field.. In the present study, we present a method for single cell RNA sequencing of gustatory geniculate ganglion neurons and compare the results obtained to two prior published works. Additionally, independent reanalysis of the raw data from these previous studies confirms molecular heterogeneity of ganglion neurons. Multiple gustatory clusters are found, and we compare cluster markers identified by the original works and those identified in the present study. Across all datasets and analyses, specific clusters show a high degree of correlation including a somatosensory cluster (Phox2b-, Piezo2+, Fxyd2+), a potential sweet-best cluster (Phox2b+, Spon1+, Olfm3+), and a potential sour-best cluster (Phox2b+, Penk+, Htr3a+). Additionally, a putative mechanosensitive gustatory cluster with an unknown functional role is identified (Phox2b+, Piezo2+, Calb1+). Other gustatory clusters (Phox2b+) are more varied across analyses, but are marked by Olfm3. Which, if any, clusters comprise umami-best, bitter-best, or salty-best fibers will require further study.
Length-dependent accumulation of double-stranded RNAs in plastids affects RNA interference efficiency in the Colorado potato beetle
Authors: He Wanwan , Xu Wenbo , Xu Letian , Fu Kaiyun , Guo Wenchao , Bock Ralph , Zhang Jiang
Published: October 2019

Transplastomic potato plants expressing double-stranded RNA (dsRNA) targeted against essential genes of the Colorado potato beetle (CPB) can be lethal to larvae by triggering an RNA interference (RNAi) response. High accumulation levels of dsRNAs in plastids are crucial to confer an efficient RNAi response in the insects. However, whether length and sequence of the dsRNA determine the efficacy of RNAi and/or influence the level of dsRNA accumulation in plastids is not known. Here we compared the RNAi efficacy of different lengths of dsRNA targeted against the CPB β–Actin gene (ACT) by feeding in vitro-synthesized dsRNAs to larvae. We show that, while the 60 bp dsRNA induced only a relatively low RNAi response in CPB, dsRNAs of 200 bp and longer caused high mortality and similar larval growth retardation. When the dsRNAs were expressed from the plastid (chloroplast) genome of potato plants, we found that their accumulation levels were correlated with length. dsRNA accumulation levels were positively associated with the observed mortality, suppression of larval growth and suppression of target gene expression. Importantly, transplastomic potato plants expressing the 200 bp dsRNA were better protected from CPB than plants expressing the 297 bp dsRNA, the best-performing line in our previous study. Our results suggest that the length of dsRNAs is an important factor that influences their accumulation levels in plastids and thus determines the strength of the insecticidal RNAi effect. Our findings will aid the design of optimized dsRNA expression constructs for plant protection by plastid-mediated RNAi.
Efficacy of chronic ultrasound neurostimulation on behaviors and distributed brain metabolism in depressive-like mice
Authors: Legrand Marc , Galineau Laurent , Novell Anthony , Planchez Barbara , Brizard Bruno , Leman Samuel , Tauber Clovis , Escoffre Jean-Michel , Lefèvre Antoine , Gosset Philippe , El-Hage Wissam , Emond Patrick , Belzung Catherine , Bouakaz Ayache
Published: October 2019

Major depression is one of the main factors contributing to the Global Burden of Disease. Current treatment strategies (e.g., antidepressants and neurostimulation techniques) of major depression show some limitations including inaccuracy and invasiveness. Ultrasound neurostimulation (USNS) has been recently introduced as a physical non-invasive method for brain tissue stimulation and has gained increasing interest. In this study, we sought to evaluate the efficacy of transcranial USNS in an unpredictable chronic mild stress (UCMS) mouse model. The results show that transcranial USNS of the infralimbic cortex reduced anxiety-related behaviors as well as some, but not all, depression-related parameters. [18F]-FDG microPET imaging and brain metabolomic analyses showed that USNS triggered the activation of targeted brain region in addition to brain areas at a distance from the targeted zone, alleviating anxiety and depression-related behaviors induced by the UCMS regimen. Transcranial ultrasound neurostimulation show therapeutic potential in some aspects of major depression.
GPI-anchored SKU5/SKS are maternally required for integument development in Arabidopsis
Authors: Zhou Ke
Published: October 2019

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) play crucial roles in various processes in eukaryotes. In Arabidopsis, SKS1, SKS2, SKS3 and SKU5 from SKU5/SKS gene family could encode GPI-anchored proteins, and they were recently reported to regulate cell polar expansion and cell wall synthesis redundantly in roots. Here, we report that, they are also redundantly crucial for seed production and seed morphogenesis in Arabidopsis through regulating maternal integument development. Their loss-of-functions resulted in disrupted development of integuments that failed to protect embryo sacs from exposure to external space due to physical restriction, and lead to female gametophytic abortion. Interestingly, those less defective ovules could be fertilized and develop into seeds normally, however, their seed morphogenesis was largely affected.

Our research made SKS1, SKS2, SKS3 an SKU5 be not only the first class of GPI-anchored proteins that could regulate maternal integument development, but also the first class of proteins that could regulate cell polar expansion in both root and integument cells besides several MAPK cascade components. Our study also underlined the regulation by integument development in reproductive processes.