bluuebunny/crossref_metadata_2025 huggingface dataset:
A computational knowledge engine for human neuroscience
Authors: Beam Elizabeth , Potts Christopher , Poldrack Russell A. , Etkin Amit
Published: July 2019

Functional neuroimaging has been a mainstay of human neuroscience for the past 25 years. The goal for this research has largely been to understand how activity across brain structures relates to mental constructs and computations. However, interpretation of fMRI data has often occurred within knowledge frameworks crafted by experts, which have the potential to reify historical trends and amplify the subjective biases that limit the replicability of findings.1In other words, we lack a comprehensive data-driven ontology for structure-function mapping in the human brain, through which we can also test the explanatory value of current dominant conceptual frameworks. Ontologies in other fields are popular tools for automated data synthesis,2, 3yet relatively few attempts have been made to engineer ontologies in a data-driven manner.4Here, we employ a computational approach to derive a data-driven ontology for neurobiological domains that synthesizes the texts and data of nearly 20,000 human neuroimaging articles. The data-driven ontology includes 6 domains, each defined by a circuit of brain structures and its associated mental functions. Several of these domains are omitted from the leading framework in neuroscience, while others uncover novel combinations of mental functions related to common brain circuitry. Crucially, the structure-function links in each domain better replicate across articles in held-out data than those mapped from the dominant frameworks in neuroscience and psychiatry. We further show that the data-driven ontology partitions the literature into modular subfields, for which the domains serve as generalizable archetypes of the structure-function patterns observed in single articles. The approach to computational ontology we present here is the most comprehensive functional characterization of human brain circuits quantifiable with fMRI. Moreover, our methods can be extended to synthesize other scientific literatures, yielding ontologies that are built up from the data of the field.
Genetic rescue without genomic swamping in wild populations
Authors: Fitzpatrick Sarah W. , Bradburd Gideon S. , Kremer Colin T. , Salerno Patricia E. , Angeloni Lisa M. , Funk W. Chris
Published: July 2019

Gene flow is an enigmatic evolutionary force because it can limit adaptation but can also help populations escape inbreeding depression. Manipulating gene flow for conservation purposes is a controversial, but potentially powerful management strategy. We use multigenerational pedigrees and genomics to test demographic and evolutionary consequences of manipulating gene flow in two isolated wild Trinidadian guppy populations. We found that on average, hybrids lived longer and reproduced more. Despite overall genome-wide homogenization, alleles potentially associated with local adaptation were not entirely swamped by gene flow. Our results suggest that combining new genomic variation from immigrants with potentially adaptive variation from the recipient population resulted in highly fit hybrids and subsequent increases in population size. Contrary to the prevailing view that gene flow constrains adaptation, our study shows that immigration can produce long-term fitness benefits in small populations without swamping locally adaptive variation.
An atomistic perspective on ADCC quenching by core-fucosylation of IgG1 Fc N-glycans from enhanced sampling molecular dynamics
Authors: Harbison Aoife , Fadda Elisa
Published: July 2019

The immunoglobulin type G (IgG) Fc N-glycans are known to modulate the interaction with membrane-bound Fc γ receptors (FcγRs), fine-tuning the antibody’s effector function in a sequence-dependent manner. Particularly interesting in this respect are the roles of galactosylation, which levels are linked to autoimmune conditions and aging, of core fucosylation, which is known to reduce significantly the antibody-dependent cellular cytotoxicity (ADCC), and of sialylation, which also reduces ADCC but only in the context of core-fucosylation. In this work we provide an atomistic level perspective through enhanced sampling computer simulations, based on replica exchange molecular dynamics (REMD), to understand the molecular determinants linking the Fc N-glycans sequence to the observed IgG1 function. Our results indicate that the two symmetrically opposed N-glycans interact extensively through their core trimannose residues. At room temperature the terminal galactose on the α(1-6) arm is restrained to the protein through a network of interactions that keep the arm outstretched, meanwhile the α(1-3) arm extends towards the solvent where a terminal sialic acid remains fully accessible. We also find that the presence of core fucose interferes with the extended sialylated α(1-3) arm, altering its conformational propensity and as a consequence of steric hindrance, significantly enhancing the Fc dynamics. Furthermore, structural analysis shows that the core fucose position within the Fc core obstructs the access of N162 glycosylated FcγRs very much like a “door-stop”, potentially decreasing the IgG/FcγR binding free energy. All of these factors could represent important clues to understand at the molecular level the dramatic reduction of ADCC as a result of core fucosylation and provide an atomistic level-of-detail framework for the design of high potency IgG1 Fc N-glycoforms.
CASLFA: CRISPR/Cas9-mediated lateral flow nucleic acid assay
Authors: Wang Xusheng , Xiong Erhu , Tian Tian , Cheng Meng , Lin Wei , Sun Jian , Zhou Xiaoming
Published: July 2019

The lateral flow assay is one of the oldest and most convenient analytical techniques for analyzing the immune response, but its applicability to precise genetic analyses is limited by the tedious and inefficient hybridization steps. Here, we have introduced a new version of the lateral flow assay, termed Cas9-mediated lateral flow nucleic acids assay (CASLFA), to address such issues. In this study, CASLFA is utilized to identifyListeria monocytogenes, genetically modified organisms (GMOs), and African swine fever virus (ASFV) at a sensitivity of hundreds of copies of genome samples with high specificity within 1 h. CASLFA satisfies some of the characteristics of a next-generation molecular diagnostics tool due to its rapidity and accuracy, allowing for point-of-care use without the need for technical expertise and complex ancillary equipment. This method has great potential for analyzing genes in resource-poor or nonlaboratory environments.
Dinoflagellates with relic endosymbiont nuclei as novel models for elucidating organellogenesis
Authors: Sarai Chihiro , Tanifuji Goro , Nakayama Takuro , Kamikawa Ryoma , Takahashi Kazuya , Miyashita Hideaki , Ishida Ken-ichiro , Iwataki Mitsunori , Inagaki Yuji
Published: July 2019

Nucleomorphs are relic endosymbiont nuclei so far found only in two algal groups, cryptophytes and chlorarachniophytes, which have been studied to model the evolutionary process integrating an endosymbiont alga into be a host-governed plastid (organellogenesis). Nevertheless, past studies suggested that DNA transfer from the endosymbiont to host nuclei had already ceased in both cryptophytes and chlorarachniophytes, implying that the organellogenesis at the genetic level has been completed in the two systems. Moreover, we have yet to pinpoint the closest free-living relative of the endosymbiotic alga engulfed by the ancestral chlorarachniophyte or cryptophyte, making difficult to infer how organellogenesis altered the endosymbiont genome. To counter the above issues, we need novel nucleomorph-bearing algae, in which from-endosymbiont-to-host DNA transfer is on-going and of which endosymbiont/plastid origins can be inferred at a fine taxonomic scale. Here, we report two previously undescribed dinoflagellates, strains MGD and TGD, with green algal endosymbionts enclosing plastids as well as relic nuclei (nucleomorphs). We provide the evidence for the presence of DNA in the two nucleomorphs and transfer of endosymbiont genes to the host (dinoflagellate) genomes. Furthermore, DNA transfer between the host and endosymbiont nuclei was found to be in progress in both MGD and TGD systems. Phylogenetic analyses successfully resolved the origins of the endosymbionts at the genus level. Combined, we conclude that the host-endosymbiont integration in MGD/TGD is less advanced than that in cryptophytes/chrorarachniophytes, and propose the two dinoflagellates as new models for elucidating organellogenesis.
Multicellular tumor spheroids- an effectivein vitromodel for understanding drug resistance in head and neck cancer
Authors: Azharuddin Mohammad , Roberg Karin , Dhara Ashis Kumar , Jain Mayur Vilas , D’arcy Padraig , Hinkula Jorma , Slater Nigel K H , Patra Hirak K
Published: July 2019

A hallmark of cancer is the ability to develop resistance against therapeutic agents. Therefore, developing effectivein vitrostrategies to identify drug resistance remains of paramount importance for treatment success. A way cancer cells achieve drug resistance is through the expression of efflux pumps that actively pump drugs out of the cells. To date, several studies have investigated the potential of using 3D multicellular tumor spheroids (MCSs) to assess drug resistance; however, a unified system that uses MCSs to differentiate between multi drug resistant (MDR) and non-MDR cells does not exist. In the present report, we have used MCSs obtained from post-diagnosed, pre-treated (PDPT) patient derived head and neck squamous cancer cells that often become treatment resistant, to develop an integrated approach combining clinical drug response and cytotoxicity screening, real-time drug uptake monitoring, and drug transporter activity assessment using flow cytometry in the presence and absence of their respective specific inhibitors. The present report shows a comparative response to MDR, drug efflux capability, and reactive oxygen species (ROS) activity to assess the resistance profile of PDPT patient-derived MCSs and two-dimensional cultures of the same set of cells. We show that MCSs serve as robust and reliable models for the clinical evaluation of drug resistance. Our proposed strategy can thus have potential clinical applicability for profiling drug resistance in cancers with unknown resistance profiles, which consequentially can indicate benefit from downstream therapy.
Histone code dictates fate biasing of neural crest cells to melanocyte lineage
Authors: Raja Desingu Ayyappa , Subramaniam Yogaspoorthi , Gotherwal Vishvabandhu , Tanwar Jyoti , Motiani Rajender , Sivasubbu Sridhar , Gokhale Rajesh S , Natarajan Vivek T
Published: July 2019

In the neural crest lineage, progressive fate-restriction and stem cell assignment are critical for both development and regeneration. While the fate-commitment events have distinct transcriptional footprints, fate-biasing is often transitory and metastable, and is thought to be moulded by epigenetic programs. Hence molecular basis of specification is difficult to define. In this study, we establish a role of a histone variantH2a.z.2in specification of melanocyte lineage from multipotent neural crest cells. Silencing ofH2a.z.2reduces the number of melanocyte precursors in developing zebrafish embryos, and from mouse embryonic stem cellsin vitro. We demonstrate that this histone variant occupies nucleosomes in the promoter of key melanocyte determinantMitf, and enhances its induction. CRISPR-Cas9 based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby our study establishes a histone based specification code upstream to the core gene regulatory network in the neural crest lineage of melanocytes. This epigenetic code renders a poised state to the promoter of key determinant and enhances activation by external instructive signals thereby establishing melanocyte fate identity.
The relative impact of evolving pleiotropy and mutational correlation on trait divergence
Authors: Chebib Jobran , Guillaume Frédéric
Published: July 2019

Both pleiotropic connectivity and mutational correlations can restrict the decoupling of traits under divergent selection, but it is unknown which is more important in trait evolution. In order to address this question, we create a model that permits within-population variation in both pleiotropic connectivity and mutational correlation, and compare their relative importance to trait evolution. Specifically, we developed an individual-based, stochastic model where mutations can affect whether a locus affects a trait and the extent of mutational correlations in a population. We find that traits can decouple whether there is evolution in pleiotropic connectivity or mutational correlation but when both can evolve then evolution in pleiotropic connectivity is more likely to allow for decoupling to occur. The most common genotype found in this case is characterized by having one locus that maintains connectivity to all traits and another that loses connectivity to the traits under stabilizing selection (subfunctionalization). This genotype is favoured because it allows the subfunctionalized locus to accumulate greater effect size alleles, contributing to increasingly divergent trait values in the traits under divergent selection without changing the trait values of the other traits (genetic modularization). These results provide evidence that partial subfunctionalization of pleiotropic loci may be a common mechanism of trait decoupling under regimes of corridor selection.
GenEPi: Piezo1-based fluorescent reporter for visualizing mechanical stimuli with high spatiotemporal resolution
Authors: Yaganoglu Sine , Helassa Nordine , Gaub Benjamin M. , Welling Maaike , Shi Jian , Müller Daniel J. , Török Katalin , Pantazis Periklis
Published: July 2019

Mechanosensing is a ubiquitous process to translate external mechanical stimuli into biological responses during development, homeostasis, and disease. However, non-invasive investigation of cellular mechanosensing in complex and intact live tissue remains challenging. Here, we developed GenEPi, a genetically-encoded fluorescent intensiometric reporter for mechanical stimuli based on Piezo1, an essential mechanosensitive ion channel found in vertebrates. We show that GenEPi has high specificity and spatiotemporal resolution for Piezo1-dependent mechanical stimuli, exemplified by resolving repetitive mechanical stimuli of spontaneously contracting cardiomyocytes within microtissues, in a non-invasive manner.
Potential for transmission ofElizabethkingia anophelisbyAedes albopictusand the role of microbial interactions in Zika virus competence
Authors: Onyango MG , Payne AF , Stout J , Dieme C , Kuo L , Kramer LD , Ciota AT
Published: July 2019

Elizabethkingia anophelishas been the cause of four outbreaks with significant morbidity and mortality. Its transmission routes remain unknown and no point source of infection has been identified. Here we show thatE. anopheliscan be found in the saliva ofAedesmosquitoes, suggesting the novel possibility of vector-borne transmission of this bacterium. We additionally characterized diverse microbial communities inAedesmidguts, salivary glands and saliva. To the best of our knowledge, this represents the first description of the microbiome ofAedessaliva. Further, we demonstrate that increased abundance ofE. anophelisis associated with decreased susceptibility and replication of Zika virus (ZIKV) in the midgut ofAedesmosquitoes, suggesting a novel transmission barrier for arboviruses transmitted byAedesmosquitoes. Together, these results demonstrate the complex relationships between the mosquito, the midgut microbial community and arboviruses and offer insights into the epidemiology and control of emerging bacterial and viral pathogens.

Author Summary

Elizabethkingia anophelishas in the recent past caused outbreaks different parts of the world resulting both in morbidity and mortality. Until now, to the best of our knowledge, no study has been able to demonstrate that this bacterium can be transmitted by mosquitoes. We have demonstrated for the first time thatElizabethkingia anophelisis present in the saliva of both infected and non-infectedAedesmosquitoes. Further, we have shown that it confers an inhibitory effect on Zika virus establishment in the midguts ofAedesmosquitoes. Together, these results potentially display the potential for vector borne transmission ofE. anophelisas well as a novel transmission barrier of ZIKV. Lastly, we have for the first time characterized salivary microbes ofAedesmosquitoes necessitating the investigation of the impact of salivary microbes in severity of disease in vertebrate hosts.
Dynamic Ins2 gene activity defines β-cell maturity states
Authors: Chu Chieh Min Jamie , Modi Honey , Skovsø Søs , Ellis Cara , Krentz Nicole A.J. , Zhao Yiwei Bernie , Cen Haoning , Noursadeghi N , Panzhinskiy Evgeniy , Hu Xiaoke , Dionne Derek A. , Xia Yi Han , Xuan Shouhong , Huising Mark O. , Kieffer Timothy J. , Lynn Francis C. , Johnson James D.
Published: July 2019

Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS and single cell RNA sequencing, in β-cells from Ins2GFP knock-in mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ~25% of β-cells exhibited significantly higher activity at the conserved insulin gene Ins2. Live cell imaging captured Ins2 gene activity dynamics in single β-cells over days. Autocorrelation analysis revealed a subset of cells with oscillating behavior, with mean oscillation periods of 17 hours. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single cell RNA sequencing showed that Ins2(GFP)HIGH β-cells were enriched for markers of β-cell maturity. Ins2(GFP)HIGH β-cells were also significantly less viable at all glucose concentrations and in the context of ER stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human β-cells, can be accounted for by dynamic states of insulin gene activity.

Blurb

Previously reported pancreatic β-cell heterogeneity reflects β-cell state transitions.
A Comparison of Deep Neural Networks for Seizure Detection in EEG Signals
Authors: Boonyakitanont Poomipat , Lek-uthai Apiwat , Chomtho Krisnachai , Songsiri Jitkomut
Published: July 2019

This paper aims to apply machine learning techniques to an automated epileptic seizure detection using EEG signals to help neurologists in a time-consuming diagnostic process. We employ two approaches based on convolution neural networks (CNNs) and artificial neural networks (ANNs) to provide a probability of seizure occurrence in a windowed EEG recording of 18 channels. In order to extract relevant features based on time, frequency, and time-frequency domains for these networks, we consider an improvement of the Bayesian error rate from a baseline. Features of which the improvement rates are higher than the significant level are considered. These dominant features extracted from all EEG channels are concatenated as the input for ANN with 7 hidden layers, while the input of CNN is taken as raw multi-channel EEG signals. Using multi-concept of deep CNN in image processing, we exploit 2D-filter decomposition to handle the signal in spatial and temporal domains. Our experiments based on CHB-MIT Scalp EEG Database showed that both ANN and CNN were able to perform with the overall accuracy of up to 99.07% and F1-score of up to 77.04%. ANN with dominant features is more capable of detecting seizure events than CNN whereas CNN requiring no feature extraction is slightly better than ANN in classification accuracy.
The role of recombination on genome-wide patterns of local ancestry exemplified by supplemented Brook Charr populations
Authors: Leitwein Maeva , Cayuela Hugo , Ferchaud Anne-Laure , Normandeau Éric , Gagnaire Pierre-Alexandre , Bernatchez Louis
Published: July 2019

Assessing the immediate and long-term evolutionary consequences of human-mediated hybridization is of major concern for conservation biology. Several studies have documented how selection in interaction with recombination modulates introgression at a genome-wide scale, but few have considered the dynamics of this process within and between chromosomes. Here, we used an exploited freshwater fish, the Brook Charr (Salvelinus fontinalis) for which decades of stocking practices have resulted in admixture between wild populations and an introduced domestic strain to assess both the temporal dynamics and local chromosomal variation in domestic ancestry. We provide a detailed picture of the domestic ancestry patterns across the genome using about 33,000 mapped SNPs genotyped in 611 individuals from 24 supplemented populations. For each lake, we distinguished early and late-generation hybrids using admixture tracts information. To assess the selective outcomes following admixture we then evaluated the relationship between recombination and admixture proportions at three different scales: the whole genome, chromosomes and within 2Mb windows. This allowed us to detect the signature of varied evolutionary mechanisms, as reflected by the finding of genomic regions where the introgression of domestic haplotypes are favored or disfavored. Among these, the main factor modulating local ancestry was likely the presence of deleterious recessive mutations in the wild populations, which can be efficiently hidden to selection in the presence of long admixture tracts. Overall, our results emphasize the relevance of taking into consideration local ancestry information to assess both the temporal and chromosomal variation in local ancestry toward better understanding post-hybridization evolutionary outcomes.
Adult-born hippocampal neurons undergo extended development and are morphologically distinct from neonatally-born neurons
Authors: Cole John Darby , Espinueva Delane , Seib Désirée R. , Ash Alyssa M. , Cooke Matthew B. , Cahill Shaina P. , O’Leary Timothy , Kwan Sharon S. , Snyder Jason S.
Published: July 2019

During immature stages, adult-born neurons pass through critical periods for survival and plasticity. It is generally assumed that by 2 months of age adult-born neurons are mature and equivalent to the broader neuronal population, raising questions of how they might contribute to hippocampal function in old age when neurogenesis has declined. However, few have examined adult-born neurons beyond the critical period, or directly compared them to neurons born in infancy. Here, we used a retrovirus to visualize functionally-relevant morphological features of 2- to 24-week-old adult-born neurons in male rats. From 2-7 weeks neurons grew and attained a relatively mature phenotype. However, several features of 7-week-old neurons suggested a later wave of growth: these neurons had larger nuclei, thicker dendrites and more dendritic filopodia than all other groups. Indeed, between 7-24 weeks, adult-born neurons gained additional dendritic branches, grew a 2ndprimary dendrite, acquired more mushroom spines and had enlarged mossy fiber presynaptic terminals. Compared to neonatally-born neurons, old adult-born neurons had greater spine density, larger presynaptic terminals, and more putative efferent filopodial contacts onto inhibitory neurons. By integrating rates of cell birth and growth across the lifespan, we estimate that adult neurogenesis ultimately produces half of the cells and the majority of spines in the dentate gyrus. Critically, protracted development contributes to the plasticity of the hippocampus through to the end of life, even after cell production declines. Persistent differences from neonatally-born neurons may additionally endow adult-born neurons with unique functions even after they have matured.

SIGNIFICANCE STATEMENT

Neurogenesis occurs in the hippocampus throughout adult life and contributes to memory and emotion. It is generally assumed that new neurons have the greatest impact on behavior when they are immature and plastic. However, since neurogenesis declines dramatically with age, it is unclear how they might contribute to behavior later in life when cell proliferation has slowed. Here we find that newborn neurons mature over many months in rats, and end up with distinct morphological features compared to neurons born in infancy. Using a mathematical model, we estimate that a large fraction of neurons is added in adulthood. Moreover, their extended growth produces a reserve of plasticity that persists even after neurogenesis has declined to low rates.
A Comprehensive Evaluation of Methods for Mendelian Randomization Using Realistic Simulations and an Analysis of 38 Biomarkers for Risk of Type-2 Diabetes
Authors: Qi Guanghao , Chatterjee Nilanjan
Published: July 2019

Background

Mendelian randomization (MR) has provided major opportunities for understanding the causal relationship among complex traits. Previous studies have often evaluated MR methods based on simulations that do not adequately reflect the data-generating mechanism in GWAS and there are often discrepancies in performance of MR methods in simulations and real datasets.

Methods

We use a simulation framework that generates data on full GWAS for two traits under realistic model for effect-size distribution coherent with heritability, co-heritability and polygenicity typically observed for complex traits. We further use recent data generated from GWAS of 38 biomarkers in the UK Biobank to investigate their causal effects on risk of type-2 diabetes using externally available GWAS summary-statistics.

Results

Simulation studies show that weighted mode and MRMix are the only two methods which maintain correct type-I error rate in a diverse set of scenarios. Between the two methods, MRMix tends to be more powerful for larger GWAS while the opposite being true for smaller sample sizes. Among the other methods, random-effect IVW, MR-Robust and MR-RAPS tend to perform best in maintaining low mean squared error when the InSIDE assumption is satisfied, but can produce large bias when InSIDE is violated. In real data analysis, some biomarkers showed major heterogeneity in estimates of their causal effects on risk of type-2 diabetes across the different methods, with patterns similar to those observed in simulation studies.

Conclusions

Relative performance of different MR methods depends heavily on sample sizes of underlying GWAS, proportion of valid instruments and validity of the InSIDE assumption.

Key Messages

Many previous simulations studies to evaluate Mendelian randomization methods do not adequately reflect the data-generating mechanism of genome-wide association studies (GWAS).

We use a simulation framework that generates data on full GWASs under realistic model informed by recent studies on effect-size distribution. We also used very recent GWAS data available on a large number of biomarkers to evaluate their causal effect on type-2 diabetes using alternative methods.

Among the 10 methods that were compared, relative performance of different methods depends heavily on sample sizes of underlying GWAS, proportion of valid instruments and validity of the InSIDE assumption.

Weighted mode and MRMix are the only two methods that maintain correct type I error rate in a diverse set of scenarios.
An implicit lipid model for efficient reaction-diffusion simulations of protein binding to surfaces of arbitrary topology
Authors: Fu Yiben , Yogurtcu Osman N. , Kothari Ruchita , Thorkelsdottir Gudrun , Sodt Alexander J. , Johnson Margaret E.
Published: July 2019

Localization of proteins to a membrane is an essential step in a broad range of biological processes such as signaling, virion formation, and clathrin-mediated endocytosis. The strength and specificity of proteins binding to a membrane depend on the lipid composition. Single-particle reaction-diffusion methods offer a powerful tool for capturing lipid-specific binding to membrane surfaces by treating lipids explicitly as individual diffusible binding sites. However, modeling lipid particle populations is expensive. Here we present an algorithm for reversible binding of proteins to continuum surfaces with implicit lipids, providing dramatic speed-ups to many body simulations. Our algorithm can be readily integrated into most reaction-diffusion software packages. We characterize changes to kinetics that emerge from explicit versus implicit lipids as well as surface adsorption models, showing excellent agreement between our method and the full explicit lipid model. Compared to models of surface adsorption, which couple together binding affinity and lipid concentration, our implicit lipid model decouples them to provide more flexibility for controlling surface binding properties and lipid inhomogeneity, and thus reproducing binding kinetics and equilibria. Crucially, we demonstrate our method’s application to membranes of arbitrary curvature and topology, modeled via a subdivision limit surface, again showing excellent agreement with explicit lipid simulations. Unlike adsorption models, our method retains the ability to bind lipids after proteins are localized to the surface (through e.g. a protein-protein interaction), which can greatly increase stability of multi-protein complexes on the surface. Our method will enable efficient cell-scale simulations involving proteins localizing to realistic membrane models, which is a critical step for predictive modeling and quantification of in vitro and in vivo dynamics.
Improved identification and differentiation from epileptiform activity of human hippocampal sharpwave-ripples during NREM sleep
Authors: Jiang Xi , Gonzalez-Martinez Jorge , Cash Sydney S. , Chauvel Patrick , Gale John , Halgren Eric
Published: July 2019

In rodents, pyramidal cell firing patterns from waking may be replayed in NREM sleep during hippocampal sharpwave-ripples (HC-SWR). In humans, HC-SWR have only been recorded with electrodes implanted to localize epileptogenesis. Here, we characterize human HC-SWR with rigorous rejection of epileptiform activity, requiring multiple oscillations and coordinated sharpwaves. We demonstrated typical SWR in those rare HC recordings which lack interictal epileptiform spikes (IIS), and with no or minimal seizure involvement. These HC-SWR have a similar rate (~12/min) and apparent intra-HC topography (ripple maximum in putative stratum pyramidale, slow wave in radiatum) as rodents, though with lower frequency (~85Hz compared to ~140Hz in rodents). Similar SWR are found in HC with IIS, but no significant seizure involvement. These SWR were modulated by behavior, being largely absent (<2/min) except during NREM sleep in both stage 2 (~9/min) and stage 3 (~15/min), distinguishing them from IIS. This study quantifies the basic characteristics of a strictly selected sample of SWR recorded in relatively healthy human hippocampi.
Coordination of human hippocampal sharpwave-ripples during NREM sleep with cortical theta bursts, spindles, downstates and upstates
Authors: Jiang Xi , Gonzalez-Martinez Jorge , Halgren Eric
Published: July 2019

In rodents, waking firing patterns replay in NREM sleep during hippocampal sharpwave-ripples (HC-SWR), correlated with neocortical graphoelements (NC-GE). NC-GE include theta-bursts, spindles, downstates and upstates. In humans, consolidation during sleep is correlated with scalp-recorded spindles and down-upstates, but HC-SWR cannot be recorded non-invasively. Here we show in humans of both sexes that HC-SWR are highly correlated with NC-GE during NREM, with significantly more related HC-SWR/NC-GE for downstates or upstates than theta-bursts or spindles, in N2 than N3, in posterior than anterior HC, in frontal than occipital cortex, and ipsilaterally than contralaterally. The preferences interacted, e.g. frontal spindles co-occurred frequently with posterior HC-SWR in N2. These preferred GE, stages and locations for HC-SWR/NC-GE interactions may index selective consolidation activity, although that was not tested in this study. SWR recorded in different HC regions seldom co-occurred, and were related to GE in different cortical areas, showing that HC-NC interact in multiple transient, widespread but discrete, networks. NC-GE tend to occur with consistent temporal relationships to HC-SWR, and to each other. Cortical theta-bursts usually precede HC-SWR, where they may help define cortical input triggering HC-SWR firing. HC-SWR often follow cortical downstate onsets, surrounded by locally-decreased broadband power, suggesting a mechanism synchronizing cortical, thalamic and hippocampal activities. Widespread cortical upstates and spindles follow HC-SWR, consistent with the hypothesized contribution by hippocampal firing during HC-SWR to cortical firing-patterns during upstates and spindles. Overall, our results describe how hippocampal and cortical oscillations are coordinated in humans during events that are critical for memory consolidation in rodents.

Significance Statement

Hippocampal sharpwave-ripples, essential for memory consolidation, mark when hippocampal neurons replay waking firing patterns. In rodents, cortical sleep waves coordinate the transfer of temporary hippocampal to permanent cortical memories, but their relationship with human HC-SWR remains unclear. We show that human hippocampal sharpwave-ripples co-occur with all varieties of cortical sleep waves, in all cortical regions, and in all stages of Non-REM sleep but with overall preferences for each of these. We found that sharpwave-ripples in different parts of the hippocampus usually occurred independently of each other, and preferentially interacted with different cortical areas. We found that sharpwave-ripples typically occur after certain types of cortical waves, and before others, suggesting how the cortico-hippocampo-cortical interaction may be organized in time and space.
Evaluating probabilistic programming and fast variational Bayesian inference in phylogenetics
Authors: Fourment Mathieu , Darling Aaron E.
Published: July 2019

Abstract

Recent advances in statistical machine learning techniques have led to the creation of probabilistic programming frameworks. These frameworks enable probabilistic models to be rapidly prototyped and fit to data using scalable approximation methods such as variational inference. In this work, we explore the use of the Stan language for probabilistic programming in application to phylogenetic models. We show that many commonly used phylogenetic models including the general time reversible (GTR) substitution model, rate heterogeneity among sites, and a range of coalescent models can be implemented using a probabilistic programming language. The posterior probability distributions obtained via the black box variational inference engine in Stan were compared to those obtained with reference implementations of Markov chain Monte Carlo (MCMC) for phylogenetic inference. We find that black box variational inference in Stan is less accurate than MCMC methods for phylogenetic models, but requires far less compute time. Finally, we evaluate a custom implementation of mean-field variational inference on the Jukes-Cantor substitution model and show that a specialized implementation of variational inference can be two orders of magnitude faster and more accurate than a general purpose probabilistic implementation.
Enhanced leaky sex expression is an adaptive plastic response to pollen limitation in the dioecious plantMercurialis annua
Authors: Cossard Guillaume G. , Pannell John R.
Published: July 2019

Phenotypic plasticity is almost ubiquitous across the tree of life, but clear demonstrations that it is adaptive are rare. In dioecious plants, males and females frequently show ‘leaky’ sex expression, with individuals occasionally producing flowers of the opposite sex. Here, we demonstrate that leaky sex expression in the wind-pollinated dioecious herbMercurialis annuais plastically responsive to its mating context. We compared experimental populations of females growing either with or without males. Females growing in the absence of males were leakier in their sex expression than controls with males, producing more than twice as many male flowers. Moreover, because greater leakiness was more highly represented in the population’s progeny, we conclude that enhanced leakiness in sex expression is adaptive inM. annua. We discuss differences in the degree of plasticity between ploidal races ofMercurialis annuain terms of likely differences in the reliability of the signal plants may perceive for the presence of males in their populations. Our results provide a striking instance of adaptive plasticity in the reproductive behavior of plants and draw attention to possible constraints on plasticity when the environmental signals that individuals receive are unreliable.
Priors and Payoffs in Confidence Judgments
Authors: Locke Shannon M. , Gaffin-Cahn Elon , Hosseinizaveh Nadia , Mamassian Pascal , Landy Michael S.
Published: July 2019

1

Priors and payoffs are known to affect perceptual decision-making, but little is understood about how they influence confidence judgments. For optimal perceptual decision-making, both priors and payoffs should be considered when selecting a response. However, for confidence to reflect the probability of being correct in a perceptual decision, priors should affect confidence but payoffs should not. To experimentally test whether human observers follow this normative behavior, we conducted an orientation-discrimination task with varied priors and payoffs, probing both perceptual and metacognitive decision-making. We then examined the placement of discrimination and confidence criteria according to several plausible Signal Detection Theory models. In the normative model, observers use the optimal discrimination criterion (i.e., the criterion that maximizes expected gain) and confidence criteria that shift with the discrimination criterion that maximizes accuracy (i.e., are not affected by payoffs). No observer was consistent with this model, with the majority exhibiting non-normative confidence behavior. One subset of observers ignored both priors and payoffs for confidence, always fixing the confidence criteria around the neutral discrimination criterion. The other group of observers incorrectly incorporated payoffs into their confidence by always shifting their confidence criteria with the same gains-maximizing criterion used for discrimination. Such metacognitive mistakes could have negative consequences outside the laboratory setting, particularly when priors or payoffs are not matched for all the possible decision alternatives.
The ARRIVE guidelines 2019: updated guidelines for reporting animal research
Authors: Percie du Sert Nathalie , Hurst Viki , Ahluwalia Amrita , Alam Sabina , Avey Marc T. , Baker Monya , Browne William J. , Clark Alejandra , Cuthill Innes C. , Dirnagl Ulrich , Emerson Michael , Garner Paul , Holgate Stephen T. , Howells David W. , Karp Natasha A. , Lidster Katie , MacCallum Catriona J. , Macleod Malcolm , Petersen Ole , Rawle Frances , Reynolds Penny , Rooney Kieron , Sena Emily S. , Silberberg Shai D. , Steckler Thomas , Würbel Hanno
Published: July 2019

Reproducible science requires transparent reporting. The ARRIVE guidelines were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved.

Here we introduce ARRIVE 2019. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise the items and split the guidelines into two sets, the ARRIVE Essential 10, which constitute the minimum requirement, and the Recommended Set, which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers to verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document that serves 1) to explain the rationale behind each item in the guidelines, 2) to clarify key concepts and 3) to provide illustrative examples. We aim through these changes to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Differential pulmonary immunopathologic response of domestic sheep (Ovis aries) and bighorn sheep (Ovis canadensis) to Mycoplasma ovipneumoniae infection: a retrospective study
Authors: Grossman Paige C. , Schneider David A. , Knowles Donald P. , Highland Margaret A.
Published: July 2019

Mycoplasma ovipneumoniaeis a respiratory pathogen that can impact domestic sheep (Ovis aries; DS) and bighorn sheep (Ovis canadensis; BHS). Experimental and field data have indicated BHS are more susceptible than DS to developing polymicrobial pneumonia associated withMycoplasma ovipneumoniaeinfection. We hypothesized that DS and BHS have a differential immunopathologic pulmonary response toM. ovipneumoniaeinfection. A retrospective study was performed using formalin-fixed, paraffin-embedded (FFPE) lung tissue from DS and BHS without and withM. ovipneumoniaedetected in the lung tissue (n=8 per group). While eachM. ovipneumoniaepositive lung sample had microscopic changes typical of infection, including hyperplasia of intrapulmonary bronchus-associated lymphoid tissue (BALT) and respiratory epithelium, DS exhibited a more robust and well-organized BALT formation as compared to BHS. Immunohistochemistry was performed with antibodies reactive in FFPE tissues and specific for leukocyte and cytokine markers: T cell marker CD3, B cell markers CD20 and CD79a, macrophage markers CD163 and Iba1, and cytokine IL-17. Digital analysis was used to quantitate chromogen deposition in regions of interest (ROIs), including alveolar and bronchiolar areas, and bronchiolar subregions (epithelium and BALT). Main effects and interaction of species and infection status were analyzed by beta regression and Bonferroni corrections were performed on pairwise comparisons (PBon<0.05 significance). Significant species differences were identified for bronchiolar CD3 (PBon=0.0023) and CD163 (PBon=0.0224), alveolar CD163 (PBon=0.0057), and for IL-17 in each of the ROIs (alveolar:PBon=0.0009; BALT:PBon=0.0083; epithelium:PBon=0.0007). Infected BHS had a higher abundance of bronchiolar CD3 (PBon=0.0005) and CD163 (PBon=0.0162), and alveolar CD163 (PBon=0.0073). While IL-17 significantly increased with infection in BHS BALT (PBon=0.0179) and alveolar (0.0006) ROIs, abundance in DS showed an insignificant decrease in these ROIs and a significant decrease in epithelial abundance (PBon=0.0019). These findings support the hypothesis that DS and BHS have a differential immunopathologic response toM. ovipneumoniaeinfection.
Trace amine-associated receptor gene polymorphism increases drug craving
Authors: Loftis Jennifer M. , Lasarev Michael , Shi Xiao , Lapidus Jodi , Janowsky Aaron , Hoffman William F. , Huckans Marilyn
Published: July 2019

BACKGROUND

Methamphetamine (MA) is a potent agonist at the trace amine-associated receptor 1 (TAAR1). This study evaluated a common variant (CV) in the human TAAR1 gene, synonymous single nucleotide polymorphism (SNP) V288V, to determine the involvement of TAAR1 in MA dependence.

METHODS

Participants (n = 106) with active MA dependence (MA-ACT), in remission from MA dependence (MA-REM), with active polysubstance dependence, in remission from polysubstance dependence, and with no history of substance dependence completed neuropsychiatric symptom questionnaires and provided blood samples. In vitro expression and function of CV and wild type TAAR1 receptors were also measured.

RESULTS

The V288V polymorphism demonstrated a 40% increase in TAAR1 protein expression in cell culture, but message sequence and protein function were unchanged, suggesting an increase in translation efficiency. Principal components analysis resolved neuropsychiatric symptoms into four components, PC1 (depression, anxiety, memory, and fatigue), PC2 (pain), PC3 (drug and alcohol craving), and PC4 (sleep disturbances). Analyses of study group and TAAR1 genotype revealed a significant interaction for PC3 (craving response) (p = 0.003). The control group showed no difference in PC3 associated with TAAR1, while adjusted mean craving for the MA-ACT and MA-REM groups, among those with at least one copy of V288V, was estimated to be, respectively, 1.55 (p = 0.036) and 1.77 (p = 0.071) times the adjusted mean craving for those without the TAAR1 SNP.

CONCLUSIONS

Neuroadaptation to chronic MA use may be altered by TAAR1 genotype and result in increased dopamine signaling and craving in individuals with the V288V genotype.
The effects of biodegradable mulch film on the growth, yield, and water use efficiency of cotton and maize in an arid region
Authors: Deng Lu , Yu Ruide , Wang Qian
Published: July 2019

Plastic residual film pollution in China is serious, and the use of degradable mulch film instead of plastic mulch can effectively alleviate this situation. The substitution of common polyethylene plastic mulch film with biodegradable mulch film in the agricultural production of cotton and maize in an arid region was investigated in the present study. Using bare soil as the control, we compared the effects of common polyethylene plastic film and biodegradable mulch film on crop growth, yield, and water use efficiency (WUE) in maize and cotton. The results indicated that: (1) the biodegradable mulch film in this region remained intact for 60 days after being laid down, significantly degrading after 120 days, and was associated with increased soil temperature, moisture conservation, and degradability in comparison to a bare soil control. (2) Both the biodegradable mulch film and the polyethylene plastic film significantly increased various physiological parameters, such as crop height, stalk diameter, and leaf area. (3) The biodegradable mulch film significantly increased maize and cotton crop yield by 69.4–76.2% and 65.2–71.9%, respectively, compared to the bare soil control. (4) Compared to the bare soil control, the biodegradable mulch film effectively increased WUE in the crops by 64.5–73.1%. In summary, biodegradable mulch film had comparable results to the common polyethylene plastic film in increasing soil temperature, moisture conservation, crop growth, yield, and WUE. As the biodegradable mulch film causes no residual pollution, it is thus preferable to common plastic mulch film for agricultural applications in arid regions and supports the sustainable development of agroecosystems.