bluuebunny/crossref_metadata_2025 huggingface dataset:
Observation and modelling of vegetation spirals and arcs in isotropic environmental conditions: dissipative structures in arid landscapes
Authors: Tlidi M. , Clerc M. G. , Escaff D. , Couteron P. , Messaoudi M. , Khaffou M. , Makhoute A.
Published: November 2018

We report for the first time on the formation of spirals like vegetation patterns in isotropic and uniform environmental conditions. The vegetation spirals are not waves and they do not rotate. They belong to the class of dissipative structures found out of equilibrium. Isolated or interacting spirals and arcs observed in South America (Bolivia) and North Africa (Morocco) are interpreted as a result of curvature instability that affects the circular shape of localized patches. The biomass exhibits a dynamical behaviour with arcs that transform into spirals. Interpretation of observations and of the predictions provided by the theory is illustrated by recent measurements of peculiar plant morphology (the alfa plant, orStipa tenacissimaL.) originated from northwestern Africa and the southern part of the Iberian Peninsula.

This article is part of the theme issue ‘Dissipative structures in matter out of equilibrium: from chemistry, photonics and biology (part 2)’.
SynerClust: a highly scalable, synteny-aware orthologue clustering tool
Authors: Georgescu Christophe H. , Manson Abigail L. , Griggs Alexander D. , Desjardins Christopher A. , Pironti Alejandro , Wapinski Ilan , Abeel Thomas , Haas Brian J. , Earl Ashlee M.
Published: November 2018

Accurate orthologue identification is a vital component of bacterial comparative genomic studies, but many popular sequence-similarity-based approaches do not scale well to the large numbers of genomes that are now generated routinely. Furthermore, most approaches do not take gene synteny into account, which is useful information for disentangling paralogues. Here, we present SynerClust, a user-friendly synteny-aware tool based on synergy that can process thousands of genomes. SynerClust was designed to analyse genomes with high levels of local synteny, particularly prokaryotes, which have operon structure. SynerClust’s run-time is optimized by selecting cluster representatives at each node in the phylogeny; thus, avoiding the need for exhaustive pairwise similarity searches. In benchmarking against Roary, Hieranoid2, PanX and Reciprocal Best Hit, SynerClust was able to more completely identify sets of core genes for datasets that included diverse strains, while using substantially less memory, and with scalability comparable to the fastest tools. Due to its scalability, ease of installation and use, and suitability for a variety of computing environments, orthogroup clustering using SynerClust will enable many large-scale prokaryotic comparative genomics efforts.
Dams have varying impacts on fish communities across latitudes: A quantitative synthesis
Authors: Turgeon Katrine , Turpin Christian , Gregory-Eaves Irene
Published: November 2018

Dams are recognized to impact aquatic biodiversity and ecosystem functions, but the magnitude of effects vary across studies. By using a meta-analytical approach, we examined the effects of impoundment on fish community across three large biomes. The impacts of dams on richness and diversity differed across biomes, with significant declines in the tropics, lower amplitude but similar directional changes in temperate reservoirs, and no changes in boreal reservoirs. Our analysis also showed that non-native species increased significantly in tropical and temperate reservoirs, but not in boreal reservoirs. In contrast, temporal trajectories in fish assemblage metrics were common across regions, with all biomes showing an increase in mean trophic position and in the proportion of generalist species after impoundment. Such changes in fish assemblages may affect food web stability and merit closer study. Across the literature examined, predominant factors or mechanisms that render fish assemblages susceptible to impacts from dams were: 1) the transformation of the lotic environment into a lentic environment; 2) habitat fragmentation and 3) invasive or non-native species. Collectively our results highlight that an understanding of the regional context and a suite of metrics are needed to make robust predictions about how fish will respond to river impoundments.
Mapping the Computational Similarity of Individual Neurons within Large-scale Ensemble Recordings using the SIMNETS analysis framework
Authors: Hynes Jacqueline B. , Brandman David M. , Zimmermann Jonas B. , Donoghue John P. , Vargas-Irwin Carlos E.
Published: November 2018

The expansion of large-scale neural recording capabilities has provided new opportunities to examine multi-scale cortical network activity at single neuron resolution. At the same time, the growing scale and complexity of these datasets introduce new conceptual and technical challenges beyond what can be addressed using traditional analysis techniques. Here, we present SIMNETS, a mathematically rigorous and efficient unsupervised relational analysis framework designed to generate intuitive, low-dimensional neuron maps that support a multi-scale view of the computational similarity (CS) relations among individual neurons. The critical innovation is the use of a novel measure of computational similarity that is based on comparing the intrinsic structure of latent spaces representing the spiking output of individual neurons. We use three publicly available neural population test datasets from the visual, motor, and hippocampal CA1 brain regions to validate the SIMNETS framework and demonstrate how it can be used to identify putative subnetworks (i.e., clusters of neurons with similar computational properties). Our analysis pipeline includes a novel statistical test designed to evaluate the likelihood of detecting spurious neuron clusters to validate network structure results. The SIMNETS framework can facilitate linking computational geometry representations across scales, from single neurons to subnetworks, within large-scale neural recording data.
New players in the regulatory network of Vibrio parahaemolyticus Type VI secretion system 1
Authors: Ben-Yaakov Rotem , Salomon Dor
Published: November 2018

Type VI secretion systems (T6SSs) are widespread, tightly regulated, protein delivery apparatuses used by Gram-negative bacteria to outcompete their neighbors. The pathogen, Vibrio parahaemolyticus, encodes two T6SSs. These T6SSs are differentially regulated by external conditions. T6SS1, an antibacterial system predominantly found in pathogenic isolates, requires warm marine-like conditions and surface sensing for activation. The regulatory network that governs this activation is not well understood. In this work, we devised a screening methodology that allows us to easily monitor the outcome of bacterial competitions and thus, to identify mutants that are defective in T6SS1-mediated bacterial killing. The methodology, termed Bacterial Competition Fluorescence (BaCoF), relies on detection of a fluorescent signal as an indicator of the survival and growth of a T6SS-sensitive, GFP-expressing prey that has been co-cultured with mutants derived from a T6SS+ attacker of interest. Using BaCoF, we screened a random transposon insertion mutant library and identified genes required for V. parahaemolyticus T6SS1 activation, among them TfoY and Tmk. We used epistasis experiments to determine the relationships between the newly identified components and other regulators that were previously described. Thus, we present here a detailed biological understanding of the T6SS1 regulatory network.
Cultural Selection Shapes Network Structure
Authors: Smolla Marco , Akcay Erol
Published: November 2018

Cultural evolution relies on the social transmission of cultural traits across a population, along the ties of an underlying social network that emerges from non-random interactions among individuals. Research indicates that the structure of those interaction networks affects information spread, and thus a population's ability for cumulative culture. However, how network structure itself is driven by population-culture co-evolution remains largely unclear. We use a simple but realistic model of complex dynamic social networks to investigate how populations negotiate the trade-off between acquiring new skills and getting better at existing skills, and how this trade-off, in turn, shapes the social structure of the population. Our results reveal unexpected eco-evolutionary feedback from culture onto social network structure and vice versa. We show that selecting for generalists (favouring a broad repertoire of skills) results in sparsely connected networks with highly diverse skill sets, whereas selecting for specialists (favouring skill proficiency) results in densely connected networks and a population that specializes on the same few skills on which everyone is an expert. Surprisingly, cultural selection for specialisation can act as an 'ecological trap' where it can take a long time for a specialist population to adapt to a generalist world. Our model advances our understanding of the complex feedbacks in cultural evolution and demonstrates how individual-level behaviour can lead to the emergence of population-level structure.
Integrating water, sanitation, handwashing, and nutrition interventions to reduce child soil-transmitted helminth andGiardiainfections: a cluster-randomized controlled trial in rural Kenya
Authors: Pickering Amy J. , Njenga Sammy M. , Steinbaum Lauren , Swarthout Jenna , Lin Audrie , Arnold Benjamin F. , Stewart Christine P. , Dentz Holly N. , Mureithi MaryAnne , Chieng Benard , Wolfe Marlene , Mahoney Ryan , Kihara Jimmy , Byrd Kendra , Rao Gouthami , Meerkerk Theodora , Cheruiyot Priscah , Papaiakovou Marina , Pilotte Nils , Williams Steven A. , Colford John M. , Null Clair
Published: November 2018

Background.

Helminth and protozoan infections affect >1 billion children globally. Improved water, sanitation, handwashing, and nutrition could be more sustainable control strategies for parasite infections than mass drug administration (MDA), while providing other quality of life benefits.

Methods and Findings.

We enrolled geographic clusters of pregnant women into a cluster-randomized controlled trial that tested six interventions: disinfecting drinking water(W), improved sanitation(S), handwashing with soap(H), combined WSH, improved nutrition(N), and combined WSHN. We assessed intervention effects on parasite infections by measuringAscaris lumbricoides,Trichuris trichiura, hookworm, andGiardia duodenalisamong individual children born to enrolled mothers and their older siblings (ClinicalTrials.govNCT01704105). We collected stool specimens from 9077 total children in 622 clusters, including 2346 children in control, 1117 in water, 1160 in sanitation, 1141 in handwashing, 1064 in WSH, 1072 in nutrition, and 1177 in WSHN. In the control group, 23% of children were infected withAscaris lumbricoides, 1% withTrichuris trichuria, 2% with hookworm and 39% withGiardia duodenalis. After two years of intervention exposure,Ascarisinfection prevalence was 18% lower in the water treatment arm (95% confidence interval (CI) 0%, 33%), 22% lower in the WSH arm (CI 4%, 37%), and 22% lower in the WSHN arm (CI 4%, 36%) compared to control. Individual sanitation, handwashing, and nutrition did not significantly reduceAscarisinfection on their own, and integrating nutrition with WSH did not provide additional benefit.Trichurisand hookworm were rarely detected, resulting in imprecise effect estimates. No intervention reducedGiardia. Reanalysis of stool samples by quantitative polymerase chain reaction (qPCR) confirmed the reductions inAscarisinfections measured by microscopy in the WSH and WSHN groups. Lab technicians and data analysts were blinded to treatment assignment, but participants and sample collectors were not blinded. The trial was funded by the Bill & Melinda Gates Foundation and USAID.

Conclusions.

Our results suggest integration of improved water quality, sanitation, and handwashing could contribute to sustainable control strategies forAscarisinfections, particularly in similar settings with recent or ongoing deworming programs. Water treatment alone was similarly effective to integrated WSH, providing new evidence that drinking water should be given increased attention as a transmission pathway forAscaris.
7-Transmembrane Helical (7TMH) Proteins: Pseudo-Symmetry and Conformational Plasticity
Authors: Youkharibache Philippe , Tran Alexander , Abrol Ravinder
Published: November 2018

Membrane proteins sharing 7 transmembrane helices (7-TMH) dominate the polytopic TMH proteome. They cannot be grouped under a monolithic fold or superfold, however, a parallel structural analysis of folds around that magic number of 7-TMH in distinct 6/7/8-TMH protein superfamilies (SWEET, PnuC, TRIC, FocA, Aquaporin, GPCRs, AND MFS), reveals a common homology, not in their structural fold, but in their systematic pseudo-symmetric construction. Our analysis leads to guiding principles of intragenic duplication and pseudo-symmetric assembly of ancestral 3 or 4 Transmembrane Helix (3/4-TMH) protodomains/protofolds. A parallel deconstruction and reconstruction of these domains provides a structural and mechanistic framework for the evolution path of current pseudo-symmetrical transmembrane helical (TMH) proteins. It highlights the conformational plasticity inherent to fold formation itself. The sequence/structure analysis of different 6/7/8-TMH superfamilies provides a unifying theme of their evolutionary process involving the intragenic duplication of protodomains with varying degrees of sequence and fold divergence under conformational and functional constraints.
Leafhopper Viral Pathogens: Ultrastructure of salivary gland infection of Taastrup-like virus inPsammotettix alienusDahlbom; and a novel Rhabdovirus inHomalodisca vitripennis(Germar) Hemiptera: Cicadellidae
Authors: Lundsgaard Thorben , Hunter Wayne B. , Adkins Scott
Published: November 2018

Viruses that are pathogenic to insect pests can be exploited as biological control agents. Viruses that are pathogenic to beneficial insects and other arthropods, as in honey bees, silk worms, and shrimp, cause millions of dollars of losses to those industries. Current advances in next generation sequencing technologies along with molecular and cellular biology have produced a wealth of information about insect viruses and their potential applications. Leafhoppers cause economic losses as vectors of plant pathogens which significantly reduce the worlds’ food crops. Each year more viruses are discovered primarily through the use of next generation sequencing of the leafhopper hosts. The diversity of viruses from leafhoppers demonstrates a wide range of taxonomic members that includes genomes of DNA or RNA from families like: Reoviridae, Iridoviridae, Dicistroviridae, Iflaviridae, and others yet to be classified. Discussed is a recent viral pathogen isolated from the leafhopperPsammotettix alienus, name Taastrup Virus. Taastrup virus (TV) is a novel virus with a RNA genome, a Filovirus-like morphology, being tentatively placed within theMononegavirales. AdultPsammotettix alienusinfected with TV, showed the highest concentration of virions in salivary glands, consisting of a principal gland (type I-VI-cells) and an accessory gland. Examination of thin sections revealed enveloped particles, about 1300 nm long and 62 nm in diameter, located singly or in paracrystalline arrays in canaliculi of type III- and IV-cells. In gland cells with TV particles in canaliculi, granular masses up to 15 μm in diameter were present in the cytoplasm. These masses are believed to be viroplasms, the sites for viral replication. TV particles were observed at the connection between a canaliculus and the salivary duct system. A TV-like virus with strongly similar morphology was discovered in the ornamental plant,Liriope, near Fort Pierce, Florida, USA. When the virus was inoculated to a leafhopper cell culture, HvWH, made from the glassy-winged sharpshooter,Homalodisca vitripennis(Germar), the cells rapidly degraded with 100% mortality in 48 hours. These two instances are the only reported cases of this newly discovered viral pathogen of leafhoppers.
Lipid analysis of CO2-rich subsurface aquifers suggests an autotrophy-based deep biosphere with lysolipids enriched in CPR bacteria
Authors: Probst Alexander J. , Elling Felix J. , Castelle Cindy J. , Zhu Qingzeng , Elvert Marcus , Birarda Giovanni , Holman Hoi-Ying , Lane Katherine R. , Ladd Bethany , Ryan M. Cathryn , Woyke Tanja , Hinrichs Kai-Uwe , Banfield Jillian F.
Published: November 2018

Sediment-hosted CO2-rich aquifers deep below the Colorado Plateau (USA) contain a remarkable diversity of uncultivated microorganisms, including Candidate Phyla Radiation (CPR) bacteria that are putative symbionts unable to synthesize membrane lipids. The origin of organic carbon in these ecosystems is unknown and the source of CPR membrane lipids remains elusive. We collected cells from deep groundwater brought to the surface by eruptions of Crystal Geyser, sequenced the community, and analyzed the whole community lipidome over time. Characteristic stable carbon isotopic compositions of microbial lipids suggest that bacterial and archaeal CO2 fixation ongoing in the deep subsurface provides organic carbon for the complex communities that reside there. Coupled lipidomic-metagenomic analysis indicates that CPR bacteria lack complete lipid biosynthesis pathways but still possess regular lipid membranes. These lipids may therefore originate from other community members, which also adapt to high in situ pressure by increasing fatty acid unsaturation. An unusually high abundance of lysolipids attributed to CPR bacteria may represent an adaptation to membrane curvature stress induced by their small cell sizes. Our findings provide new insights into the carbon cycle in the deep subsurface and suggest the redistribution of lipids into putative symbionts within this community.
The landscape of viral associations in human cancers
Authors: Zapatka Marc , Borozan Ivan , Brewer Daniel S. , Iskar Murat , Grundhoff Adam , Alawi Malik , Desai Nikita , Sültmann Holger , Moch Holger ,   PCAWG Pathogens Working Group,   ICGC/TCGA Pan-cancer Analysis of Whole Genomes Network, Cooper Colin S. , Eils Roland , Ferretti Vincent , Lichter Peter
Published: November 2018

Potential viral pathogens were systematically investigated in the whole-genome and transcriptome sequencing of 2,656 donors as part of the Pan-Cancer Analysis of Whole Genomes using a consensus approach integrating three independent pathogen detection pipelines. Viruses were detected in 382 genomic and 68 transcriptome data sets. We extensively searched and characterized numerous features of virus-positive cancers integrating various PCAWG datasets. We show the high prevalence of known tumor associated viruses such as EBV, HBV and several HPV types. Our systematic analysis revealed that HPV presence was significantly exclusive with well-known driver mutations in head/neck cancer. A strong association was observed between HPV infection and the APOBEC mutational signatures, suggesting the role of impaired mechanism of antiviral cellular defense as a driving force in the development of cervical, bladder and head neck carcinoma. Viral integration into the host genome was observed for HBV, HPV16, HPV18 and AAV2 and associated with a local increase in copy number variations. The recurrent viral integrations at theTERTpromoter were coupled to high telomerase expression uncovering a further mechanism to activate this tumor driving process. High levels of endogenous retrovirus ERV1 expression is linked to worse survival outcome in kidney cancer.
Orc4 spatiotemporally stabilizes centromeric chromatin
Authors: Sreekumar Lakshmi , Kumari Kiran , Bakshi Asif , Varshney Neha , Thimmappa Bhagya C. , Guin Krishnendu , Narlikar Leelavati , Padinhateeri Ranjith , Siddharthan Rahul , Sanyal Kaustuv
Published: November 2018

Spatiotemporal regulation in DNA replication maintains kinetochore stability. The epigenetically regulated centromeres (CENs) in the budding yeastCandida albicanshave unique DNA sequences, replicate early and are clustered throughout the cell cycle. In this study, the genome-wide occupancy of replication initiation protein Orc4 reveals its abundance at all CENs inC. albicans. Orc4 associates with four different DNA motifs, one of which coincides with tRNA genes. Hi-C combined with genome-wide replication timing analyses identify enriched interactions among early or late replicating Orc4-bound regions. A simulated polymer model of chromosomes reveals that early replicating and strongly enriched Orc4-bound sites localize towards the kinetochores. Orc4 is constitutively localized to CENs, and both Orc4 and Mcm2 stabilize CENPA. CENPA chaperone Scm3 localizes at the kinetochore during anaphase, coinciding with the loading time of CENPA. We propose that this spatiotemporal nuclear localization of Orc4, with Mcm2 and Scm3, recruits CENPA and stabilizes centromeric chromatin.
Cognitive functions and jugular venous reflux in severe mitral regurgitation
Authors: Sung Shih-Hsien , Lee Ching-Wei , Wang Pei-Ning , Lee Hsiang-Ying , Chen Chen-Huan , Chung Chih-Ping
Published: November 2018

Cardiac diseases with elevated central venous pressure have higher frequency of jugular venous reflux (JVR), which is associated with decreased cerebral blood flow and white matter hyperintensities. Whether patients with severe mitral-regurgitation (SMR) have poorer cognitive functions and whether JVR is involved were determined. Patients with SMR and age/sex-matched controls were prospectively recruited. Neuropsychological tests such as global cognitive (Mini-Mental State Examination, MMSE), verbal memory, executive, and visuospatial domains were performed. Cardiac parameters by cardiac catheterisation and echocardiography, and the frequency of JVR by colour-coded duplex ultrasonography were obtained. Forty patients with SMR and 40 controls (71.1±12.2, 38–89 years; 75% men) were included. Compared with the controls, patients with SMR had lower scores in all neuropsychological tests but only MMSE and visuospatial test scores were statistically significant after adjusting for age, sex, and educational level. We further adjusted for cardiovascular risk factors; the significance remained in the visuospatial test but diminished in MMSE. Multivariate linear regression analyses adjusted for age, sex, and educational level showed that JVR combined with high right-atrial-pressure (RAP > 50th-percentile, 12 mmHg) was significantly associated with poorer performances in both MMSE [right JVR: B coefficient(95% confidence interval, p)=-2.83(−5.46–0.20, 0.036); left JVR: −2.77(−5.52–0.02, 0.048)] and visuospatial test [right JVR: −4.52(−8.89–0.16, 0.043); left JVR: −4.56(−8.81–0.30, 0.037)], with significances that remained after further adjusting for cardiovascular risk factors. Our results suggest that retrogradely-transmitted venous pressure might be involved in the mechanisms mediating the relationship between cardiac diseases and brain functions.
Phasic norepinephrine is a neural interrupt signal for unexpected events in rapidly unfolding sensory sequences – evidence from pupillometry
Authors: Zhao Sijia , Chait Maria , Dick Fred , Dayan Peter , Furukawa Shigeto , Liao Hsin-I
Published: November 2018

The ability to track the statistics of our surroundings is a key computational challenge. A prominent theory (Dayan & Yu, 2006) proposes that the brain monitors for ‘unexpected uncertainty’ – events which deviate substantially from model predictions, indicating model failure. Norepinephrine (NE) is thought to play a key role in this process by serving as an interrupt signal, initiating model-resetting. However, evidence is from paradigms where participants actively monitored stimulus statistics. To determine whether NE routinely reports the statistical structure of our surroundings, even when not behaviourally relevant, we used rapid tone-pip sequences that contained perceptually salient pattern-changes associated with abrupt structural violations vs. emergence of regular structure. Phasic pupil dilations (PDR) were monitored to assess NE. We reveal a remarkable specificity: When not behaviourally relevant, only abrupt structural violations evoked a PDR. The results demonstrate that NE tracks ‘unexpected uncertainty’ on rapid time scales relevant to sensory signals.
Widespread conservation of chromatin accessibility patterns and transcription factor binding in human and chimpanzee induced pluripotent stem cells
Authors: Romero Irene Gallego , Gopalakrishnan Shyam , Gilad Yoav
Published: November 2018

Changes in gene regulation have been shown to contribute to phenotypic differences between closely related species, most notably in primates. It is likely that a subset of inter-species regulatory differences can be explained by changes in chromatin accessibility and transcription factor binding, yet there is a paucity of comparative data sets with which to investigate this. Using ATAC-seq, we profiled genome-wide chromatin accessibility in a matched set of 6 human and 6 chimpanzee (Pan troglodytes, our closest living relative) induced pluripotent stem cells from which we have previously collected gene expression data. We examined chromatin accessibility patterns near 20,745 orthologous transcriptions start sites and used a footprinting algorithm to predict transcription factor binding activity in each species. We found that the majority of chromatin accessibility patterns and transcription factor activity are conserved between these two closely related species. Interestingly, interspecies divergence in chromatin accessibility and transcription factor binding in pluripotent cells appear to contribute not to differences in the pluripotent state, but to downstream developmental processes. Put together, our findings suggest that the pluripotent state is extremely stable and potentially subject to stronger evolutionary constraint than other somatic tissues.
Metastable regimes and tipping points of biochemical networks with potential applications in precision medicine
Authors: Samal Satya Swarup , Krishnan Jeyashree , Esfahani Ali Hadizadeh , Lüders Christoph , Weber Andreas , Radulescu Ovidiu
Published: November 2018

The concept of attractor of dynamic biochemical networks has been used to explain cell types and cell alterations in health and disease. We have recently proposed an extension of the notion of attractor to take into account metastable regimes, deﬁned as long lived dynamical states of the network. These regimes correspond to slow dynamics on low dimensional invariant manifolds of the biochemical networks. Methods based on tropical geometry allow to compute the metastable regimes and represent them as polyhedra in the space of logarithms of the species concentrations. We are looking for sensitive parameters and tipping points of the networks by analyzing how these polyhedra depend on the model parameters. Using the coupled MAPK and PI3K/Akt signaling networks as an example, we test the idea that large changes of the metastable states can be associated to cancer disease speciﬁc alterations of the network. In particular, we show that for model parameters representing protein concentrations, the protein differential level between tumors of different types is reasonably reﬂected in the sensitivity scores, with sensitive parameters corresponding to differential proteins.
The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
Authors: Hari Priya , Millar Fraser R. , Tarrats Nuria , Birch Jodie , Rink Curtis J. , Fernández-Duran Irene , Muir Morwenna , Finch Andrew J. , Brunton Valerie G. , Passos João F. , Morton Jennifer P. , Boulter Luke , Acosta Juan Carlos
Published: November 2018

Cellular senescence is a stress response program characterised by a robust cell cycle arrest and the induction of a pro-inflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumour suppressors p53-p21CIP1, p16INK4a and p15INK4b, and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAA) that, in turn, function as the damage associated molecular patterns (DAMPs) signalling through TLR2 in OIS. Finally, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.
Melatonin attenuates mitochondrial and metabolic dysfunction caused by leptin deficiency
Authors: Potes Yaiza , Díaz-Luis Andrea , Bermejo-Millo Juan C , Pérez-Martínez Zulema , de Luxán-Delgado Beatriz , Rubio-González Adrian , Menéndez-Valle Ivan , Gutiérrez-Rodríguez José , Solano Juan J , Caballero Beatriz , Vega-Naredo Ignacio , Coto-Montes Ana
Published: November 2018

Leptin, as a nutritional inhibitor by repressing food intake, is critical compromised in the major common forms of obesity. Skeletal muscle is the main effector tissue for energy expenditure modifications by the effect of endocrine axes, such as leptin signaling. Our study has been carried out using skeletal muscle from leptin-deficient animal model, in order to ascertain the importance of this hormone in eating disorders. Here we report that leptin-deficiency stimulates an uncontrolled oxidative phosphorylation metabolism, resulting in an excess of energy production that culminates in mitochondrial dysfunction. Thus, different nutrient sensing pathways are perturbed, loosing proteostasis and promoting lipid anabolism, that induces myofiber degeneration and drives oxidative type I fiber conversion. Melatonin treatment plays a significant role in regulating energy homeostasis and fuel utilization. This study reveals melatonin to be a decisive mitochondrial function-fate regulator, with implications for resembling physiological energy requirements and targeting glycolytic type II fibers recovery.
A computationally efficient Bayesian Seemingly Unrelated Regressions model for high-dimensional Quantitative Trait Loci discovery
Authors: Bottolo L. , Banterle M. , Richardson S. , Ala-Korpela M. , Järvelin M-R. , Lewin A.
Published: November 2018

Motivation

Our work is motivated by the search for metabolite Quantitative Trait Loci (QTL) in a cohort of more than 5,000 people. There are 158 metabolites measured by NMR spectroscopy measured in the 31-year follow-up of the Northern Finland Birth Cohort 1966 (NFBC66). These metabolites, as with many multivariate phenotypes produced by high-throughput biomarker technology, exhibit strong correlation structures. Existing approaches for combining such data with genetic variants for multivariate QTL analysis generally ignore phenotypic correlations or make restrictive assumptions about the associations between phenotypes and genetic loci.

Results

We present a computationally efficient Bayesian Seemingly Unrelated Regressions (SUR) model for high-dimensional data, with cell-sparse variable selection and sparse graphical structure for covariance selection. Cell-sparsity allows different phenotype responses to be associated with different genetic predictors and the graphical structure is used to represent the conditional dependencies between phenotype variables. To achieve feasible computation of the large model space, we exploit a factorisation of the covariance matrix. Applying the model to the NFBC66 data with 9,000 directly-genotyped Single Nucleotide Polymorphisms, we are able to simultaneously estimate genotype-phenotype associations and the residual dependence structure amongst the metabolites at the same time.

Availability and implementation

The R packageBayesSURwith full documentation is available athttps://cran.r-project.org/web/packages/BayesSUR/

Contact

alex.lewin@lshtm.ac.uk
Filamentous aggregates are fragmented by the proteasome holoenzyme
Authors: Cliffe Rachel , Sang Jason C , Kundel Franziska , Finley Daniel , Klenerman David , Ye Yu
Published: November 2018

Filamentous aggregates (fibrils) are regarded as the final stage in the assembly of amyloidogenic proteins and are formed in many neurodegenerative diseases. Accumulation of aggregates occurs as a result of an imbalance between their formation and removal. Although there have been numerous studies of the aggregation process in vitro, far fewer studies of aggregate disassembly and degradation are available. Here we use single-aggregate imaging to show that large fibrils assembled from full-length tau are substrates of the 26S proteasome holoenzyme, which fragments them into small aggregates. TEM further revealed that these small aggregate species had no distinct structure. The intact proteasome holoenzyme is required to effectively target fibrils. Interestingly, while degradation of monomeric tau was not inhibited by ATPγS, fibril fragmentation was predominantly dependent on the ATPase activity of the proteasome. The proteasome holoenzyme was also found to target fibrils assembled from α-synuclein (αS), suggesting that its fibril fragmenting function may be a general mechanism. The fragmented species produced by the proteasome showed significant toxicity to human cell lines compared to intact fibrils. Together, our results indicate that the proteasome holoenzyme possesses a novel fragmentation function that disassembles large fibrils into smaller and more cytotoxic species.
Negative mood induction effects on problem solving task in women with eating disorders: a multi-method examination
Authors: French Melanie N. , Eneva Kalina , Arlt Jean M. , Yiu Angelina , Chen Eunice Y.
Published: November 2018

Eating disorders (EDs) are a serious public health concern, affecting about 5.2% of American women. The effects of negative affect on problem-solving and its psychophysiological correlates are poorly understood in this population. This study examined respiratory sinus arrhythmia (RSA) and skin conductance responses of 102 women with EDs (Binge eating disorder [BED]: n = 57, Anorexia nervosa: n = 13, Bulimia nervosa [BN]: n = 32) and 24 healthy controls (HCs) at baseline, and then during: a negative mood induction task, an adapted Means Ends Problem-Solving (MEPS) task and recovery. The MEPS Task included four interpersonal scenarios: 1) binge-eating when sad, 2) job dissatisfaction, 3) feeling rejected by friends, and 4) jealousy in a relationship. ED groups reported more negative and less positive emotions than HCs. After a negative mood induction, women with BED provided significantly less effective problem-solving strategies compared to HCs and women with BN for the binge-eating MEPS scenario. Relative to baseline and the negative mood induction, all participants exhibited significantly higher skin conductance response and skin conductance levels throughout the MEPS scenarios and recovery. BED showed significantly lower RSA levels than individuals with BN and HCs throughout the protocol. The multimethod findings suggest individuals with BED are likely to solve problems by binge-eating when in a negative affective state.
A case study on the detailed reproducibility of a human cell atlas project
Authors: Hua Kui , Zhang Xuegong
Published: November 2018

Reproducibility is a defining feature of a scientific discovery. Reproducibility can be at different levels for different types of study. The purpose of the Human Cell Atlas (HCA) project is to build maps of molecular signatures of all human cell types and states to serve as references for future discoveries. Constructing such a complex reference atlas must involve the assembly and aggregation of data from multiple labs, probably generated with different technologies. It has much higher requirements on reproducibility than individual research projects. To add another layer of complexity, the bioinformatics procedures involved for single-cell data have high flexibility and diversity. There are many factors in the processing and analysis of single-cell RNA-seq data that can shape the final results in different ways. To study what levels of reproducibility can be reached in current practices, we conducted a detailed reproduction study for a well-documented recent publication on the atlas of human blood dendritic cells as an example to break down the bioinformatics steps and factors that are crucial for the reproducibility at different levels. We found that the major scientific discovery can be well reproduced after some efforts, but there are also some differences in some details that may cause uncertainty in the future reference. This study provides a detailed case observation on the on-going discussions of the type of standards the HCA community should take when releasing data and publications to guarantee the reproducibility and reliability of the future atlas.
Transformation of event representations along middle temporal gyrus
Authors: Leshinskaya Anna , Thompson-Schill Sharon L.
Published: November 2018

When learning about events through visual experience, one must not only identify which events are visually similar, but also retrieve those events’ associates—which may be visually dissimilar—and recognize when different events have similar predictive relations. How are these demands balanced? To address this question, we taught participants the predictive structures among four events, which appeared in four different sequences, each cued by a distinct object. In each, one event (‘cause’) was predictably followed by another (‘effect’). Sequences in the same relational category had similar predictive structure, while across categories, the effect and cause events were reversed. Using fMRI data, we measuredassociative coding, indicated by correlated responses between effect and cause events;perceptual coding, indicated by correlated responses to visually similar events; andrelational category coding, indicated by correlated responses to objects in the same relational category. All three models characterized responses within right middle temporal gyrus (MTG), but in different ways: perceptual and associative coding diverged along the posterior to anterior axis, while relational categories emerged anteriorly in tandem with associative coding. Thus, along the posterior-anterior axis of MTG, the representation of the visual attributes of events is transformed to a representation of both specific and generalizable relational attributes.
Direct binding of Cdt2 to PCNA is important for targeting the CRL4Cdt2 E3 ligase activity to Cdt1
Authors: Hayashi Akiyo , Giakoumakis Nickolaos Nikiforos , Heidebrecht Tatjana , Ishii Takashi , Panagopoulos Andreas , Caillat Christophe , Takahara Michiyo , Hibbert Richard G. , Suenaga Naohiro , Stadnik-Spiewak Magda , Takahashi Tatsuro , Shiomi Yasushi , Taraviras Stavros , von Castelmur Eleonore , Lygerou Zoi , Perrakis Anastassis , Nishitani Hideo
Published: November 2018

The CRL4Cdt2 ubiquitin ligase complex is an essential regulator of cell-cycle progression and genome stability, ubiquitinating substrates such as p21, Set8 and Cdt1, via a display of substrate degrons on PCNA. Here, we examine the hierarchy of the ligase and substrate recruitment kinetics onto PCNA at sites of DNA replication. We demonstrate that the C-terminal end of Cdt2 bears a PCNA interaction protein motif (PIP box, Cdt2PIP), which is necessary and sufficient for binding of Cdt2 to PCNA. Cdt2PIP binds PCNA directly with high affinity, two orders of magnitude tighter than the PIP box of Cdt1. X-ray crystallographic structures of PCNA bound to Cdt2PIP and Cdt1PIP show that the peptides occupy all three binding sites of the trimeric PCNA ring. Mutating Cdt2PIP weakens the interaction with PCNA, rendering CRL4Cdt2 less effective in Cdt1 ubiquitination and leading to defects in Cdt1 degradation. The molecular mechanism we present suggests a new paradigm for bringing substrates to the CRL4-type ligase, where the substrate receptor and substrates bind to a common multivalent docking platform to enable subsequent ubiquitination.

Summary blurb

The C-terminal end of Cdt2 contains a PIP-box for binding to PCNA to promote CRL4Cdt2 function, creating a new paradigm, where the substrate receptor and substrates bind to a common multivalent docking platform for ubiquitination.
Reorganization of budding yeast cytoplasm upon energy depletion
Authors: Marini Guendalina , Nüske Elisabeth , Leng Weihua , Alberti Simon , Pigino Gaia
Published: November 2018

Yeast cells, when exposed to stress, can enter a protective state in which cell division, growth and metabolism are downregulated. They remain viable in this state until nutrients become available again. How cells enter this protective survival state and what happens at a cellular and subcellular level is largely unknown. In this study, we used electron tomography to investigate the stress-induced ultrastructural changes in the cytoplasm of yeast cells. After ATP depletion, we observed a significant cytosolic compaction and an extensive cytoplasmic reorganization, as well as the emergence of distinct membrane-bound and membrane-less organelles. By using correlative light and electron microscopy (CLEM), we further demonstrate that one of these membrane-less organelles is generated by the reversible polymerization into large bundles of filaments of the eukaryotic translation initiation factor 2B (eIF2B), an essential enzyme in the initiation of protein synthesis. The changes we observe are part of a stress-induced survival strategy, allowing yeast cells to save energy, protect proteins from degradation, and inhibit protein functionality by forming assemblies of said proteins.
Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease
Authors: Konki Mikko , Malonzo Maia , Karlsson Ida K. , Lindgren Noora , Ghimire Bishwa , Smolander Johannes , Scheinin Noora M. , Ollikainen Miina , Laiho Asta , Elo Laura L. , Lönnberg Tapio , Röyttä Matias , Pedersen Nancy L. , Kaprio Jaakko , Lähdesmäki Harri , Rinne Juha , Lund Riikka J.
Published: November 2018

Alzheimer’s disease (AD) results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. As life style factors largely modulate the disease risk, we hypothesised that the disease associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. Reduced Representation Bisulfite Sequencing, single cell RNA-sequencing and gene array data were utilised to examine DNA methylation signatures and associated gene expression changes in blood and hippocampus, and targeted bisulfite sequencing in cross cohort validation. Our results reveal that discordant twin pairs have disease associated differences in their peripheral blood epigenomes. A subset of affected genes, e.g.ADARB2contain differentially methylated sites also in anterior hippocampus. The DNA methylation differences seem to influence gene expression in brain rather than in blood cells. The affected genes are associated with neuronal functions and pathologies. These DNA methylation signatures are valuable disease marker candidates and may provide insights into the molecular mechanisms of pathogenesis.
Lateral ventricle volume trajectories predict response inhibition in older age - a longitudinal brain imaging and machine learning approach
Authors: Lundervold Astri J. , Vik Alexandra , Lundervold Arvid
Published: November 2018

Objective:

In a three-wave ~6 yrs longitudinal study we investigated if expansion of lateral ventricle (LV) volumes (regarded as a proxy for brain parenchyma loss) predicts performance on a test of response inhibition.

Participants and Methods:

Anatomical trajectories of left (LH) and right (RH) lateral ventricle volumes across the three study-waves were quantified using the Longitudinal Stream in Freesurfer 5.3 and modelled using a linear mixed-effects (LME) algorithm. All participants (N = 74, mean age 60.7 yrs at inclusion, 48 females) performed the Color-Word Interference Test (CWIT). Response time on the third condition was used as a measure of response inhibition (RI) and divided into three classes (fast, medium and slow). The Extreme Gradient Boosting (XGBoost) algorithm was used for calculating the relative importance of selected LV volume features from the LME model in predicting RI class. Finally, the two most important extracted features were fed into a 10-fold cross-validation framework, estimating the accuracy, precision and recall of the RI class prediction.

Results:

Four LME based features were selected to characterize LV volume trajectories: steepness of LV volume change and the LV volume at the time of inclusion, each from the right and left hemisphere. The XGBoost procedure selected the steepness measure from the right and the volume at inclusion from the left hemisphere as the two most important features to predict RI performance. The 10-fold cross validation procedure showed a recall, precision and accuracy score (.40 - .50) that were clearly above chance level.

Conclusion:

Measures of the LV volume trajectories gave a fairly good prediction of response inhibition performance, confirming the role of LV volume as a biomarker of cognitive function in older adults. Future studies should investigate the value of the lateral ventricle volume trajectories as predictors of cognitive preservation or decline into older age.
Associations between impulsivity, risk behavior and HIV, HBV, HCV and syphilis seroprevalence among female prisoners in Indonesia: A cross-sectional study
Authors: Arends Rachel M. , Nelwan Erni J. , Soediro Ratna , van Crevel Reinout , Alisjahbana Bachti , Pohan Herdiman T. , von Borries A. Katinka L. , Schene Aart H. , van der Ven André J. A. M. , Schellekens Arnt F. A.
Published: November 2018

HIV, hepatitis B and C, and syphilis share common transmission routes of which primarily unsafe sexual contact and injecting drug use are important. Impulsivity is a major factor contributing to this transmission risk behavior, however comprehensive studies within female, prison, and Asian populations are scarce. This cross-sectional study aims to delineate the contributions of different aspects of impulsivity to transmission risk behavior, among female inmates living in a prison in Jakarta (N=214). The relationships between various aspects of impulsivity, risky behavior and seropositivity were tested using analyses of variance and logistic regression analyses. Motor impulsivity was related to alcohol use, reward-related impulsivity to drug use, and cognitive/goal-directed impulsivity to sexual risk behavior. Finally, goal-directed impulsivity was also directly associated with seropositivity. Specific aspects of impulsivity are associated with different types of risky behaviors in Indonesian female prisoners, what can be relevant for future studies on infection prevention strategies for such a population.