bluuebunny/crossref_metadata_2025 huggingface dataset:
Striking differences in virulence, transmission, and sporocyst growth dynamics between two schistosome populations
Authors: Clec’h Winka Le , Diaz Robbie , Chevalier Frédéric D. , McDew-White Marina , Anderson Timothy J.C.
Published: June 2019

Background

Parasite traits associated with transmission success, such as the number of infective stages released from the host, are expected to be optimized by natural selection. However, in the trematode parasite Schistosoma mansoni, a key transmission trait – the number of cercariae larvae shed from infected Biomphalaria spp. snails – varies significantly within and between different parasite populations and selection experiments demonstrate that this variation has a strong genetic basis. In this study, we compared the transmission strategies of two laboratory schistosome population and their consequences for their snail host.

Methods

We infected inbred Biomphalaria glabrata snails using two Schistosoma mansoni parasite populations (SmBRE and SmLE), both isolated from Brazil and maintained in the laboratory for decades. We compared life history traits of these two parasite populations by quantifying sporocyst growth within infected snails (assayed using qPCR), output of cercaria larvae, and impact on snail host physiological response (i.e. hemoglobin rate, laccase-like activity) and survival.

Results

We identified striking differences in virulence and transmission between the two studied parasite populations. SmBRE (low shedder (LS) parasite population) sheds very low numbers of cercariae, and causes minimal impact on the snail physiological response (i.e. laccase-like activity, hemoglobin rate and snail survival). In contrast, SmLE (high shedder (HS) parasite population) sheds 8-fold more cercariae (mean ± se cercariae per shedding: 284±19 vs 2352±113), causes high snail mortality, and has strong impact on snail physiology. We found that HS sporocysts grow more rapidly inside the snail host, comprising up to 60% of cells within infected snails, compared to LS sporocysts which comprised up to 31%. Cercarial production is strongly correlated to the number of S. mansoni sporocyst cells present within the snail host tissue, although the proportion of sporocyst cells alone does not explain the low cercarial shedding of SmBRE.

Conclusions

We demonstrated the existence of alternative transmission strategies in the S. mansoni parasite consistent with trade-offs between parasite transmission and host survival: a “boom-bust” strategy characterized by high virulence, high transmission and short duration infections and a “slow and steady” strategy with low virulence, low transmission but long duration of snail host infections.
Extramacrochaete promotes branch and bouton number via the sequestration of Daughterless in the cytoplasm of neurons
Authors: Waddell Edward A. , Viveiros Jennifer M. , Robinson Erin L. , Sharoni Michal A. , Latcheva Nina K. , Marenda Daniel R.
Published: June 2019

The class I basic Helix Loop Helix (bHLH) proteins are highly conserved transcription factors that are ubiquitously expressed. A wealth of literature on class I bHLH proteins have shown that these proteins must homodimerize or heterodimerize with tissue specific HLH proteins in order to bind DNA at E box (CANNTG) consensus sequences to control tissue specific transcription. Due to its ubiquitous expression, class I bHLH proteins are also extensively regulated post-translationally, mostly through dimerization. Previously, we reported that in addition to its role in promoting neurogenesis, the class I bHLH protein Daughterless also functions in mature neurons to restrict axon branching and synapse number. Here, we show that part of the molecular logic that specifies how Daughterless functions in neurogenesis is also conserved in neurons. We show that the type V HLH protein Extramacrochaete binds to and represses Daughterless function by sequestering Daughterless to the cytoplasm. This work provides initial insights into the mechanisms underlying the function of Daughterless and Extramacrochatae in neurons while providing a novel understanding of how Extramacrochaetae functions to restricts Daughterless activity within the cell.
Unsupervised decoding of single-trial EEG reveals unique states of functional brain connectivity that drive rapid speech categorization decisions
Authors: Al-Fahad Rakib , Yeasin Mohammed , Bidelman Gavin M.
Published: June 2019

Categorical perception (CP) is an inherent property of speech perception. The response time (RT) of listeners’ perceptual speech identification are highly sensitive to individual differences. While the neural correlates of CP have been well studied in terms of the regional contributions of the brain to behavior, functional connectivity patterns that signify individual differences in listeners’ speed (RT) for speech categorization is less clear. To address these questions, we applied several computational approaches to the EEG including graph mining, machine learning (i.e., support vector machine), and stability selection to investigate the unique brain states (functional neural connectivity) that predict the speed of listeners’ behavioral decisions. We infer that (i) the listeners’ perceptual speed is directly related to dynamic variations in their brain connectomics, (ii) global network assortativity and efficiency distinguished fast, medium, and slow RT, (iii) the functional network underlying speeded decisions increases in negative assortativity (i.e., became disassortative) for slower RTs, (iv) slower categorical speech decisions cause excessive use of neural resources and more aberrant information flow within the CP circuitry, (v) slower perceivers tended to utilize functional brain networks excessively (or inappropriately) whereas fast perceivers (with lower global efficiency) utilized the same neural pathways but with more restricted organization. Our results showed that neural classifiers (SVM) coupled with stability selection correctly classify behavioral RTs from functional connectivity alone with over 90% accuracy (AUC=0.9). Our results corroborate previous studies by confirming the engagement of similar temporal (STG), parietal, motor, and prefrontal regions in CP using an entirely data-driven approach.
Diffusion of kinesin motors on cargo can enhance binding and run lengths during intracellular transport
Authors: Bovyn Matthew , Reddy Babu , Gross Steven , Allard Jun
Published: June 2019

Cellular cargos, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. Many experimental and computational studies of cargos with rigidly attached motors, in contrast to many biological cargos that have lipid surfaces that may allow surface mobility of motors. We extend a mechanochemical 3D computational model by adding coupled-viscosity effects to compare different motor arrangements and mobilities. We show that organizational changes can optimize for different objectives: Cargos with clustered motors are transported efficiently, but are slow to bind to microtubules, whereas those with motors dispersed rigidly on their surface bind microtubules quickly, but are transported inefficiently. Finally, cargos with freely-diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results suggest that experimentally observed changes in motor organization may be a control point for transport.
A “feet digging” swash zone sampling method for the sandy beach bivalveDonax deltoides(Bivalvia: Donacidae)
Authors: Totterman Stephen
Published: June 2019

A “feet digging” method for sampling the sandy beach bivalveDonax deltoideswas evaluated by comparison to quadrat-based results from eleven beaches in subtropical eastern Australia. The method was developed from a recreational fishing technique that involves twisting one’s feet into the thixotropic sand to dislodge buried clams which are then recovered by hand. Several plots are sampled across the swash zone in one five-minute sampling unit and the process is replicated at several locations along the beach. Mean feet digging clam counts were proportional to mean transect linear clam densities (r= 0.98). Clam length-frequency distributions from feet digging were similar to those from quadrat sampling except that feet digging was not effective for clams < 16 mm. Feet digging counts are sensitive to both across shore (tidal) and alongshore variation in clam abundance and were less precise than those from quadrat-based methods (CV1.2× larger). However, feet digging is fast and the method should be useful for low cost surveys ofDonax deltoidesand similar “surf clams”.
On-scalp MEG SQUIDs are sensitive to early somatosensory activity unseen by conventional MEG
Authors: Andersen Lau M. , Pfeiffer Christoph , Ruffieux Silvia , Riaz Bushra , Winkler Dag , Schneiderman Justin F. , Lundqvist Daniel
Published: June 2019

Magnetoencephalography (MEG) has a unique capacity to resolve the spatio-temporal development of brain activity from non-invasive measurements. Conventional MEG, however, relies on sensors that sample from a distance (20-40 mm) to the head due to thermal insulation requirements (the MEG sensors function at 4 K in a helmet). A gain in signal strength and spatial resolution may be achieved if sensors are moved closer to the head. Here, we report a study comparing measurements from a seven-channel on-scalp SQUID MEG system to those from a conventional (in-helmet) SQUID MEG system.

We compared spatio-temporal resolution between on-scalp and conventional MEG by comparing the discrimination accuracy for neural activity patterns resulting from stimulating five different phalanges of the right hand. Because of proximity and sensor density differences between on-scalp and conventional MEG, we hypothesized that on-scalp MEG would allow for a more high-resolved assessment of these activity patterns, and therefore also a better classification performance in discriminating between neural activations from the different phalanges.

We observed that on-scalp MEG provided better classification performance during an early post-stimulus period (15-30 ms). This corresponded to electroencephalographic (EEG) response components N16 and P23, and was an unexpected observation as these components are usually not observed in conventional MEG. They indicate that on-scalp MEG opens up for a richer registration of the cortical signal, allowing for sensitivity to what are potentially sources in the thalamo-cortical radiation and to quasi-radial sources.

We had originally expected that on-scalp MEG would provide better classification accuracy based on activity in proximity to the P60m component compared to conventional MEG. This component indeed allowed for the best classification performance for both MEG systems (60-75%, chance 50%). However, we did not find that on-scalp MEG allowed for better classification than conventional MEG at this latency. We believe this may be due to the limited sensor coverage in the recording, in combination with our strategy for positioning the on-scalp MEG sensors. We discuss how sensor density and coverage as well as between-phalange source field dissimilarities may influence our hypothesis testing, which we believe to be useful for future benchmarking measurements.
Non-invasive prenatal testing by low coverage genomic sequencing: Detection limits of screened chromosomal microdeletions
Authors: Kucharik Marcel , Gnip Andrej , Hyblova Michaela , Budis Jaroslav , Strieskova Lucia , Harsanyova Maria , Duris Frantisek , Radvanszky Jan , Minarik Gabriel , Szemes Tomas
Published: June 2019

Objective

To study the detection limits of chromosomal microaberrations in non-invasive prenatal testing with aim for five target microdeletion syndromes, including DiGeorge, Prader-Willi/Angelman, 1p36, Cri-Du-Chat, and Wolf-Hirschhorn syndromes.

Method

We used known cases of pathogenic deletions from ISCA database to specifically define regions critical for the target syndromes. Our approach to detect microdeletions, from whole genome sequencing data, is based on sample normalization and read counting for individual bins. We performed both an in-silico study using artificially created data sets and a laboratory test on mixed DNA samples, with known microdeletions, to assess the sensitivity of prediction for varying fetal fractions, deletion lengths, and sequencing read counts.

Results

The in-silico study showed sensitivity of 79.3% for 10% fetal fraction with 20M read count, which further increased to 98.4% if we searched only for deletions longer than 3Mb. The test on laboratory-prepared mixed samples was in agreement with in-silico results, while we were able to correctly detect 24 out of 29 control samples.

Conclusion

Our results suggest that it is possible to incorporate microaberration detection into basic NIPT as part of the offered screening/diagnostics procedure, however, accuracy and reliability depends on several specific factors.

What’s already known about this topic?

Microdeletion detection accuracy, similarly to most common trisomies detection, was found to be dependent mostly on technical and biological parameters of the test and tested samples, such as coverage of target region, fetal fraction, size and positions of the deletions.

What does this study add?

Estimation of relevant regions for five chosen microdeletion syndromes. Confirmation and improvement upon previous methods. Systematic evaluation of sensitivity of microdeletion detection with read counts from 10M to 20M.
Basicity of N5 in semiquinone enhances the rate of respiratory electron outflow inShewanella oneidensisMR-1
Authors: Tokunou Yoshihide , Saito Keisuke , Hasegawa Ryo , Nealson Kenneth H. , Hashimoto Kazuhito , Ishikita Hiroshi , Okamoto Akihiro
Published: June 2019

Extracellular electron transport (EET) occurs in environmental iron-reducing bacteria and is mediated by an outer membrane multi-heme cytochrome complex (Cyts). It has critical implications for global mineral cycling and electrochemical microbial catalysis. The rate of EET mediated by multiple heme redox centers significantly increases in the presence of flavins and quinones. Their electron free energy does not entirely account for the fact that differential effects on EET rate enhancement vary significantly by factors ≥100. Here, we report on whole-cell electrochemical analysis ofShewanella oneidensisMR-1 using six flavin analogs and four quinones. We demonstrated that protonation of the nitrogen atom at position 5 (N5) of the isoalloxazine ring is essential for electron outflow acceleration as a bound non-covalent cofactor of Cyts. EET mediated by Cyts was accelerated at a rate dependent on pKa(N5). The EET rate largely decreased in response to the addition of deuterated water (D2O), while low concentration of D2O (4 %) had little impact on electron free energy difference of the heme and non-covalent bound cofactors, strongly suggesting that the protonation of N5 limits the rate of EET. Our findings directly link EET kinetics to proton transport reaction via N5 and provide a basis for the development of novel strategies for controlling EET-associated biological reactions.

Significance statement

The potential of various small molecules such as flavins and quinones to enhance the rate of extracellular electron transport (EET) has been exploited to develop environmental energy conversion systems. Flavins and quinones have similar molecular structures but their abilities to enhance EET vary by >100× inShewanella oneidensisMR-1. These large differences are inconsistent with conventional models, which rely on redox potentials or diffusion constant of shuttling electron mediators. In this study, we demonstrated that the basicity of the nitrogen atom of the isoalloxazine ring (N5) enhances the rate of electron outflow when a flavin or quinone is a non-covalent cofactor ofS. oneidensisMR-1 outer membranec-type cytochromes.
Relation Extraction Between Bacteria and Biotopes from Biomedical Texts with Attention Mechanisms and Domain-Specific Contextual Representations
Authors: Jettakul Amarin , Wichadakul Duangdao , Vateekul Peerapon
Published: June 2019

The Bacteria Biotope (BB) task is biomedical relation extraction (RE) that aims to study the interaction between bacteria and their locations. This task is considered to pertain to fundamental knowledge in applied microbiology. Some previous investigations have used feature-based models; others have presented deep-learning-based models such as convolutional and recurrent neural networks used with the shortest dependency paths (SDPs). Although SDPs contain valuable and concise information, sections of significant information necessary to define bacterial location relationships are often neglected. In addition, the traditional word embedding used in previous studies may suffer from word ambiguation across linguistic contexts.

Here, we present a deep learning model for biomedical RE. The model incorporates feature combinations of SDPs and full sentences with various attention mechanisms. We also used pre-trained contextual representations based on domain-specific vocabularies. In order to assess the model’s robustness, we introduced a mean F1 score on many models using different random seeds. The experiments were conducted on the standard BB corpus in BioNLP-ST’16. Our experimental results revealed that the model performed better (in terms of both maximum and average F1 scores; 60.77% and 57.63%, respectively) compared with other existing models.

We demonstrated that our proposed contributions to this task can be used to extract rich lexical, syntactic, and semantic features that effectively boost the model’s performance. Moreover, we analyzed the trade-off between precision and recall in order to choose the proper cut-off to use in real-world applications.
Transposable element over-accumulation in autopolyploids results from relaxed purifying selection and provides variants for rapid local adaptation
Authors: Baduel P. , Quadrana L. , Hunter B. , Bomblies K. , Colot V.
Published: June 2019

Polyploidization is frequently associated with increased transposable element (TE) content. However, what drives TE dynamics following whole genome duplication (WGD) and the evolutionary implications remain unclear. Here, we leveraged whole-genome resequencing data of ∼300 individual Arabidopsis arenosa plants, a well characterized natural diploid-autotetraploid species, to address these questions. Based on 43,176 polymorphic TE insertions we detected in these genomes, we demonstrate that relaxed purifying selection rather than transposition bursts is the main driver of TE over-accumulation after WGD. Furthermore, the increased pool of TE insertions in tetraploids is especially enriched within or near abiotic and biotic stress response genes. Notably, we uncovered one such insertion in a major flowering-time repressor gene and found that the resulting allele is specific to the rapid-cycling tetraploid lineage that colonized mainland railways. Together, our findings indicate that tetrasomy by itself leads to an enhanced tolerance to accumulating genic TE variants, some of which can potentially contribute to local adaptation.
Feedback regulation of BMP signaling byC. eleganscuticle collagens
Authors: Madaan Uday , Faure Lionel , Chowdhury Albar , Ahmed Shahrear , Ciccarelli Emma J. , Gumienny Tina L. , Savage-Dunn Cathy
Published: June 2019

Cellular responsiveness to environmental cues, including changes in extracellular matrix (ECM), is critical for normal processes such as development and wound healing, but can go awry, as in oncogenesis and fibrosis. One type of molecular pathway allowing this responsiveness is the bone morphogenetic protein (BMP) signaling pathway. Due to their broad and potent functions, BMPs and their signaling pathways are highly regulated at multiple levels. InCaenorhabditis elegans, the BMP ligand DBL-1 is a major regulator of body size. We have previously shown that DBL-1/BMP signaling determines body size through transcriptional regulation of cuticle collagen genes. We have now obtained evidence of feedback regulation of DBL-1/BMP by collagen genes. We analyzed four DBL-1-regulated collagen genes that affect body size. Here we show that inactivation of any one of these cuticle collagen genes reduces DBL-1/BMP signaling, as measured by a Smad activity reporter. Furthermore, we find that depletion of these collagens reduces GFP::DBL-1 fluorescence, and acts unexpectedly at the level ofdbl-1transcription. We therefore conclude that cuticle, a type of ECM, impinges on DBL-1/BMP expression and signaling. In contrast to other characterized examples, however, the feedback regulation of DBL-1/BMP signaling by collagens is likely to be contact-independent, due to the physical separation of the cuticle from DBL-1-expressing cells in the ventral nerve cord. Our results provide an entry point into a novel mechanism of regulation of BMP signaling, with broader implications for mechanical regulation of gene expression in general.
Feature extraction approach in single-cell gene expression profiling for cell-type marker identification
Authors: Adossa Nigatu A. , Schauser Leif , Gregersen Vivi G. , Elo Laura L.
Published: June 2019

Background

Recent advances in single-cell gene expression profiling technology have revolutionized the understanding of molecular processes underlying developmental cell and tissue differentiation, enabling the discovery of novel cell-types and molecular markers that characterize developmental trajectories. Common approaches for identifying marker genes are based on pairwise statistical testing for differential gene expression between cell-types in heterogeneous cell populations, which is challenging due to unequal sample sizes and variance between groups resulting in little statistical power and inflated type I errors.

Results

We developed an alternative feature extraction method, Marker gene Identification for Cell-type Identity (MICTI) that encodes the cell-type specific expression information to each gene in every single-cell. This approach identifies features (genes) that are cell-type specific for a given cell-type in heterogeneous cell population. To validate this approach, we used (i) simulated single cell RNA-seq data, (ii) human pancreatic islet single-cell RNA-seq data and (iii) a simulated mixture of human single-cell RNA-seq data related to immune cells, particularly B cells, CD4+ memory cells, CD8+ memory cells, dendritic cells, fibroblast cells, and lymphoblast cells. For all cases, we were able to identify established cell-type-specific markers.

Conclusions

Our approach represents a highly efficient and fast method as an alternative to differential expression analysis for molecular marker identification in heterogeneous single-cell RNA-seq data.
ADAMTS-1 and Syndecan-4 intersect in the regulation of cell migration and angiogenesis
Authors: Lambert Jordi , Makin Kate , Akbareian Sophia , Johnson Robert , Robinson Stephen D , Edwards Dylan R.
Published: June 2019

The extracellular proteoglycanase ADAMTS-1 has critical roles in organogenesis and angiogenesis. We demonstrate here the functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan-4 in influencing adhesion, migration, and angiogenesis in vitro. Knockdown of ADAMTS-1 in fibroblasts and endothelial cells resulted in a parallel reduction in cell surface syndecan-4 that was not due to altered syndecan-4 expression or internalization, but was attributable to increased expression and activity of matrix metalloproteinase-9 (MMP-9), a known syndecan-4 sheddase. Knockdown of either syndecan-4 or ADAMTS-1 led to enhanced endothelial cell responses to exogenous vascular endothelial growth factor (VEGF), and increased microvessel sprouting in ex vivo aortic ring assays, correlating with reduced ability of the cells to sequester VEGF. On fibronectin but not type 1 collagen matrices, endothelial cells with knockdown of either ADAMTS-1 or syndecan-4 elicited increased migration and showed similarly altered focal adhesion (FA) morphologies, with a higher proportion of larger FA’s and formation of long fibrillar integrin α5-containing FA’s. However, integrin α5-null endothelial cells also displayed enhanced migration in response to ADAMTS-1/syndecan-4 knockdown, indicating that integrin α5 was not the mediator of the altered migratory behaviour. Plating of naïve endothelial cells on cell-conditioned matrix from ADAMTS-1/syndecan-4 knockdown cells demonstrated that the altered behaviour was matrix dependent. Fibulin-1, a known ECM co-factor of ADAMTS-1, was expressed at reduced levels in ADAMTS-1/syndecan-4 knockdown cells. These findings support the notion that ADAMTS-1 and syndecan-4 are functionally interconnected in regulating cell migration and angiogenesis, via the involvement of MMP-9 and fibulin-1 as collaborators
Improving ATAC-seq Data Analysis with AIAP, a Quality Control and Integrative Analysis Package
Authors: Liu Shaopeng , Li Daofeng , Lyu Cheng , Gontarz Paul , Miao Benpeng , Madden Pamela , Wang Ting , Zhang Bo
Published: June 2019

ATAC-seq is a technique widely used to investigate genome-wide chromatin accessibility. The recently published Omni-ATAC-seq protocol substantially improves the signal/noise ratio and reduces the input cell number. High-quality data are critical to ensure accurate analysis. Several tools have been developed for assessing sequencing quality and insertion size distribution for ATAC-seq data; however, key quality control (QC) metrics have not yet been established to accurately determine the quality of ATAC-seq data. Here, we optimized the analysis strategy for ATAC-seq and defined a series of QC metrics, including reads under peak ratio (RUPr), background (BG), promoter enrichment (ProEn), subsampling enrichment (SubEn), and other measurements. We incorporated these QC tests into our recently developed ATAC-seq Integrative Analysis Package (AIAP) to provide a complete ATAC-seq analysis system, including quality assurance, improved peak calling, and downstream differential analysis. We demonstrated a significant improvement of sensitivity (20%~60%) in both peak calling and differential analysis by processing paired-end ATAC-seq datasets using AIAP. AIAP is compiled into Docker/Singularity, and with one command line execution, it generates a comprehensive QC report. We used ENCODE ATAC-seq data to benchmark and generate QC recommendations, and developed qATACViewer for the user-friendly interaction with the QC report.
Engineering oleaginous yeast Yarrowia lipolytica for violacein production: extraction, quantitative measurement and culture optimization
Authors: Tong Yingjia , Zhou Jingwen , Zhang Liang , Xu Peng
Published: June 2019

Violacein is a naturally occurring anticancer therapeutic with deep purple color. Yeast fermentation represents an alternative approach to efficiently manufacturing violacein from inexpensive feedstocks. In this work, we optimized the extraction protocol to improve violacein recovery ratio and purity from yeast culture, including the variations of organic solvents, the choice of mechanical shear stress, incubation time and the use of cell wall-degrading enzymes. We also established the quantitative correlation between HPLC and microplate reader method. We demonstrated that both HPLC and microplate reader are technically equivalent to measure violacein from yeast culture. Furthermore, we optimized the yeast cultivation conditions, including carbon/nitrogen ratio and pH conditions. Our results indicated that ethyl acetate is the best extraction solvent with glass beads grinding the cell pellets, the maximum violacein and deoxyviolacein production was 70.04 mg/L and 5.28 mg/L in shake flasks, respectively. Violacein purity reaches 86.92% at C/N ratio of 60, with addition of 10 g/L CaCO3 to control the media pH. Taken together, the development of efficient extraction protocol, quantitative correlation between HPLC and microplate reader, and the optimization of culture conditions set a new stage for engineering violacein production in Y. lipolytica. This information should be valuable for us to build a renewable and scalable violacein production platform from the novel host oleaginous yeast species.
Theory of active chromatin remodeling
Authors: Jiang Zhongling , Zhang Bin
Published: June 2019

Nucleosome positioning controls the accessible regions of chromatin and plays essential roles in DNA-templated processes. ATP driven remodeling enzymes are known to be crucial for its establishment in vivo, but their non-equilibrium nature has hindered the development of a unified theoretical framework for nucleosome positioning. Using a perturbation theory, we show that the effect of these enzymes can be well approximated by effective equilibrium models with rescaled temperatures and interactions. Numerical simulations support the accuracy of the theory in predicting both kinetic and steady-state quantities, including the effective temperature and the radial distribution function, in biologically relevant regimes. The energy landscape view emerging from our study provides an intuitive understanding for the impact of remodeling enzymes in either reinforcing or overwriting intrinsic signals for nucleosome positioning, and may help improve the accuracy of computational models for its prediction in silico.
Phylogenetic shifts in gene body methylation correlate with gene expression and reflect trait conservation
Authors: Seymour Danelle K. , Gaut Brandon S.
Published: June 2019

A subset of genes in plant genomes are labeled with DNA methylation specifically at CG residues. These genes, known as gene-body methylated (gbM), have a number of associated characteristics. They tend to have longer sequences, to be enriched for intermediate expression levels, and to be associated with slower rates of molecular evolution. Most importantly, gbM genes tend to maintain their level of DNA methylation between species, suggesting that this trait is under evolutionary constraint. Given the degree of conservation in gbM, we still know surprisingly little about its function in plant genomes or whether gbM is itself a target of selection. To address these questions, we surveyed DNA methylation across eight grass (Poaceae) species that span a gradient of genome sizes. We first established that genome size correlates with genome-wide DNA methylation levels, but less so for genic levels. We then leveraged genomic data to identify a set of 2,982 putative orthologs among the eight species and examined shifts of methylation status for each ortholog in a phylogenetic context. A total of 55% of orthologs exhibited a shift in gbM, but these shifts occurred predominantly on terminal branches, indicating that shifts in gbM are rarely conveyed over time. Finally, we found that the degree of conservation of gbM across species is associated with increased gene length, reduced rates of molecular evolution, and increased gene expression level, but reduced gene expression variation across species. Overall, these observations suggest a basis for evolutionary pressure to maintain gbM status over evolutionary time.
How cognitive and environmental constraints influence the reliability of simulated animats in groups
Authors: Fischer Dominik , Mostaghim Sanaz , Albantakis Larissa
Published: July 2019

Evolving in groups can either enhance or reduce an individual’s task performance. Still, we know little about the factors underlying group performance, which may be reduced to three major dimensions: (a) the individual’s ability to perform a task, (b) the dependency on environmental conditions, and (c) the perception of, and the reaction to, other group members. In our research, we investigated how these dimensions interrelate in simulated evolution experiments using adaptive agents equipped with Markov brains (“animats”). We evolved the animats to perform a spatial-navigation task under various evolutionary setups. The last generation of each evolution simulation was tested across modified conditions to evaluate and compare the animats’ reliability when faced with change. Moreover, the complexity of the evolved Markov brains was assessed based on measures of information integration. We found that, under the right conditions, specialized animats were as reliable as animats already evolved for the modified tasks, that interaction between animats was dependent on the environment and on the design of the animats, and that the task difficulty influenced the correlation between the performance of the animat and its brain complexity. Generally, our results suggest that the interrelation between the aforementioned dimensions is complex and their contribution to the group’s task performance, reliability, and brain complexity varies, which points to further dependencies. Still, our study reveals that balancing the group size and individual cognitive abilities prevents over-specialization and can help to evolve better reliability under unknown environmental situations.

Author Summary

The ability to adapt to environmental changes is an essential attribute of organisms which have had evolutionary success. We designed a simulated evolution experiment to better understand the relevant features of such organisms and the conditions under which they evolve: First, we created diverse groups of cognitive systems by evolving simulated organisms (“animats”) acting in groups on a spatial-navigation task. Second, we post-evolutionary tested the final evolved animats in new environments–not encountered before– in order to test their reliability when faced with change. Our results imply that the ability to generalize to environments with changing task demands can have complex dependencies on the cognitive design and sensor configuration of the organism itself, as well as its social or environmental conditions.
Testing and controlling for horizontal pleiotropy with the probabilistic Mendelian randomization in transcriptome-wide association studies
Authors: Yuan Zhongshang , Zhu Huanhuan , Zeng Ping , Yang Sheng , Sun Shiquan , Yang Can , Liu Jin , Zhou Xiang
Published: July 2019

Integrating association results from both genome-wide association studies (GWASs) and expression quantitative trait locus (eQTL) mapping studies has the potential to shed light on the molecular mechanisms underlying disease etiology. Several statistical methods have been recently developed to integrate GWASs with eQTL studies in the form of transcriptome-wide association studies (TWASs). These existing methods can all be viewed as a form of two sample Mendelian randomization (MR) analysis, which has been widely applied in various GWASs for inferring the causal relationship among complex traits. Unfortunately, most existing TWAS and MR methods make an unrealistic modeling assumption and assume that instrumental variables do not exhibit horizontal pleiotropic effects. However, horizontal pleiotropic effects have been recently discovered to be wide spread across complex traits, and, as we will show here, are also wide spread across gene expression traits. Therefore, not allowing for horizontal pleiotropic effects can be overly restrictive, and, as we will be show here, can lead to a substantial inflation of test statistics and subsequently false discoveries in TWAS applications. Here, we present a probabilistic MR method, which we refer to as PMR-Egger, for testing and controlling for horizontal pleiotropic effects in TWAS applications. PMR-Egger relies on an MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and, with a newly developed parameter expansion version of the expectation maximization algorithm, is scalable to hundreds of thousands of individuals. With extensive simulations, we show that PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust for various types of horizontal pleiotropic effect mis-specifications, is more powerful than existing MR approaches, and, as a by-product, can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank. In these applications, we show how PMR-Egger can lead to new biological discoveries through integrative analysis.
Tuberculosis patients display a high proportion of CD8+ T cells with a high cytotoxic potential
Authors: Chávez‐Galán Leslie , Illescas‐Eugenio Jhacqueline , Alvarez‐Sekely Magaly , Baez‐Saldaña Renata , Chávez Raúl , Lascurain Ricardo
Published: June 2019

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major cause of morbidity and mortality worldwide. In the host's immune response system, T cells play a critical role in mediating protection against Mtb infection, but the role of CD8+ T cells is still controversial. We evaluated the phenotypical characterization and cytotoxic ability of CD8+ T cells by flow cytometry‐based assay. Cytokine levels in serum were measured by multiplex cytokine assay. Our data show that cells from TB patients have an increased percentage of peripheral blood CD8+αβ+ T (p = 0.02) and CD56+CD8+ T (p = 0.02) and a decreased frequency of NKG2D+CD8+ T (p = 0.02) compared with healthy donors. Unlike CD8+ T cells from healthy donors, CD8+ T cells from TB patients exhibit greater cytotoxicity, mediated by HLA class I molecules, on autologous monocytes in the presence of mycobacterial antigens (p = 0.005). Finally, TB patients have a proinflammatory profile characterized by serum high level of TNF‐α (p = 0.02) and IL‐8 (p = 0.0001), but, interestingly, IL‐4 (p = 0.002) was also increased compared with healthy donors. Our data show evidence regarding the highly cytotoxic status of CD8+ T cells in Mtb infection. These cytotoxic cells restricted to HLA‐A, B, and C could be used to optimize strategies for designing new TB vaccines or for identifying markers of disease progression.
A 3D perspective on sediment accumulation in algal turfs: Implications of coral reef flattening
Authors: Tebbett Sterling B. , Streit Robert P. , Bellwood David R.
Published: June 2019

Globally, coral reefs are being transformed by a suite of stressors, the foremost being climate change. Increasingly, it is expected that these reconfigured reef systems will emerge with lower‐complexity and will be dominated by algal turfs. Understanding this new operating space is vital if we are to maintain the services, such as fishable biomass production, that reefs provide. However, the functionality of these systems appears to depend on the nature of the algal turfs themselves, which is in‐turn, intimately linked to the sediments they contain.

As reefs are losing complexity, we need to understand if, and to what extent, algal turf condition and complex reef structure are connected. To address this issue we took advantage of recent developments in 3D structure‐from‐motion technology to examine how complexity metrics (elevation and surface angle) related to the nature of algal turfs on a heavily climate‐impacted coral reef. This represents a novel application of this technology in the context of coral reef ecosystems.

We found that as both elevation and surface angle decreased, the nutritional value of the epilithic algal matrix also decreased while sediment accumulation increased. Furthermore, we showed that elevated surfaces were characterized by far shorter algal turfs, and are potentially herbivory hotspots, offering fertile grounds for further exploration of herbivory dynamics at sub‐metre spatial scales.

Synthesis. This study yields new insights into the operating‐space of future reefs, and suggests that as reefs flatten, sediment accumulation is likely to increase even if sediment inputs remain unchanged, altering algal turfs fundamentally. Maintaining key services provided by climate‐transformed, low‐complexity algal turf‐dominated reefs of the future, will depend on managing the complex interactions between herbivory, sediments, algal turfs and reef structural complexity.
The Switch‐Up: An Examination of Changes in Earnings Management after Receiving SEC Comment Letters
Authors: Cunningham Lauren M. , Johnson Bret A. , Johnson E. Scott , Lisic Ling Lei
Published: June 2019

The SEC has long asserted that earnings management practices result in adverse consequences for investors. We examine whether SEC oversight affects firms' accounting quality in terms of earnings management trade‐offs. We expect that increased firm‐specific regulatory scrutiny, in the form of an SEC comment letter, will induce management to switch from accrual‐based earnings management (AEM), which is a main focus of the SEC, to real‐activities‐based earnings management (REM), which is not likely to be commented on in the SEC's review process. Consistent with our predictions, we find that AEM is lower and REM is higher following the receipt of a comment letter, relative to non‐comment‐letter years and a propensity‐score‐matched sample of non‐comment‐letter firms. However, we do not find a significant difference in total earnings management (i.e., the sum of AEM and REM), suggesting that the higher REM acts as a substitute for lower AEM activity. We further find that our results are driven by accounting comments relating to estimates and accruals and not by classification‐only comments, which suggests that a comment letter that does not question specific issues associated with estimates and accruals is not a strong enough signal to induce the firm to change earnings management behavior. Additionally, the shift to REM is attenuated for firms with high institutional ownership. These results collectively suggest that the comment letter process effectively constrains AEM but has the unintended consequence of firms, on average, switching to REM.
Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease
Authors: Melchior Benoît , Mittapalli Gopi Kumar , Lai Carolyn , Duong‐Polk Karen , Stewart Joshua , Güner Bora , Hofilena Brian , Tjitro Amanda , Anderson Scott D. , Herman David S. , Dellamary Luis , Swearingen Christopher J. , Sunil K.C. , Yazici Yusuf
Published: July 2019

Dual‐specificity tyrosine phosphorylation‐regulated kinase‐1A (DYRK1A) is known to phosphorylate the microtubule‐associated tau protein. Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied.

SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC50 = 1.6 nM) and GSK‐3β (IC50 = 10.8 nM) kinase activity. Tau phosphorylation measured in cell‐based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC50 = 16 nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose‐dependent reduction of transient hypothermia‐induced phosphorylated tau in the brains of wild‐type mice compared to vehicle (47%, p < 0.001). Long‐term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3 mg/kg, QD, for 3 months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau‐positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire‐hang test compared to vehicle‐treated mice (p = 0.048).

SM07883, a potent, orally bioavailable, brain‐penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD.
Accessing rural health services: Results from a qualitative narrative gerontological study
Authors: Neville Stephen , Napier Sara , Adams Jeffery , Shannon Kay
Published: June 2019

Objective

Explore how older adults’ talk about accessing rural community health services.

Methods

A qualitative narrative gerontological approach explored issues related to accessing health services in their community. Semi‐structured digitally recorded individual interviews were undertaken with 32 community‐dwelling older people aged between 75 and 93 years. A narrative data analytic process was undertaken. The COnsolidated criteria for REporting Qualitative research guidelines were followed to ensure rigour in this study.

Results

Three collective narratives resulted from the data analytic process: (a) “accessing local health services”; (b) “accessing specialist services”; and (c) “accessing emergency services.”

Conclusions

Narrators identified a number of issues related to accessing rural health services. These included long waiting times, lack of continuity in care provision by doctors and difficulties accessing specialist and emergency services. Nurses were frequently cited as a reliable point of contact for these older people. Expansion of nursing roles would enhance the provision of rural health‐care services.
Adult congenital heart disease: Past, present and future
Authors: Brida Margarita , Gatzoulis Michael A.
Published: June 2019

The diagnosis and management of congenital heart disease (CHD), the most common inborn defect, has been a tremendous success story of modern medicine. In the 1950s, survival of children born with CHD was only approximately 15%, whereas nowadays more than 90% of these children survive well into adulthood. Consequently, the prevalence of patients with CHD has shifted away from infancy and childhood towards adulthood. Adult CHD cardiology is now encompassing not only young or middle‐aged adults but also patients with CHD over 60 years old. Many adult patients are afflicted by residual haemodynamic lesions and also face additional opportunities and/or challenges such as pregnancy, acquired heart disease, non‐cardiac pathology etc., necessitating integrated care and all medical disciplines. We are faced with a “tsunami” in terms of adult CHD numbers, disease heterogeneity and complexity of work and interventions needed. We need to secure resources, welcome more people in our field, learn from “marching with our patients”, and educate better patients, public and ourselves so that every single patient with CHD, born anywhere in the world, may reach their full life potential.
High daily salt intake had a negative impact on how well nocturnal enuresis treatment worked on children aged 7‐10 years
Authors: Tsuji Shoji , Yamaguchi Tadashi , Akagawa Yuko , Akagawa Shohei , Kino Jiro , Yamanouchi Sohsaku , Kimata Takahisa , Kaneko Kazunari
Published: June 2019

Aim

We investigated whether the daily salt intake of children with nocturnal enuresis influenced their response to 1‐desamino‐8‐D‐arginine vasopressin therapy.

Methods

This study comprised 129 children (67.4% boys) with a median age of 9.2 years (range 7.2‐10.4) with monosymptomatic nocturnal enuresis who were seen at Kansai Medical University Hospital, Osaka, Japan, from 2013 to 2017. Urinary sodium concentrations were determined using a spot urine test, and the children were divided into appropriate (n = 55) and excessive salt intake (n = 74) groups based on Japanese Government guidelines. After a month of therapy, the treatment responses were compared for 39 and 50 children, respectively.

Results

There were no significant differences in the urea nitrogen‐to‐creatinine or calcium‐to‐creatinine ratios in the two groups. However, the excessive salt intake group showed a significantly reduced treatment response to the appropriate salt intake group. In addition, the excessive and appropriate salt intake groups showed median efficacy ratios of 8.2% and 21.8%, respectively, based on intention‐to‐treat analysis (P = 0.029) and 12.0% and 30.8% based on per‐protocol analysis (P = 0.029).

Conclusion

High daily salt intake significantly reduced the efficacy of ddavp therapy for nocturnal enuresis and consumption should be controlled during treatment.