bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mediator CDK8-Cyclin C complex modulates vein patterning inDrosophilaby stimulating Mad-dependent transcription
Authors: Li Xiao , Liu Mengmeng , Ren Xingjie , Loncle Nicolas , Wang Qun , Hemba-Waduge Rajitha-Udakara-Sampath , Boube Muriel , Bourbon Henri-Marc G. , Ni Jian-Quan , Ji Jun-Yuan
Published: July 2018

Dysregulations of CDK8 and its regulatory partner CycC, two subunits of the conserved Mediator complex, have been linked to diverse human diseases such as cancer, thus it is essential to understand the regulatory network mobilizing the CDK8-CycC complex in both normal development and tumorigenesis. To identify upstream regulators or downstream effectors of CDK8, we performed a dominant modifier genetic screen inDrosophilabased on the defects in vein patterning caused by specific depletion or overexpression of CDK8 or CycC in wing imaginal discs. We identified 26 genomic loci whose haploinsufficiency can modify these CDK8-specific phenotypes. Further analysis of two deficiency lines and mutant alleles led us to identify interactions between CDK8-CycC and the components of the Decapentaplegic (Dpp, theDrosophilahomolog of TGFβ) signaling pathway. We observed that CDK8-CycC positively regulates transcription activated by Mad (Mothers against dpp), the primary transcription factor downstream of the Dpp/TGFβ signaling pathway. CDK8 can directly interact with Madin vitrothrough the linker region between the DNA-binding MH1 (Mad homology 1) domain and the carboxy terminal MH2 transactivation domain. Besides CDK8 and CycC, further analyses of other subunits of the Mediator complex have revealed six additional Mediator subunits that are required for Mad-dependent transcription in the wing discs, including Med12, Med13, Med15, Med23, Med24, and Med31. Furthermore, CDK9 and Yorkie also positively regulate Mad-dependent gene expressionin vivo. These results suggest that the Mediator complex may coordinate with other transcription cofactors in regulating Mad-dependent transcription during the wing vein patterning inDrosophila.

Significance

CDK8 is a conserved subunit of the transcription cofactor Mediator complex that bridges transcription factors with RNA Polymerase II in eukaryotes. Here we explore the role of CDK8 inDrosophilaby performing a dominant modifier genetic screen based on vein patterning defects caused by alteration of CDK8-specific activities. We show that components of the Dpp/TGFβ signaling pathway genetically interact with CDK8; CDK8 positively regulates gene expression activated by Mad, the key transcription factor downstream of Dpp/TGFβ signaling, by directly interacting with the linker region of Mad protein. Given the fundamental roles of Dpp/TGFβ signaling in regulating development and its misregulation in various diseases, understanding how Mad/Smad interacts the Mediator complex may have broad implications in understanding and treating these diseases.
Environmentally-induced epigenetic conversion of a piRNA cluster
Authors: Casier Karine , Delmarre Valérie , Gueguen Nathalie , Hermant Catherine , Viodé Elise , Vaury Chantal , Ronsseray Stéphane , Brasset Emilie , Teysset Laure , Boivin Antoine
Published: July 2018

Transposable element (TE) activity is repressed in animal gonads by PIWI-interacting RNAs (piRNAs), a class of small RNAs produced by specific loci made of TEs insertions and fragments. Current models propose that these loci are functionally defined by the maternal inheritance of piRNAs produced during the previous generation, raising the question of their first activation in the absence of piRNAs. Taking advantage of an inactive cluster ofP-element derived transgene insertions, we show here that raising flies at high temperature (29°C) instead of 25°C results in a rare but invasive epigenetic conversion of this locus into an active piRNAs producing one. The newly acquired epigenetic state is stable over many generations even when flies are switch back to 25°C. The silencing capacities, piRNA production and chromatin modifications of the cluster are all identical whether conversion occurred by maternal piRNA inheritance or by high temperature. We also demonstrate that in addition to high temperature, a single homologous transgene inserted elsewhere in the genome is required to activate the locus. We thus have identified a minimal system of three components to create a stable piRNA producing locus: 1) a locus with multiple TE derived sequences; 2) an euchromatic copy of these sequences and 3) elevated temperature. Altogether, these data report the first case of the establishment of an active piRNA cluster by environmental changes. It highlights how such variations of species natural habitat can become heritable and shape their epigenome.

SIGNIFICANCE STATEMENT

Recently, we have witnessed great progress in our understanding of the silencing of Transposable Elements (TEs) by piRNAs, a class of small RNAs produced by piRNA clusters. At each generation, piRNA clusters are supposed to be activated by homologous piRNAs inherited from the mother raising the question of the making of the first piRNAs. Here, we report the birth of a stable and functional piRNA cluster induced by high temperature without maternal inheritance of homologous piRNAs. We propose a minimal system to create a piRNA cluster: a sufficient number of repeated sequences, a euchromatic copy of these sequences and an increase in the production of antisense RNA.
Computational modeling of social face perception in humans: Leveraging the active appearance model
Authors: Guan Jinyan , Ryali Chaitanya K. , Yu Angela J.
Published: July 2018

Face processing plays a central role in human social life. Humans readily infer social traits (e.g. attractiveness and trustworthiness) from a stranger’s face. Previous attempts to characterize the facial (physiognomic) features underlying social processing have lacked either systematicity or interpretability. Here, we utilize a statistical framework to tackle this problem, by learning a vector space to represent faces, and a linear mapping from this face space into human social trait judgments. Specifically, we obtain a face space by training the Active Appearance Model on large datasets of face images. Based on human evaluations of numerous social traits on these images, we then use regression to find linear combinations of facial features (what we call Linear Trait Axis, or LTA) that best predict human social judgments. Our model achieves state-of-the-art performance in overall predictive accuracy – comparable to the best convolutional neural network and better than human prediction of other human ratings. To interpret the LTAs, we regress them against a large repertoire of geometric features. To understand the relationship between the facial features that underlie different social, emotional, and demographic traits, we present a novel “dual space analysis” that characterizes the geometric relationship among LTA vectors. It shows that facial features important for social trait perception are largely distinct from those underlying demographic and emotion perception, contrary to previous suggestions that social trait perception is driven by over-generalization of relatively primitive demographic and emotion perception processes. In addition, we present a novel correlation decomposition analysis that quantifies how correlations in trait judgments (e.g. between attractiveness and babyfacedness) independently arise from (1) shared facial features among traits, and (2) correlation in the distribution of facial features in the human population.
Mango: Distributed Visualization for Genomic Analysis
Authors: Morrow Alyssa Kramer , He George Zhixuan , Nothaft Frank Austin , Tu Eric Tongching , Paschall Justin , Yosef Nir , Joseph Anthony D.
Published: July 2018

The decreasing cost of DNA sequencing over the past decade has led to an explosion of available sequencing datasets, leaving us with terabytes to petabytes of data to explore and analyze. It is critical for analysts in research and clinical settings to be able to develop new data-driven hypotheses from these datasets through bias identification, analysis of data quality, and testing different algorithms and parameter settings. However, current interactive tools for sequence analysis are designed to run on single machines that do not scale to the size of modern genomic datasets, and rely on precomputed static views, rather than allowing direct interaction with the primary dataset. Mango is a genomic sequence visualization and analysis platform that removes these constraints regarding scalability and staticity by leveraging the power of multi-node compute clusters in the cloud to allow interactive analysis over terabytes of sequencing data. Mango provides both a genome browser graphical user interface and programmable notebook form factor to allow users of varying analytical experience to explore large sequencing datasets on both private clusters and in the cloud. These tools provide a flexible environment for interactive exploration of genomic datasets, while surpassing the computational limits of single-node genomic visualization tools.
Evaluating Named-Entity Recognition approaches in plant molecular biology
Authors: Do Huy , Than Khoat , Larmande Pierre
Published: July 2018

Text mining research is becoming an important topic in biology with the aim to extract biological entities from scientific papers in order to extend the biological knowledge. However, few thorough studies on text mining and applications are developed for plant molecular biology data, especially rice, thus resulting a lack of datasets available to train models able to detect entities such as genes, proteins and phenotypic traits. Since there is rare benchmarks for rice, we have to face various difficulties in exploiting advanced machine learning methods for accurate analysis of rice bibliography. In this article, we developed a new training datasets (Oryzabase) as the benchmark. Then, we evaluated the performance of several current approaches to find a methodology with the best results and assigned it as the state of the art method for our own technique in the future. We applied Name Entities Recognition (NER) tagger, which is built from a Long Short Term Memory (LSTM) model, and combined with Conditional Random Fields (CRFs) to extract information of rice genes and proteins. We analyzed the performance of LSTM-CRF when applying to the Oryzabase dataset and improved the results up to 86% in F1. We found that on average, the result from LSTM-CRF is more exploitable with the new benchmark.
Astrocytes amplify neuronal dendritic volume transmission
Authors: Chen Chun , Jiang ZhiYing , Fu Xin , Tasker Jeffrey G.
Published: July 2018

In addition to their support role in neurotransmitter and ion buffering, astrocytes directly regulate neurotransmission at synapses via local bidirectional signaling with neurons. Here, we reveal a new form of neuronal-astrocytic signaling that transmits retrograde dendritic signals to upstream neurons to activate recurrent synaptic circuits. Norepinephrine activates α1-adrenoreceptors in hypothalamic corticotropin releasing factor (CRF) neurons to stimulate dendritic release, which triggers an astrocytic calcium response and release of ATP; ATP stimulates action potentials in upstream glutamate and GABA neurons to activate recurrent excitatory and inhibitory synaptic circuits to the CRF neurons. Thus, norepinephrine activates a novel retrograde signaling mechanism in CRF neurons that engages astrocytes in order to extend dendritic volume transmission to reach distal presynaptic glutamate and GABA neurons, thereby amplifying volume transmission mediated by dendritic release.
Feedback-mediated signal conversion promotes viral fitness
Authors: Vardi Noam , Chaturvedi Sonali , Weinberger Leor S.
Published: July 2018

A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using trans-activators packaged in the tegument of the infecting virion particle. But, the activity of these tegument trans-activators is inherently transient—they undergo immediate proteolysis but delayed synthesis—and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear. By constructing a two-color, conditional-feedback HCMV mutant, we find that positive feedback in HCMV’s Immediate Early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain expression despite transient activation signals—akin to early electronic transistors—and expose a potential target for therapeutic intervention.
Profiling the genome-wide landscape of tandem repeat expansions
Authors: Mousavi Nima , Shleizer-Burko Sharona , Yanicky Richard , Gymrek Melissa
Published: July 2018

Tandem Repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington’s Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-generation sequencing (NGS) datasets and are not profiled by existing genome-wide tools. We present GangSTR, a novel algorithm for genome-wide genotyping of both short and expanded TRs. GangSTR extracts information from paired-end reads into a unified model to estimate maximum likelihood TR lengths. We validate GangSTR on real and simulated data and show that GangSTR outperforms alternative methods in both accuracy and speed. We apply GangSTR to a deeply sequenced trio to profile the landscape of TR expansions in a healthy family and validate novel expansions using orthogonal technologies. Our analysis reveals that healthy individuals harbor dozens of long TR alleles not captured by current genome-wide methods. GangSTR will likely enable discovery of novel disease-associated variants not currently accessible from NGS.
Temporal expectations modulate face image repetition suppression as indexed by event-related potentials
Authors: Feuerriegel Daniel , Churches Owen , Coussens Scott , Keage Hannah A.D.
Published: July 2018

Repeated exposure to a stimulus leads to reduced responses of stimulus-selective sensory neurons, an effect known as repetition suppression or stimulus-specific adaptation. Several influential models have been proposed to explain repetition suppression within hierarchically-organised sensory systems, with each specifying different mechanisms underlying repetition effects. We manipulated temporal expectations within a face repetition experiment to test a critical prediction of the predictive coding model of repetition suppression: that repetition effects will be larger following stimuli that appear at expected times compared to stimuli that appear at unexpected times. We recorded event-related potentials from 18 participants and mapped the spatiotemporal progression of repetition effects using mass univariate analyses. We then assessed whether the magnitudes of observed face image repetition effects were influenced by temporal expectations. In each trial participants saw an adapter face, followed by a 500ms or 1000ms interstimulus interval (ISI), and then a test face, which was the same or a different face identity to the adapter. Participants’ expectations for whether the test face would appear after a 500ms ISI were cued by the sex of the adapter face. Our analyses revealed multiple repetition effects with distinct scalp topographies, extending until at least 800ms from stimulus onset. An early (158-203ms) repetition effect was larger for stimuli following surprising, rather than expected, 500ms ISI durations, contrary to the model predictions of the predictive coding model of repetition suppression. Later (230-609ms) repetition effects tended to be larger following expected stimulus onset times, in line with predictive coding models. Our results indicate that the relationship between repetition suppression and temporal expectation differs across the time course of the stimulus-evoked response, suggesting multiple distinct mechanisms driving repetition suppression that operate at different latencies within the visual hierarchy.

Highlights

- Multiple face image repetition effects identified from 162-800ms post stimulus onset

- Temporal expectations influenced the magnitudes of repetition effects

- Temporal expectation effects differed for early and late stimulus-evoked responses
Pyramids and cascades: a synthesis of food chain functioning and stability
Authors: Barbier Matthieu , Loreau Michel
Published: July 2018

Food chain theory is one of the cornerstones of ecology, providing many of its basic predictions, such as biomass pyramids, trophic cascades and predator-prey oscillations. Yet, ninety years into this theory, the conditions under which these patterns may occur and persist in nature remain subject to debate. Rather than address each pattern in isolation, we propose that they must be understood together, calling for synthesis in a fragmented landscape of theoretical and empirical results. As a first step, we propose a minimal theory that combines the long-standing energetic and dynamical approaches of food chains. We chart theoretical predictions on a concise map, where two main regimes emerge: across various functioning and stability metrics, one regime is characterized by pyramidal patterns, the other by cascade patterns. The axes of this map combine key physiological and ecological variables, such as metabolic rates and self-regulation. A quantitative comparison with data sheds light on conflicting theoretical predictions and empirical puzzles, from size spectra to causes of trophic cascade strength. We conclude that drawing systematic connections between various existing approaches to food chains, and between their predictions on functioning and stability, is a crucial step in confronting this theory to real ecosystems.
Embodied precision: Intranasal oxytocin modulates multisensory integration
Authors: Crucianelli Laura , Paloyelis Yannis , Ricciardi Lucia , Jenkinson Paul M , Fotopoulou Aikaterini
Published: July 2018

Multisensory integration processes are fundamental to our sense of self as embodied beings. Bodily illusions, such as the rubber hand illusion (RHI) and the size-weight illusion (SWI), allow us to investigate how the brain resolves conflicting multisensory evidence during perceptual inference in relation to different facets of body representation. In the RHI, synchronous tactile stimulation of a participant’s hidden hand and a visible rubber hand creates illusory bodily ownership; in the SWI, the perceived size of the body can modulate the estimated weight of external objects. According to Bayesian models, such illusions arise as an attempt to explain the causes of multisensory perception and may reflect the attenuation of somatosensory precision, which is required to resolve perceptual hypotheses about conflicting multisensory input. Recent hypotheses propose that the precision or salience of sensorimotor representations is determined by modulators of synaptic gain, like dopamine, acetylcholine and oxytocin. However, these neuromodulatory hypotheses have not been tested in the context of embodied multisensory integration. The present, double-blind, placebo-controlled, crossed-over study (N = 41 healthy volunteers) aimed to investigate the effect of intranasal oxytocin (IN-OT) on multisensory integration processes, tested by means of the RHI and the SWI. Results showed that IN-OT enhanced the subjective feeling of ownership in the RHI, only when synchronous tactile stimulation was involved. Furthermore, IN-OT increased the embodied version of the SWI (quantified as weight estimation error). These findings suggest that oxytocin might modulate processes of visuo-tactile multisensory integration by increasing the precision of top-down signals against bottom-up sensory input.
Duplications and functional specialization force distinct evolution of isoflavonoid biosynthetic genes in legumes
Authors: Jiao Yin Shan , Zhao Yu , Chen Wen Feng
Published: July 2018

Isoflavonoids are specialized plant metabolites, almost exclusive to legumes, and synthesized by the phenylpropanoid pathway. Leguminous plants produce 5-deoxyflavonoids and 5-deoxyisoflavonoids that act in symbiosis with nitrogen-fixing bacteria and involved in plant pathogen and stress response. However, little is known about evolutional origin of legume-specific isoflavonoid biosynthesis pathway. Here, we explored the genome-wide analysis of key genes: chalcone synthase (CHS), chalcone reductase (CHR), isoflavone synthase (IFS) and isoflavone reductase (IFR), encoding enzymes involved in the biosynthesis of (iso) flavonoids in legumes and nonlegumes. Among them,CHS,CHRandIFRcomprise multigene families, underling the significant role of gene duplication in the evolutionary. Most duplications ofCHSwere highly the conventional leguminous type, whereas some were grouped with nonleguminousCHSgenes. We also found thatCHRhomologs in soybean andSesbania rostratapreviously reported were ambiguous and should be re-identified. Phylogenetic analysis and protein sequences alignment indicated that IFSs in legumes are highly conserved. Intriguingly, unlike other IFRs in legumes, IFR-like homologs inSophora flavescensandLupinusangustifolius shared high sequence similarity and protein structures with homologs in nonlegumes. Overall, these results offer reasonable gene annotations and comparative analysis and also provided a glimpse into evolutional route of legume-specific isoflavonoid biosynthesis.

Highlight

Isoflavonoids are specialized plant metabolites, almost exclusive to legumes. We firstly provide evidence that evolutional origin of legume-specific isoflavonoid biosynthesis may be driven by gene duplications and functional specialization.
Neural oligarchy: how synaptic plasticity breeds neurons with extreme influence
Authors: Kleberg Florence I. , Triesch Jochen
Published: July 2018

Synapses between cortical neurons are subject to constant modifications through synaptic plasticity mechanisms, which are believed to underlie learning and memory formation. The strengths of excitatory and inhibitory synapses in the cortex follow a right-skewed long-tailed distribution. Similarly, the firing rates of excitatory and inhibitory neurons also follow a right-skewed long-tailed distribution. How these distributions come about and how they maintain their shape over time is currently not well understood. Here we propose a spiking neural network model that explains the origin of these distributions as a consequence of the interaction of spike-timing dependent plasticity (STDP) of excitatory and inhibitory synapses and a multiplicative form of synaptic normalisation. Specifically, we show that the combination of additive STDP and multiplicative normalisation leads to lognormal-like distributions of excitatory and inhibitory synaptic efficacies as observed experimentally. The shape of these distributions remains stable even if spontaneous fluctuations of synaptic efficacies are added. In the same network, lognormal-like distributions of the firing rates of excitatory and inhibitory neurons result from small variability in the spiking thresholds of individual neurons. Interestingly, we find that variation in firing rates is strongly coupled to variation in synaptic efficacies: neurons with the highest firing rates develop very strong connections onto other neurons. Finally, we define an impact measure for individual neurons and demonstrate the existence of a small group of neurons with an exceptionally strong impact on the network, that arise as a result of synaptic plasticity. In summary, synaptic plasticity and small variability in neuronal parameters underlie a neural oligarchy in recurrent neural networks.

Author summary

Our brain’s neural networks are composed of billions of neurons that exchange signals via trillions of synapses. Are these neurons created equal, or do they contribute in similar ways to the network dynamics? Or do some neurons wield much more power than others? Recent experiments have shown that some neurons are much more active than the average neuron and that some synaptic connections are much stronger than the average synaptic connection. However, it is still unclear how these properties come about in the brain. Here we present a neural network model that explains these findings as a result of the interaction of synaptic plasticity mechanisms that modify synapses’ efficacies. The model reproduces recent findings on the statistics of neuronal firing rates and synaptic efficacies and predicts a small class of neurons with exceptionally high impact on the network dynamics. Such neurons may play a key role in brain disorders such as epilepsy.
Powerful Gene Set Analysis in GWAS with the Generalized Berk-Jones Statistic
Authors: Sun Ryan , Hui Shirley , Bader Gary D. , Lin Xihong , Kraft Peter
Published: July 2018

A common complementary strategy in Genome-Wide Association Studies (GWAS) is to perform Gene Set Analysis (GSA), which tests for the association between one phenotype of interest and an entire set of Single Nucleotide Polymorphisms (SNPs) residing in selected genes. While there exist many tools for performing GSA, popular methods often include a number of ad-hoc steps that are difficult to justify statistically, provide complicated interpretations based on permutation inference, and demonstrate poor operating characteristics. Additionally, the lack of gold standard gene set lists can produce misleading results and create difficulties in comparing analyses even across the same phenotype. We introduce the Generalized Berk-Jones (GBJ) statistic for GSA, a permutation-free parametric framework that offers asymptotic power guarantees in certain set-based testing settings. To adjust for confounding introduced by different gene set lists, we further develop a GBJ step-down inference technique that can discriminate between gene sets driven to significance by single genes and those demonstrating group-level effects. We compare GBJ to popular alternatives through simulation and re-analysis of summary statistics from a large breast cancer GWAS, and we show how GBJ can increase power by incorporating information from multiple signals in the same gene. In addition, we illustrate how breast cancer pathway analysis can be confounded by the frequency of FGFR2 in pathway lists. Our approach is further validated on two other datasets of summary statistics generated from GWAS of height and schizophrenia.
The effect of silencing immunity related genes on longevity in the naturally occurring Anopheles arabiensis mosquito population of Southwest Ethiopia
Authors: Debalke Serkadis , Habtewold Tibebu , Duchateau Luc , Christophides George K.
Published: July 2018

Background

In the fight against malaria, vector control remains the most important tool, butit is now severely constrained by the spread of insecticide or behavioral resistance by mosquito populations. Therefore, new vector control tools are warranted. Such novel tools include anti-mosquito vaccines or mosquito genetic modifications targeting the mosquito midgut homeostasis and reducing the mosquito lifespan beyond a stage they can transmit malaria.

Methods

We assessed the effect of RNA interference silencing of the midgut homeostasis regulators FN3D1, FN3D2, FN3D3, GPRGR9 and PGRPLC3 in populations of Anopheles arabiensis reared at nearly natural setting. We monitored the survival of gene-silenced mosquitoes and assessed the load of their midgut microbiota using flow cytometry. The effect of gene silencing was modeled by the Cox proportional hazards frailty model, and bacterial counts were first log transformed and then compared by a mixed model.

Result

Significantly higher mortality rates were observed for the FN3D1 (Hazard ratio =1.64, P=0.004), FN3D3 (HR=1.79, P<0.001) and GPRGr9 silenced mosquitoes (HR=2.00, P<0.001) as compared to a control group injected with dsRNA against a non-related bacterial gene LacZ. The bacterial load ratios for all target gene silenced mosquitoes compared to control mosquitoes were above 1, with the highest value for FN3D1 equal to 2.66 (95%CI: [0.94;7.57]) but no statistically significant difference could be demonstrated. Interestingly, there was a strong correlation (r=0.61) between the mortality hazard ratio and the bacterial count ratio of the gene-silenced mosquitoes. Increased mortality rates were reversed when the gene-silenced mosquitoes were treated with antibiotic mixtures suggesting that gut microbiota play a key role in the observed reduction of mosquito survival.

Conclusion

We demonstrate that interfering with the expression of theFN3D1, FN3D3 or GPRGr9 genes can cause a significant reduction of the longevity of An. arabiensis mosquitoes due to the disruption of the mosquito gut homeostasis.
Monte Carlo Sampling of Protein Folding by Combining an All-Atom Physics-Based Model with a Native State Bias
Authors: Wang Yong , Tian Pengfei , Boomsma Wouter , Lindorff-Larsen Kresten
Published: July 2018

Energy landscape theory suggests that native interactions are a major determinant of the folding mechanism of a protein. Thus, structure-based (Gō) models have, aided by coarse-graining techniques, shown great success in capturing the mechanisms of protein folding and conformational changes. In certain cases, however, non-native interactions and atomic details are also essential to describe the protein dynamics, prompting the development of a variety of structure-based models which include non-native interactions, and differentiate between different types of attractive potentials. Here, we describe an all-protein-atom hybrid model, termed ProfasiGo, that integrates an implicit solvent all-atom physics-based model (called Profasi) and a structure-based Gō potential, and its implementation in two software packages (PHAISTOS and ProFASi) that are developed for Monte Carlo sampling of protein molecules. We apply the ProfasiGo model to study the folding free energy landscapes of four topologically similar proteins, one of which can be folded by the simplified potential Profasi, and two that have been folded by explicit solvent, all-atom molecular dynamics simulations with the CHARMM22∗ force field. Our results reveal that the hybrid ProfasiGo model is able to capture many of the details present in the physics-based potentials, while retaining the advantages of Gō models for sampling and guiding to the native state. We expect that the model will be widely applicable to study the folding of more complex proteins, or to study conformational dynamics and integration with experimental data.
A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability
Authors: Sadler Jessica B.A. , Wenzel Dawn M. , Williams Lauren K. , Guindo-Martínez Marta , Alam Steven L. , Mercader Josep Maria , Torrents David , Ullman Katharine S. , Sundquist Wesley I. , Martin-Serrano Juan
Published: July 2018

Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery and is tightly regulated by Charged Multivesicular body Protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4CT232 (rs35094336), increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: the CHMP4CT232 allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4CT232 exhibit increased levels of DNA damage and are sensitized to several conditions that increase chromosome mis-segregation, including DNA replication stress, inhibition of the mitotic checkpoint, and loss of p53. Our data demonstrate the biological importance of the abscission checkpoint, and suggest that dysregulation of abscission by CHMP4CT232 may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.

Significance Statement

The final step of cell division, abscission, is temporally regulated by the Aurora B kinase and CHMP4C in a conserved pathway called the abscission checkpoint which arrests abscission in the presence of lingering mitotic problems. Despite extensive study, the physiological importance of this pathway to human health has remained elusive. We now demonstrate that a cancer predisposing polymorphism in CHMP4C disrupts the abscission checkpoint and results in DNA damage accumulation. Moreover, deficits in this checkpoint synergize with p53 loss and generate aneuploidy under stress conditions that increase the frequency of chromosome missegregation. Therefore, cells expressing the cancer-associated polymorphism in CHMP4C are genetically unstable, thus suggesting a novel oncogenic mechanism that may involve the dysregulation of abscission.
Microtubules provide a viscoelastic resistance to myocyte motion
Authors: Caporizzo M. A. , Chen C. Y. , Salomon A. K. , Bedi K. , Margulies K. B. , Prosser B. L.
Published: July 2018

Background

Microtubules (MT) buckle and bear load during myocyte contraction, a behavior enhanced by post-translational detyrosination. This buckling suggests a spring-like resistance against myocyte shortening, which could store energy and aid myocyte relaxation. Despite this visual suggesting of elastic behavior, the precise mechanical contribution of the cardiac MT network remains to be defined.

Methods

Here we experimentally and computationally probe the mechanical contribution of stable microtubules and their influence on myocyte function. We use multiple approaches to interrogate viscoelasticity and cell shortening in primary murine myocytes where either MTs are depolymerized or detyrosination is suppressed, and use the results to inform a mathematical model of myocyte viscoelasticity.

Results

MT ablation by colchicine concurrently enhances both the degree of shortening and speed of relaxation, a finding inconsistent with simple spring-like microtubule behavior, and suggestive of a viscoelastic mechanism. Axial stretch and transverse indentation confirm that microtubules increase myocyte viscoelasticity. Specifically, increasing the rate of strain amplifies the MT contribution to myocyte stiffness. Suppressing MT detyrosination with parthenolide or via overexpression of tubulin tyrosine ligase (TTL) has mechanical consequences that closely resemble colchicine, suggesting that the mechanical impact of MTs relies on a detyrosination-dependent linkage with the myocyte cytoskeleton. Mathematical modeling affirms that alterations in cell shortening conferred by either MT destabilization or tyrosination can be attributed to internal changes in myocyte viscoelasticity.

Conclusions

The results suggest that the cardiac MT network regulates contractile amplitudes and kinetics by acting as a cytoskeletal shock-absorber, whereby MTs provide breakable cross-links between the sarcomeric and non-sarcomeric cytoskeleton that resist rapid length changes during both shortening and stretch.
LiF-MS: Mapping unstructured peptide-protein interactions using Ligand-Footprinting Mass Spectrometry
Authors: Parker Benjamin , Goncz Edward , Krist David T. , Statsyuk Alexander , Nesvizhskii Alexey I. , Weiss Eric
Published: July 2018

Unstructured peptides, or linear motifs, present a poorly understood molecular language within the context of cellular signaling. These modular regions are often short, unstructured and interact weakly and transiently with folded target proteins. Thus, they are difficult to study with conventional structural biology methods. We present Ligand-Footprinting Mass Spectrometry, or LiF-MS, as a method of mapping the binding sites and dynamic disorder of these peptides on folded protein domains. LiF-MS uses a cleavable crosslinker to mark regions of a protein contacted by a bound linear motif. We demonstrate this method can detect both conformation ensembles and binding orientations of a linear motif in its binding pocket to amino-acid-level detail. Furthermore, marked amino acids can be used as constraints in peptide-protein docking simulations to improve model quality. In conclusion, LiF-MS proves a simple and novel method of elucidating peptide docking structural data not accessible by other methods in the context of a purified system.
Massive variation of short tandem repeats with functional consequences across strains of Arabidopsis thaliana
Authors: Press Maximilian O. , McCoy Rajiv C. , Hall Ashley N. , Akey Joshua M. , Queitsch Christine
Published: July 2018

Short tandem repeat (STR) mutations may comprise more than half of the mutations in eukaryotic coding DNA, yet STR variation is rarely examined as a contributor to complex traits. We assessed this contribution across a collection of 96 strains of Arabidopsis thaliana, genotyping 2046 STR loci each, using highly parallel STR sequencing with molecular inversion probes. We found that 95% of examined STRs are polymorphic, with a median of six alleles per STR across these strains. STR expansions (large copy number increases) are found in most strains, several of which have evident functional effects. These include three of six intronic STR expansions we found to be associated with intron retention. Coding STRs were depleted of variation relative to noncoding STRs, and we detected a total of 56 coding STRs (11%) showing low variation consistent with the action of purifying selection. In contrast, some STRs show hypervariable patterns consistent with diversifying selection. Finally, we detected 133 novel STR-phenotype associations under stringent criteria, most of which could not be detected with SNPs alone, and validated some with follow-up experiments. Our results support the conclusion that STRs constitute a large, unascertained reservoir of functionally relevant genomic variation.
Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses
Authors: Ohtani Hitoshi , Liu Minmin , Zhou Wanding , Liang Gangning , Jones Peter A.
Published: July 2018

We provide a comprehensive genomic and epigenomic map of the more than 500,000 endogenous retroviruses (ERVs) and fragments that populate the intergenic regions of the human genome. The repressive epigenetic marks associated with the ERVs, particularly long terminal repeats (LTRs), show a remarkable switch in silencing mechanisms, depending on the evolutionary age of the LTRs. Young LTRs tend to be CpG rich and are mainly suppressed by DNA methylation, whereas intermediate age LTRs are associated predominantly with histone modifications, particularly histone H3 lysine 9 (H3K9) methylation. Young LTRs can be reactivated by treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) alone, but their level of expression is much increased by 5-aza-CdR treatment plus knockdown of one of several H3K9 methyltransferases or of the H3K27 methyltransferase EZH2. The removal of cytosine methylation led to rapid, widespread increases in H3K9me3 in the LTRs. Intermediate age LTRs had lower CpG densities and were not up-regulated by 5-aza-CdR treatment, but they were sensitive to knockdown of H3K9 methyltransferases. Unlike the situation in embryonic stem cells, the polycomb repressive complex (PRC2) has a minor role in LTR suppression by itself and is only a player after removal of cytosine methylation in the analyzed cancer cell line. Up-regulation of LTRs and induction of “viral mimicry” is rapidly becoming of interest for predicting cancer patient response to epigenetic therapies. Understanding the mechanism for LTR suppression is of major importance in order to improve patient treatment strategies.
Understanding Finnish student craft teachers’ conceptions of sustainability
Authors: Väänänen Niina , Vartiainen Leena , Kaipainen Minna , Pitkäniemi Harri , Pöllänen Sinikka
Published: July 2018

Purpose

This study aims to explore student craft teachers’ conceptions of sustainable craft. This is an important issue because the Finnish National Curriculum of Basic Education emphasises sustainability, especially in craft education, and teachers play a vital role in preparing pupils to meet the future challenges. Because the concept of sustainable craft is open-ended, there is a need to rethink pedagogy in craft education and higher education.

Design/methodology/approach

The data were collected in the form of essays from future craft teachers (N41) studying craft science in the Finnish higher education system. The essays concerned both general conceptions of sustainable craft and reflections on the student teachers’ craft practices. The data were analysed using grounded theory to gain a deep understanding of how student craft teachers conceptualise sustainable craft. The data were quantified and statistically assessed for dependencies between variables and transferability of results.

Findings

The study revealed that sustainable craft is conceptualised as a system and that student teachers approach sustainability from different orientations: practice, product, immaterial and holistic.

Originality/value

The emerging theory offers a new concrete tool for understanding the abstract concept of sustainability in higher education and suggests that sustainability can be addressed through tangible methods of craft. This theory proposes craft as a tool to conceptualise of sustainability for broader use in education for sustainability (ESD) and as a concrete tool for developing pedagogy for ESD.
Tourist cities as embodied places of learning: walking in the “feelds” of Shanghai and Lisbon
Authors: Küpers Wendelin , Wee Desmond
Published: July 2018

Purpose

Walking is considered as a particular relationship for rhythmic moving in cityscapes and as method for understanding. The purpose of this paper is to explore the significance of an embodied way of sensing and making sense, of knowing and learning that is relevant for tourism education and studies and other forms of experiential learning.

Design/methodology/approach

The paper uses a conceptual, discursive and research-based approach based on a phenomenological understanding of embodied learning. Empirical “data” from two educational tours (Edutour) in Lisbon and Shanghai are presented, contextualized and interpreted.

Findings

Walking through cityscape related to projects is an “effective” embodied practice of learning in which senses “make sense.” The empirical material and experiences that emerged during Edutour demonstrated the significance of walking as form of embodied knowing, learning and interrelating to place and paces of a tourist city.

Originality/value

The idea of walking as method within tourist cities is hardly explored. Hence, this constitutes a unique, innovative and interpretative event in which new approaches, such as “fielding” and “reflactions” “in the feeld”, defy more traditional concepts. It emphasizes the role of the city as a medium and remains a valuable contribution for tourism and education research.
Identification and evaluation for the dynamic signals caused by pressure fluctuation of aerostatic slider
Authors: Chen Dongju , Han Jihong , Cui Xianxian , Fan Jinwei
Published: July 2018

Purpose

To identify the dynamic feature of the aerostatic slider caused by gas film, an evaluation system by a piezoelectric acceleration sensor is presented in time and frequency domain.

Design/methodology/approach

The dynamic pressure fluctuation is evaluated by the wavelet transform, cross correlation analysis and power spectral density (PSD). Wavelet transform is used to process the measured result of the aerostatic slider and the signal is decomposed into high-frequency and low-frequency signal. Correlation analysis method is used to evaluate the impact of the initial gas gap on the fluctuation in time domain.

Findings

According to the PSD analysis of the processed signal in the frequency domain, the natural frequency of the aerostatic slider is identified from the measured signal in frequency domain; this method provides a basis for the identification of guideway errors.

Research limitations/implications

The method can also be applied to the error identification of other components of the machine tool.

Originality/value

Wavelet transform is used to process the measured result of the aerostatic slider by acceleration sensor, and the signal is decomposed into high-frequency and low-frequency signal. Correlation analysis method is used to evaluate the impact of the initial gas gap on the fluctuation in time domain. According to the PSD analysis of the processed signal in the frequency domain, the natural frequency of the aerostatic slider is identified from the measured signal in frequency domain; this method provides a basis for the identification of slider errors.
A cross-platform parallel programming model for fluid-film lubrication optimization
Authors: Wang Nen-Zi , Chen Hsin-Yi
Published: July 2018

Purpose

A cross-platform paradigm (computing model), which combines the graphical user interface of MATLAB and parallel Fortran programming, for fluid-film lubrication analysis is proposed. The purpose of this paper is to take the advantages of effective multithreaded computing of OpenMP and MATLAB’s user-friendly interface and real-time display capability.

Design/methodology/approach

A validation of computing performance of MATLAB and Fortran coding for solving two simple sliders by iterative solution methods is conducted. The online display of the particles’ search process is incorporated in the MATLAB coding, and the execution of the air foil bearing optimum design is conducted by using OpenMP multithreaded computing in the background. The optimization analysis is conducted by particle swarm optimization method for an air foil bearing design.

Findings

It is found that the MATLAB programs require prolonged execution times than those by using Fortran computing in iterative methods. The execution time of the air foil bearing optimum design is significantly minimized by using the OpenMP computing. As a result, the cross-platform paradigm can provide a useful graphical user interface. And very little code rewritting of the original numerical models is required, which is usually optimized for either serial or parallel computing.

Research limitations/implications

Iterative methods are commonly applied in fluid-film lubrication analyses. In this study, iterative methods are used as the solution methods, which may not be an effective way to compute in the MATLAB’s setting.

Originality/value

In this study, a cross-platform paradigm consisting of a standalone MATLAB and Fortran codes is proposed. The approach combines the best of the two paradigms and each coding can be modified or maintained independently for different applications.