bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental abnormalities in cortical GABAergic system in mice lacking mGlu3 metabotropic glutamate receptors
Authors: Imbriglio Tiziana , Verhaeghe Remy , Martinello Katiuscia , Pascarelli Maria Teresa , Chece Giuseppina , Bucci Domenico , Notartomaso Serena , Quattromani Miriana , Mascio Giada , Scalabrì Francesco , Simeone Antonio , Maccari Stefania , Del Percio Claudio , Wieloch Tadeusz , Fucile Sergio , Babiloni Claudio , Battaglia Giuseppe , Limatola Cristina , Nicoletti Ferdinando , Cannella Milena
Published: October 2019

Polymorphic variants of the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are linked to schizophrenia. Because abnormalities of cortical GABAergic interneurons lie at the core of the pathophysiology of schizophrenia, we examined whether mGlu3 receptors influence the developmental trajectory of cortical GABAergic transmission in the postnatal life. mGlu3‐/‐ mice showed robust changes in the expression of interneuron‐related genes in the prefrontal cortex (PFC), including large reductions in the expression of parvalbumin (PV) and the GluN1 subunit of NMDA receptors. The number of cortical cells enwrapped by perineuronal nets was increased in mGlu3‐/‐ mice, suggesting that mGlu3 receptors shape the temporal window of plasticity of PV+ interneurons. Electrophysiological measurements of GABAA receptor‐mediated responses revealed a more depolarized reversal potential of GABA currents in the somata of PFC pyramidal neurons in mGlu3‐/‐ mice at postnatal d 9 associated with a reduced expression of the K+/Cl‐ symporter. Finally, adult mGlu3‐/‐ mice showed lower power in electroencephalographic rhythms at 1‐45 Hz in quiet wakefulness as compared with their wild‐type counterparts. These findings suggest that mGlu3 receptors have a strong impact on the development of cortical GABAergic transmission and cortical neural synchronization mechanisms corroborating the concept that genetic variants of mGlu3 receptors may predispose to psychiatric disorders.— Imbriglio, T., Verhaeghe, R., Martinello, K., Pascarelli, M. T., Chece, G., Bucci, D., Notartomaso, S., Quattromani, M., Mascio, G., Scalabrì, F., Simeone, A., Maccari, S., Del Percio, C., Wieloch, T., Fucile, S., Babiloni, C., Battaglia, G., Limatola, C., Nicoletti, F., Cannella, M. Developmental abnormalities in cortical GABAergic system in mice lacking mGlu3 metabotropic glutamate receptors. FASEB J. 33, 14204‐14220 (2019). www.fasebj.org
Detecting Local Genetic Correlations with Scan Statistics
Authors: Guo Hanmin , Li James J. , Lu Qiongshi , Hou Lin
Published: October 2019

Genetic correlation analysis has quickly gained popularity in the past few years and provided insights into the genetic etiology of numerous complex diseases. However, existing approaches oversimplify the shared genetic architecture between different phenotypes and cannot effectively identify precise genetic regions contributing to the genetic correlation. In this work, we introduce LOGODetect, a powerful and efficient statistical method to identify small genome segments harboring local genetic correlation signals. LOGODetect automatically identifies genetic regions showing consistent associations with multiple phenotypes through a scan statistic approach. It uses summary association statistics from genome-wide association studies (GWAS) as input and is robust to sample overlap between studies. Applied to five phenotypically distinct but genetically correlated psychiatric disorders, we identified 49 non-overlapping genome regions associated with multiple disorders, including multiple hub regions showing concordant effects on more than two disorders. Our method addresses critical limitations in existing analytic strategies and may have wide applications in post-GWAS analysis.
CRISPRCasIdentifier: Machine learning for accurate identification and classification of CRISPR-Cas systems
Authors: Padilha Victor A. , Alkhnbashi Omer S. , Shah Shiraz A. , de Carvalho André C. P. L. F. , Backofen Rolf
Published: November 2019

CRISPR-Cas genes are extraordinarily diverse and evolve rapidly when compared to other prokaryotic genes. With the rapid increase in newly sequenced archaeal and bacterial genomes, manual identification of CRISPR-Cas systems is no longer viable. Thus, an automated approach is required for advancing our understanding of the evolution and diversity of these systems, and for finding new candidates for genome engineering in eukaryotic models. In this paper, we introduce a holistic strategy that combines regression and classification models for improving the quality of protein cascades, predicting their subtypes, detecting signature genes and extracting potential rules that reveal functional modules for CRISPR.
RepCOOL: Computational Drug Repositioning Via Integrating Heterogeneous Biological Networks
Authors: Fahimian Ghazale , Zahiri Javad , Arab Seyed Sh. , Sajedi Reza H.
Published: October 2019

Background

It often takes more than 10 years and costs more than one billion dollars to develop a new drug for a disease and bring it to the market. Drug repositioning can significantly reduce costs and times in drug development. Recently, computational drug repositioning attracted a considerable amount of attention among researchers, and a plethora of computational drug repositioning methods have been proposed.

Methods

In this study, we propose a novel network-based method, named RepCOOL, for drug repositioning. RepCOOL integrates various heterogeneous biological networks to suggest new drug candidates for a given disease.

Results

The proposed method showed a promising performance on benchmark datasets via rigorous cross-validation. Final drug repositioning model has been built based on random forest classifier, after examining various machine learning algorithms. Finally, in a case study, four FDA approved drugs were suggested for breast cancer stage II.

Conclusion

Results show the strength of the proposed method in detecting true drug-disease relationships. RepCOOL suggested four new drugs for breast cancer stage II namely Doxorubicin, Paclitaxel, Trastuzumab and Tamoxifen.
Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral
Authors: Tanner Elizabeth J , Jung Seung-Yong , Glazier Joshua , Thompson Cassandra , Zhou Yuqi , Martin Benjamin , Son Hye-In , Riley James L , Weinberger Leor S
Published: October 2019

Population-level control of HIV-1 faces recognized challenges, including the evolution of viral resistance and adherence issues in resource-limited settings. It has long been proposed that viral deletion mutants that conditionally self-renew at the expense of the wild-type virus (i.e., Defective Interfering Particles, DIPs1) could constitute a long-term intervention that circumvents adherence challenges and has a high genetic barrier to resistance, echoing recent approaches2. Theories predict3, 4that DIPs could be engineered into a therapy for HIV-1 (i.e.,Therapeuticinterfering particles or ‘TIPs’) provided they stably persist in patients (R0>1) by spreading to new cells during active infection (hence, a self-replenishing antiviral). To date, DIPs amenable to such engineering have remained elusive for HIV-1. Here we report the discovery of an HIV-1 DIP and its subsequent engineering into a TIP. The TIP interferes with HIV-1 replication at multiple stages of the viral lifecycle, including genome packaging, virion maturation, and reverse transcription, essentially acting as a combination antiviral. In humanized mice, the TIP suppressed HIV-1 replication by ten-fold and significantly protected CD4+ T cells from HIV-1 mediated depletion. These data provide proof-of-concept for a class of biologic with the potential to circumvent significant barriers to HIV-1 control.
Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism
Authors: Cribbs Adam P , Terlecki-Zaniewicz Stefan , Philpott Martin , Baardman Jeroen , Ahern David , Lindow Morten , Obad Susanna , Oerum Henrik , Sampey Brante , Mander Palwinder , Penn Henry , Wordsworth Paul , Bowness Paul , Prinjha Rab K , de Winther Menno , Feldmann Marc , Oppermann Udo
Published: October 2019

T helper (Th) cells are CD4+ effector T cells that play an instrumental role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation, whereas in mature Th17 cells an altered transcriptional program leads to a profound metabolic reprogramming with concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single cell analysis reveals a specific shift from highly inflammatory cell subsets towards a resting state upon demethylase inhibition. The root cause of the observed anti-inflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1 and c-myc. Overall, this leads to reduced mitochondrial biogenesis resulting in a metabolic switch with concomitant anti-inflammatory effects. These data are consistent with an opposing effect of GSK-J4 on Th17 T-cell differentiation pathways directly related to proliferation and effector cytokine profiles.
Reward Prediction Error Signaling during Reinforcement Learning in Social Anxiety Disorder is altered by Social Observation
Authors: Becker Michael P. I. , Voegler Rolf , Peterburs Jutta , Hofmann David , Bellebaum Christian , Straube Thomas
Published: October 2019

BACKGROUND

Dysfunctional expectations of impending social or performance outcomes are core features of Social Anxiety Disorder (SAD) but often lack formal definition in clinical research. Reinforcement learning (RL) models offer a framework to define changes in outcome expectations in a formal way by computing the prediction error (PE). This study quantifies the updating of expectations by PEs in SAD and investigates alterations in RL regions associated with PE signaling.

METHOD

48 adult participants (24 diagnosed with SAD and 24 age-, gender-, and education- matched healthy controls (HC)) underwent event-related functional magnetic resonance imaging while learning from probabilistic feedback. Crucially, both groups completed two parallel versions of the task: one in which they learned under scrutiny (social observation) and one in which they learned without being overtly evaluated (non-social control condition).

RESULTS

Coupling to prediction errors in SAD was elevated in dorsomedial prefrontal cortex (DMPFC) when learning under observation. These findings provide the first evidence that PE signaling during social performance situations in SAD is associated with hypersensitive response signatures in DMPFC, a brain region associated with using others’ value standards as a proxy for one’s own value standards. Dynamic Causal Modelling further revealed that RPE-modulated connectivity from ventral pallidum to DMPFC during observation was reduced in SAD.

CONCLUSIONS

The present results corroborate a crucial role of DMPFC in SAD, which corresponds to dysfunctional expectations about others’ alleged performance standards that play a prominent role in current models of the disorder.
Studying the precuneus reveals structure-function-affect correlation in long-term meditators
Authors: Berkovich-Ohana Aviva , Furman-Haran Edna , Malach Rafael , Arieli Amos , Harel Michal , Gilaie-Dotan Sharon
Published: October 2019

Understanding the relationship between brain structure, function and self-reports has hardly been addressed until now in meditation research. Here we demonstrate such relationship, using Mindfulness meditation (MM). MM aims to reduce thought-related processes and enhance bodily awareness, thereby reducing identification with thought content and deconstructing maladaptive self-schema. We thus hypothesized that structure of the default mode network (DMN) regions, associated with spontaneous thoughts and self-representation, would negatively correlate with MM experience and self-reported positive affect, while positively correlating with DMN resting-state function.

Cross-sectionally comparing a unique group of adept MM practitioners and meditation-naïve matched controls using voxel based morphometry revealed that gray matter (GM) density of the left precuneus (L-Prc) was negatively correlated with MM expertise. Furthermore, GM density of the L-Prc was positively correlated with resting state and task related functional (fMRI) measures within the L-Prc in the MM practitioners, but not in the controls. Finally, the L-Prc’s GM density negatively correlated with positive affect across all participants.

Our findings may shed light on understanding structure-function-self reports relationship. While our approach enables studying suggestive correlations in expert MM practitioners, longitudinal studies are required for direct insights concerning the question of causality.

Significance statement

Understanding the relationship between brain structure and function, individual differences and self-reports, is an important goal of neuroscience. Yet, these factors were hardly investigated together in meditation research. The precuneus is part of the default mode network (DMN) involved in thought related processes. Mindfulness meditation (MM) is a mental practice aiming to reduce thought related processes. Here, by cross-sectionally comparing adept meditators and controls, we found that in the precuneus of MM practitioners, structure associated with function. Overall, structure negatively correlated with practice length, as well as with positive affect scores. The structure-function correlation was only significant in the meditators group, possibly implying that prolonged meditation improved structure and function attunement in the DMN. More generally, this study demonstrates that mental practice can be related to conjoint structural and functional effects, as well as to affective self-reports.
Subcutaneous vaccination with a live attenuated Yersinia pseudotuberculosis plague vaccine
Authors: Derbise Anne , Guillas Chloé , Gerke Christiane , Carniel Elisabeth , Pizarro-Cerdà Javier , Demeure Christian E.
Published: October 2019

A single oral inoculation to mice of the live attenuated Yersinia pseudotuberculosis VTnF1 strain producing an F1 pseudocapsule protects against bubonic and pneumonic plague. However oral vaccination can fail in humans exposed to frequent intestinal infections. We evaluated in mice the efficacy of subcutaneous vaccine injection as an alternative way to induce protective immunity, while reducing the dose and avoiding strain release in nature. A single subcutaneous dose of up to 108 CFU induced dose-dependent antibody production. At the dose of 107 CFU, i.e. 10 times less than via the oral route, it caused a modest skin reaction and protected 100% against bubonic and 80% against pneumonic plague, caused by high doses of Yersinia pestis. Bacteria migrating to lymph nodes and spleen, but not feces, were rapidly eliminated. Thus, subcutaneous injection of VTnF1 would represent a good alternative when dissemination in nature and human intestinal responsiveness are limitations.
Degradation of non-coding RNAs promotes recycling of termination factors at sites of transcription
Authors: Villa Tommaso , Barucco Mara , Martin-Niclos Maria-Jose , Jacquier Alain , Libri Domenico
Published: October 2019

A large share of the non-coding transcriptome in yeast is controlled by the Nrd1-Nab3-Sen1 (NNS) complex, which promotes transcription termination of non-coding RNA (ncRNA) genes, and by the nuclear exosome, which limits the steady state levels of the transcripts produced. How unconstrained ncRNA levels impact RNA metabolism and gene expression are longstanding and important question. Here we show that degradation of ncRNAs by the exosome is required for freeing Nrd1 and Nab3 from the released transcript after termination. In exosome mutants, these factors are sequestered by ncRNAs and cannot be efficiently recycled to sites of transcription, inducing termination defects at NNS targets. ncRNA-dependent, genome-wide termination defects can be recapitulated by the expression of a degradation-resistant, circular RNA containing a natural NNS target in exosome proficient cells. Our results have important implications for the mechanism of termination, the general impact of ncRNAs abundance and the importance of nuclear ncRNA degradation.
3D neural network-based particle tracking reveals spatial heterogeneity of the cytosol
Authors: McLaughlin Grace A , Langdon Erin M , Crutchley John M , Holt Liam J , Forest Mark Gregory , Newby Jay M , Gladfelter Amy S
Published: October 2019

The spatial structure and physical properties of the cytosol are not well understood. Measurements of the material state of the cytosol are challenging due to its spatial and temporal heterogeneity, the lack of truly passive probes, and the need for probes of many sizes to accurately describe the state across scales. Recent development of genetically encoded multimeric nanoparticles (GEMs) has opened up study of the cytosol at the length scales of multiprotein complexes (20-60 nm). Using these probes to spatially resolve diffusivity of a cytoplasmic volume within a cell requires accurate and automated 3D tracking methods. We developed an image analysis pipeline for whole-cell imaging of GEMs in the context of large, multinucleate fungi where there is evidence of functional compartmentalization of the cytosol for both the nuclear division cycle and branching. We apply a neural network to track particles in 3D, generate surface meshes to project data on representations of the cell, and create dynamic visualizations of local diffusivities. Using this pipeline, we have found that there is remarkable variability in the properties of the cytosol both within a single cell and between cells. By analyzing the spatial diffusivity patterns, we saw an enrichment of low diffusivity zones at hyphal tips and near some nuclei. These results show that the physical state of the cytosol varies spatially within a single cell and exhibits significant cell-to-cell variability. Thus, molecular crowding contributes to heterogeneity within individual cells and across populations.
A single nucleotide polymorphism of PLIN2 is associated with nonalcoholic steatohepatitis and causes phenotypic changes in hepatocyte lipid droplets
Authors: Faulkner Claire S , White Collin , Jophlin Loretta L
Published: October 2019

Perilipin 2 (PLIN2) is a lipid droplet-associated protein which regulates cellular lipid storage and is highly expressed in the liver. Previous studies of a missense single nucleotide polymorphism (SNP) in PLIN2, Ser251Pro, (i.e. rs3556875) have shown this SNP to cause decreased lipolysis and increased intracellular lipid accumulation. To explore if this SNP is associated with nonalcoholic steatohepatitis (NASH), we genotyped 116 adults with NASH and 67 age- and gender-matched controls. rs3556875 was significantly associated with NASH with an allelic odds ratio of 2.98 (95% confidence interval 1.12 - 7.31, p=0.02) and in a dominant inheritance model. In an in vitro model of hepatic steatosis, expression of the Pro251 variant protein led to phenotypic changes in intracellular lipid droplets, yielding smaller diameter and up to 7 fold more lipid droplets per cell when compared to wild type PLIN2. In conclusion, the Ser251Pro SNP of PLIN2 may convey risk for NASH and causes phenotypic changes in hepatocyte lipid droplets.
A functional spiking-neuron model of activity-silent working memory in humans based on calcium-mediated short-term synaptic plasticity
Authors: Pals Matthijs , Stewart Terrence C. , Akyürek Elkan G. , Borst Jelmer P.
Published: October 2019

In this paper, we present a functional spiking-neuron model of human working memory (WM). This model combines neural firing for encoding of information with activity-silent maintenance. While it used to be widely assumed that information in WM is maintained through persistent recurrent activity, recent studies have shown that information can be maintained without persistent firing; instead, information can be stored in activity-silent states. A candidate mechanism underlying this type of storage is short-term synaptic plasticity (STSP), by which the strength of connections between neurons rapidly changes to encode new information. To demonstrate that STSP can lead to functional behavior, we integrated STSP by means of calcium-mediated synaptic facilitation in a large-scale spiking-neuron model and added a decision mechanism. The model was used to simulate a recent study that measured behavior and EEG activity of participants in three delayed-response tasks. In these tasks, one or two visual gratings had to be maintained in WM, and compared to subsequent probes. The original study demonstrated that WM contents and its priority status could be decoded from neural activity elicited by a task-irrelevant stimulus displayed during the activity-silent maintenance period. In support of our model, we show that it can perform these tasks, and that both its behavior as well as its neural representations are in agreement with the human data. We conclude that information in WM can be effectively maintained in activity-silent states by means of calcium-mediated STSP.

Author Summary

Mentally maintaining information for short periods of time in working memory is crucial for human adaptive behavior. It was recently shown that the human brain does not only store information through neural firing – as was widely believed – but also maintains information in activity-silent states. Here, we present a detailed neural model of how this could happen in our brain through short-term synaptic plasticity: rapidly adapting the connection strengths between neurons in response to incoming information. By reactivating the adapted network, the stored information can be read out later. We show that our model can perform three working memory tasks as accurately as human participants can, while using similar mental representations. We conclude that our model is a plausible and effective neural implementation of human working memory.
Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons
Authors: Otsu Yo , Donneger Florian , Schwartz Eric J , Poncer Jean Christophe
Published: October 2019

Transmembrane chloride gradients govern the efficacy and polarity of GABA signaling in neurons and are usually maintained by the activity of cation chloride cotransporters, such as KCC2 and NKCC1. Whereas their role is well established in cortical principal neurons, it remains poorly documented in GABAergic interneurons. We used complementary electrophysiological approaches to compare the effects of GABAAR activation in adult mouse hippocampal parvalbumin interneurons (PV INs) and pyramidal cells (PCs). Loose cell attached, tight-seal and gramicidin-perforated patch recordings all show GABAAR-mediated transmission is slightly depolarizing and yet inhibitory in both PV INs and PCs. Focal GABA uncaging in whole-cell recordings reveal that KCC2 and NKCC1 are functional in both PV INs and PCs but differentially contribute to transmembrane chloride gradients in their soma and dendrites. Blocking KCC2 function depolarizes the reversal potential of GABAAR-mediated currents in PV INs and PCs, often beyond firing threshold, showing KCC2 is essential to maintain the inhibitory effect of GABAARs. Finally, we show that repetitive 10 Hz activation of GABAARs in both PV INs and PCs leads to a progressive decline of the postsynaptic response independently of the ion flux direction or KCC2 function. This suggests intraneuronal chloride buildup may not predominantly contribute to activity-dependent plasticity of GABAergic synapses in this frequency range. Altogether our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal PV INs and PCs and suggest KCC2 downregulation in the pathology may affect the valence of GABA signaling in both cell types.

Key point summary

Cation-chloride cotransporters (CCCs) play a critical role in controlling the efficacy and polarity of GABAA receptor (GABAAR)-mediated transmission in the brain, yet their expression and function in GABAergic interneurons has been overlooked.

We compared the polarity of GABA signaling and the function of CCCs in mouse hippocampal pyramidal neurons and parvalbumin-expressing interneurons.

Under resting conditions, GABAAR activation was mostly depolarizing and yet inhibitory in both cell types. KCC2 blockade further depolarized the reversal potential of GABAAR-mediated currents often above action potential threshold.

However, during repetitive GABAAR activation, the postsynaptic response declined independently of the ion flux direction or KCC2 function, suggesting intracellular chloride buildup is not responsible for this form of plasticity.

Our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal pyramidal neurons and parvalbumin interneurons.
Cumulus: a cloud-based data analysis framework for large-scale single-cell and single-nucleus RNA-seq
Authors: Li Bo , Gould Joshua , Yang Yiming , Sarkizova Siranush , Tabaka Marcin , Ashenberg Orr , Rosen Yanay , Slyper Michal , Kowalczyk Monika S , Villani Alexandra-Chloé , Tickle Timothy , Hacohen Nir , Rozenblatt-Rosen Orit , Regev Aviv
Published: October 2019

Massively parallel single-cell and single-nucleus RNA-seq (sc/snRNA-seq) have opened the way to systematic tissue atlases in health and disease, but as the scale of data generation is growing, so does the need for computational pipelines for scaled analysis. Here, we developed Cumulus, a cloud-based framework for analyzing large scale sc/snRNA-seq datasets. Cumulus combines the power of cloud computing with improvements in algorithm implementations to achieve high scalability, low cost, user-friendliness, and integrated support for a comprehensive set of features. We benchmark Cumulus on the Human Cell Atlas Census of Immune Cells dataset of bone marrow cells and show that it substantially improves efficiency over conventional frameworks, while maintaining or improving the quality of results, enabling large-scale studies.
Discovery of a prevalent picornavirus by visualizing zebrafish immune responses
Authors: Balla Keir M. , Rice Marlen C. , Gagnon James A. , Elde Nels C.
Published: October 2019

The discovery of new viruses currently outpaces our capacity for experimental examination of infection biology. To better couple virus discovery with immunology, we genetically modified zebrafish to visually report on virus infections. After generating a strain that expresses green fluorescent protein (GFP) under an interferon-stimulated gene promoter, we repeatedly observed transgenic larvae spontaneously expressing GFP days after hatching. RNA sequencing of GFP-positive zebrafish revealed a picornavirus distantly related to known viruses. We detected this virus in publicly available sequencing data from seemingly asymptomatic zebrafish in research institutes world-wide. These data revealed widespread tissue tropism and identified the clonal CG2 strain as notably vulnerable to picornavirus infection. Infection induces the expression of numerous antiviral immune defense genes in zebrafish, an effect also evident in public data. Our study describes a prevalent picornavirus that infects zebrafish, and provides new strategies for simultaneously discovering viruses and their impact on vertebrate hosts.
Comparative analysis of seed size, germination, and vegetative allocation in annual and herbaceous perennial crops and their wild relatives inLupinusandPhaseolus(Fabaceae)
Authors: Herron Sterling A. , Rubin Matthew J. , Ciotir Claudia , Crews Timothy E. , Van Tassel David L. , Miller Allison J.
Published: October 2019

Herbaceous perennial species are receiving increased attention for their potential to provide both edible products and ecosystem services in agricultural systems. Many legumes (Fabaceae Lindl.) are of special interest due to nitrogen fixation carried out by bacteria in their roots and their production of protein-rich, edible seeds. However, herbaceous perennial legumes have yet to enter widespread use as pulse crops, and the response of wild, herbaceous, perennial species to artificial selection for increased seed yield remains under investigation. Here we compare cultivated and wild accessions of congeneric annual and herbaceous perennial legume species to investigate associations of lifespan and cultivation with seed size, germination, and first year vegetative growth patterns, and to characterize covariation among traits. We use “cultivated” to describe accessions with a history of human planting and use, which encompasses a continuum of domestication. Analyses focused on three annual and eight perennialLupinusspecies, and three annual and four perennialPhaseolusspecies. We found a significant association of both lifespan and cultivation status with seed size (weight, area, length), germination proportion, node number, stem diameter, shoot dry mass, and root dry mass. Wild seed size was greater in annuals forLupinusand greater for perennials inPhaseolus. Germination was lower in wild perennials than wild annuals in both genera, and vegetative allocation was roughly equivalent across lifespans in wildPhaseolus. Relative to wild forms, both cultivated annual and cultivated perennial accessions exhibited greater seed size, lower germination proportion, and larger overall plant size. Seed size traits were positively correlated with vegetative growth traits, and all biomass traits examined here were positively correlated. This study highlights some basic similarities and differences between annual and herbaceous perennial legumes, and provides insights into how perennial legumes might respond to artificial selection compared to annual species.
Spondweni virus causes fetal harm in a mouse model of vertical transmission and is transmitted byAedes aegyptimosquitoes
Authors: Jaeger Anna S. , Weiler Andrea M. , Moriarty Ryan V. , Rybarczyk Sierra , O’Connor Shelby L. , O’Connor David H. , Seelig Davis M. , Fritsch Michael K. , Friedrich Thomas C. , Aliota Matthew T.
Published: October 2019

Spondweni virus (SPONV) is the most closely related known flavivirus to Zika virus (ZIKV). Its pathogenic potential and vector specificity have not been well defined. SPONV has been found predominantly in Africa, but was recently detected in a pool ofCulex quinquefasciatusmosquitoes in Haiti. Here we show that SPONV can cause significant fetal harm, including demise, comparable to ZIKV, in a mouse model of vertical transmission. Following maternal inoculation, we detected infectious SPONV in placentas and fetuses, along with significant fetal and placental histopathology, together indicating vertical transmission. To test vector competence, we exposedAedes aegyptiandCulex quinquefasciatusmosquitoes to SPONV-infected bloodmeals.Aedes aegypticould efficiently transmit SPONV, whereasCulex quinquefasciatuscould not. Our results suggest that SPONV has the same features that made ZIKV a public health risk.
Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome
Authors: Bender Sébastien , Javaugue Vincent , Saintamand Alexis , Ayala Maria Victoria , Alizadeh Mehdi , Filloux Matthieu , Pascal Virginie , Gachard Nathalie , Lavergne David , Auroy Fabienne , Cogne Michel , Bridoux Frank , Sirac Christophe , Jaccard Arnaud
Published: October 2019

POEMS syndrome is a rare multisystem disease due to an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected, due to the highly restrictive usage of two λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations following PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (RACE-RepSeq), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 85% of patients with POEMS syndrome, including some in whom bone marrow tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ+monoclonal PCs. Twenty-four of the 30 LC clonal sequences found (80%) were derived from the IGLV1-40 and IGLV1-44 germline genes, two from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid and specific tool to detect low-abundance PC clones in BM, and assign them to POEMS syndrome, with all the consequences for therapeutic options hereby.
Analysing the safe and just operating space of agriculture in the world: past, present and future
Authors: Roy Ajishnu , Pramanick Kousik
Published: October 2019

Agriculture, along with industry and household sector are three major sectors of human consumption. Agriculture has proved to be a major contributor to exceeding planetary boundaries. Here, we have explored the impact of agriculture in the Earth system processes, through eight dimensions of planetary boundaries or safe operating spaces: climate change (10.73%), freshwater use (91.56%), arable land use (37.27%), nitrogen use (95.77%), phosphorus use (87.28%), ecological footprint (19.42%), atmospheric pollution (2.52% - 38.08%) and novel entities. In this work, we have also shown role of agriculture to the socio-economic development dimensions: gender equality, employment and economic growth. We have shown that the safe operating limits for agriculture are going to decline by almost 55% (climate change), 300% (freshwater use), 50-55% (arable land use), 180% (nitrogen use), 265% (phosphorus use) and 20% (ecological footprint) in 2050, if the most inefficient way of consumption is chosen and continued. To alleviate the role of agriculture in transgressing planetary boundaries, it is indispensable to comprehend how many roles of agriculture is playing and where which target should be set to framework the national agricultural policies in coherence with attaining sustainable development goals of UN by 2030.
Bayesian Neural Networks for Cellular Image Classification and Uncertainty Analysis
Authors: Deodato Giacomo , Ball Christopher , Zhang Xian
Published: October 2019

Over the last decades, deep learning models have rapidly gained popularity for their ability to achieve state-of-the-art performances in different inference settings. Novel domains of application define a new set of requirements that transcend accurate predictions and depend on uncertainty measures. The aims of this study are to implement Bayesian neural networks and use the corresponding uncertainty estimates to improve predictions and perform dataset analysis. We identify two main advantages in modeling the predictive uncertainty of deep neural networks performing classification tasks. The first is the possibility to discard highly uncertain predictions to increase model accuracy. The second is the identification of unfamiliar patterns in the data that correspond to outliers in the model representation of the training data distribution. Such outliers can be further characterized as either corrupted observations or data belonging to different domains. Both advantages are well demonstrated on benchmark datasets. Furthermore we apply the Bayesian approach to a biomedical imaging dataset where cancer cells are treated with diverse drugs, and show how one can increase classification accuracy and identify noise in the ground truth labels with uncertainty analysis.
Leveraging multiple layers of data to predict Drosophila complex traits
Authors: Morgante Fabio , Huang Wen , Sørensen Peter , Maltecca Christian , Mackay Trudy F. C.
Published: November 2019

An important challenge in genetics is to be able to predict complex traits accurately. Despite recent advances, prediction accuracy for most complex traits remains low. Here, we used the Drosophila Genetic Reference Panel (DGRP), a collection of 200 lines with whole-genome sequences and deep RNA sequencing data, to evaluate the usefulness of using high-quality gene expression levels compared to relying on genotypes for predicting three complex traits. We found that expression levels provided higher accuracy than genotypes for starvation resistance, similar accuracy for chill coma recovery, and lower accuracy for startle response. Models including both genotype and expressions levels did not outperform the best single component model. However, accuracy increased considerably for all the three traits when we included another layer of information, i.e., gene ontology (GO). We found that a limited number of GO terms, some of which had a clear biological interpretation, were strongly predictive of the traits. In summary, this study shows that integrating different sources of information can improve prediction accuracy, especially when large samples are not available.
Somatic Truth Data from Cell Lineage
Authors: Shand Megan , Soto Jose , Lichtenstein Lee , Benjamin David , Farjoun Yossi , Brody Yehuda , Maruvka Yosef E. , Blainey Paul C. , Banks Eric
Published: October 2019

Existing somatic benchmark datasets for human sequencing data use germline variants, synthetic methods, or expensive validations, none of which are satisfactory for providing a large collection of true somatic variation across a whole genome. Here we propose a dataset of short somatic mutations, that are validated using a known cell lineage. The dataset contains 56,974 (2,687 unique) Single Nucleotide Variations (SNV), 6,370 (316 unique) small Insertions and Deletions (Indels), and 144 (8 unique) Copy Number Variants (CNV) across 98 in silico mixed truth sets with a high confidence region covering 2.7 gigabases per mixture. The data is publicly available for use as a benchmarking dataset for somatic short mutation discovery pipelines.
Integrative Multi-Omics Analysis of Barley Genotypes Shows Differential Salt-Induced Osmotic Barriers and Response Phases Among Rootzones
Authors: Wing Ho Ho William , Hill Camilla B. , Doblin Monika S. , Shelden Megan C. , van de Meene Allison , Rupasinghe Thusitha , Bacic Antony , Roessner Ute
Published: October 2019

The mechanisms underlying rootzone-localised responses to salinity stress during early stage of barley development remains fragmentary and elusive. Here, we performed a comprehensive detection of the multi-root-omes (transcriptomes, metabolomes, lipidomes) of a domesticated barley cultivar (Clipper) and a landrace (Sahara) with seedling root growth maintained and restricted in response to salt stress, respectively. Novel generalized linear models were designed to determine differentially expressed genes (DEG) or abundant metabolites (DAM) specific to salt treatments, genotypes, or rootzones (meristematic Z1, elongation Z2, maturation Z3). Based on pathway over-representation of the DEG and DAM, phenylpropanoid biosynthesis is the most statistically over-represented biological pathways among all salinity responses observed. Together with the histological evidence, an intense salt-induced lignin impregnation was found only at the stelic cell wall of Clipper Z2, comparing to a unique elevation of suberin deposition across Sahara Z2. This suggests two differential salt-induced modulations of apoplastic flow between the genotypes. Based on global correlation network construction of the DEG and DAM, callose deposition that potentially adjusted the symplastic flow in roots was almost independent of salinity in rootzones of Clipper, but was markedly decreased in that of Sahara. Through closer examinations of molecular and hormonal clues, we further demonstrate that the salinity response in rootzones of Clipper were mostly at recovery phase, comparing to Sahara with rootzones retained at quiescence. Taken together, we propose that two distinctive salt tolerance mechanisms could exist in Clipper (growth-sustaining) and Sahara (salt-shielding), providing important clues for improving crop plasticity to cope with the deteriorating global salinization of soil.
BlackSheep: A Bioconductor and Bioconda package for differential extreme value analysis
Authors: Blumenberg Lili , Kawaler Emily , Cornwell MacIntosh , Smith Shaleigh , Ruggles Kelly , Fenyö David
Published: October 2019

Unbiased assays such as shotgun proteomics and RNA-seq provide high-resolution molecular characterization of tumors. These assays measure molecules with highly varied distributions, making interpretation and hypothesis testing challenging. Samples with the most extreme measurements for a molecule can reveal the most interesting biological insights, yet are often excluded from analysis. Furthermore, rare disease subtypes are, by definition, underrepresented in cancer cohorts. To provide a strategy for identifying molecules aberrantly enriched in small sample cohorts, we present BlackSheep--a package for non-parametric description and differential analysis of genome-wide data, available at https://github.com/ruggleslab/blackSheep. BlackSheep is a complementary tool to other differential expression analysis methods that may be underpowered when analyzing small subgroups in a larger cohort.
Mitochondrial ascorbate synthesis acts as a pro-oxidant pathway and down-regulate energy supply in plants
Authors: Morales Luis Miguel Mazorra , Silva Gláucia Michelle Cosme , Santana Diederson Bortolini , Pireda Saulo F. , Cogo Antonio Jesus Dorighetto , Heringer Angelo Schuabb , de Oliveira Tadeu dos Reis , Reis Ricardo S. , dos Santos Prado Luís Alfredo , de Oliveira André Vicente , Silveira Vanildo , Cunha Maura Da , Barros Claudia F. , Facanha Arnoldo R. , Baldet Pierre , Bartoli Carlos , da Silva Marcelo Gomes , de Oliveira Jurandi Gonçalves
Published: October 2019

Attempts to improve the ascorbate (AsA) content of plants are still dealing with the limited understanding of why exists a wide variability of this powerful anti-oxidant molecule in different plant sources, species and environmental situations. In plant mitochondria, the last step of AsA synthesis is catalyzed by the enzyme L-galactone-1,4-lactone dehydrogenase (L-GalLDH). By using GalLDH-RNAi silencing plant lines, biochemical and proteomic approaches, we here discovered that, in addition to accumulate this antioxidant, mitochondria synthesize AsA to down-regulate the respiratory activity and the cellular energy provision. The work reveals that the AsA synthesis pathway within mitochondria is a branched electron transfer process that channels electrons towards the alternative oxidase, interfering with conventional electron transport. It was unexpectedly found that significant hydrogen peroxide is generated during AsA synthesis, which affects the AsA level. The induced AsA synthesis shows proteomic alterations of mitochondrial and extra-mitochondrial proteins related to oxidative and energetic metabolism. The most identified proteins were known components of plant responses to high light acclimation, programmed cell death, oxidative stress, senescence, cell expansion, iron and phosphorus starvation, different abiotic stress/pathogen attack responses and others. We propose that changing the electron flux associated with AsA synthesis might be part of a new mechanism by which the L-GalLDH enzyme would adapt plant mitochondria to fluctuating energy demands and redox status occurring under different physiological contexts.
Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in non-human primates
Authors: Bourdenx M. , Nioche A. , Dovero S. , Arotcarena M.-L. , Camus S. , Porras G. , Thiolat M.-L. , Rougier N. P. , Prigent A. , Aubert P. , Bohic S. , Sandt C. , Laferrière F. , Doudnikoff E. , Kruse N. , Mollenhauer B. , Novello S. , Morari M. , Leste-Lasserre T. , Trigo Damas I. , Goillandeau M. , Perier C. , Estrada C. , Garcia-Carrillo N. , Recasens A. , Vaikath N. N. , El-Agnaf O. M. A. , Herrero M. Trinidad , Derkinderen P. , Vila M. , Obeso J. A. , Dehay B. , Bezard E.
Published: October 2019

Abstract

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates (termed ‘Lewy bodies’), is a well-established characteristic of Parkinson’s disease. Much evidence, accumulated from multiple experimental models has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.
FrogCap: A modular sequence capture probe set for phylogenomics and population genetics for all frogs, assessed across multiple phylogenetic scales
Authors: Hutter Carl R. , Cobb Kerry A. , Portik Daniel M. , Travers Scott L. , Wood Perry L. , Brown Rafe M.
Published: October 2019

Despite the increasing use of high-throughput sequencing in phylogenetics, many phylogenetic relationships remain difficult to resolve because of conflict between gene trees and species trees. Selection of different types of markers (i.e. protein-coding exons, non-coding introns, ultra-conserved elements) is becoming important to alleviate these phylogenomic challenges. For evolutionary studies in frogs, we introduce the new publicly available FrogCap suite of genomic resources, which is a large and flexible collection of probes corresponding to ∼15,000 markers that unifies previous frog sequencing work. FrogCap is designed to be modular, such that subsets of markers can be selected based on the phylogenetic scale of the intended study. FrogCap uses a variety of molecular marker types that include newly obtained exons and introns, previously sequenced UCEs, and Sanger-sequencing markers, which span a range of alignment lengths (100–12,000 base pairs). We tested three probe sets from FrogCap using 105 samples across five phylogenetic scales, comparing probes designed using a consensus- or genome-based approach. We also tested the effects of using different bait kit sizes on depth of coverage and missing data. We found that larger bait kits did not result in lowered depth of coverage or increased missing data. We also found that sensitivity, specificity, and missing data are not related to genetic distance in the consensus-based probe design, suggesting that this approach has greater success and overcomes a major hurdle in probe design. We observed sequence capture success (in terms of missing data, quantity of sequence data, recovered marker length, and number of informative sites) and compared them at all phylogenetic scales. The incorporation of different molecular marker types allowed recovery of the variation required for resolving difficult phylogenetic relationships and for performing population genetic studies. Altogether, FrogCap is a valuable and adaptable resource for performing high-throughput sequencing projects across variable timescales.