bluuebunny/crossref_metadata_2025 huggingface dataset:
Benchmarking network propagation methods for disease gene identification
Authors: Picart-Armada Sergio , Barrett Steven J. , Willé David R. , Perera-Lluna Alexandre , Gutteridge Alex , Dessailly Benoit H.
Published: October 2018

Background

In-silico identification of potential disease genes has become an essential aspect of drug target discovery. Recent studies suggest that one powerful way to identify successful targets is through the use of genetic and genomic information. Given a known disease gene, leveraging intermolecular connections via networks and pathways seems a natural way to identify other genes and proteins that are involved in similar biological processes, and that can therefore be analysed as additional targets.

Results

Here, we systematically tested the ability of 12 varied network-based algorithms to identify target genes and cross-validated these using gene-disease data from Open Targets on 22 common diseases. We considered two biological networks, six performance metrics and compared two types of input gene-disease association scores. We also compared several cross-validation schemes and showed that different choices had a remarkable impact on the performance estimates. When seeding biological networks with known drug targets, we found that machine learning and diffusion-based methods are able to find novel targets, showing around 2-4 true hits in the top 20 suggestions. Seeding the networks with genes associated to disease by genetics resulted in poorer performance, below 1 true hit on average. We also observed that the use of a larger network, although noisier, improved overall performance.

Conclusions

We conclude that machine learning and diffusion-based prioritisers are suited for drug discovery in practice and improve over simpler neighbour-voting methods. We also demonstrate the large effect of several factors on prediction performance, especially the validation strategy, input biological network, and definition of seed disease genes.
Factors influencing leaf- and root-associated communities of bacteria and fungi across 33 plant orders in a grassland
Authors: Toju Hirokazu , Kurokawa Hiroko , Kenta Tanaka
Published: October 2018

In terrestrial ecosystems, plants interact with diverse taxonomic groups of bacteria and fungi in the phyllosphere and rhizosphere. Although recent studies based on high-throughput DNA sequencing have drastically increased our understanding of plant-associated microbiomes, we still have limited knowledge of how plant species in a species-rich community differ in their leaf and root microbiome compositions. In a cool-temperate semi-natural grassland in Japan, we compared leaf- and root-associated microbiomes across 138 plant species belonging to 33 plant orders. Based on the whole-microbiome inventory data, we analyzed how sampling season as well as the taxonomy, nativeness (native or alien), lifeform (herbaceous or woody), and mycorrhizal type of host plants could contribute to variation in microbiome compositions among co-occurring plant species. The data also allowed us to explore prokaryote and fungal lineages showing preferences for specific host characteristics. The list of microbial taxa showing significant host preferences involved those potentially having some impacts on survival, growth, or environmental resistance of host plants. Overall, this study provides a platform for understanding how plant and microbial communities are linked with each other at the ecosystem level.
Growth-factor like gene regulation is separable from survival and maturation in antibody secreting cells
Authors: Stephenson Sophie , Care Matthew A , Fan Im , Zougman Alexandre , Westhead David R , Doody Gina M , Tooze Reuben M
Published: October 2018

Recurrent mutational activation of the MAP kinase pathway in plasma cell myeloma implicates growth factor-like signaling responses in the biology of antibody secreting cells (ASCs). Physiological ASCs survive in niche microenvironments, but how niche signals are propagated and integrated is poorly understood. Here we dissect such a response in human ASCs using an in vitro model. Applying time course expression data and parsimonious gene correlation networking analysis (PGCNA), we map expression changes that occur during the maturation of proliferating plasmablast to quiescent plasma cell under survival conditions including the potential niche signal TGFB3. This analysis demonstrates a convergent pattern of differentiation, linking UPR/ER stress to secretory optimization, co-ordinated with cell cycle exit. TGFB3 supports ASC survival while having a limited effect on gene expression including up-regulation of CXCR4. This is associated with a significant shift in response to SDF1 in ASCs with amplified ERK1/2 activation, growth factor-like immediate early gene regulation and EGR1 protein expression. Similarly, ASCs responding to survival conditions initially induce partially overlapping sets of immediate early genes, without sustaining the response. Thus, in human ASCs growth factor-like gene regulation is transiently imposed by niche signals but is not sustained during subsequent survival and maturation.
Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening
Authors: Arenaz Callao María Pilar , González del Río Rubén , Quintana Ainhoa Lucía , Thompson Charles J. , Mendoza-Losana Alfonso , Ramón-García Santiago
Published: October 2018

The potential use of clinically approved beta-lactams for Buruli ulcer (BU) treatment was investigated with representative classes analyzed in vitro for activity against Mycobacterium ulcerans. Beta-lactams tested were effective alone and displayed a strong synergistic profile in combination with antibiotics currently used to treat BU, i.e. rifampicin and clarithromycin; this activity was further potentiated in the presence of the beta-lactamase inhibitor clavulanate. In addition, quadruple combinations of rifampicin, clarithromycin, clavulanate and beta-lactams resulted in multiplicative reductions in their minimal inhibitory concentration (MIC) values. The MIC of amoxicillin against a panel of clinical isolates decreased more than 200-fold within this quadruple combination. Amoxicillin/clavulanate formulations are readily available with clinical pedigree, low toxicity, and orally and pediatric available; thus, supporting its potential inclusion as a new anti-BU drug in current combination therapies.
Muller’s ratchet as a mechanism of frailty and multimorbidity
Authors: Govindaraju Diddahally R. , Innan Hideki
Published: October 2018

Mutation accumulation has been proposed as a cause of senescence. In this process, both constitutional and recurrent mutations accumulate gradually and differentially among differentiating cells, tissues and organs, in relation to stage and age, analogous to Muller’s ratchet in asexually reproducing organisms. Latent and cascading deleterious effects of mutations might initiate steady “accumulation of deficits” in cells, leading to cellular senescence, and functional decline of tissues and organs, and ultimately manifest as frailties and disease. We investigated a few of these aspects in cell populations through modeling and simulation using the Moran birth-death process, under varied scenarios of mutation accumulation. Our results agree with the principle of Muller’s ratchet. The ratchet speed in a given tissue depends on the population size of cells, mutation rate, and selection coefficient. Additionally, deleterious mutations seem to rapidly accumulate particularly early in the life-course, during which the rate of cell division is high, thereby exerting a greater effect on cellular senescence. The speed of the ratchet afterward varies greatly between cells nested in tissues and tissues within organs due to heterogeneity in the life span and turnover rate of specific cell types. Importantly, the ratchet accelerates with age, resulting in a synergistic fitness decay in cell populations. We extend Fisher’s average excess concept and rank order scale to interpret differential phenotypic effects of mutation load in a given tissue. We conclude that classical evolutionary genetic models could explain partially, the origins of frailty, subclinical conditions, morbidity and health consequences of senescence.

Significance

Frailty is defined as physiological and functional decline of organs and organ systems, due to deficit accumulation from stochastic damages within the organism with advanced age. Equivalently, with age, both constitutional and somatic mutations accumulate gradually and differentially among cells, cell lineages, tissues, and organs. Since most mutations are deleterious, accumulation of random and recurrent mutations could create a “load,” on the genome and contextually express in the epigenome and phenotype spaces. Here we extend Muller’s ratchet principle to explain frailty and multi-morbidity using the Moran model and simulations. Our results agree with the Muller’s ratchet principle. We emphasize the need for considering cumulative effects of the entire spectrum of mutations for explaining the origin of frailty, sub-clinical conditions, and morbidity.
Computational noise in reward-guided learning drives behavioral variability in volatile environments
Authors: Findling Charles , Skvortsova Vasilisa , Dromnelle Rémi , Palminteri Stefano , Wyart Valentin
Published: October 2018

When learning the value of actions in volatile environments, humans often make seemingly irrational decisions which fail to maximize expected value. We reasoned that these ‘non-greedy’ decisions, instead of reflecting information seeking during choice, may be caused by computational noise in the learning of action values. Here, using reinforcement learning (RL) models of behavior and multimodal neurophysiological data, we show that the majority of non-greedy decisions stems from this learning noise. The trial-to-trial variability of sequential learning steps and their impact on behavior could be predicted both by BOLD responses to obtained rewards in the dorsal anterior cingulate cortex (dACC) and by phasic pupillary dilation – suggestive of neuromodulatory fluctuations driven by the locus coeruleus-norepinephrine (LC-NE) system. Together, these findings indicate that most of behavioral variability, rather than reflecting human exploration, is due to the limited computational precision of reward-guided learning.
Comparative analysis of active sites in P-loop nucleoside triphosphatases suggests an ancestral activation mechanism
Authors: Shalaeva Daria N. , Cherepanov Dmitry A. , Galperin Michael Y. , Mulkidjanian Armen Y.
Published: October 2018

P-loop nucleoside triphosphatases (NTPases) share common Walker A (P-loop) and Walker B sequence motifs and depend on activating moieties (Arg or Lys fingers or a K+ion). In search for a common catalytic mechanism, we combined structure comparisons of active sites in major classes of P-loop NTPases with molecular dynamics (MD) simulations of the Ras GTPase, a well-studied oncoprotein. Comparative structure analysis showed that positively charged activating moieties interact with gamma-phosphate groups of NTP substrates in all major classes of P-loop NTPases. In MD simulations, interaction of the activating Arg finger with the Mg-GTP-Ras complex led to the rotation of the gamma-phosphate group by 40 degrees enabling its interaction with the backbone amide group of Gly13. In all analyzed structures, the residue that corresponds to Gly13 of Ras was in a position to stabilize gamma-phosphate after its rotation, suggesting a common ancestral activation mechanism within the entire superfamily.
SMAP: exploiting high-throughput sequencing data of patient derived xenografts
Authors: Blum Yuna , de Reyniès Aurélien , Dusetti Nelson , Iovanna Juan , Marisa Laetitia , Nicolle Rémy
Published: October 2018

Background

Patient-derived xenograft is the model of reference in oncology fordrug response analyses. Xenografts samples have the specificity to be composedof cells from both the graft and the host species. Sequencing analysis ofxenograft samples therefore requires specific processing methods to properlyreconstruct genomic profiles of both the host and graft compartments.

Results

We propose a novel xenograft sequencing process pipeline termedSMAP for Simultaneous mapping. SMAP integrates the distinction of host andgraft sequencing reads to the mapping process by simultaneously aligning to bothgenome references. We show that SMAP increases accuracy of species-assignmentwhile reducing the number of discarded ambiguous reads compared to otherexisting methods. Moreover, SMAP includes a module called SMAP-fuz toimprove the detection of chimeric transcript fusion in xenograft RNAseq data. Finally, we apply SMAP on a real dataset and show the relevance of pathway andcell population analysis of the tumoral and stromal compartments.

Conclusions

In high-throughput sequencing analysis of xenografts, our resultsshow that: i. the use of ad hoc sequence processing methods is essential, ii. highsequence homology does not introduce a significant bias when proper methodsare used and iii. the detection of fusion transcripts can be improved using ourapproach. SMAP is available on GitHub: cit-bioinfo.github.io/SMAP.
OsJAZ9 overexpression improves potassium deficiency tolerance in rice by modulating jasmonic acid levels and signaling
Authors: Singh Ajit Pal , Pandey Bipin K. , Mehra Poonam , Chandan Ravindra Kumar , Jha Gopaljee , Giri Jitender
Published: October 2018

Potassium (K) which makes around 2-10% of plants total dry biomass, when become deficient, makes the plants highly susceptible to both abiotic and biotic stresses. Recent evidences suggest overlapping transcriptional responses to K deficiency and Jasmonate (JA) treatment in plants. However, a link between these responses was missing. Notably, K deficiency and JA application produce similar phenotypic and transcriptional responses. Here, we used molecular, physiological and morphological studies to analyze the role of OsJAZ9 in JA homeostasis, K deficiency and sheath blight resistance. We raised OsJAZ9 overexpression, knockdown, translational reporter and C-terminal deleted translational reporter lines in rice to establish the role of JA signaling in K ion homeostasis and OsJAZ9 as a critical component of JA signaling for K deficiency response. OsJAZ9 overexpression and knockdown provide K deficiency tolerance and sensitivity, respectively, by modulating various K transporters and root system architecture. Furthermore, RNA Seq and JA profiling revealed an elevation of JA responsive genes and JA levels in OsJAZ9 OE lines under K deficiency. Our data provide clear evidence on the crucial role of JAZ repressor, OsJAZ9 in improving K deficiency tolerance in rice by altering JA levels and signaling.
Single-cell transcriptomics of the aged mouse brain reveals convergent, divergent and unique aging signatures
Authors: Ximerakis Methodios , Lipnick Scott L. , Simmons Sean K. , Adiconis Xian , Innes Brendan T. , Dionne Danielle , Nguyen Lan , Mayweather Brittany A. , Ozek Ceren , Niziolek Zachary , Butty Vincent L. , Isserlin Ruth , Buchanan Sean M. , Levine Stuart R. , Regev Aviv , Bader Gary D , Levin Joshua Z. , Rubin Lee L.
Published: October 2018

The mammalian brain is complex, with multiple cell types performing a variety of diverse functions, but exactly how the brain is affected with aging remains largely unknown. Here we performed a single-cell transcriptomic analysis of young and old mouse brains. We provide a comprehensive dataset of aging-related genes, pathways and ligand-receptor interactions in nearly all brain cell types. Our analysis identified gene signatures that vary in a coordinated manner across cell types and gene sets that are regulated in a cell type specific manner, even at times in opposite directions. Thus, our data reveals that aging, rather than inducing a universal program drives a distinct transcriptional course in each cell population. These data provide an important resource for the aging community and highlight key molecular processes, including ribosomal biogenesis, underlying aging. We believe that this large-scale dataset, which is publicly accessible online (aging-mouse-brain), will facilitate additional discoveries directed towards understanding and modifying the aging process.
Targeted RNA NextGenSeq profiling in oncology using single molecule molecular inversion probes
Authors: Lenting Krissie , van den Heuvel Corina N.A.M. , van Ewijk Anne , Tindall Elizabeth , Wei Ge , Kusters Benno , te Dorsthorst Maarten , ter Laan Mark , Huynen Martijn A. , Leenders William P.
Published: October 2018

Hundreds of biology-based precision drugs are available that neutralize aberrant molecular pathways in cancer. Molecular heterogeneity and the lack of reliable companion diagnostic biomarkers for many drugs makes targeted treatment of cancer inaccurate for many individuals, leading to futile overtreatment. To acquire a comprehensive insight in aberrant actionable biological pathways in individual cancers we applied a cost-effective targeted RNA next generation sequencing (NGS) technique. The test allows NGS-based measurement of transcript levels and splice variants of hundreds of genes with established roles in the biological behavior in many cancer types. We here present proof of concept that the technique generates a correct molecular diagnosis and a prognosis for glioma patients. The test not only confirmed known brain cancer-associated molecular aberrations but also identified aberrant expression levels of actionable genes and mutations that are associated with other cancer types. Targeted RNA-NGS is therefore a highly attractive method to guide precision therapy for the individual patient based on pathway analysis.
In vitro characterization of human articular chondrocytes and chondroprogenitors derived from normal and osteoarthritic knee joints
Authors: Vinod Elizabeth , Kachroo Upasana , Sathishkumar Solomon , Boopalan P.R.J.V.C
Published: October 2018

Objective

Cell based therapy optimization is constantly underway since regeneration of genuine hyaline cartilage is under par. Although single source derivation of chondrocytes and chondroprogenitors is advantageous, lack of a characteristic differentiating marker obscures clear identification of either cell type which is essential to create a biological profile and is also required to assess cell type superiority for cartilage repair. This study was the first attempt where characterization was performed on the two cell populations derived from the same human articular cartilage samples.

Design

Cells obtained from normal/osteoarthritic knee joints were expanded in culture (up to passage 10). Characterization studies was performed using flow cytometry, gene expression was studied using RT-PCR, growth kinetics and tri-lineage differentiation was also studied to construct a better biological profile of chondroprogenitors as well as chondrocytes.

Results and conclusions

Our results suggest that sorting based on CD34(-), CD166(+) and CD146(+), instead of isolation using fibronectin adhesion assay (based on CD49e+/CD29+), would yield a population of cells primarily composed of chondroprogenitors which when derived from normal as opposed to osteoarthritic cartilage, could provide translatable results in terms of enhanced chondrogenesis and reduced hypertrophy; both indispensable for the field of cartilage regeneration.
Loose social organisation of AB strain zebrafish groups in a two-patch environment
Authors: Séguret Axel , Collignon Bertrand , Cazenille Léo , Chemtob Yohann , Halloy José
Published: October 2018

We study the collective behaviour of zebrafish shoals of different numbers of individuals (1, 2, 3, 5, 7, 10 and 20 AB zebrafishDanio rerio) in a constraint environment composed of two identical square rooms connected by a corridor. This simple set-up is similar to a natural patchy environment. We track the positions and the identities of the fish and compute the metrics at the group and at the individual levels. First, we show that the number of fish affects the behaviour of each individual in a group, the cohesion of the groups, the preferential interactions and the transition dynamics between the two rooms. Second, during collective departures, we show that the rankings of exit correspond to the topological organisations of the fish prior to their collective departure. This spatial organisation appears in the group a few seconds before a collective departure. These results provide new evidences on the spatial organisation of the groups and the effect of the number of fish on individual and collective behaviours in a patchy environment.
The origin of fungi-culture in termites was associated with a shift to a mycolytic gut bacteria community
Authors: Hu Haofu , Rodrigues da Costa Rafael , Pilgaard Bo , Schiøtt Morten , Lange Lene , Poulsen Michael
Published: October 2018

Termites forage on a range of substrates, and it has been suggested that diet shapes the composition and function of termite gut bacterial communities. Through comparative analyses of gut metagenomes in nine termite species with distinct diets, we characterise bacterial community compositions and identify biomass-degrading enzymes and the bacterial taxa that encode them. We find that fungus-growing termite guts are enriched in fungal cell wall-degrading and proteolytic enzymes, while wood-feeding termite gut communities are enriched for plant cell wall-degrading enzymes. Interestingly, wood-feeding termite gut bacteria code for abundant chitinolytic enzymes, suggesting that fungal biomass within the decaying wood likely contributes to gut bacteria or termite host nutrition. Across diets, the dominant biomass-degrading enzymes are predominantly coded for by the most abundant bacterial taxa, suggesting tight links between diet and gut community composition, with the most marked shift being the communities coding for the mycolytic capacity of the fungus-growing termite gut.
Integrating brain methylome with GWAS for psychiatric risk gene discovery
Authors: Han Shizhong , Lin Ying , Wang Minghui , Goes Fernando S. , Tan Kai , Zandi Peter , Hyde Thomas , Weinberger Daniel R. , Potash James B. , Kleinman Joel E. , Jaffe Andrew E.
Published: October 2018

DNA methylation (DNAm) is heritable and plays a role in brain development and function through transcriptional regulation. Aberrant DNAm in human brain has been linked to psychiatric disorders, potentially as mediators of common genetic risk variants. In this study, we hypothesize that common risk variants for psychiatric disorders may act through affecting DNAm level in human brain. We first aimed to investigate the heritability pattern of DNAm levels in the human prefrontal cortex. Secondly, through imputation-driven methylome-wide association study (MWAS), we aimed to identify CpG sites whose methylation levels are genetically associated and that show methylation-trait associations in the prefrontal cortex of patients with schizophrenia or bipolar disorder. Our heritability analysis showed that, of ~370,000 CpG sites measured with the Illumina HumanMethylation450 microarray, 17% were heritable (p < 0.05), with a mean heritability of 0.22. Heritable CpG sites were enriched in intergenic regions, CpG shore, and regulatory regions in prefrontal cortex. Our MWAS approach identified known and potentially novel risk genes harboring CpG sites of methylation-trait associations for schizophrenia or bipolar disorder, which were not detectable using three alternative strategies (blood-based methylome reference, transcriptome-wide association study, and two gene-based association tests). Gene set enrichment analysis for genes with methylation-trait association evidence revealed pathways clearly related to neuronal functions, but also highlighted additional biological mechanisms that may underlie psychiatric disorders, such as microRNA-related regulation. In conclusion, our results showed the power of integrating brain methylation data with GWAS for psychiatric risk gene discovery, with potential applications in brain-related disorders or traits.
Electrochemical Evaluation of Ion Substituted-Hydroxyapatite on HeLa Cells Plasma Membrane Potential
Authors: Asimeng Bernard Owusu , Tiburu Elvis Kwason , Kuafmann Elsie Effah , Peamka Lily , Hayford Claude Fiifi , Essien-Baidoo Samuel , Dzikunu Obed Korshie , Anani Prince Atsu
Published: October 2018

This study reports the electrochemical activities of a novel ion substituted-Hydroxyapatite material in contact with HeLa cells. The work was performed to evaluate the inhibitory effects of various concentrations of the material on the ion transfer mechanisms in HeLa cells. The materials (n=2: HAp1 and HAp3) were prepared at different stirring times fromAchatina achatinasnail shells and phosphate-containing solution. The structure of the materials and the trace elements concentration were evaluated using x-ray diffractometry and infrared spectrometry as well as atomic absorption spectroscopy. Electrochemical studies conducted on the cells, after 30 min of exposure to the materials, demonstrated differential responses as elucidated by cyclic voltammetry. The voltammograms revealed HAp1 to be non-redox whereas HAp3 was redox active. Minimal concentrations of HAp1 showed high anodic peak current when compared to the HeLa cells alone, indicating a hyperpolarization of the cells. The peak current gradually reduced as the concentration of HAp1 was increased, and then a sudden rise suggesting inhibition of the cell action potential. HAp3 showed a wavy pattern of the anodic peak current when the material concentration was varied. Peak currents of 0.92 and 0.57 nA were recorded for HAp1 and HAp3, respectively at the highest concentration of 5μL. The results suggest that different inhibitory mechanisms are at play on the voltage-gated ion channels of the cells, indicating the possibility of using the materials to achieve different cancer proliferation inhibition.
Modelling sex-specific crossover patterning in Arabidopsis
Authors: Lloyd Andrew , Jenczewski Eric
Published: October 2018

Interference is a major force governing the patterning of meiotic crossovers. A leading model describing how interference influences crossover-patterning is the beam film model, a mechanical model based on the accumulation and redistribution of crossover-promoting stress along the chromosome axis. We use the beam-film model in conjunction with a large Arabidopsis reciprocal back-cross data set to gain mechanistic insights into the differences between male and female meiosis and crossover patterning. Beam-film modelling suggests that the underlying mechanics of crossover patterning and interference are identical in the two sexes, with the large difference in recombination rates and distributions able to be entirely explained by the shorter chromosome axes in females. The modelling supports previous indications that fewer crossovers occur via the class II pathway in female meiosis and that this could be explained by reduced DNA double strand breaks in female meiosis, paralleling the observed reduction in synaptonemal complex length between the two sexes. We also demonstrate that changes in the strength of suppression of neighboring class I crossovers can have opposite effects on effective interference depending on the distance between two genetic intervals.
A confirmation bias in perceptual decision-making due to hierarchical approximate inference
Authors: Lange Richard D. , Chattoraj Ankani , Beck Jeffrey M. , Yates Jacob L. , Haefner Ralf M.
Published: October 2018

Making good decisions requires updating beliefs according to new evidence. This is a dynamical process that is prone to biases: in some cases, beliefs become entrenched and resistant to new evidence (leading to primacy effects), while in other cases, beliefs fade over time and rely primarily on later evidence (leading to recency effects). How and why either type of bias dominates in a given context is an important open question. Here, we study this question in classic perceptual decision-making tasks, where, puzzlingly, previous empirical studies differ in the kinds of biases they observe, ranging from primacy to recency, despite seemingly equivalent tasks. We present a new model, based on hierarchical approximate inference and derived from normative principles, that not only explains both primacy and recency effects in existing studies, but also predicts how the type of bias should depend on the statistics of stimuli in a given task. We verify this prediction in a novel visual discrimination task with human observers, finding that each observer’s temporal bias changed as the result of changing the key stimulus statistics identified by our model. By fitting an extended drift-diffusion model to our data we rule out an alternative explanation for primacy effects due to bounded integration. Taken together, our results resolve a major discrepancy among existing perceptual decision-making studies, and suggest that a key source of bias in human decision-making is approximate hierarchical inference.
Effects of Oral Domoic Acid Exposure on Maternal Reproduction and Infant Birth Characteristics in a Preclinical Nonhuman Primate Model
Authors: Burbacher Thomas M. , Grant Kimberly S. , Petroff Rebekah , Shum Sara , Crouthamel Brenda , Stanley Courtney , McKain Noelle , Jing Jing , Isoherranen Nina
Published: October 2018

Domoic Acid (DA) is a naturally-occurring excitotoxin, produced by marine algae, which can bioaccumulate in shellfish and finfish. The consumption of seafood contaminated with DA is associated with gastrointestinal illness that, in the case of high DA exposure, can evolve into a spectrum of responses ranging from agitation to hallucinations, memory loss, seizures and coma. Because algal blooms that produce DA are becoming more widespread and very little is known about the dangers of chronic, low-dose exposure, we initiated a preclinical study focused on the reproductive and developmental effects of DA in a nonhuman primate model. To this end, 32 adult femaleMacaca fascicularismonkeys were orally exposed to 0, 0.075 or 0.15 mg/kg/day DA on a daily basis, prior to and during pregnancy. Females were bred to non-exposed males and infants were evaluated at birth. Results from this study provided no evidence of changes in DA plasma concentrations with chronic exposure. DA exposure was not associated with reproductive toxicity or adverse changes in the physical characteristics of newborns. However, in an unanticipated finding, our clinical observations battery revealed the presence of subtle neurological effects in the form of intentional tremors in the exposed adult females. While females in both dose groups displayed increased tremoring, the effect was dose-dependent and observed at a higher frequency in females exposed to 0.15 mg/kg/day. These results demonstrate that chronic, low-level exposure to DA is associated with injury to the adult CNS and suggest that current regulatory guidelines designed to protect human health may not be adequate for high-frequency shellfish consumers.

Highlights

1) Domoic acid acts as a tremoragen after chronic, low-dose oral exposure in adults.

2) Exposure across pregnancy does not result in maternal reproductive toxicity.

3) In-utero exposure does not adversely impact physical characteristics of exposed newborns.

4) Current regulatory guidelines may not adequately protect high-frequency shellfish consumers from DA-induced neurological injury.
Vocal motor experiences consolidate the vocal motor circuitry and accelerate future vocal skill development
Authors: Vellema Michiel , Rocha Mariana Diales , Bascones Sabrina , Zsebők Sándor , Dreier Jes , Leitner Stefan , Van der Linden Annemie , Brewer Jonathan , Gahr Manfred
Published: October 2018

Complex motor skills take considerable time and practice to learn. Without continued practice the level of skill performance quickly degrades, posing a problem for the timely utilization of skilled motor responses. Here we quantified the recurring development of vocal motor skills and the accompanying changes in synaptic connectivity in the brain of a songbird, while manipulating skill performance by consecutively administrating and withdrawing testosterone. We demonstrate that a songbird with prior singing experience can significantly accelerate the re-acquisition of vocal performance. We further demonstrate that an increase in vocal performance is accompanied by a pronounced synaptic pruning in the forebrain vocal motor area HVC, a reduction that is not reversed when birds stop singing. These results provide evidence that lasting synaptic changes in the motor circuitry are associated with the savings of motor skills, enabling a rapid recovery of motor performance under environmental time constraints.
Discovery of allosteric non-covalent KRAS inhibitors that bind with sub-micromolar affinity and disrupt effector binding
Authors: McCarthy Michael J. , Pagba Cynthia V. , Prakash Priyanka , Naji Ali , van der Hoeven Dharini , Liang Hong , Gupta Amit K. , Zhou Yong , Cho Kwang-Jin , Hancock John F. , Gorfe Alemayehu A.
Published: October 2018

Approximately 15% of all human tumors harbor mutant KRAS, a membrane-associated small GTPase and a notorious oncogene. Somatic mutations that render KRAS constitutively active lead to uncontrolled cell growth, survival, proliferation, and eventually cancer. KRAS is thus a critical anticancer drug target. However, despite aggressive efforts in recent years, there is no drug on the market that directly targets KRAS. In the current work, we combined molecular simulation and high-throughput virtual screening with a battery of cell-based and biophysical assays to discover a novel, pyrazolopyrimidine-based allosteric KRAS inhibitor that exhibits promising biochemical properties. The compound selectively binds to active KRAS with sub-micromolar affinity, slightly modulates exchange factor activity, disrupts effector Raf binding, significantly reduces signal transduction through mutant KRAS and inhibits cancer cell growth. Moreover, by studying two of its analogues, we identified key chemical features of the compound that are critical for affinity, effect on effector binding and mode of action. We propose a set of specific interactions with key residues at the switch regions of KRAS as critical for abrogating effector binding and reducing the rate of nucleotide exchange. Together, these findings not only demonstrate the viability of direct KRAS inhibition and offer guidance for future optimization efforts, but also show that pyrazolopyrimidine-based compounds may represent a first-in-class lead toward a clinically relevant targeting of KRAS by allosteric non-covalent inhibitors.
Dysregulated Oscillatory Connectivity in the Visual System in Autism Spectrum Disorder
Authors: Seymour R.A. , Rippon G. , Gooding-Williams G. , Schoffelen J.M. , Kessler K.
Published: October 2018

Autism Spectrum Disorder is increasingly associated with atypical perceptual and sensory symptoms. Here we explore the hypothesis that aberrant sensory processing in Autism Spectrum Disorder could be linked to atypical intra- (local) and inter-regional (global) brain connectivity. To elucidate oscillatory dynamics and connectivity in the visual domain we used magnetoencephalography and a simple visual grating paradigm with a group of 18 adolescent autistic participants and 18 typically developing controls. Both groups showed similar increases in gamma (40-80Hz) and decreases in alpha (8-13Hz) frequency power in occipital cortex. However, systematic group differences emerged when analysing intra- and inter-regional connectivity in detail. Firstly, directed connectivity was estimated using non-parametric Granger causality between visual areas V1 and V4. Feedforward V1-to-V4 connectivity, mediated by gamma oscillations, was equivalent between Autism Spectrum Disorder and control groups, but importantly, feedback V4-to-V1 connectivity, mediated by alpha (8-13Hz) oscillations, was significantly reduced in the Autism Spectrum Disorder group. This reduction was positively correlated with autistic quotient scores, consistent with an atypical visual hierarchy in autism, characterised by reduced top-down modulation of visual input via alpha-band oscillations. Secondly, at the local level in V1, coupling of alpha-phase to gamma amplitude (alpha-gamma phase amplitude coupling, PAC) was reduced in the Autism Spectrum Disorder group. This implies dysregulated local visual processing, with gamma oscillations decoupled from patterns of wider alpha-band phase synchrony (i.e. reduced PAC), possibly due to an excitation-inhibition imbalance. More generally, these results are in agreement with predictive coding accounts of neurotypical perception and indicate that visual processes in autism are less modulated by contextual feedback information.
A wave of WNT signalling balanced by secreted inhibitors controls primitive streak formation in micropattern colonies of human embryonic stem cells
Authors: Martyn I. , Brivanlou A.H. , Siggia E.D.
Published: October 2018

Long range signalling by morphogens and their inhibitors define embryonic patterning yet quantitative data and models are rare, especially in humans. Here we use a human embryonic stem cell “gastruloid” system to model formation of the primitive streak (PS) by WNT. In the pluripotent state E-CADHERIN (E-CAD) transduces boundary forces to focus WNT signalling to colony border. Following application of WNT ligand, E-CAD mediates a wave of epithelial-to-mesenchymal (EMT) conversion analogous to PS extension in an embryo. By knocking out the secreted WNT inhibitors active in our system, we show that DKK1 alone controls the extent and duration of patterning. The NODAL inhibitor CERBERUS1 acts downstream of WNT to refine the endoderm versus mesoderm fate choice. Our EMT wave is a generic property of a bistable system with diffusion and a single quantitative model describes both the wave and our knockout data.
Streptococcus agalactiaeinduces placental macrophages to release extracellular traps loaded with tissue remodeling enzymes via an oxidative-burst-dependent mechanism
Authors: Doster Ryan S. , Sutton Jessica A. , Rogers Lisa M. , Aronoff David M. , Gaddy Jennifer A.
Published: October 2018

Streptococcus agalactiae, or Group BStreptococcus(GBS), is a common perinatal pathogen. GBS colonization of the vaginal mucosa during pregnancy is a risk factor for invasive infection of the fetal membranes (chorioamnionitis) and its consequences such as membrane rupture, preterm labor, stillbirth, and neonatal sepsis. Placental macrophages, or Hofbauer cells, are fetally-derived macrophages present within placental and fetal membrane tissues that perform vital functions for fetal and placental development, including supporting angiogenesis, tissue remodeling, and regulation of maternal-fetal tolerance. Although placental macrophages, as tissue-resident innate phagocytes, are likely to engage invasive bacteria such as GBS, there is limited information regarding how these cells respond to bacterial infection. Here, we demonstratein vitrothat placental macrophages release macrophage extracellular traps (METs) in response to bacterial infection. Placental macrophage METs contain proteins including histones, myeloperoxidase, and neutrophil elastase similar to neutrophil extracellular traps and are capable of killing GBS cells. MET release from these cells occurs by a process that depends on the production of reactive oxygen species. Placental macrophage METs also contain matrix metalloproteases that are released in response to GBS and could contribute to fetal membrane weakening during infection. MET structures were identified within human fetal membrane tissues infectedex vivo, suggesting that placental macrophages release METs in response to bacterial infection during chorioamnionitis.

Importance

Streptococcus agalactiae, also known as Group BStreptococcus(GBS), is a common pathogen during pregnancy where infection can result in chorioamnionitis, preterm premature rupture of membranes (PPROM), preterm labor, stillbirth, and neonatal sepsis. Mechanisms by which GBS infection results in adverse pregnancy outcomes are still incompletely understood. This study evaluated interactions between GBS and placental macrophages. The data demonstrate that in response to infection, placental macrophages release extracellular traps capable of killing GBS. Additionally, this work establishes that proteins associated with extracellular trap fibers include several matrix metalloproteinases that have been associated with chorioamnionitis. In the context of pregnancy, placental macrophage responses to bacterial infection might have beneficial and adverse consequences, including protective effects against bacterial invasion but also releasing important mediators of membrane breakdown that could contribute to membrane rupture or preterm labor.
Tibanna: software for scalable execution of portable pipelines on the cloud
Authors: Lee Soohyun , Johnson Jeremy , Vitzthum Carl , Kırlı Koray , Alver Burak H. , Park Peter J.
Published: October 2018

We introduce Tibanna, an open-source software tool for automated execution of bioinformatics pipelines on Amazon Web Services (AWS). Tibanna accepts reproducible and portable pipeline standards including Common Workflow Language (CWL), Workflow Description Language (WDL) and Docker. It adopts a strategy of isolation and optimization of individual executions, combined with a serverless scheduling approach. Pipelines are executed and monitored using local commands or the Python Application Programming Interface (API) and cloud configuration is automatically handled. Tibanna is well suited for projects with a range of computational requirements, including those with large and widely fluctuating loads. Notably, it has been used to process terabytes of data for the 4D Nucleome (4DN) Network.

Availability

Source code is available on GitHub at https://github.com/4dn-dcic/tibanna.
A Multi-State Birth-Death model for Bayesian inference of lineage-specific birth and death rates
Authors: Barido-Sottani Joëlle , Vaughan Timothy G. , Stadler Tanja
Published: October 2018

Heterogeneous populations can lead to important differences in birth and death rates across a phylogeny Taking this heterogeneity into account is thus critical to obtain accurate estimates of the underlying population dynamics. We present a new multi-state birth-death model (MSBD) that can estimate lineage-specific birth and death rates. For species phylogenies, this corresponds to estimating lineage-dependent speciation and extinction rates. Contrary to existing models, we do not require a prior hypothesis on a trait driving the rate differences and we allow the same rates to be present in different parts of the phylogeny. Using simulated datasets, we show that the MSBD model can reliably infer the presence of multiple evolutionary regimes, their positions in the tree, and the birth and death rates associated with each. We also present a re-analysis of two empirical datasets and compare the results obtained by MSBD and by the existing software BAMM. The MSBD model is implemented as a package in the Bayesian inference software BEAST2, which allows joint inference of the phylogeny and the model parameters.

Significance statement

Phylogenetic trees can inform about the underlying speciation and extinction processes within a species clade. Many different factors, for instance environmental changes or morphological changes, can lead to differences in macroevolutionary dynamics within a clade. We present here a new multi-state birth-death (MSBD) model that can detect these differences and estimate both the position of changes in the tree and the associated macroevolutionary parameters. The MSBD model does not require a prior hypothesis on which trait is driving the changes in dynamics and is thus applicable to a wide range of datasets. It is implemented as an extension to the existing framework BEAST2.
Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix
Authors: Metzler-Baddeley Claudia , Mole Jilu P. , Leonaviciute Erika , Sims Rebecca , Kidd Emma J. , Ertefai Benjamin , Kelso-Mitchell Aurora , Gidney Florence , Fasano Fabrizio , Evans John , Jones Derek K , Baddeley Roland J.
Published: October 2018

Midlife obesity is a risk factor of late onset Alzheimer’s disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, one possibility is that obesity-related neuroinflammation may contribute to the development of LOAD. Neuroinflammation is closely linked to white matter myelin loss, and this can be measuredin vivowith quantitative magnetization transfer (qMT) imaging. Here, we investigated whether differences in obesity measures, i.e., in Waist Hip Ratio (WHR), abdominal visceral and subcutaneous fat volume fractions and Body Mass Index (BMI), were associated with reductions in qMT indices of apparent myelin in temporal white matter pathways involved in LOAD (i.e., the fornix, the parahippocampal cingulum and the uncinate fasciculus compared with whole brain and cortico-spinal white matter) in 166 cognitively healthy individuals (38-71 years of age). Obesity-related effects on myelin-sensitive markers were contrasted with differences in apparent axon density from dual-shell diffusion Neurite Orientation Dispersion and Density Imaging (NODDI). Differences in WHR and in visceral fat volume fractions were negatively correlated with differences in qMT estimates of apparent myelin and tissue metabolism in the fornix but not with any other microstructural components. These correlations were not explained by demographic (age, sex, education), health (hypertension, alcohol consumption, sedentary lifestyle) or genetic (APOEgenotype, family history of dementia) risk factors of LOAD. Furthermore, differences in the ratio of plasma concentrations of leptin and adiponectin were also positively correlated with differences in C-Reactive Protein concentrations, and contributed significantly to the correlations between central obesity and myelin-sensitive metrics in the fornix. These results are consistent with the view that visceral fat-related chronic inflammation may damage white matter myelin in limbic regions, known to be vulnerable to LOAD pathology.
Specificity of RNA folding and its association with evolutionarily adaptive mRNA secondary structure
Authors: Yu Gongwang , Zhu Hanbing , Chen Xiaoshu , Yang Jian-Rong
Published: October 2018

Secondary structure is a fundamental feature for both noncoding and messenger RNA. However, our understandings about the secondary structure of mRNA, especially for the coding regions, remain elusive, likely due to translation and the lack of RNA binding proteins that sustain the consensus structure, such as those bind to noncoding RNA. Indeed, mRNA has recently been found to bear pervasive alternative structures, whose overall evolutionary and functional significance remained untested. We hereby approached this problem by estimating folding specificity, the probability that a fragment of RNA folds back to the same partner once re-folded. We showed that folding specificity for mRNA is lower than noncoding RNA, and displays moderate evolutionary conservation between orthologs and between paralogs. More importantly, we found that specific rather than alternative folding is more likely evolutionarily adaptive, since it is more frequently associated with functionally important genes or sites within a gene. Additional analysis in combination with ribosome density suggests the capability of modulating ribosome movement as one potential functional advantage provided by specific folding. Our findings revealed a novel facet of RNA structome with important functional and evolutionary implications, and points to a potential way of disentangling mRNA secondary structures maintained by natural selection from molecular noise.