bluuebunny/crossref_metadata_2025 huggingface dataset:
Relative model fit does not predict topological accuracy in single-gene protein phylogenetics
Authors: Spielman Stephanie J.
Published: July 2019

It is regarded as best practice in phylogenetic reconstruction to perform relative model selection to determine an appropriate evolutionary model for the data. This procedure ranks a set of candidate models according to their goodness-of-fit to the data, commonly using an information theoretic criterion. Users then specify the best-ranking model for inference. While it is often assumed that better-fitting models translate to increase accuracy, recent studies have shown that the specific model employed may not substantially affect inferences. We examine whether there is a systematic relationship between relative model fit and topological inference accuracy in protein phylogenetics, using simulations and real sequences. Simulations employed site-heterogeneous mechanistic codon models that are distinct from protein-level phylogenetic inference models. This strategy allows us to investigate how protein models performs when they are mis-specified to the data, as will be the case for any real sequence analysis. We broadly find that phylogenies inferred across models with vastly different fits to the data produce highly consistent topologies. We additionally find that all models infer similar proportions of false positive splits, raising the possibility that all available models of protein evolution are similarly misspecified. Moreover, we find that the parameter-richGTRmodel, whose amino-acid exchangeabilities are free parameters, performs similarly to models with fixed exchangeabilities, although the inference precision associated withGTRmodels was not examined. We conclude that, while relative model selection may not hinder phylogenetic analysis on protein data, it may not offer specific predictable improvements and is not a reliable proxy for accuracy.
Detection of simple and complexde novomutations without, with, or with multiple reference sequences
Authors: Garimella Kiran V , Iqbal Zamin , Krause Michael A. , Campino Susana , Kekre Mihir , Drury Eleanor , Kwiatkowski Dominic , Sa Juliana M. , Wellems Thomas E. , McVean Gil
Published: July 2019

The characterization ofde novomutations in regions of high sequence and structural diversity from whole genome sequencing data remains highly challenging. Complex structural variants tend to arise in regions of high repetitiveness and low complexity, challenging bothde novoassembly, where short-reads do not capture the long-range context required for resolution, and mapping approaches, where improper alignment of reads to a reference genome that is highly diverged from that of the sample can lead to false or partial calls. Long-read technologies can potentially solve such problems but are currently unfeasible to use at scale. Here we present Corticall, a graph-based method that combines the advantages of multiple technologies and prior data sources to detect arbitrary classes of genetic variant. We construct multi-sample, coloured de Bruijn graphs from shortread data for all samples, align long-read-derived haplotypes and multiple reference data sources to restore graph connectivity information, and call variants using graph path-finding algorithms and a model for simultaneous alignment and recombination. We validate and evaluate the approach using extensive simulations and use it to characterize the rate and spectrum ofde novomutation events in 119 progeny from fourPlasmodium falciparumexperimental crosses, using long-read data on the parents to inform reconstructions of the progeny and to detect several known and novel non-allelic homologous recombination events.
Engineering Phage Host-Range and Suppressing Bacterial Resistance Through Phage Tail Fiber Mutagenesis
Authors: Yehl Kevin , Lemire Sébastien , Yang Andrew C. , Ando Hiroki , Mimee Mark , Der Torossian Torres Marcelo , de la Fuente-Nunez Cesar , Lu Timothy K.
Published: July 2019

The rapid emergence of antibiotic-resistant infections is prompting increased interest in phage-based antimicrobials. However, acquisition of resistance by bacteria is a major issue in the successful development of phage therapies. Through natural evolution and structural modeling, we identified host-range determining regions (HRDR) in the T3 phage tail fiber protein and developed a high-throughput strategy to genetically engineer these regions through site-directed mutagenesis. Inspired by antibody specificity engineering, this approach generates deep functional diversity (>107different members), while minimizing disruptions to the overall protein structure, resulting in synthetic “phagebodies”. We showed that mutating HRDRs yields phagebodies with altered host-ranges. Select phagebodies enable long-term suppression of bacterial growth by preventing the appearance of resistance in vitro and are functional in vivo using a mouse skin infection model. We anticipate this approach may facilitate the creation of next-generation antimicrobials that slow resistance development and could be extended to other viral scaffolds for a broad range of applications.

Highlights

Vastly diverse phagebody libraries containing 107different members were created.

Structure-informed engineering of viral tail fibers efficiently generated host-range alterations.

Phagebodies prevented the development of bacterial resistance across long timescalesin vitroand are functionalin vivo.
Targeted demethylation of H3K9me3 and H3K36me3 improves somatic cell reprogramming into cloned preimplantation but not postimplantation bovine concepti
Authors: Meng Fanli , Stamms Kathrin , Bennewitz Romina , Green Andria , Oback Fleur , Turner Pavla , Wei Jingwei , Oback Björn
Published: July 2019

Correct reprogramming of epigenetic marks in the donor nuclei is a prerequisite for successful cloning by somatic cell transfer. In several mammalian species, repressive histone (H) lysine (K) trimethylation (me3) marks, in particular H3K9me3, form a major barrier to somatic cell reprogramming into pluripotency and totipotency. We engineered bovine embryonic fibroblasts for the doxycycline-inducible expression of Kdm4b, a demethylase that removes histone 3 lysine 9 trimethylation (H3K9me3) and H3K36me3 marks. Upon inducing Kdm4b, H3K9me3 and H3K36me3 levels reduced ∼3-fold and ∼5-fold, respectively, compared to non-induced controls. Donor cell quiescence has been previously associated with reduced somatic trimethylation levels and increased cloning efficiency in cattle. Simultaneously inducing Kdm4b expression (via doxycycline) and quiescence (via serum starvation), further reduced global H3K9me3 and H3K36me3 levels by a total of 18-fold and 35-fold, respectively, compared to non-induced, non-starved control fibroblasts. Following somatic cell transfer, Kdm4b-BEF fibroblasts reprogrammed significantly better into cloned blastocysts than non-induced donor cells. However, detrimethylated donors and sustained Kdm4b-induction during embryo culture did not increase rates of post-blastocyst development from implantation to survival into adulthood. In summary, KDM4B only improved somatic cell reprogramming into early preimplantation stages, highlighting the need for alternative experimental approaches to reliably improve somatic cloning efficiency in cattle.
Model to link cell shape and polarity with organogenesis
Authors: Nielsen Bjarke Frost , Nissen Silas Boye , Sneppen Kim , Trusina Ala , Mathiesen Joachim
Published: July 2019

How do tubes — gut or neural tube — form from flat sheets of polarized cells? The prevalent view is that it is a two-step process: first cells wedge to bend the sheet, then cells intercalate and extend the initial invagination into a tube. We computationally challenged this model by asking if one mechanism (either cell wedging or intercalation) may suffice for the entire sheet-to-tube transition. Using a physical model with epithelial cells represented by polarized point particles, we show that either cell intercalation or wedging alone can be sufficient and each can both bend the sheet and extend the tube. When working in parallel, the two mechanisms increase the robustness of the tube formation. The successful simulations of Drosophila salivary gland, Sea urchin gastrulation and mammalian neurulation support the generality of our results.
Hippocampal-striatal functional connectivity supports processing of temporal expectations from associative memory
Authors: van de Ven Vincent , Lee Chanju , Lifanov Julia , Kochs Sarach , Jansma Henk , Weerd Peter De
Published: July 2019

The hippocampus and dorsal striatum are both associated with temporal processing, but they are thought to play distinct roles. The hippocampus has been reported to contribute to storing temporal structure of events in memory, whereas the striatum contributes to temporal motor preparation and reward anticipation. Here, we asked whether the striatum cooperates with the hippocampus in processing the temporal context of memorized visual associations. In our task, participants were trained to implicitly form temporal expectations for one of two possible time intervals associated to specific cue-target associations, and subsequently were scanned using 7T functional magnetic resonance imaging. During scanning, learned temporal expectations could be violated when the pairs were presented at either the learned or not-learned time intervals. When temporal expectations were not met during testing trials, activity in hippocampal subfields CA3/CA2 and CA1 decreased while right putamen activity increased, compared to when temporal expectations were met. Further, psycho-physiological interactions showed that functional connectivity between left CA1 and caudate, as well as between putamen and caudate, decreased when temporal expectations were not met. Our results indicate that the hippocampus and striatum cooperate to process implicit temporal expectation from mnemonic associations, with different but complementary contributions from caudate and putamen. Our findings provide further support for a hippocampal-striatal network in temporal associative processing.
Compaction dynamics during progenitor cell self-assembly reveal granular mechanics
Authors: Smeets Bart , Pešek Jiří , Deckers Thomas , Hall Gabriella Nilsson , Cuvelier Maxim , Ongenae Steven , Bloemen Veerle , Luyten Frank P , Papantoniou Ioannis , Ramon Herman
Published: July 2019

We study the self-assembly dynamics of human progenitor cells in agarose micro-wells that are used for production of chondrogenic organoids. Using image analysis on time-lapse microscopy, we estimate the aggregate area in function of time for a large number of aggregates. In control conditions, the aggregate radius follows an exponential relaxation that is consistent with the dewetting dynamics of a liquid film. Introducing Y-27632 Rho kinase inhibitor, the compatibility with the liquid model is lost, and slowed down relaxation dynamics are observed. We demonstrate that these aggregates behave as granular piles undergoing compaction, with a density relaxation that follows a stretched exponential. Using simulations with an individual cell-based model, we construct a phase diagram of cell aggregates that suggests that the aggregate in presence of Rho kinase inhibitor approaches the glass transition.
Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders – findings from a Danish population-based study
Authors: Liu Xueping , Nudel Ron , Thompson Wesley K. , Appadurai Vivek , Schork Andrew J. , Buil Alfonso , Rasmussen Simon , Allesøe Rosa L. , Werge Thomas , Mors Ole , Børglum Anders D. , Hougaard David M. , Mortensen Preben B. , Nordentoft Merete , Benros Michael E.
Published: July 2019

Background

Previous studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders.

Methods

We used diagnostic information for patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on two diseases. The genetic factors were investigated using GWAS and HLA imputation data based on iPSYCH cohort.

Results

Among 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1,383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two diseases (P=2.67×10-7, OR=1.38, 95%CI=1.22-1.56), with an overall bidirectional association wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR=1.13, 95%CI: 1.07-1.21, P=7.95×10-5) and vice versa (HR=1.27, 95%CI=1.16-1.39, P=8.77×10-15). Though PRSs were significantly correlated with both types of diagnosis, PRSs had little effect on the bidirectional relationship. Importantly, we for the first time observed 12 human leukocyte antigen (HLA) loci and 20 HLA alleles strongly associated with overall autoimmune diseases, but we did not find significant evidence of their associations with overall mental disorders.

Conclusions

Our findings confirm the overall comorbidity and bidirectionality between autoimmune and mental disorders and discover HLA genes which are significantly associated with overall autoimmune diseases, but not with overall mental disorders.
Effects of amotosalen treatment on human platelet lysate bioactivity
Authors: Christensen Christian , Jonsdottir-Buch Sandra Mjoll , Sigurjonsson Olafur Eysteinn
Published: July 2019

Background

Clinical application of mesenchymal stromal cells (MSCs) usually requires an in vitro expansion step to reach clinically relevant numbers. In vitro cell expansion necessitates supplementation of basal mammalian cell culture medium with growth factors. To avoid using supplements containing animal substances, human platelet lysates (hPL) produced from expired and pathogen inactivated platelet concentrates can be used in place of fetal bovine serum. Due to lack of experience and global diversity in bacterial detection strategies, most transfusion units are currently not pathogen inactivated. As blood banks are the sole source of platelet concentrates for hPL production, it is important to ensure product safety and standardized production methods. To achieve these aims, we assessed the quality of hPL produced from expired platelet concentrates with pathogen inactivation applied after platelet lysis, as well as its ability to support MSC proliferation and tri-lineage differentiation.

Methodology/principal findings

Bone marrow-derived MSCs (BM-MSCs) were expanded and differentiated using hPL derived from pathogen inactivated platelet lysates (hPL-PIPL), with pathogen inactivation applied after lysis of expired platelets. Results were compared to those using hPL produced from conventional expired pathogen inactivated human platelet concentrates (hPL-PIPC), with pathogen inactivation applied after soon after blood donation. hPL-PIPL treatment had lower concentrations of soluble growth factors and cytokines than hPL-PIPC treatment. When used as supplementation in cell culture, BM-MSCs proliferated at a reduced rate, but more consistently, in hPL-PIPL than in hPL-PIPC. The ability to support tri-lineage differentiation was comparable between lysates.

Conclusion/significance

These results suggest that functional hPL can be produced from expired and untreated platelet lysates by applying pathogen inactivation after platelet lysis. When carried out post-expiration, pathogen inactivation can provide a valuable tool to further standardize global hPL production methods, increase the pool of starting material, and meet the future demand for animal-free supplements in human cell culturing.
A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity
Authors: Ivy Autumn S. , Yu Tim , Kramár Enikö , Parievsky Sonia , Sohn Fred , Vu Thao
Published: July 2019

Aerobic exercise is a powerful modulator of learning and memory. Molecular mechanisms underlying the cognitive benefits of exercise are well documented in adult rodents. Animal models of exercise targeting specific postnatal periods of hippocampal development and plasticity are lacking. Here we characterize a model of early-life exercise (ELE) in male and female mice designed with the goal of identifying critical periods by which exercise may have a lasting impact on hippocampal memory and synaptic plasticity. Mice freely accessed a running wheel during three postnatal periods: the 4th postnatal week (juvenile ELE, P21-27), 6th postnatal week (adolescent ELE, P35-41), or 4th-6th postnatal weeks (juvenile-adolescent ELE, P21-41). All exercise groups significantly increased their running distances over time. When exposed to a weak learning stimulus, mice that had exercised during the juvenile period were able to form lasting long-term memory for a hippocampus-dependent spatial memory task. Electrophysiological experiments revealed enhanced long-term potentiation in hippocampal CA1 the juvenile-adolescent ELE group only. Furthermore, basal synaptic transmission was significantly increased in all mice that exercised during the juvenile period. Our results suggest early-life exercise can enable hippocampal memory, synaptic plasticity, and basal synaptic physiology when occurring during postnatal periods of hippocampal maturation.
Fossil amber reveals springtails’ longstanding dispersal by social insects
Authors: Ninon Robin , Cyrille D’haese , Phillip Barden
Published: July 2019

Dispersal is essential for terrestrial organisms living in disjunct habitats and constitutes a significant challenge for the evolution of wingless taxa. Springtails (Collembola), the sister-group of all insects (with dipluran), are reported since the Lower Devonian and thought to have originally been subterranean. The order Symphypleona is reported since the early Cretaceous with genera distributed on every continent, implying an ability to disperse over oceans although never reported in marine water contrary to other springtail orders. Despite being highly widespread, modern springtails are generally rarely reported in any kind of biotic association. Interestingly, the fossil record has provided occasional occurrences of Symphypleona attached by the antennae onto the bodies of larger arthropods. Here, we document the case of a ~16 Ma old fossil association: a winged termite and ant displaying not some, but 25 springtails attached or closely connected to the body. The collembola exhibit rare features for fossils, reflecting their courtship and phoretic behaviors. By observing the modes of attachment of springtails on different arthropods, the sex representation and ratios in springtail antennal anatomies in new and previously reported cases, we infer a likely mechanism for dispersal in Symphypleona. By revealing hidden evidence of modern springtail associations with other invertebrates such as ants and termites, new compelling assemblages of fossil springtails and the drastic increase of eusocial insects’ abundance over Cenozoic (ants/termites comprising more than the third of insects in Miocene amber), we stress that attachment with winged casts of ants and termites may have been a mechanism for the worldwide dispersal of this significant springtail lineage. Moreover, by comparing the general constraints applying to the other wingless soil-dwelling arthropods known to disperse through phoresy, we suggest biases in the collection and observation of phoretic Symphypleona related to their reflexive detachment and infer that this behavior continues today. The specific case of tree resin entrapment represents the (so far) only condition uncovering the actual dispersal mechanism of springtails - one of the oldest terrestrial arthropod lineages living today. Associations with soil-dwelling social insects over time would have been at the origin of this behavioural specialization.
RNA processing machineries in Archaea: the 5’-3’ exoribonuclease aRNase J of the β-CASP family is engaged specifically with the helicase ASH-Ski2 and the 3’-5’ exoribonucleolytic RNA exosome machinery
Authors: Phung Duy Khanh , Etienne Clarisse , Batista Manon , Langendijk-Genevaux Petra , Moalic Yann , Laurent Sébastien , Morales Violette , Jebbar Mohamed , Fichant Gwennaele , Bouvier Marie , Flament Didier , Clouet-d’Orval Béatrice
Published: July 2019

A network of RNA helicases, endoribonucleases, and exoribonucleases regulates the quantity and quality of cellular RNAs. To date, mechanistic studies focused on bacterial and eukaryal systems due to the challenge of identifying the main drivers of RNA decay and processing in Archaea. Here, our data support that aRNase J, a 5’-3’ exoribonuclease of the β-CASP family conserved in Euryarchaea, engages specifically with a Ski2-like helicase and the RNA exosome to potentially exert control over RNA surveillance, and that this occurs in the vicinity of the ribosome. Proteomic landscapes and direct protein-protein interaction analyses demonstrated that aRNase J interplay with ASH-Ski2 and the Csl4 cap exosome subunit. These in vitro data are strengthened by our phylogenomic studies showing a taxonomic co-distribution of aRNase J and ASH-Ski2 among the archaeal phylogeny. Finally, our T. barophilus whole-cell extract fractionation experiments provide evidences that an aRNase J/ASH-Ski2 complex might exist in vivo and hint at an association of aRNase J with the ribosome or polysomes that is stressed in absence of ASH-Ski2. While aRNase J homologues are found among bacteria, the RNA exosome and the Ski2-like RNA helicase have eukaryotic homologues, underlining the mosaic aspect of archaeal RNA machines. Altogether, these results suggest, for the first time, a fundamental role of β-CASP RNase/helicase complex in archaeal RNA metabolism. Finally, our results position aRNase J at the junction of RNA surveillance and translation processes, thus opening new perspectives and evolutionary scenario on RNA processing players in Archaea.
Hummingbird iridescence: an unsuspected structural diversity influences colouration at multiple scales
Authors: Gruson Hugo , Elias Marianne , Andraud Christine , Djediat Chakib , Berthier Serge , Doutrelant Claire , Gomez Doris
Published: July 2019

Abstract

Iridescent colours are colours that change depending on the angle of illumination or observation. They are produced when light is reflected by multilayer structures or diffracted by gratings. While this phenomenon is well understood for simple optical systems, it remains unclear how complex biological structures interact with light to produce iridescence. There are very few comparative studies at interspecific level (often focusing on a single colour patch for each species), resulting in an underestimation of structure diversity. Using an interdisciplinary approach combining physics and biology, we here quantify the colour and structure of 36 hummingbirds species evenly distributed across the phylogeny. We explore at least 2 patches per species, which are assumed to be under different selective regimes. For each patch, we measure structural features (number of layers, layer width, irregularity, spacing, etc.) of the feathers at different scales using both optical and electronic microscopy and we measure colour using a novel approach we developed to encompass the full complexity of iridescence, including its angular dependency. We discover an unsuspected diversity of structures producing iridescence in hummingbirds. We also study the effect of several structural features on the colour of the resulting signal, using both an empirical and modelling approach. Our findings demonstrate the need to take into account multiple patches per species and suggest possible evolutionary pressures causing the evolutionary transitions from one melanosome type to another.
Assembly of hundreds of novel bacterial genomes from the chicken caecum
Authors: Glendinning Laura , Stewart Robert D. , Pallen Mark J. , Watson Kellie A. , Watson Mick
Published: July 2019

Chickens are a highly important source of protein for a large proportion of the human population. The caecal microbiota plays a crucial role in chicken nutrition through the production of short chain fatty acids, nitrogen recycling and amino acid production. In this study we sequenced DNA from caecal contents samples taken from 24 chickens belonging to either a fast or slower growing breed consuming either a vegetable-only diet or a diet containing fish meal. We utilised 1.6T of Illumina data to construct 469 draft metagenome-assembled bacterial genomes, including 460 novel strains, 283 novel species and 42 novel genera. We compared our genomes to data from eight EU countries and show that these genomes are abundant within European chicken flocks. We also compared the abundance of our genomes, and the carbohydrate active enzymes they produce, between our chicken groups and demonstrate that there are both breed- and diet-specific microbiomes, as well as an overlapping core microbiome. This data will form the basis for future studies examining the composition and function of the chicken caecal microbiota.
Changes in interictal pretreatment and posttreatment EEG in childhood absence epilepsy
Authors: Glaba Pawel , Latka Miroslaw , Krause Małgorzata , Kuryło Marta , Jernajczyk Wojciech , Walas Wojciech , West Bruce J.
Published: July 2019

Spike and wave discharges (SWDs) are the characteristic manifestation of childhood absence epilepsy (CAE). It has long been believed that they unpredictably emerge from otherwise almost normal interictal EEG. Herein, we demonstrate that pretreatment closed-eyes theta and beta EEG wavelet powers of CAE patients (20 girls and 10 boys, mean age 7.4 ± 1.9 years) are much higher than those of age-matched controls at multiple sites of 10-20 system. For example, at C4 site, we observed a 91% and 62% increase in power of theta and beta rhythms, respectively. We were able to compare the baseline and posttreatment wavelet power in 16 patients. The pharmacotherapy brought about a statistically significant decrease in delta and theta wavelet power in all the channels, e.g. for C4 the reduction was equal to 45% (delta) and 65% (theta). We also observed a less pronounced attenuation of posttreatment beta rhythm in several channels. We hypothesize that the increased theta and beta powers result from cortical hyperexcitability and propensity for epileptic spikes generation, respectively. We argue that the distinct features of CAE wavelet power spectrum may be used to define an EEG biomarker which could be used for diagnosis and monitoring of patients.
A unified framework for geneset network analysis
Authors: Fanfani Viola , Stracquadanio Giovanni
Published: July 2019

Gene and protein interaction experiments provide unique opportunities to study their wiring in a cell. Integrating this information with high-throughput functional genomics data can help identifying networks associated with complex diseases and phenotypes.

Here we propose a unified statistical framework to test network properties of single and multiple genesets. We focused on testing whether a geneset exhibits network properties and if two genesets are strongly interacting with each other.

We then assessed power and false discovery rate of the proposed tests, showing that tests based on a probabilistic model of gene and protein interaction are the most robust.

We implemented our tests in an open-source framework, called Python Geneset Network Analysis (PyGNA), which provides an integrated environment for network studies. While most available tools are designed as web applications, we designed PyGNA to be easily integrated into existing high-performance data analysis pipelines.

Our software is available on GitHub (http://github.com/stracquadaniolab/pygna) and can be easily installed from PyPi or anaconda.
Nucleosome scaffolding by Brd4 tandem bromodomains in acetylation-dependent chromatin compartmentalization
Authors: Olp Michael D. , Jackson Vaughn , Smith Brian C.
Published: July 2019

Bromodomain binding of acetyl-lysine residues is a crucial step in many epigenetic mechanisms governing transcription. Nearly half of human bromodomains exist in tandem with at least one other bromodomain on a single protein. The Bromodomain and ExtraTerminal domain (BET) familyof proteins (BrdT, Brd2, Brd3 and Brd4) each encode two bromodomains at theirN-termini and are important regulators of acetylation-dependent transcription in homeostasis and disease. Previous efforts have focused on identifying protein acetylation sites bound by individual bromodomains. However, the mechanisms through which tandem bromodomains act cooperatively on chromatin are largely unknown. Here, we first used small angle x-ray scattering combined with Rosettaab initiomodeling to explore conformational space available to BET tandem bromodomains. For Brd4, the flexible tandem bromodomain linker allows for distances between the two acetyl-lysine binding sites ranging from 15 to 157 Å. Using a bioluminescence resonance energy transfer assay, we show a clear distance dependence for Brd4 tandem bromodomain bivalent binding of multiply acetylated histone H4 peptides. However, isothermal titration calorimetry studies revealed Brd4 binding affinity toward multiply acetylated peptides does not correlate with the potential for bivalent binding. We used sucrose gradient assays to provide direct evidencein vitrothat Brd4 tandem bromodomains can simultaneously bind and scaffold multiple acetylated nucleosomes. Intriguingly, our bioinformatic analysis of deposited chromatin immunoprecipitation sequencing data indicates that Brd4 colocalizes with subsets of histone acetyl-lysine sites across transcriptionally active chromatin compartments. These findings support our hypothesis that scaffolding of acetylated nucleosomes by Brd4 tandem bromodomains contributes to higher-order chromatin architecture.
Resolving the connectome – Spectrally-specific functional connectivity networks and their distinct contributions to behaviour
Authors: Becker Robert , Hervais-Adelman Alexis
Published: July 2019

The resting brain exhibits spontaneous patterns of activity that reflect features of the underlying neural substrate. Examination of inter-areal coupling of resting state oscillatory activity has revealed that the brain’s resting activity is composed of functional networks, whose topographies differ depending upon oscillatory frequency, suggesting a role for carrier frequency as a means of creating multiplexed, or functionally segregated, communication channels between brain areas. Using canonical correlation analysis, we examined spectrally resolved resting-state connectivity patterns derived from MEG recordings to determine the relationship between connectivity intrinsic to different frequency channels and a battery of over a hundred behavioural and demographic indicators, in a group of 89 young healthy participants. We demonstrate that each of the classical frequency bands in the range 1-40Hz (delta, theta, alpha, beta and gamma) delineates a subnetwork that is behaviourally relevant, spatially distinct, and whose expression is either negatively or positively predictive of individual traits, with the strongest link in the alpha band being negative and networks oscillating at different frequencies, such as theta, beta and gamma carrying positive function.
Hierarchical and dynamic regulation of defense-responsive specialized metabolism by WRKY and MYB transcription factors
Authors: Barco Brenden , Clay Nicole K.
Published: July 2019

The plant kingdom produces hundreds of thousands of specialized bioactive metabolites, some with pharmaceutical and biotechnological importance. Their biosynthesis and function have been studied for decades, but comparatively less is known about how transcription factors with overlapping functions and contrasting regulatory activities coordinately control the dynamics and output of plant specialized metabolism. Here, we performed temporal studies on pathogen-infected intact host plants with perturbed transcription factors. We identified WRKY33 as the condition-dependent master regulator and MYB51 as the dual functional regulator in a hierarchical gene network likely responsible for the gene expression dynamics and metabolic fluxes in the camalexin and 4-hydroxy-indole-3-carbonylnitrile (4OH-ICN) pathways. This network may have also facilitated the regulatory capture of the newly evolved 4OH-ICN pathway in Arabidopsis thaliana by the more-conserved transcription factor MYB51. It has long been held that the plasticity of plant specialized metabolism and the canalization of development (Waddington, 1942) should be differently regulated; our findings imply a common hierarchical regulatory architecture orchestrated by transcription factors for specialized metabolism and development, making it an attractive target for metabolic engineering.
The heterogeneous functional architecture of the posteromedial cortex is associated with selective functional connectivity differences in Alzheimer’s disease
Authors: Khan Wasim , Amad Ali , Giampietro Vincent , Werden Emilio , De Simoni Sara , O’Muircheartaigh Jonathan , Westman Eric , O’Daly Owen , Williams Steve C.R. , Brodtmann Amy
Published: July 2019

The posteromedial cortex (PMC) is a key region involved in the development and progression of Alzheimer’s disease (AD). Previous studies have demonstrated a heterogenous functional architecture of the region, with different subdivisions reflecting distinct connectivity profiles. However, little is understood about PMC functional connectivity and its differential vulnerability to AD pathogenesis. Using a data-driven approach, we applied a constrained independent component analysis (ICA) on healthy adults from the Human Connectome Project (HCP) to characterise the distinct functional subdivisions and unique functional-anatomic connectivity patterns of the PMC. These connectivity profiles were subsequently quantified in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, to examine functional connectivity differences in (1) AD patients and cognitively normal (CN) participants and (2) the entire AD pathological spectrum, ranging from CN participants and participants with subjective memory complaints (SMC), through to those with mild cognitive impairment (MCI), and finally, patients diagnosed with AD. Our findings revealed decreased functional connectivity in the anterior precuneus, dorsal posterior cingulate cortex, and the central precuneus in AD patients compared to CN participants. Functional abnormalities in these subdivisions were also related to high amyloid burden and lower hippocampal volumes. Across the entire AD spectrum, functional connectivity of the central precuneus was associated with disease progression and specific deficits in memory and executive function. These findings provide new evidence showing that specific vulnerabilities in PMC functional connectivity are associated with large-scale network disruptions in AD and that these patterns may be useful for elucidating potential biomarkers for measuring disease progression in future work.
Nitric Oxide Mediates Neuro-Glial Interaction that Shapes Drosophila Circadian Behavior
Authors: Kozlov Anatoly , Nagoshi Emi
Published: July 2019

Drosophila circadian behavior relies on the network of heterogeneous groups of clock neurons. Short -and long-range signaling within the pacemaker circuit coordinates molecular and neural rhythms of clock neurons to generate coherent behavioral output. The neurochemistry of circadian behavior is complex and remains incompletely understood. Here we demonstrate that the gaseous messenger nitric oxide (NO) is a signaling molecule linking circadian pacemaker to rhythmic locomotor activity. We show that two independent mutants lacking nitric oxide synthase (NOS) have severely disturbed locomotor behavior both in light-dark cycles and constant darkness, although molecular clocks in the main pacemaker neurons are unaffected. Behavioral phenotypes are due in part to the malformation of neurites of the main pacemaker neurons, s-LNvs. Using cell-type selective and stage-specific gain -and loss-of-function of NOS, we demonstrate that NO secreted from diverse cellular clusters non-cell-autonomously affect molecular and behavioral rhythms. We further identify glia as a major source of NO that regulates circadian locomotor output. These results reveal for the first time the critical role of NO signaling in the Drosophila circadian system and highlight the importance of neuro-glial interaction in the neural circuit output.

Author summary

Circadian rhythms are daily cycles of physiological and behavioral processes found in most plants and animals on our planet from cyanobacteria to humans. Circadian rhythms allow organisms to anticipate routine daily and annual changes of environmental conditions and efficiently adapt to them. Fruit fly Drosophila melanogaster is an excellent model to study this phenomenon, as its versatile toolkit enables the study of genetic, molecular and neuronal mechanisms of rhythm generation. Here we report for the first time that gasotransmitter nitric oxide (NO) has a broad, multi-faceted impact on Drosophila circadian rhythms, which takes place both during the development and the adulthood. We also show that one of the important contributors of NO to circadian rhythms are glial cells. The second finding highlights that circadian rhythms of higher organisms are not simply controlled by the small number of pacemaker neurons but are generated by the system that consists of many different players, including glia.
A predictive model of intercellular tension and cell-matrix mechanical interactions in a multicellular geometry
Authors: Scott Lewis E. , Griggs Lauren A. , Narayanan Vani , Conway Daniel E. , Lemmon Christopher A. , Weinberg Seth H.
Published: July 2019

Epithelial cells form continuous sheets of cells that exist in tensional homeostasis. Homeostasis is maintained through cell-to-cell adhesions that distribute tension and balance forces between cells and their underlying matrix. Disruption of tensional homeostasis can lead to Epithelial-Mesenchymal Transition (EMT), which is a transdifferentiation process in which epithelial cells adopt a mesenchymal phenotype, where cell-cell adhesion is lost and individual cell migration is acquired. This process is critical during embryogenesis and wound healing, but is also dysregulated in many disease states. To further understand the role of intercellular tension in spatial patterning of epithelial cell monolayers, we developed a multicellular computational model of cell-cell and cell-substrate forces. This work builds on a hybrid Cellular Potts-finite element model to evaluate cell-matrix mechanical feedback of an adherent multicellular cluster. Thermodynamically-constrained cells migrate by generating traction forces on a finite element substrate to minimize the total energy of the system. Junctional forces at cell-cell contacts balance these traction forces, thereby producing a mechanically stable epithelial monolayer. Simulations were compared to in vitro experiments using fluorescence-based junction force sensors in clusters of cells undergoing EMT. Results indicate that the multicellular CPM model can reproduce many aspects of EMT, including epithelial monolayer formation dynamics, changes in cell geometry, and spatial patterning of cell geometry and cell-cell forces in an epithelial colony.

Author summary

Epithelial cells line all organs of the human body and act as a protective barrier by forming a continuous sheet. These cells exert force on both their neighboring cells as well as the underlying extracellular matrix, which is a network of proteins that creates the structure of tissues. Here we develop a model that encompasses both cell-cell forces and cell-matrix forces in an epithelial cell sheet. The model accounts for cell migration and proliferation, and regulates how cell-cell adhesions are formed. We demonstrate how the interplay between cell-cell forces and cell-matrix forces can regulate the formation of the epithelial cell sheet, the organization of cells within the sheet, and the pattern of cell geometries and cell forces within the sheet. We compare computational results with experiments in which epithelial cell sheets are disrupted and cell-cell junction forces are measured, and demonstrate that the model captures many aspects of epithelial cell dynamics observed experimentally.
Assessing the performance of genome-wide association studies for predicting disease risk
Authors: Patron Jonas , Serra-Cayuela Arnau , Han Beomsoo , Li Carin , Wishart David Scott
Published: July 2019

To date more than 3700 genome-wide association studies (GWAS) have been published that look at the genetic contributions of single nucleotide polymorphisms (SNPs) to human conditions or human phenotypes. Through these studies many highly significant SNPs have been identified for hundreds of diseases or medical conditions. However, the extent to which GWAS-identified SNPs or combinations of SNP biomarkers can predict disease risk is not well known. One of the most commonly used approaches to assess the performance of predictive biomarkers is to determine the area under the receiver-operator characteristic curve (AUROC). We have developed an R package called G-WIZ to generate ROC curves and calculate the AUROC using summary-level GWAS data. We first tested the performance of G-WIZ by using AUROC values derived from patient-level SNP data, as well as literature-reported AUROC values. We found that G-WIZ predicts the AUROC with <3% error. Next, we used the summary level GWAS data from GWAS Central to determine the ROC curves and AUROC values for 569 different GWA studies spanning 219 different conditions. Using these data we found a small number of GWA studies with SNP-derived risk predictors that have very high AUROCs (>0.75). On the other hand, the average GWA study produces a multi-SNP risk predictor with an AUROC of 0.55. Detailed AUROC comparisons indicate that most SNP-derived risk predictions are not as good as clinically based disease risk predictors. All our calculations (ROC curves, AUROCs, explained heritability) are in a publicly accessible database called GWAS-ROCS (http://gwasrocs.ca). The G-WIZ code is freely available for download athttps://github.com/jonaspatronjp/GWIZ-Rscript/.
The methodological quality of animal studies: A cross-sectional study based on the SYRCLE’s risk of bias tool
Authors: Zhang Weiyi , Jiang Yanbiao , Shang Zhizhong , Zhang Nan , Tao Gongcai , Zhang Ting , Hu Kaiyan , Li Yanfei , Shi Xiue , Zhang Yanying , Yang Jiao , Ma Bin , Yang Kehu
Published: July 2019

Objective

To assess the methodological quality of animal studies published in China and abroad using the SYRCLE’s risk of bias tool, and to provide references to improve the methodological quality of animal studies to encourage high quality preclinical studies.

Methods

An electronic search was performed in the Chinese Scientific Citation Database (CSCD) and Web of Science from 2014 to October 2018. Document screening and data extraction were performed independently by four researchers. The methodological quality of the included studies was assessed using the SYRCLE’s risk of bias tool. Statistical analysis was performed using SPSS23.

Results

A total of 2764 animal studies were included. Of the studies, 984 were published in English and 1780 were in Chinese. The citation frequency of more than 90% of the included studies was less than 5. The results of methodological quality assessment showed that 36.36% (8/22) of the sub-items were rated as “low risk” in more than 50% of the included studies, of which 75% (6/8) were rated as “low risk” in more than 80% of the included studies. A total of 59.09% (13/22) of the sub-items were rated as “low risk” in less than 30% of the included studies, of which 92.31% (12/13) were rated as “low risk” in less than 10% of the included studies. The incidence of “low risk” Chinese studies regarding performance bias, detection bias and reporting bias were lower than English studies. For foreign studies, more attention should be paid to selection bias, attrition bias, and reporting bias.

Conclusion

We identified limitations in the methodological quality of animal experiment studies published in China and abroad. We therefore suggest that it is necessary to take targeted measures to popularize the SYRCLE’s risk of bias tool to effectively improve the design and implementation of animal experiments, and guide study development.
Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review
Authors: Lopes dos Santos Igor , Greick Batista Dias Penna Karlla , Aparecida dos Santos Carneiro Megmar , Silva Dalla Libera Larisse , Enocencio Porto Ramos Jéssica , Aparecida Saddi Vera
Published: July 2019

Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. However, only a few systematic reviews emphasize the most relevant miRs able to contribute to the establishment of new prognostic biomarkers in CRC patients. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 102 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the miRs in order to use them in clinical practice.