bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex classification using long-range temporal dependence of resting-state functional MRI time series
Authors: Dhamala Elvisha , Jamison Keith W. , Sabuncu Mert R. , Kuceyeski Amy
Published: October 2019

A thorough understanding of sex differences, if any, that exist in the brains of healthy individuals is crucial for the study of neurological illnesses that exhibit differences in clinical and behavioural phenotypes between males and females. In this work, we evaluate sex differences in regional temporal dependence of resting-state brain activity using 195 male-female pairs (aged 22-37) from the Human Connectome Project. Male-female pairs are strictly matched for total grey matter volume. We find that males have more persistent long-range temporal dependence than females in regions within temporal, parietal, and occipital cortices. Machine learning algorithms trained on regional temporal dependence measures achieve sex classification accuracies of up to 81%. Regions with the strongest feature importance in the sex classification task included cerebellum, amygdala, frontal cortex, and occipital cortex. Additionally, we find that even after males and females are strictly matched on total grey matter volume, significant regional volumetric sex differences persist in many cortical and subcortical regions. Our results indicate males have larger cerebella, hippocampi, parahippocampi, thalami, caudates, and amygdalae while females have larger cingulates, precunei, frontal cortices, and parietal cortices. Sex classification based on regional volume achieves accuracies of up to 85%; cerebellum, cingulate cortex, and temporal cortex are the most important features. These findings highlight the important role of strict volume matching when studying brain-based sex differences. Differential patterns in regional temporal dependence between males and females identifies a potential neurobiological substrate underlying sex differences in functional brain activation patterns and the behaviours with which they correlate.
γH2AX in the S Phase After UV Irradiation Corresponds to DNA Replication and Not to the Extent of DNA Damage
Authors: Dhuppar Shivnarayan , Roy Sitara , Mazumder Aprotim
Published: October 2019

Ultraviolet (UV) radiation is a major environmental mutagen. Exposure to UV leads to a sharp peak of γH2AX – the phosphorylated form of a histone variant H2AX – in the S phase within an asynchronous population of cells. γH2AX is often considered as a definitive marker of DNA damage inside a cell. In this report we show that γH2AX in the S phase cells after UV irradiation does not report on the extent of primary DNA damage in the form of cyclobutane pyrimidine dimers or on the extent of its secondary manifestations as DNA double strand breaks or in the inhibition of global transcription. Instead γH2AX in the S phase corresponds to the sites of active replication at the time of UV irradiation – despite which, the cells complete the replication of their genomes and arrest within the G2 phase. Moreover, cells in all the phases of the cell cycle develop similar levels of DNA damage. Our study suggests that it is not DNA damage but the response elicited, which peaks in the S phase upon UV damage.
The spatial heterogeneity of the gut limits bacteriophage predation leading to the coexistence of antagonist populations of bacteria and their viruses
Authors: Lourenço Marta , Chaffringeon Lorenzo , Lamy-Besnier Quentin , Campagne Pascal , Eberl Claudia , Bérard Marion , Stecher Bärbel , Debarbieux Laurent , De Sordi Luisa
Published: October 2019

Bacteria and their viruses, bacteriophages (phages), are the most abundant components of the mammalian gut microbiota where these two entities coexist over time. The ecological dynamics underlying the coexistence between these two antagonistic populations in the gut are unknown. We challenged a murine synthetic bacterial community with a set of virulent phages, to study the factors allowing phages-bacteria coexistence in the gut. We found that coexistence was neither dependent on an arms race between bacteria and phages, nor on the ability of phages to extend host range. Instead, our data suggest that some phage-inaccessible sites in the mucosa of the ileum serve as a spatial refuge for bacteria, which from there disseminate in the gut lumen. Luminal phages amplify by infecting luminal bacteria maintaining phage throughout the gut. We conclude that the heterogeneous distribution of microbes in the gut contributes to the long-term coexistence of phages with phage-susceptible bacteria. This observation could explain the persistence in the human gut of intestinal phages, such as the crAssphage, as well as the low efficiency of oral phage therapy against enteric pathogens in animal models and clinical trials.
GraphAligner: Rapid and Versatile Sequence-to-Graph Alignment
Authors: Rautiainen Mikko , Marschall Tobias
Published: October 2019

Genome graphscan represent genetic variation and sequence uncertainty. Aligning sequences to genome graphs is key to many applications, including error correction, genome assembly, and genotyping of variants in a pan-genome graph. Yet, so far this step is often prohibitively slow. We present GraphAligner, a tool for aligning long reads to genome graphs. Compared to state-of-the-art tools, GraphAligner is 12x faster and uses 5x less memory, making it as efficient as aligning reads to linear reference genomes. When employing GraphAligner for error correction, we find it to be almost 3x more accurate and over 15x faster than extant tools.

Availability Package manager

https://anaconda.org/bioconda/graphalignerand source code:https://github.com/maickrau/GraphAligner
Changes in cross-frequency coupling following closed-loop auditory stimulation in non-rapid eye movement sleep
Authors: Elena Krugliakova , Carina Volk , Valeria Jaramillo , Georgia Sousouri , Reto Huber
Published: October 2019

The activity of different brain networks in non-rapid eye movement (NREM) sleep is regulated locally in an experience-dependent manner, reflecting the extent of the network load during wakefulness. In particular, improved task performance after sleep correlates with the local post-learning power increase of neocortical slow waves and faster oscillations such as sleep spindles and their temporal coupling. Recently, it was demonstrated that by targeting slow waves in a particular region at a particular phase with closed-loop auditory stimulation it is possible to locally manipulate slow-wave activity and interact with training-induced neuroplastic changes. Based on this finding, we tested whether closed-loop auditory stimulation targeting the up-phase of slow-waves over the right sensorimotor area might affect power in delta, theta and sigma bands and coupling between these oscillations within the circumscribed region. We demonstrate that while closed-loop auditory stimulation globally enhances power in delta, theta and sigma bands, changes in cross-frequency coupling of these oscillations were more spatially restricted. In particular, stimulation induced a significant decrease of delta-theta coupling in frontal channels, within the area of the strongest baseline coupling between these frequency bands. In contrast, a significant increase in delta-sigma coupling was observed over the right parietal area, located directly posterior to the target electrode. These findings suggest that closed-loop auditory stimulation locally modulates coupling between delta phase and sigma power in a targeted region, which could be used to manipulate sleep-dependent memory formation within the brain network of interest.
Statistical Analysis of Spatial Expression Pattern for Spatially Resolved Transcriptomic Studies
Authors: Sun Shiquan , Zhu Jiaqiang , Zhou Xiang
Published: October 2019

Recent development of various spatially resolved transcriptomic techniques has enabled gene expression profiling on complex tissues with spatial localization information. Identifying genes that display spatial expression pattern in these studies is an important first step towards characterizing the spatial transcriptomic landscape. Detecting spatially expressed genes requires the development of statistical methods that can properly model spatial count data, provide effective type I error control, have sufficient statistical power, and are computationally efficient. Here, we developed such a method, SPARK. SPARK directly models count data generated from various spatial resolved transcriptomic techniques through generalized linear spatial models. With a new efficient penalized quasi-likelihood based algorithm, SPARK is scalable to data sets with tens of thousands of genes measured on tens of thousands of samples. Importantly, SPARK relies on newly developed statistical formulas for hypothesis testing, producing well-calibratedp-values and yielding high statistical power. We illustrate the benefits of SPARK through extensive simulations and in-depth analysis of four published spatially resolved transcriptomic data sets. In the real data applications, SPARK is up to ten times more powerful than existing approaches. The high power of SPARK allows us to identify new genes and pathways that reveal new biology in the data that otherwise cannot be revealed by existing approaches.
From behavior to circuit modeling of light-seeking navigation in zebrafish larvae
Authors: Karpenko Sophia , Wolf Sébastien , Lafaye Julie , Goc Guillaume Le , Panier Thomas , Bormuth Volker , Candelier Raphaël , Debrégeas Georges
Published: October 2019

Bridging brain-scale circuit dynamics and organism-scale behavior is a central challenge in neuroscience. It requires the concurrent development of minimal behavioral and neural circuit models that can quantitatively capture basic sensorimotor operations. Here we focus on light-seeking navigation in zebrafish larvae. Using a virtual reality assay, we first characterize how motor and visual stimulation sequences govern the selection of discrete swim-bout events that subserve the fish navigation in the presence of a distant light source. These mechanisms are combined into a comprehensive Markov-chain model of navigation that quantitatively predict the stationary distribution of the fish’s body orientation under any given illumination profile. We then map this behavioral description onto a neuronal model of the ARTR, a small neural circuit involved in the orientation-selection of swim bouts. We demonstrate that this visually-biased decision-making circuit can similarly capture the statistics of both spontaneous and contrast-driven navigation.
Ketamine anesthesia induces gain enhancement via recurrent excitation in granular input layers of the auditory cortex
Authors: Deane Katrina E. , Brunk Michael G. K. , Curran Andrew W. , Zempeltzi Marina M. , Ma Jing , Lin Xiao , Abela Francesca , Aksit Sümeyra , Deliano Matthias , Ohl Frank W. , Happel Max F. K.
Published: October 2019

The N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, is commonly used as an anesthetic agent and has more recently gained attention as an antidepressant. Ketamine has been linked to increased stimulus-locked excitability, inhibition of interneurons, and modulation of intrinsic neuronal oscillations. However, the functional network mechanisms are still elusive. A better understanding of these anesthetic network effects may improve upon previous interpretations of seminal studies conducted under anesthesia and have widespread relevance for neuroscience with awake and anesthetized subjects as well as in medicine. Here, we investigated the effects of anesthetic doses of ketamine (15mg kg−1/h i.p.) on the network activity after pure tone stimulation within the auditory cortex of male Mongolian gerbils (Meriones unguiculatus). We used laminar current source density (CSD) analysis and subsequent layer-specific continuous wavelet analysis to investigate spatiotemporal response dynamics on cortical columnar processing in awake and ketamine-anesthetized animals. We found thalamocortical input processing within granular layers III/IV to be significantly increased under ketamine. This effect on early thalamocortical input processing was not due to changes in cross-trial phase coherence. Rather, the layer-dependent gain enhancement under ketamine was attributed to a broadband increase in amplitude reflecting an increase in recurrent excitation. The time-frequency analysis is further indicative of a prolonged period of stimulus-induced excitation possibly due to a reduced coupling of excitation and inhibition in granular input circuits—in line with the common hypothesis of cortical disinhibition via NMDA-mediated suppression of GABAergic interneurons.

Statement of significance

Ketamine is a common anesthetic agent and is known to alter excitability and neuronal synchronicity in the cortex. We reveal here that anesthetic doses of ketamine increase recurrent excitation of thalamic input in the granular layers of the auditory cortex of Mongolian gerbils. This leads to a layer-specific gain enhancement of the time-locked response to external stimuli. Analysis of tone-evoked amplitudes and cross-trial variability of cortical current sources and sinks indicate a mechanism of cortical disinhibition via NMDA-mediated suppression of GABAergic interneurons. Our findings might help to understand the functional mechanisms of the clinical effects of ketamine promoting the development of new therapeutic agents with lower side effects.
What is in a lichen? A metagenomic approach to reconstruct the holo-genome of Umbilicaria pustulata
Authors: Tzovaras Bastian Greshake , Segers Francisca H.I.D. , Bicker Anne , Grande Francesco Dal , Otte Jürgen , Anvar Seyed Yahya , Hankeln Thomas , Schmitt Imke , Ebersberger Ingo
Published: October 2019

Lichens are valuable models in symbiosis research and promising sources of biosynthetic genes for biotechnological applications. Most lichenized fungi grow slowly, resist aposymbiotic cultivation, and are generally poor candidates for experimentation. Obtaining contiguous, high quality genomes for such symbiotic communities is technically challenging. Here we present the first assembly of a lichen holo-genome from metagenomic whole genome shotgun data comprising both PacBio long reads and Illumina short reads. The nuclear genomes of the two primary components of the lichen symbiosis – the fungus Umbilicaria pustulata (33 Mbp) and the green alga Trebouxia sp. (53 Mbp) – were assembled at contiguities comparable to single-species assemblies. The analysis of the read coverage pattern revealed a relative cellular abundance of approximately 20:1 (fungus:alga). Gap-free, circular sequences for all organellar genomes were obtained. The community of lichen-associated bacteria is dominated by Acidobacteriaceae, and the two largest bacterial contigs belong to the genus Acidobacterium. Gene set analyses showed no evidence of horizontal gene transfer from algae or bacteria into the fungal genome. Our data suggest a lineage-specific loss of a putative gibberellin-20-oxidase in the fungus, a gene fusion in the fungal mitochondrion, and a relocation of an algal chloroplast gene to the algal nucleus. Major technical obstacles during reconstruction of the holo-genome were coverage differences among individual genomes surpassing three orders of magnitude. Moreover, we show that G/C-rich inverted repeats paired with non-random sequencing error in PacBio data can result in missing gene predictions. This likely poses a general problem for genome assemblies based on long reads.
Evidence for a role for BK channels in the regulation of ADAM17 activity
Authors: Yoshida Minae , Willis Dean
Published: October 2019

Large-conductance voltage and calcium activated channels, KCa1.1, have a large single conductance (~p250) and are highly selective for potassium ions. As a result they have been termed big potassium channels (BK channels). Because of the channel’s ability to integrate multiple physical and chemical signals they have received much attention in excitable cells. In comparison they have received relatively little attention in non-excitable cells in those of the immune system. Here we report evidence that the BK channel regulates ADAM17 activity. Upon macrophage activation, BK channels translocate to the cell membrane. Genetic or pharmacological inhibition of the cell membrane BK channels resulted in elevated TNF-α release and increased metalloproteinase a disintegrin and metalloproteinase domain 17 (ADAM17) activity. Inhibitors of BK channels also increased IL-6Rα release, a second ADAM17 substrate. In comparison, a BK channel opener decreases TNF-α release. Taken together, our results demonstrate a novel mechanism by which ion channel regulates ADAM17 activity. Given the broad range of ADAM17 substrates, this finding has implications in many fields of cell biology including immunology, neurology and cancer biology.
CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex
Authors: Gerbracht Jennifer V. , Boehm Volker , Britto-Borges Thiago , Kallabis Sebastian , Wiederstein Janica L. , Ciriello Simona , Aschemeier Dominik U. , Krüger Marcus , Frese Christian K. , Altmüller Janine , Dieterich Christoph , Gehring Niels H.
Published: October 2019

The exon junction complex (EJC) is an essential constituent and regulator of spliced messenger ribonucleoprotein particles (mRNPs) in metazoans. As a core component of the EJC, CASC3 was described to be pivotal for EJC-dependent nuclear and cytoplasmic processes. However, recent evidence suggests that CASC3 functions differently from other EJC core proteins. Here, we have established human CASC3 knockout cell lines to elucidate the cellular role of CASC3. In the knockout cells, overall EJC composition and EJC-dependent splicing are unchanged. A transcriptome-wide analysis reveals that hundreds of mRNA isoforms targeted by nonsense-mediated decay (NMD) are upregulated. Mechanistically, recruiting CASC3 to reporter mRNAs by direct tethering or via binding to the EJC stimulates mRNA decay and endonucleolytic cleavage at the termination codon. Building on existing EJC-NMD models, we propose that CASC3 equips the EJC with the ability to communicate with the NMD machinery in the cytoplasm. Collectively, our results characterize CASC3 as a peripheral EJC protein that tailors the transcriptome by promoting the degradation of EJC-dependent NMD substrates.
Selective disruption of synaptic BMP signaling by a Smad mutation adjacent to the highly conserved H2 helix
Authors: Nguyen Tho Huu , Han Tae Hee , Newfeld Stuart , Serpe Mihaela
Published: October 2019

Bone morphogenetic proteins (BMPs) shape normal development and function via canonical and non-canonical signaling pathways. When activating the canonical pathway, BMPs initiate signaling by binding to transmembrane receptors that phosphorylate pathway effectors, the Smad proteins, inducing their translocation into the nucleus and thus regulation of target genes. Phosphorylated Smads also accumulate at cellular junctions, but this non-canonical signaling modality remains less defined. We have recently reported that phosphorylated Smad (pMad inDrosophila) accumulates at synaptic junctions in complexes with genetically distinct composition and regulation. Here we examined a wide collection ofDrosophila Madalleles and searched for molecular features relevant to pMad accumulation at synaptic junctions. We found that strongMadalleles generally disrupt both synaptic and nuclear pMad accumulation, whereas moderateMadalleles have a wider range of phenotypes and could selectively impact different BMP signaling modalities. Interestingly, synaptic pMad appeared more sensitive to net reduction in Mad levels than nuclear pMad. Importantly, a previously uncharacterized allele,Mad8, showed markedly reduced synaptic pMad levels but only moderately diminished nuclear pMad signals. The postsynaptic composition and electrophysiological properties ofMad8NMJs were similarly altered. Using biochemical approaches, we examined how single point mutations such as S359L, present inMad8, could influence the Mad-receptor interface and we identified a key molecular determinant, the H2 helix. Our study highlights the biological relevance of the Smad-dependent, non-canonical BMP signaling and uncovers a highly conserved structural feature of Smads, critical for normal development and function.
IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection
Authors: Cubero Elia Moreno , Balint Stefan , Alrubayyi Aljawharah , Ogbe Ane , Matthews Rebecca , Burns Fiona , Rowland-Jones Sarah , Borrow Persephone , Schurich Anna , Dustin Michael , Peppa Dimitra
Published: October 2019

Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation including Natural Killer (NK) cell responses. Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive NK cell dysregulation. In this study we examined the metabolic processes that characterise NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in human cytomegalovirus (HCMV) infected HIV-1 seronegative individuals. However, the bioenergetic advantage of adaptive CD57+NKG2C+ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS) and limited fuel flexibility upon CD16 stimulation. Defective OXPHOS was accompanied by increased mitochondrial depolarisation and structural alterations indicative of mitochondrial dysfunction, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for receptor stimulation was alleviated upon IL-15 pre-treatment enhancing mammalian target of rapamycin complex1 (mTORC1) activity and NK cell functionality in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.
Rad53 controls DNA unwinding after helicase-polymerase uncoupling at DNA replication forks
Authors: Devbhandari Sujan , Remus Dirk
Published: October 2019

The coordination of DNA unwinding and synthesis at replication forks promotes efficient and faithful replication of chromosomal DNA. Using the reconstituted budding yeast DNA replication system, we demonstrate that Pol ε variants harboring catalytic point mutations in the Pol2 polymerase domain, contrary to Pol2 polymerase domain deletions, inhibit DNA synthesis at replication forks by displacing Pol δ from PCNA/primer-template junctions, causing excessive DNA unwinding by the replicative DNA helicase, CMG, uncoupled from DNA synthesis. Mutations that suppress the inhibition of Pol δ by Pol ε restore viability in Pol2 polymerase point mutant cells. We also observe uninterrupted DNA unwinding at replication forks upon dNTP depletion or chemical inhibition of DNA polymerases, demonstrating that leading strand synthesis is not tightly coupled to DNA unwinding by CMG. Importantly, the Rad53 kinase controls excessive DNA unwinding at replication forks by limiting CMG helicase activity, suggesting a mechanism for fork-stabilization by the replication checkpoint.
Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior
Authors: Flanigan Meghan E. , Aleyasin Hossein , Li Long , Burnett C. Joseph , Chan Kenny L. , LeClair Katherine B. , Lucas Elizabeth K. , Matikainen-Ankney Bridget , Janssen William , Takahashi Aki , Menard Caroline , Pfau Madeline L. , Golden Sam A. , Bouchard Sylvain , Calipari Erin S. , Nestler Eric J. , DiLeone Ralph J. , Yamanaka Akihiro , Huntley George W. , Clem Roger L. , Russo Scott J.
Published: October 2019

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have a wide variety of negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, repeated domination of subordinate social targets is reinforcing. Here, we show that orexin neurons originating from the lateral hypothalamus activate a small population of GABAergic interneurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) to promote aggression and conditioned place preference (CPP) for aggression-paired contexts. Our study suggests that the orexin system is a potential target for the development of novel therapies aimed at reducing aggressive behaviors and provides the first functional evidence of a local inhibitory circuit within the LHb.
Perception and memory have distinct spatial tuning properties in human visual cortex
Authors: Favila Serra E. , Kuhl Brice A. , Winawer Jonathan
Published: October 2019

Reactivation of earlier perceptual activity is thought to underlie long-term memory recall. Despite evidence for this view, it is unknown whether mnemonic activity exhibits the same tuning properties as feedforward perceptual activity. Here, we leveraged population receptive field models to parameterize fMRI activity in human visual cortex during spatial memory retrieval. Though retinotopic organization was present during both perception and memory, large systematic differences in tuning were also evident. Notably, whereas there was a three-fold decline in spatial precision from early to late visual areas during perception, this property was entirely abolished during memory retrieval. This difference could not be explained by reduced signal-to-noise or poor performance on memory trials. Instead, by simulating top-down activity in a network model of cortex, we demonstrate that this property is well-explained by the hierarchical structure of the visual system. Our results provide insight into the computational constraints governing memory reactivation in sensory cortex.
Hitching a Ride: Mechanics of Organelle Transport Through Linker-Mediated Hitchhiking
Authors: Mogre Saurabh S. , Christensen Jenna R. , Reck-Peterson Samara L. , Koslover Elena F.
Published: October 2019

In contrast to the canonical picture of transport by direct attachment to motor proteins, recent evidence shows that a number of intracellular ‘cargos’ navigate the cytoplasm by hitchhiking on motor-driven ‘carrier’ organelles. We describe a quantitative model of intracellular cargo transport via hitchhiking, examining the efficiency of hitchhiking initiation as a function of geometric and mechanical parameters. We focus specifically on the parameter regime relevant to the hitchhiking motion of peroxisome organelles in fungal hyphae. Our work predicts the dependence of transport initiation rates on the distribution of cytoskeletal tracks and carrier organelles, as well as the number, length and flexibility of the linker proteins that mediate contact between the carrier and the hitchhiking cargo. Furthermore, we demonstrate that attaching organelles to microtubules can result in a substantial enhancement of the hitchhiking initiation rate in tubular geometries such as those found in fungal hyphae. This enhancement is expected to increase the overall transport rate of hitchhiking organelles, and lead to greater efficiency in organelle dispersion. Our results leverage a quantitative physical model to highlight the importance of organelle encounter dynamics in non-canonical intracellular transport.

SIGNIFICANCE

A variety of cellular components are transported via hitchhiking by attaching to other motile organelles. Defects in the molecular machinery responsible for organelle hitchhiking may be linked with neurodegenerative disorders. To date, no comprehensive physical models of this non-canonical mode of transport have been developed. In particular, the connection between molecular- and organelle-scale properties of hitchhiking components and their effect on cellular-scale transport has remained unclear. Here, we investigate the mechanics of hitchhiking initiation and explore organelle interactions that can modulate the efficiency of this process.
Wnt signaling activates gene expression in the absence of theC. elegansDREAM repressor complex in somatic cells
Authors: Cherian Jerrin R. , Petrella Lisa N.
Published: October 2019

Establishment and maintenance of proper gene expression is a requirement for normal growth and development. The DREAM complex inCaenorhabditis elegansfunctions as a transcriptional repressor of germline genes in somatic cells. At 26°C, DREAM complex mutants show temperature associated increase in misexpression of germline genes in somatic cells and High Temperature Arrest (HTA) of worms at the first larval stage. To identify transcription factors required for the ectopic expression of germline genes in DREAM complex mutants, we conducted an RNA interference screen against 123 transcription factors capable of binding DREAM target promoter loci for suppression of the HTA phenotype inlin-54mutants. We found 15 embryonically expressed transcription factors that suppress the HTA phenotype inlin-54mutants. Five of the transcription factors found in the initial screen interact with the Wnt signaling pathways. In a subsequent RNAi suppression screen of Wnt signaling factors we found that knock-down of the non-canonical Wnt/PCP pathway factorsvang-1,prkl-1andfmi-1inlin-54mutant background resulted in strong suppression of the HTA phenotype. Animals mutant for bothlin-54andvang-1showed almost complete suppression of the HTA phenotype,pgl-1misexpression, and fertility defects associated withlin-54single mutants at 26°C. We propose a model whereby a set of embryonically expressed transcription factors, and the Wnt/PCP pathway, act opportunistically to activate DREAM complex target genes in somatic cells of DREAM complex mutants at 26°C.
Contrasting dates of rainforest fragmentation in Africa inferred from trees with different dispersal abilities
Authors: Piñeiro Rosalía , Hardy Olivier J. , Tovar Carolina , Gopalakrishnan Shyam , Vieira Filipe Garrett , Gilbert M Thomas P
Published: October 2019

The rainforests of Tropical Africa have fluctuated over time. Although today the forest cover is continuous in Central Africa this may have not always been the case, as the scarce fossil record in this region suggests that more arid conditions might have significantly reduced the density of trees during the Ice Ages. Our aim was to investigate whether the dry ice-age periods left a genetic signature on tree species that can be used to date the past fragmentation of the rainforest. We sequenced reduced representation libraries of 182 samples representing five Legume tree species that are widespread in African rainforests and seven outgroups. Phylogenetic analyses identified an early divergent lineage for all species in West Africa (Upper Guinea), and two clades in Central Africa: Lower Guinea-North and Lower Guinea-South. As the structure separating the Northern and Southern clades cannot be explained by geographic barriers, we tested other hypotheses using demographic model testing. The best estimates recovered using ∂a∂I indicate that the two clades split between the Upper Pliocene and the Pleistocene, a date compatible with forest fragmentation driven by ice-age climatic oscillations. Furthermore, we found remarkably older split dates for the shade-tolerant tree species with non-assisted seed dispersal than for light-demanding long-distance wind-dispersed trees. We also show that the genetic diversity significantly declines with the distance from ice-age refugia in the two long-distance dispersed species only. Different recolonisation abilities after recurrent cycles of forest fragmentation seem to explain why we observe congruent genetic spatial structures across species with contrasted timescales.

SIGNIFICANCE STATEMENT

Although today the rainforest cover is continuous in Central Africa, the scarce fossil record suggests that arid conditions during the Ice Ages might have reduced the density of trees during the Ice Ages. However, the vast majority of the fossil pollen records preserved in Tropical Africa is too young to inform about this period. Investigating whether the past climate change left a genetic signature on trees can thus be useful to date past forest fragmentation. However, most genetic studies available to date lack resolution as they use limited numbers of loci. In this study we use modern DNA technology to study five Legume trees. Our results show significant differentiation of the populations of each species at a date compatible with forest fragmentation driven by ice-age climatic oscillations. Contrasted timescales were obtained for each species, which probably reflects their different recolonisation abilities after forest fragmentation.
Nonlinear convergence boosts information coding in circuits with parallel outputs
Authors: Gutierrez Gabrielle J. , Rieke Fred , Shea-Brown Eric T.
Published: October 2019

Neural circuits are structured with layers of converging and diverging connectivity, and selectivity-inducing nonlinearities at neurons and synapses. These components have the potential to hamper an accurate encoding of the circuit inputs. Past computational studies have optimized the nonlinearities of single neurons, or connection weights in networks, to maximize encoded information, but have not grappled with the simultaneous impact of convergent circuit structure and nonlinear response functions for efficient coding. Our approach is to compare model circuits with different combinations of convergence, divergence, and nonlinear neurons to discover how interactions between these components affect coding efficiency. We find that a convergent circuit with divergent parallel pathways can encode more information with nonlinear subunits than with linear subunits, despite the compressive loss induced by the convergence and the nonlinearities when considered individually. These results show that the combination of selective nonlinearities and a convergent architecture - both elements that reduce information when acting separately - can promote efficient coding.

Significance Statement

Computation in neural circuits relies on a common set of motifs, including divergence of common inputs to parallel pathways, convergence of multiple inputs to a single neuron, and nonlinearities that select some signals over others. Convergence and circuit nonlinearities, considered individually, can lead to a loss of information about inputs. Past work has detailed how optimized nonlinearities and circuit weights can maximize information, but here, we show that incorporating non-invertible nonlinearities into a circuit with divergence and convergence, can enhance encoded information despite the suboptimality of these components individually. This study extends a broad literature on efficient coding to convergent circuits. Our results suggest that neural circuits may preserve more information using suboptimal components than one might expect.
Identifying Sialylation Linkages at the Glycopeptide Level by Glycosyltransferase Labeling Assisted Mass Spectrometry (GLAMS)
Authors: Zhu He , Wang Shuaishuai , Liu Ding , Ding Lang , Chen Congcong , Liu Yunpeng , Wu Zhigang , Bollag Roni , Liu Kebin , Yin Jun , Ma Cheng , Li Lei , Wang Peng George
Published: October 2019

Precise assignment of sialylation linkages at the glycopeptide level is of importance in bottom-up glycoproteomics, and is also an indispensable step to understand the function of glycoproteins in pathogen-host interactions and cancer progression. Even though some efforts have been dedicated to the discrimination of α2,3/α2,6-sialylated isomers, unambiguous identification of sialoglycopeptide isomers is still needed. Herein, an innovative strategy of glycosyltransferase labeling assisted mass spectrometry (GLAMS) was developed. After specific enzymatic labeling, oxonium ions from higher-energy C-trap dissociation (HCD) fragmentation of α2,3-sailoglycopeptides generate unique reporters to distinctly differentiate those of α2,6-sailoglycopeptide isomers. Using this strategy, a total of 1,236 linkage-specific sialoglycopeptides were successfully identified from 161 glycoproteins in human serum.

Abstract Figure
Codon usage bias creates a ramp of hydrogen bonding at the 5′-end in prokaryotic ORFeomes
Authors: Villada Juan C. , Duran Maria F. , Lee Patrick K. H.
Published: October 2019

Codon usage bias exerts control over a wide variety of molecular processes. The positioning of synonymous codons within coding sequences (CDSs) dictates protein expression by mechanisms such as local translation efficiency, mRNA Gibbs free energy, and protein co-translational folding. In this work, we explore how codon variants affect the position-dependent content of hydrogen bonding, which in turn influences energy requirements for unwinding double-stranded DNA. By analyzing over 14,000 bacterial, archaeal, and fungal ORFeomes, we found thatBacteriaandArchaeaexhibit an exponential ramp of hydrogen bonding at the 5′-end of CDSs, while a similar ramp was not found inFungi. The ramp develops within the first 20 codon positions in prokaryotes, eventually reaching a steady carrying capacity of hydrogen bonding that does not differ fromFungi. Selection against uniformity tests proved that selection acts against synonymous codons with high content of hydrogen bonding at the 5′-end of prokaryotic ORFeomes. Overall, this study provides novel insights into the molecular feature of hydrogen bonding that is governed by the genetic code at the 5′-end of CDSs. A web-based application to analyze the position-dependent hydrogen bonding of ORFeomes has been developed and is publicly available (https://juanvillada.shinyapps.io/hbonds/).
A Chromatin Accessibility Atlas of the Developing Human Telencephalon
Authors: Markenscoff-Papadimitriou Eirene , Whalen Sean , Przytycki Pawel , Thomas Reuben , Binyameen Fadya , Nowakowski Tomasz J. , Sanders Stephan J. , State Matthew W. , Pollard Katherine S. , Rubenstein John L.
Published: October 2019

Gene expression differs between cell types and regions within complex tissues such as the developing brain. To discover regulatory elements underlying this specificity, we generated genome-wide maps of chromatin accessibility in eleven anatomically-defined regions of the developing human telencephalon, including upper and deep layers of the prefrontal cortex. We predicted a subset of open chromatin regions (18%) that are most likely to be active enhancers, many of which are dynamic with 26% differing between early and late mid-gestation and 28% present in only one brain region. These region-specific predicted regulatory elements (pREs) are enriched proximal to genes with expression differences across regions and developmental stages and harbor distinct sequence motifs that suggest potential upstream regulators of regional and temporal transcription. We leverage this atlas to identify regulators of genes associated with autism spectrum disorder (ASD) including an enhancer of BCL11A, validated in mouse, and two functional de novo mutations in individuals with ASD in an enhancer of SLC6A1, validated in neuroblastoma cells. These applications demonstrate the utility of this atlas for decoding neurodevelopmental gene regulation in health and disease.

To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from eleven dissected regions of the mid-gestation human telencephalon, including upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed regional differences in chromatin accessibility, including many specific to one brain region, and were correlated with gene expression differences across the same regions and gestational ages. pREs allowed us to map neurodevelopmental disorder risk genes to developing telencephalic regions, and we identified three functional de novo noncoding variants in pREs that alter enhancer function. In addition, transgenic experiments in mouse validated enhancer activity for a pRE proximal to BCL11A, showing how this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.
Genome-wide association study of gastrointestinal disorders reinforces the link between the digestive tract and the nervous system
Authors: Wu Yeda , Murray Graham K. , Byrne Enda M. , Sidorenko Julia , Visscher Peter M. , Wray Naomi R.
Published: October 2019

Genetic factors are recognized to contribute to common gastrointestinal (GI) diseases such as gastro-oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). We conducted genome-wide association analyses based on 456,414 individuals and identified 27 independent and significant loci for GORD, PUD and IBS, including SNPs associated with PUD at or near genesMUC1, FUT2, PSCAandCCKBR, for which there are previously established roles inHelicobacter pyloriinfection, response to counteract infection-related damage, gastric acid secretion and gastrointestinal motility. Post-GWAS analyses implicate putative functional links between the nervous system and gastrointestinal tract for GORD, PUD and IBS, including the central nervous system, the enteric nervous system and their connection. Mendelian Randomisation analyses imply potentially bi-directional causality (the risk of GORD in liability to major depression and the risk of major depression in liability to GORD) or pleiotropic effect between them. A stronger genetic similarity among GORD, PUD and IBS than between these disorders and IBD is reported. These findings advance understanding the role of genetic variants in the etiology of GORD, PUD and IBS and add biological insights into the link between the nervous system and the gastrointestinal tract.
Addressing age related hearing loss through engineering accessible and affordable hearing technology
Authors: Sinha Soham , Irani Urvaksh D. , Manchaiah Vinaya , Bhamla M. Saad
Published: October 2019

Hearing Aids have dominated the audiological market for decades. While the costs of the electronic components have reduced substantially, the cost of a hearing aid has risen steadily to the point that it has become unaffordable for the vast majority of the population with Age Related Hearing Loss (ARHL). Here, we present an ultra-low-cost, affordable and accessible hearing aid device (‘LoCHAid’), specifically targeted for ARHL in elderly patients. The LoCHAid costs only 98 cents (< $1) to mass manufacture and can be personalized for each user through a 3D-printable case. It is designed to be an over-the-counter (OTC) self-serviceable solution for elderly individuals with ARHL. Electroacoustic measurements show that the device meets most of the targets set out by the WHO Preferred Product Profile and Consumer Technology Association for Hearing Aids. The frequency response of the hearing aid shows selectable gain in the range of 4-8 kHz, and mild to moderate gain between 200-1000 Hz, and shows very limited total distortion (1%). Simulated gain measurements show that the LoCHAid is well fitted to a range of ARHL profiles for males and females between the ages of 60-79 years. Overall, the measurements show that the device has the potential to benefit individuals with ARHL. Thus, our proposed design addresses a long-standing and grand challenge of affordable and accessible hearing technology for every elderly person on this planet.
Voltage-sensitive dye imaging reveals inhibitory modulation of ongoing cortical activity
Authors: Newton Taylor H. , Abdellah Marwan , Chevtchenko Grigori , Muller Eilif B. , Markram Henry
Published: October 2019

Voltage-sensitive dye imaging (VSDI) is a powerful technique for interrogating membrane potential dynamics in assemblies of cortical neurons, but with effective resolution limits that confound interpretation. In particular, it is unclear how VSDI signals relate to population firing rates. To address this limitation, we developed an in silico model of VSDI in a biologically faithful digital reconstruction of rodent neocortical microcircuitry. Using this model, we extend previous experimental observations regarding the cellular origins of VSDI, finding that the signal is driven primarily by neurons in layers 2/3 and 5. We proceed by exploring experimentally inaccessible circuit properties to show that during periods of spontaneous activity, membrane potential fluctuations are anticorrelated with population firing rates. Furthermore, we manipulate network connections to show that this effect depends on recurrent connectivity and is modulated by external input. We conclude that VSDI primarily reflects inhibitory responses to ongoing excitatory dynamics.
Errors associated with compound specific δ15N analysis of amino acids in preserved fish samples purified by high pressure liquid chromatography
Authors: Swalethorp Rasmus , Aluwihare Lihini , Thompson Andrew R. , Ohman Mark D. , Landry Michael R.
Published: October 2019

Compound specific isotopic analysis of amino acids (CSIA-AA) is increasingly used in ecological and biogeochemical studies tracking the origin and fate of nitrogen (N). Its advantages include the potential for resolving finer-scale trophic dynamics than possible with standard bulk SIA and for reconstructing historical changes in the food webs of consumers from analyses of specimens in preserved sample archives. For the latter, assessing the effects of chemical preservatives on δ15NAA has been inconclusive because the conventional CSIA approach for derivatized AAs by gas chromatography – combustion – isotope ratio mass spectrometry (GC-C-IRMS) has analytical errors (0.4 - 1.0 ‰) in the range expected from chemical preservation. Here, we show improved analytical precision (0.15 ± 0.08 ‰) for 11 underivatized AA standards analyzed by high pressure liquid chromatography followed by offline elemental analysis – IRMS (HPLC/EA-IRMS), an approach originally developed by Broek and McCarthy (2014). Using this method, we report the first high-precision tests of preservation effects on δ15NAA in Northern Anchovy (Engraulis mordax) kept 1½-year in ethanol and up to 27-years in formaldehyde. We found minimal methodological induced fractionation for 8 AAs, and preservation effects on δ15N were similar regardless of duration and preservative used. Although some of the AAs differed significantly from frozen control samples (average +1.0 ± 0.8 ‰), changes in δ15N in the source AA Phenylalanine and trophic position estimates were statistically insignificant. Our results are encouraging for resolving fine-scale natural variability using HPLC/EA-IRMS on chemically preserved specimens and for ultimately reconstructing biogeochemical records and trophic dynamics over long time scales.