bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen
Authors: Salem Rany M. , Todd Jennifer N. , Sandholm Niina , Cole Joanne B. , Chen Wei-Min , Andrews Darrel , Pezzolesi Marcus G. , McKeigue Paul M. , Hiraki Linda T. , Qiu Chengxiang , Nair Viji , Liao Chen Di , Cao Jing Jing , Valo Erkka , Onengut-Gumuscu Suna , Smiles Adam M. , McGurnaghan Stuart J. , Haukka Jani K. , Harjutsalo Valma , Brennan Eoin P. , van Zuydam Natalie , Ahlqvist Emma , Doyle Ross , Ahluwalia Tarunveer S. , Lajer Maria , Hughes Maria F. , Park Jihwan , Skupien Jan , Spiliopoulou Athina , Liu Andrew , Menon Rajasree , Boustany-Kari Carine M. , Kang Hyun M. , Nelson Robert G. , Klein Ronald , Klein Barbara E. , Lee Kristine E. , Gao Xiaoyu , Mauer Michael , Maeastroni Silvia , Caramori Maria Luiza , de Boer Ian H. , Miller Rachel G. , Guo Jingchuan , Boright Andrew P. , Tregouet David , Gyorgy Beata , Snell-Bergeon Janet K. , Maahs David M. , Bull Shelley B. , Canty Angelo J. , Palmer Colin N.A. , Stechemesser Lars , Paulweber Bernhard , Weitgasser Raimund , Sokolovska Jelizaveta , Rovīte Vita , Pīrāgs Valdis , Prakapiene Edita , Radzeviciene Lina , Verkauskiene Rasa , Panduru Nicolae Mircea , Groop Leif C. , McCarthy Mark I. , Gu Harvest F. , Möllsten Anna , Falhammar Henrik , Brismar Kerstin ,   GENIE Consortium,   DCCT/EDIC Research Group,   SUMMIT Consortium, Martin Finian , Rossing Peter , Costacou Tina , Zerbini Gianpaolo , Marre Michel , Hadjadj Samy , McKnight Amy J. , Forsblom Carol , McKay Gareth , Godson Catherine , Peter Maxwell A. , Kretzler Matthias , Susztak Katalin , Colhoun Helen M. , Krolewski Andrzej , Paterson Andrew D. , Groop Per-Henrik , Rich Stephen S. , Hirschhorn Joel N. , Florez Jose C.
Published: December 2018

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain(COL4A3)gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD(BMP7)or renal biology (COLEC11andDDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.
SCeQTL: an R package for identifying eQTL from single-cell parallel sequencing data
Authors: Hu Yue , Zhang Xuegong
Published: December 2018

With the development of single-cell sequencing technologies, parallel sequencing the transcriptome and genome is becoming available and will bring us the opportunity to uncover association between genotype and phenotype at single-cell level. Due to the special characteristics of single-cell sequencing data, new method is needed to identify eQTL from single-cell data. We developed an R package SCeQTL that uses zero-inflated negative binomial regression to do eQTL analysis on single-cell data. It can distinguish two type of gene-expression differences among different genotype groups. It can also be used for finding gene expression variations associated with other grouping factors like cell lineages or cell types.
Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis
Authors: Roussarie Jean-Pierre , Yao Victoria , Plautz Zakary , Kasturia Shirin , Albornoz Christian , Schmidt Eric F , Brichta Lars , Barnea-Cramer Alona , Heintz Nathaniel , Hof Patrick , Heiman Myriam , Flajolet Marc , Troyanskaya Olga , Greengard Paul
Published: December 2018

A major obstacle to treating Alzheimer’s disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, which is a key characteristic of the disease. Here we present a framework to integrate high-quality neuron-type specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, withpostmortemhuman functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for AD vulnerable and resistant neurons, identify specific genes and pathways associated with AD pathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by both amyloid accumulation and aging. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.
Substrate inhibition imposes fitness penalty at high protein stability
Authors: Adkar Bharat V. , Bhattacharyya Sanchari , Gilson Amy I. , Zhang Wenli , Shakhnovich Eugene I.
Published: December 2018

Proteins are only moderately stable. It has long been debated whether this narrow range of stabilities is solely a result of neutral drift towards lower stability or purifying selection against excess stability is also at work — for which no experimental evidence was found so far. Here we show that mutations outside the active site in the essentialE. colienzyme adenylate kinase result in stability-dependent increase in substrate inhibition by AMP, thereby impairing overall enzyme activity at high stability. Such inhibition caused substantial fitness defects not only in the presence of excess substrate but also under physiological conditions. In the latter case, substrate inhibition caused differential accumulation of AMP in the stationary phase for the inhibition prone mutants. Further, we show that changes in flux through Adk could accurately describe the variation in fitness effects. Taken together, these data suggest that selection against substrate inhibition and hence excess stability may have resulted in a narrow range of optimal stability observed for modern proteins.
Evidence for natural selection and barrier leakage in candidate loci underlying speciation in wood ants
Authors: Kulmuni J , Nouhaud P , Pluckrose L , Satokangas I , Dhaygude K , Butlin RK
Published: December 2018

While speciation underlies novel biodiversity, it is poorly understood how natural selection shapes genomes during speciation. Selection is assumed to act against gene flow at barrier loci, promoting reproductive isolation and speciation. However, evidence for gene flow and selection is often indirect. Here we utilize haplodiploidy to identify candidate barrier loci in hybrids between two wood ant species and integrate survival analysis to directly measure if natural selection is acting at candidate barrier loci. We find multiple candidate barrier loci but surprisingly, proportion of them show leakage between samples collected ten years apart, natural selection favoring leakage in the latest sample. Barrier leakage and natural selection for introgressed alleles could be due to environment-dependent selection, emphasizing the need to consider temporal variation in natural selection in future speciation work. Integrating data on survival allows us to move beyond genome scans, demonstrating natural selection acting on hybrid genomes in real-time.
Domains of the TF protein important in regulating its own palmitoylation
Authors: Ramsey Jolene , Chavez Marbella , Mukhopadhyay Suchetana
Published: December 2018

Sindbis virus particles contain the viral proteins capsid, E1 and E2, and low levels of a small membrane protein called TF. TF is produced during a (-1) programmed ribosomal frameshifting event during the translation of the structural polyprotein. TF from Sindbis virus-infected cells is present in two palmitoylated states, basal and maximal; unpalmitoylated TF is not detectable. Mutagenesis studies demonstrated that without palmitoylation, TF is not incorporated into released virions, suggesting palmitoylation of TF is a regulated step in virus assembly. In this work, we identified Domains within the TF protein that regulate its palmitoylation state. Mutations and insertions in Domain III, a region proposed to be in the cytoplasmic loop of TF, increase levels of unpalmitoylated TF found during an infection and even allow incorporation of unpalmitoylated TF into virions. Mutations in Domain IV, the TF unique region, are likely to impact the balance between basal and maximal palmitoylation.
Synaptic combinatorial molecular mechanisms generate repertoires of innate and learned behavior
Authors: Komiyama Noboru H. , van de Lagemaat Louie N. , Stanford Lianne E. , Pettit Charles M. , Strathdee Douglas J. , Strathdee Karen E. , Fricker David G. , Tuck Eleanor J. , Elsegood Kathryn A. , Ryan Tomás J. , Nithianantharajah Jess , Skene Nathan G. , Croning Mike D. R. , Grant Seth G. N.
Published: December 2018

Although molecular mechanisms underpinning specific behaviors have been described, whether there are mechanisms that orchestrate a behavioral repertoire is unknown. To test if the postsynaptic proteome of excitatory synapses could impart such a mechanism we conducted the largest genetic study of mammalian synapses yet undertaken. A repertoire of sixteen innate and learned behaviors was assessed from 290,850 measures in 55 lines of mutant mice carrying targeted mutations in the principal classes of postsynaptic proteins. Each innate and learned behavior used a different combination of proteins. These combinations were comprised of proteins that amplified or attenuated the magnitude of each behavioral response. All behaviors required proteins found in PSD95 supercomplexes. We show the vertebrate increase in proteome complexity drove an expansion in behavioral repertoires and generated susceptibility to a wide range of diseases. Our results reveal a molecular mechanism that generates a versatile and complex behavioral repertoire that is central to human behavioral disorders.
Causal inference in the multisensory brain
Authors: Cao Yinan , Summerfield Christopher , Park Hame , Giordano Bruno L. , Kayser Christoph
Published: December 2018

When combining information across different senses humans need to flexibly select cues of a common origin whilst avoiding distraction from irrelevant inputs. The brain could solve this challenge using a hierarchical principle, by deriving rapidly a fused sensory estimate for computational expediency and, later and if required, filtering out irrelevant signals based on the inferred sensory cause(s). Analysing time- and source-resolved human magnetoencephalographic data we unveil a systematic spatio-temporal cascade of the relevant computations, starting with early segregated unisensory representations, continuing with sensory fusion in parietal-temporal regions and culminating as causal inference in the frontal lobe. Our results reconcile previous computational accounts of multisensory perception by showing that prefrontal cortex guides flexible integrative behaviour based on candidate representations established in sensory and association cortices, thereby framing multisensory integration in the generalised context of adaptive behaviour.
A combinatorial postsynaptic molecular mechanism converts patterns of nerve impulses into the behavioral repertoire
Authors: Kopanitsa Maksym V. , van de Lagemaat Louie N. , Afinowi Nurudeen O. , Strathdee Douglas J. , Strathdee Karen E. , Fricker David G. , Tuck Eleanor J. , Elsegood Kathryn A. , Croning Mike D. R. , Komiyama Noboru H. , Grant Seth G. N.
Published: December 2018

How is the information encoded within patterns of nerve impulses converted into diverse behavioral responses? To address this question, we conducted the largest genetic study to date of the electrophysiological and behavioral properties of synapses. Postsynaptic responses to elementary patterns of activity in the hippocampal CA1 region were measured in 58 lines of mice carrying mutations in the principal classes of excitatory postsynaptic proteins. A combinatorial molecular mechanism was identified in which distinct subsets of proteins amplified or attenuated responses across timescales from milliseconds to an hour. The same mechanism controlled the diversity and magnitude of innate and learned behavioral responses. PSD95 supercomplex proteins were central components of this synaptic machinery. The capacity of vertebrate synapses to compute activity patterns increased with genome evolution and is impaired by disease-relevant mutations. We propose that this species-conserved molecular mechanism converts the temporally encoded information in nerve impulses into the repertoire of innate and learned behavior.
Fitness of reciprocal F1hybrids betweenRhinanthus minorandRhinanthus majorunder controlled conditions and in the field
Authors: Wesselingh Renate A. , Hořčicová Šárka , Mirzaei Khaled
Published: December 2018

The performance of first-generation hybrids determines to a large extent the long-term outcome of hybridization in natural populations. F1hybrids can facilitate further gene flow between the two parental species, especially in animal-pollinated flowering plants. We studied the performance of reciprocal F1hybrids betweenRhinanthus minorandR. major, two hemiparasitic, annual, self-compatible plant species, from seed germination to seed production under controlled conditions and in the field. We sowed seeds with known ancestry outdoors before winter and followed the complete life cycle until plant death in July the following season. While germination under laboratory conditions was much lower for the F1hybrid formed onR. majorcompared to the reciprocal hybrid formed onR. minor, this difference disappeared under field conditions, pointing at an artefact caused by the experimental conditions during germination in the lab rather than at an intrinsic genetic incompatibility. Both F1hybrids performed as well as or sometimes better thanR. minor, which had a higher fitness thanR. majorin one of the two years in the greenhouse and in the field transplant experiment. The results confirm findings from naturally mixed populations, where F1hybrids appear as soon as the two species meet and which leads to extensive advanced-hybrid formation and introgression in subsequent generations.
Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair
Authors: Wienert Beeke , Feng Sharon J , Locke Melissa , Nguyen David N , Wyman Stacia K , Kazane Katelynn R , MARSON ALEX , Richardson Chris D , Corn Jacob E
Published: December 2018

Repair of double strand DNA breaks (DSBs) can result in gene disruption or precise gene modification via homology directed repair (HDR) from a templating donor DNA. During genome editing, altering cellular responses to DSBs may be an effective strategy to rebalance editing outcomes towards HDR and away from other repair pathways. To identify factors that regulate HDR from a double-stranded DNA donor (dsDonor), we utilized a pooled screen to define the consequences of thousands of individual gene knockdowns during Cas9-initiated HDR from a double strand plasmid donor. We find that templated dsDonor repair pathways are mostly genetically distinct from single strand donor DNA (ssDonor) repair but share aspects that include dependency upon the Fanconi Anemia (FA) pathway. We also identified several factors whose knockdown increases HDR and thus act as repressors of gene modification. Screening available small molecule inhibitors of these repressors revealed that the cell division cycle 7-related protein kinase (CDC7) inhibitor XL413 increases the efficiency of HDR by 2-3 fold in many contexts, including primary T-cells. XL413 stimulates HDR through cell cycle regulation, inducing an early S-phase cell cycle arrest that, to the best of our knowledge, is uncharacterized for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for boosting the efficiency of gene modification.
Cheating emergences in the arbuscular mycorrhizal mutualism: a network and phylogenetic analysis
Authors: Perez-Lamarque Benoît , Selosse Marc-André , Öpik Maarja , Morlon Hélène , Martos Florent
Published: December 2018

While mutualisms are widespread and essential in ecosystem functioning, the emergence of uncooperative cheaters threatens their stability, unless there are functional or evolutionary mechanisms limiting cheaters interactions.

Here, we evaluated the constraints upon mycoheterotrophic (MH) cheating plants in the mutualistic interaction network of autotrophic (AT) plants and arbuscular mycorrhizal fungi. For this purpose, we assembled a world-scale network of >25,000 interactions in order to investigate(i)the specialization and(ii)the phylogenetic distribution of MH or AT plants and their respective fungal partners.

We show that MH cheating repeatedly evolved in the vascular flora, suggesting low phylogenetic constraint for plants. However, MH cheaters are significantly more specialized than AT plants, and their fungi also appear more specialized and more closely related than fungi of AT plants, which suggest that cheaters are specifically isolated into modules by functional constraints

This unprecedented comparison of MH vs. AT plants thus reveals that MH cheating is most likely constrained by the specialization of phylogenetically conserved cheating-susceptible fungi, which suggests mechanisms for avoidance of these fungi. Beyond the mycorrhizal symbiosis, our approach highlights an empirical multiple-partners mutualistic system illustrating that the overall persistence of mutualism can be linked to functional constraints upon cheating emergences.
Motivation and Cognitive Control in Depression
Authors: Grahek Ivan , Shenhav Amitai , Musslick Sebastian , Krebs Ruth M. , Koster Ernst H.W.
Published: December 2018

Depression is linked to deficits in cognitive control and a host of other cognitive impairments arise as a consequence of these deficits. Despite of their important role in depression, there are no mechanistic models of cognitive control deficits in depression. In this paper we propose how these deficits can emerge from the interaction between motivational and cognitive processes. We review depression-related impairments in key components of motivation along with new cognitive neuroscience models that focus on the role of motivation in the decision-making about cognitive control allocation. Based on this review we propose a unifying framework which connects motivational and cognitive control deficits in depression. This framework is rooted in computational models of cognitive control and offers a mechanistic understanding of cognitive control deficits in depression.
Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis
Authors: Nandakumar Satish K , McFarland Sean K , Mateyka Laura Marlene , Lareau Caleb A , Ulirsch Jacob C , Ludwig Leif S , Agarwal Gaurav , Engreitz Jesse M , Przychodzen Bartlomiej , McConkey Marie , Cowley Glenn S , Doench John G , Maciejewski Jaroslaw , Ebert Benjamin L , Root David E , Sankaran Vijay G.
Published: December 2018

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding genomic regions and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in relevant biological pathways, allowing regulators of human erythropoiesis and blood disease modifiers to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.
Single-copy Knock-In Loci for Defined Gene Expression in C. elegans
Authors: Silva-Garcia Carlos G , Heintz Caroline , Dutta Sneha , Clark Nicole M , Lanjuin Anne , Mair William B
Published: December 2018

We have generated a single-copy knock-in loci for defined gene expression (SKI LODGE) system to insert any cDNA by CRISPR/Cas9 at defined safe harbors in the Caenorhabditis elegans genome. Utilizing a single crRNA guide, which also acts as a Co-CRISPR enrichment marker, any cDNA sequence can be introduced as a single integrated copy, regulated by different tissue-specific promoters. The SKI LODGE system provides a fast, economical and effective approach for generating single-copy non-silenced transgenes in C. elegans.
Fibroblast growth factor receptors function redundantly during zebrafish embryonic development
Authors: Leerberg Dena M , Hopton Rachel E , Draper Bruce W
Published: December 2018

Fibroblast growth factor (Fgf) signaling regulates many processes during development. In many cases, one tissue layer secretes an Fgf ligand that binds and activates an Fgf receptor (Fgfr) expressed by a neighboring tissue. Although many Fgf ligands have known requirements in development, less is known about the requirements for the receptors. We have generated null mutations in each of the five fgfr genes in zebrafish. Considering the many requirements for Fgf signaling throughout development and that null mutations in the mouse Fgfr1 and Fgfr2 genes are embryonic lethal, it was surprising that all zebrafish homozygous mutants are viable and fertile, with no discernable embryonic defect. Instead, we have discovered surprising complexity of the Fgf pathway, where multiple receptors are involved in coordinating developmental processes. For example, mutations in the ligand fgf8a cause loss of the midbrain-hindbrain boundary, whereas in the fgfr mutants, this phenotype is only seen in embryos that are triple mutant for fgfr1a;fgfr1b;fgfr2, but not in any single and double mutant combinations. We show that this apparent fgfr redundancy is also seen during the development of several other tissues, including posterior mesoderm, pectoral fins, viscerocranium, and neurocranium. These data therefore begin to define the Fgfrs that function with a particular Fgf ligand to regulate early development in zebrafish.
Heat stress reveals high molecular mass proteasomes inArabidopsis thalianasuspension cells cultures
Authors: Aristizábal Daniel , Rivas Viridiana , Cassab Gladys , Lledías Fernando
Published: December 2018

Because of their sessile nature, plants have evolved complex and robust mechanisms to respond to adverse environments. Stress conditions trigger an increase in protein turnover and degradation. Proteasomes are essential to the cell for removing, in a highly regulated manner, partially denatured or oxidized proteins thus minimizing their cytotoxicity. We observed that suspension cells ofArabidopsis thalianatreated with high temperature (37 °C) directed the assembly of high molecular mass proteasomes. The removal of a 75% of the original ubiquitin conjugates and the maintenance of protein carbonyls at basal levels correlated with a specific proteasome profiles. The profiles obtained by the separation of different proteasomes populations by Blue-Native Polyacrylamide Gel Electrophoresis and western blot analysis suggest that synthesis, assembly, and heavy ubiquitination of 20S (CP) subunits are promoted by heat stress.
3DeFDR: Identifying cell type-specific looping interactions with empirical false discovery rate guided thresholding
Authors: Fernandez Lindsey , Gilgenast Thomas G. , Phillips-Cremins Jennifer E.
Published: December 2018

The mammalian genome is connected into tens of thousands of long-range looping interactions critically linked to spatiotemporal gene expression regulation. An important unanswered question is to what extent looping interactions change across developmental models, genetic perturbations, drug treatments, and disease states. Although methods exist for calling loops in single biological conditions, there is a severe shortage of computational tools for rigorous assessment of cell type-specific looping interactions across multiple biological conditions. Here we present 3DeFDR, a simple and effective statistical tool for classifying dynamic looping interactions across biological conditions from Chromosome-Conformation-Capture-Carbon-Copy (5C) data. 3DeFDR parses chromatin contacts into invariant and cell type-specific classes by thresholding on differences in modeled interaction strength signal across two or three cellular states. Thresholds are iteratively adjusted based on a target empirical false discovery rate computed between real and simulated 5C maps. 3DeFDR enables the sensitive detection of high-confidence looping interactions and markedly reduces false positives when benchmarked against a classic analysis of variance (ANOVA) test, our newly formulated parametric likelihood ratio test (3DLRT), and the leading Hi-C differential interaction caller diffHic. 3DeFDR also sensitively and specifically calls loops in Mb-scale genomic regions parsed from Hi-C data. Our work provides a statistical framework and an open-source coding library for identifying dynamic long-range looping interactions in high-resolution 5C data from multiple cellular conditions.
Medial prefrontal cortex activity reflects ordinal retrieval modes and hippocampal activity reflects temporal context retrieval modes
Authors: Reeders Puck C. , Hamm Amanda G. , Allen Timothy A. , Mattfeld Aaron T.
Published: December 2018

Remembering sequences of events defines episodic memory, but retrieval can be driven by both ordinality and temporal contexts. Whether these modes of retrieval operate at the same time or not remains unclear. Theoretically, medial prefrontal cortex (mPFC) confers ordinality, while the hippocampus (HC) associates events in gradually changing temporal contexts. Here, we looked for evidence of each with BOLD fMRI in a sequence task that taxes both retrieval modes. To test ordinal modes, items were transferred between sequences but retained their position (e.g., AB3). Ordinal modes activated mPFC, but not HC. To test temporal contexts, we examined items that skipped ahead across lag distances (e.g., ABD). HC, but not mPFC, tracked temporal contexts. There was a mPFC and HC by retrieval mode interaction. These current results suggest that the mPFC and HC are concurrently engaged in different retrieval modes in support of remembering when an event occurred.

Significance Statement

Memory for sequences of events is a defining aspect of everyday episodic memory allowing our brain to separate unique experiences that otherwise have overlapping sensory and spatial content. Sequence memory is impaired in typical aging and in disorders such as Alzheimer’s disease. The results of the current study provide new evidence that two retrieval modes concurrently arise during sequence memory, and they have distinct neural correlates. The medial prefrontal cortex contributes to an ordinal retrieval mode, while at the same time, the hippocampus contributes a gradually-changing temporal context mode of retrieval. These data shed new light on why typical episodic memory requires both the medial prefrontal cortex and the hippocampus, and suggests a functional dissociation between the medial prefrontal cortex and hippocampus across these modes of retrieval.
Neurocomputational underpinnings of expected surprise
Authors: Lecaignard Françoise , Bertrand Olivier , Caclin Anne , Mattout Jérémie
Published: December 2018

Predictive coding accounts of brain functions profoundly influence current approaches to perceptual synthesis. However, a fundamental paradox has emerged, that may be very relevant for understanding hallucinations, psychosis or cognitive inflexibility. This paradox is that in some situations surprise or prediction error related responses can decrease when predicted and yet, they can increase when we know they are predictable. This paradox is resolved by recognizing that brain responses reflect precision weighted prediction error. This then presses us to disambiguate the contributions of precision and prediction error in electrophysiology. We report, for the first time, an experimental paradigm that may be able to meet this challenge. We examined brain responses to unexpected and expected surprising sounds, assuming that the latter yield a smaller prediction error but much more amplified by a larger precision weight. Importantly, addressing this modulation requires the modelling of trial-by-trial variations of brain responses, that we reconstructed within a fronto-temporal network by combining EEG and MEG. Our results reveal an adaptive learning of surprise with larger integration of past (relevant) information in the context of expected surprises. Within the auditory hierarchy, this adaptation was found tied down to specific connections and reveals in particular and crucially precision encoding through neuronal excitability. Strikingly, these fine processes are automated as sound sequences were unattended. These findings directly speak to applications in psychiatry, where it has been suggested that a specifically impaired precision weighting is at the heart of several conditions such as schizophrenia and autism.
Non-CG methylation and multiple epigenetic layers associate child abuse with immune and small GTPase dysregulation
Authors: Lutz Pierre-Eric , Chay Marc-Aurèle , Pacis Alain , Chen Gary G , Aouabed Zahia , Maffioletti Elisabetta , Théroux Jean-François , Grenier Jean-Christophe , Yang Jennie , Aguirre Maria , Ernst Carl , Redensek Adriana , van Kempen Léon C. , Yalcin Ipek , Kwan Tony , Mechawar Naguib , Pastinen Tomi , Turecki Gustavo
Published: December 2018

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we described molecular cross-talk among multiple epigenetic mechanisms, including 6 histone marks, DNA methylation and the transcriptome, in subjects with a history of ELA and controls. We first uncovered, in the healthy brain, previously unknown interactions among epigenetic layers, in particular related to non-CG methylation in the CAC context. We then showed that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicated that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides new insights into epigenetic brain regulation as a function of early-life experience.
Linking Demyelination to Compound Action Potential Dispersion with a Spike-Diffuse-Spike Approach
Authors: Naud Richard , Longtin André
Published: December 2018

To establish and exploit novel biomarkers of demyelinating diseases requires a mechanistic understanding of axonal propagation. Here, we present a novel computational framework called the stochastic spike-diffuse-spike (SSDS) model for assessing the effects of demyelination on axonal transmission. It models transmission through nodal and internodal compartments with two types of operations: a stochastic integrate-and-fire operation captures nodal excitability and a linear filtering operation describes internodal propagation. The effects of demyelinated segments on the probability of transmission, transmission delay and spike time jitter are explored. We argue that demyelination induced impedance mismatch prevents propagation mostly when the action potential leaves a demyelinated region, not when it enters a demyelinated region. In addition, we model sodium channel remodeling as a homeostatic control of nodal excitability. We find that the effects of mild demyelination on transmission probability and delay can be largely counterbalanced by an increase in excitability at the nodes surrounding the demyelination. The spike timing jitter, however, reflects the level of demyelination whether excitability is fixed or is allowed to change in compensation. This jitter can accumulate over long axons and leads to a broadening of the compound action potential, linking microscopic defects to a mesoscopic observable. Our findings articulate why action potential jitter and compound action potential dispersion can serve as potential markers of weak and sporadic demyelination.
Professional medical writing support and the quality, ethics and timeliness of clinical trial reporting: a systematic review
Authors: Evuarherhe Obaro , Gattrell William , White Richard , Winchester Christopher Charles
Published: December 2018

Background: Many authors choose to work with professional medical writers when reporting the results of clinical trials. We conducted a systematic review to examine the relationship between professional medical writing support (PMWS) and the quality, ethics and timeliness of publications reporting clinical trials.
Methods: Using terms related to medical writer and observational study, we searched MEDLINE and Embase (no date limits), as well as abstracts and posters from meetings of the International Society for Medical Publication Professionals (ISMPP; 2014-2017). We also hand-searched the journals Medical Writing and The Write Stuff (2014-2017), and the bibliographies of studies identified in the electronic searches. We screened the results to identify studies that compared the quality, ethics and timeliness of clinical trial publications written with and without declared PMWS.
Results: Our searches identified 97 potentially relevant studies, of which 89 were excluded during screening and full paper review. The remaining eight studies compared 849 publications with PMWS with 2073 articles developed without such support. In these eight studies, PMWS was shown to be associated with: increased adherence to Consolidated Standards of Reporting Trials (CONSORT) guidelines (in 3/3 studies in which this was assessed); publication in journals with an impact factor (one study); a higher quality of written English (one study); and a lower likelihood of reporting non-pre-specified outcomes (one study). PMWS was not associated with increased adherence to CONSORT for Abstracts guidelines (one study) or with the impact of published articles (mean number of citations per year, mean number of article views per year and Altmetric score; one study). In studies that assessed timeliness of publication, PMWS was associated with a reduced time from last patient visit in clinical trials to primary publication (one study), whereas time from submission to acceptance showed inconsistent results (two studies).
Conclusions: This systematic review of eight observational studies suggests that PMWS increases the overall quality of reporting of clinical trials and may improve the timeliness of publication.
Evolution of sperm competition: Natural variation and genetic determinants ofCaenorhabditis eleganssperm size
Authors: Gimond Clotilde , Vielle Anne , Silva-Soares Nuno , Zdraljevic Stefan , McGrath Patrick T. , Andersen Erik C. , Braendle Christian
Published: December 2018

Sperm morphology is critical for sperm competition and thus for reproductive fitness. In the male-hermaphrodite nematodeCaenorhabditis elegans, sperm size is a key feature of sperm competitive ability. Yet despite extensive research, the molecular mechanisms regulatingC. eleganssperm size and the genetic basis underlying its natural variation remain unknown. Examining 97 genetically distinctC. elegansstrains, we observe significant heritable variation in male sperm size but genome-wide association mapping did not yield any QTL (Quantitative Trait Loci). While we confirm larger male sperm to consistently outcompete smaller hermaphrodite sperm, we find natural variation in male sperm size to poorly predict male fertility and competitive ability. In addition, although hermaphrodite sperm size also shows significant natural variation, male and hermaphrodite sperm size do not correlate, implying a sex-specific genetic regulation of sperm size. To elucidate the molecular basis of intraspecific sperm size variation, we focused on recently diverged laboratory strains, which evolved extreme sperm size differences. Using mutants and quantitative complementation tests, we demonstrate that variation in the genenurf-1– previously shown to underlie the evolution of improved hermaphrodite reproduction – also explains the evolution of reduced male sperm size. This result illustrates how adaptive changes inC. eleganshermaphrodite function can cause the deterioration of a male-specific fitness trait due to a sexually antagonistic variant, representing an example of intralocus sexual conflict with resolution at the molecular level. Our results further provide first insights into the genetic determinants ofC. eleganssperm size, pointing at an involvement of the NURF chromatin remodelling complex.
Different molecular signatures in lung cancer types from integrative bioinformatic analyses of RNASeq data
Authors: Lucchetta Marta , Piedade Isabelle da , Mounir Mohamed , Vabistsevits Marina , Terkelsen Thilde , Papaleo Elena
Published: December 2018

Background

Genomic initiatives such as The Cancer Genome Atlas (TCGA) project contain data on profiling of thousands of tumors with different-omics approaches, providing a valuable source of information which may be used to decipher cancer signaling and related alterations. Managing and analyzing data from large-scale projects such as TCGA is a demanding task. Indeed, it is difficult to dissect the high complexity hidden in genomic data and to adequately account for tumor heterogeneity.

Results

In this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patient samples from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC). In particular, we used RNA-Seq gene expression data to identify both co-expression modules and differentially expressed genes to accurately discriminate between LUAD and LUSC. Moreover, we identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, as well as two dual role genes. Our results have also been cross-validated against other transcriptomics data of lung cancer patients.

Conclusions

Our integrative approach allowed to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC is linked to the activation of three specific oncogenic pathways which promote the evasion of antitumor immune response, providing new future directions for the design of target therapies.
Analysis of small RNA silencing in Zymoseptoria tritici – wheat interactions
Authors: Kettles Graeme J. , Hofinger Bernhard J. , Hu Pingsha , Bayon Carlos , Rudd Jason J. , Balmer Dirk , Courbot Mikael , Hammond-Kosack Kim E. , Scalliet Gabriel , Kanyuka Kostya
Published: December 2018

Cross-kingdom small RNA (sRNA) silencing has recently emerged as a mechanism facilitating fungal colonization and disease development. Here we characterized RNAi pathways in Zymoseptoria tritici, a major fungal pathogen of wheat, and assessed their contribution to pathogenesis. Computational analysis of fungal sRNA and host mRNA sequencing datasets was used to define the global sRNA populations in Z. tritici and predict their mRNA targets in wheat. 389 in planta-induced sRNA loci were identified. sRNAs generated from some of these loci were predicted to target wheat mRNAs including those potentially involved in pathogen defense. However, molecular approaches failed to validate targeting of selected wheat mRNAs by fungal sRNAs. Mutant strains of Z. tritici carrying deletions of genes encoding key components of RNAi such as Dicer-like (DCL) and Argounate (AGO) proteins were generated, and virulence bioassays suggested that these are dispensable for full infection of wheat. Nonetheless, our results did suggest the existence of non-canonical DCL-independent pathway(s) for sRNA biogenesis in Z. tritici. dsRNA targeting essential fungal genes applied in vitro or generated from an RNA virus vector in planta in a procedure known as HIGS (Host-Induced Gene Silencing) was ineffective in preventing Z. tritici growth or disease. We also demonstrated that Z. tritici is incapable of dsRNA uptake. Collectively, our data suggest that RNAi approaches for gene function analyses in this fungal species and potentially also as a control measure may not be as effective as has been demonstrated for some other plant pathogenic fungi.
A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies
Authors: Nourse Jamie , Danckwardt Sven
Published: December 2018

Therapeutic targeting of blood coagulation is a challenging task as it interferes with the delicate balance of pro- and anticoagulant activities. Anticoagulants are employed in millions of thrombophilic patients worldwide each year. The treatment and prevention of venous thromboembolism has changed drastically with the replacement of traditional anticoagulant vitamin K antagonists by direct oral anticoagulants (DOACs), which selectively target coagulation factors Xa or IIa. However for a growing population with comorbidities satisfying therapeutic options are still lacking and the quest for novel therapeutics continues. Recently targeting factors XI or XII have emerged as new therapeutic strategies. As these factors play important roles in thrombosis, nevertheless are practically functionally dispensable for hemostasis, they may potentially overcome the functional obstacle of treating or preventing thrombosis without affecting hemostasis. Based on the recent elucidation of the hemostatic miRNA targetome, we introduce and discuss a hitherto unrecognized rationale for the therapeutic targeting of factor XI. This is based on mimicking endogenous factor XI expression control by therapeutic delivery of miRNA mimics. We discuss the functional difference between various gene targeting approaches, and propose the hemostatic system to represent an ideal model for assessment of the efficacy and safety of such therapeutic components, ushering in a novel therapeutic era with broad applicability.
iCn3D, a Web-based 3D Viewer for Sharing 1D/2D/3D Representations of Biomolecular Structures
Authors: Wang Jiyao , Youkharibache Philippe , Zhang Dachuan , Lanczycki Christopher J. , Geer Renata C. , Madej Thomas , Phan Lon , Ward Minghong , Lu Shennan , Marchler Gabriele H. , Wang Yanli , Bryant Stephen H. , Geer Lewis Y. , Marchler-Bauer Aron
Published: December 2018

iCn3D (I-see-in-3D) is a web-based 3D molecular structure viewer focusing on the interactive structural analysis. It can simultaneously show 3D structure, 2D molecular contacts, and 1D protein and nucleotide sequences through an integrated sequence/annotation browser. Pre-defined and arbitrary molecular features can be selected in any of the 1D/2D/3D windows as sets of residues and these selections are synchronized dynamically in all displays. Biological annotations such as protein domains, single nucleotide variations, etc. can be shown as tracks in the 1D sequence/annotation browser. These customized displays can be shared with colleagues or publishers via a simple URL. iCn3D can display structure-structure alignment obtained from NCBI’s VAST+ service. It can also display the alignment of a sequence with a structure as identified by BLAST, and thus relate 3D structure to a large fraction of all known proteins. iCn3D can also display electron density maps or electron microscopy (EM) density maps, and export files for 3D printing. The following example URL exemplifies some of the 1D/2D/3D representations: https://www.ncbi.nlm.nih.gov/Structure/icn3d/full.html?mmdbid=1TUP&showanno=1&show2d=1&showsets=1.

Availability and implementation

iCn3D is freely available to the public. Its source code is available at https://github.com/ncbi/icn3d.

Supplementary information

User instructions are available at Bioinformatics online
Lasagna: Multifaceted Protein-Protein Interaction Prediction Based on Siamese Residual RCNN
Authors: Chen Muhao , Ju Chelsea Jui-Ting , Zhou Guangyu , Zhang Tianran , Chen Xuelu , Chang Kai-Wei , Zaniolo Carlo , Wang Wei
Published: December 2018

Sequence-based protein-protein interaction (PPI) prediction represents a fundamental computational biology problem. To address this problem, extensive research efforts have been made to extract predefined features from the sequences. Based on these features, statistical algorithms are learned to classify the PPIs. However, such explicit features are usually costly to extract, and typically have limited coverage on the PPI information. Hence, we present an end-to-end framework, Lasagna, for PPI predictions using only the primary sequences of a protein pair. Lasagna incorporates a deep residual recurrent convolutional neural network in the Siamese learning architecture, which leverages both robust local features and contextualized information that are significant for capturing the mutual influence of protein sequences. Our framework relieves the data pre-processing efforts that are required by other systems, and generalizes well to different application scenarios. Experimental evaluations show that Lasagna outperforms various state-of-the-art systems on the binary PPI prediction problem. Moreover, it shows a promising performance on more challenging problems of interaction type prediction and binding affinity estimation, where existing approaches fall short.
G-Dash: A Genome Dashboard Integrating Modeling and Informatics
Authors: Li Zilong , Sun Ran , Bishop Thomas C
Published: December 2018

Genomics is a sequence based informatics science and a structure based molecular material science. There are few tools available that unite these approaches in a scientifically robust manner. Here we describe G-Dash, a web based prototype of a genomics dashboard, specifically designed to integrate informatics and 4D material studies of chromatin. G-Dash unites our Interactive Chromatin Modeling(ICM) tools with the Biodalliance genome browser and the JSMol molecular viewer to rapidly fold any DNA sequence into atomic or coarse-grained models of DNA, nucleosomes or chromatin. As a chromatin modeling tool, G-Dash enables users to specify nucleosome positions from various experimental or theoretical sources, interactively manipulate nucleosomes, and assign different conformational states to each nucleosome. As an informatics tool, data associated with 3D structures are displayed as tracks in a genome browser. The exchange of data between informatics and structure is bi-directional so any informatics track can inform a molecular structure (e.g. color by function) and structure features can be displayed as informatics tracks in a genome browser(e.g. Roll, Slide, or Twist). As a sample application, models of the CHA1 promoter based on experimentally determined nucleosome positions are explored with G-Dash. Steric clashes and DNA knotting are observed but can be resolved with G-Dash's minimal coarse-grained model without significant variation in structure. Results raise questions about the interpretation of nucleosome positioning data and promoter structures. In this regard, G-Dash is a novel tool for investigating structure-function relationships for regions of the genome ranging from base pairs to chromosomes and for generating, validating and testing mechanistic hypotheses.