bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological tuning of microRNAs in FAP-derived Extracellular Vesicles by HDAC inhibitors promotes regeneration and reduces fibrosis in dystrophic muscles
Authors: Sandonà M. , Consalvi S. , Tucciarone L. , Bardi M. De , Scimeca M. , Angelini D. , Buffa V. , D’Amico A. , Bertini E. , Cazzaniga S. , Bettica P. , Bouché M. , Bongiovanni A. , Puri P.L. , Saccone V.
Published: February 2020

Functional interactions between cellular components of the muscle stem cell (MuSC) niche regulate the regenerative ability of skeletal muscles in physiological and pathological conditions; however, the identity of the mediators of these interactions remains largely unknown. We show here that fibro-adipogenic progenitor (FAP)-derived Extracellular Vesicles (EVs) mediate microRNA transfer to MuSCs, and that exposure of dystrophic FAPs to HDAC inhibitors (HDACi) increases the intra-EV levels of a subset of microRNAs (miRs), which cooperatively target biological processes of therapeutic interest, including regeneration, fibrosis and inflammation. In particular, we found that increased levels of miR206 in EVs released from FAPs of muscles from Duchenne dystrophic patients or mice (mdx) exposed to HDACi were associated with enhanced regeneration and inhibition of fibrosis of dystrophic muscles. Consistently, EVs from HDACi-treated dystrophic FAPs could stimulated MuSC activation and expansion ex vivo, and promoted regeneration, while inhibiting fibrosis and inflammation of dystrophic muscles, upon intramuscular transplantation, in vivo. These data reveal a potential for pharmacological modulation of FAP-derived EV’s content as novel strategy for focal therapeutic interventions in Duchenne Muscular Dystrophy (DMD) and possibly other muscular diseases.

Brief Summary

Extracellular Vesicles from HDACi-treated dystrophic FAPs promote regeneration, while inhibiting fibrosis and inflammation of dystrophic muscles
Genome-Wide Identification of Epigenetic Regulators inQuercus suber
Authors: Silva HG , Sobral RS , Magalhães AP , Morais-Cecílio L , Costa MMR
Published: February 2020

Modifications of DNA and histones, including methylation and acetylation, are critical for the epigenetic regulation of gene expression during plant development, particularly during environmental adaptation processes. However, information on the enzymes catalyzing all these modifications in perennial trees, such asQuercus suber, is still not available. In this study, several epigenetic modifier proteins, including eight DNA methyltransferases (DNA Mtases), three DNA demethylases (DDMEs) and ninety-one histone modifiers including thirty-five histone methyltransferases (HMTs), twenty-six histone demethylases (HDMTs), eight histone acetyltransferases (HATs) and twenty-two histone acetylases (HDACs) were identified inQ. suber. Phylogenetic analyses of the DNA and histone modifier proteins were performed using several plant species homologs, enabling the classification of theQ. suberproteins. Additionalin silicoanalysis showed that someQ. suberDNA Mtases, DMEs and histone modifiers have the typical domains found in the plant model Arabidopsis, which might suggest a conserved functional role. A link between the expression levels of each gene in differentQ. subertissues (buds, flowers, acorns, embryos, cork and roots) with the functions already known for their closest homologs in other species was also established. Therefore, the data generated here are important for future studies exploring the role of epigenetic regulators in this economically important species.
TheStreptomycesvolatile 3-octanone alters auxin/cytokinin and growth inArabidopsis thalianavia the gene familyKISS ME DEADLY
Authors: Dotson Bradley R. , Verschut Vasiliki , Flärdh Klas , Becher Paul G. , Rasmusson Allan G.
Published: February 2020

Plants enhance their growth in the presence of particular soil bacteria due to volatile compounds affecting the homeostasis of plant growth hormones. However, the mechanisms of volatile compound signaling and plant perception has been unclear. This study identifies the bioactive volatile 3-octanone as a plant growth stimulating volatile, constitutively emitted by the soil bacteriumStreptomyces coelicolorgrown on a rich medium. When 3-octanone is applied to developingArabidopsis thalianaseedlings, a family-wide induction of the Kelch-repeat F-box genes known asKISS ME DEADLY(KMD) subsequently alters auxin/cytokinin homeostasis to promote the growth of lateral roots and inhibit the primary root. Loss of function of theKMDfamily or other alterations of auxin/cytokinin homeostasis suppresses the volatile-induced growth response. This reveals a function ofKMDs in the pathway of microbial volatile perception and plant growth responses.

Significance Statement

Volatiles from soil microbes are profound stimulators of plant growth. This work identifies for the first time a plant hormone signaling regulator, the gene familyKISS ME DEADLY(KMD), to be an early essential step in plant growth promotion by a soil bacterial volatile, 3-octanone. TheKMD-regulated gene network alters the tissue sensitivity balance for the growth hormones auxin and cytokinin, modifying root growth rate and architecture. Previously, the Kelch repeat F-box gene family ofKMDs have been shown to be important down-regulators of both positive cytokinin signaling and phenylpropanoid biosynthesis, but upstream cues were unknown. This report places theKMDfamily regulation of plant growth and defense into its biotic context.
Emergence and diversification of a highly invasive chestnut pathogen lineage across south-eastern Europe
Authors: Stauber Lea , Badet Thomas , Prospero Simone , Croll Daniel
Published: February 2020

Invasive microbial species constitute a major threat to biodiversity, agricultural production and human health. Invasions are often dominated by one or a small number of genotypes, yet the underlying factors driving invasions are poorly understood. The chestnut blight fungusCryphonectria parasiticafirst decimated the American chestnut and a recent outbreak threatens European chestnut trees. To unravel the mechanisms underpinning the invasion of south-eastern Europe, we sequenced 188 genomes of predominantly European strains. Genotypes outside of the invasion zone showed high levels of diversity with evidence for frequent and ongoing recombination. The invasive lineage emerged from the highly diverse European genotype pool rather than a secondary introduction from Asia. The expansion across south-eastern Europe was mostly clonal and is dominated by a single mating type suggesting a fitness advantage of asexual reproduction. Our findings show how an intermediary, highly diverse bridgehead population gave rise to an invasive, largely clonally expanding pathogen.

Data availability

All raw sequencing data is available on the NCBI Short Read Archive (BioProject PRJNA604575)
Helicobactersmall RNA regulates host adaptation and carcinogenesis
Authors: Kinoshita-Daitoku Ryo , Kiga Kotaro , Otsubo Ryota , Ogura Yoshitoshi , Sanada Takahito , Bo Zhu , Phuoc Tuan Vo , Okano Tokuju , Iida Tamako , Yokomori Rui , Kuroda Eisuke , Hirukawa Sayaka , Tanaka Mototsugu , Sood Arpana , Subsomwong Phawinee , Ashida Hiroshi , Binh Tran Thanh , Nguyen Lam Tung , Van Khien Vu , Dung Ho Dang Quy , Nakai Kenta , Suzuki Toshihiko , Yamaoka Yoshio , Hayashi Tetsuya , Mimuro Hitomi
Published: February 2020

Type-1 carcinogenicHelicobacter pylorithat is known to evolve during long-term infection, enters the stomach orally and causes gastric cancer using the carcinogenic protein CagA1. However, little is known about the adaptation mechanisms ofH. pyloriwhen the environment changes from the outside to the inside of the living body. Here we show that small non-coding RNA HPnc4160 is a crucial novel RNA molecule ofH. pylorithat negatively regulates bacterial-host adaptation and gastric cancer.H. pyloriisolated from gerbil’s stomachs eight weeks post-infection acquired mutations in the increased number of T-repeats within the upstream region of the HPnc4160 coding region, which leads to reduced HPnc4160 expression levels that also seen in cancer patients-derivedH. pylori. By comparing RNA-seq and iTRAQ analysis between wild-type andhpnc4160deficient mutant strains, we identified eight targets of HPnc4160 includingcagAand unknown factors. Mice infection experiment revealed that thehpnc4160deficient mutant had a higher number of colonized bacteria in the mice stomach than the wild-type strain, indicating that reduced expression levels of HPnc4160 was important for bacterial host adaptation. The expression level of HPnc4160 was lower in the clinical isolates derived from gastric cancer patients compared with non-cancer-derived strains, while the mRNA expression levels of target factors were higher. Our findings highlight the first discovery that HPnc4160 is an important small RNA for bacteria to adapt to the host environment leading to gastric carcinogenesis.
High-qualityde novogenome assembly ofKappaphycus alvareziibased on both PacBio and HiSeq sequencing
Authors: Jia Shangang , Wang Guoliang , Liu Guiming , Qu Jiangyong , Zhao Beilun , Jin Xinhao , Zhang Lei , Yin Jinlong , Liu Cui , Shan Guangle , Wu Shuangxiu , Song Lipu , Liu Tao , Wang Xumin , Yu Jun
Published: February 2020

The red algaeKappaphycus alvareziiis the most important aquaculture species inKappaphycus, widely distributed in tropical waters, and it has become the main crop of carrageenan production at present. The mechanisms of adaptation for high temperature, high salinity environments and carbohydrate metabolism may provide an important inspiration for marine algae study. Scientific background knowledge such as genomic data will be also essential to improve disease resistance and production traits ofK. alvarezii. 43.28 Gb short paired-end reads and 18.52 Gb single-molecule long reads ofK. alvareziiwere generated by Illumina HiSeq platform and Pacbio RSII platform respectively. Thede novogenome assembly was performed using Falcon_unzip and Canu software, and then improved with Pilon. The final assembled genome (336 Mb) consists of 888 scaffolds with a contig N50 of 849 Kb. Further annotation analyses predicted 21,422 protein-coding genes, with 61.28% functionally annotated. Here we report the draft genome and annotations ofK. alvarezii, which are valuable resources for future genomic and genetic studies inKappaphycusand other algae.
The significance of mitochondrial DNA half-life to the lifespan of post-mitotic cells
Authors: Holt Alan G , Davies Adrian M
Published: February 2020

The proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging, and age related neurodegenerative conditions. In this study we model effect of mtDNA half-life on mtDNA competition and selection.

Individual cells effectively form a closed ecosystem containing a large population of independently replicating mtDNA. We would expect competition and selection to occur between wild type mtDNA and various mutant variants. There is a symbiotic relationship between the cell and the mitochondria, and unrestricted mtDNA replication would be detrimental to the host cell. Deletion mutations of mtDNA are relatively common and give a replication advantage to the shorter sequence, as this could be lethal to the host cell, we would expect to see differences in mtDNA replication in short and long lived cells.

In this paper, we use a computer simulation of mtDNA replication, where mtDNA sequences may undergo deletion errors and give rise to mutant species that can compete with the wild type. This study focuses on longer lived cells where the wild type mtDNA is expected to be more susceptible to displacement by mutants. Our simulations confirm that deletion mutations have a replication advantage over the wild type due to decreased replication time. Wild type survival times diminished with increased mutation probabilities. The relationship between survival time and mutation rate was non-linear; a ten-fold increase in mutation probability resulted in a halving in wild type survival time.

In contrast a modest increase in the mtDNA half-life had a profound affect on the wild type survival time in the presence of deletion mutants, thereby, mitigating the replicative advantage of shorter sequence mutations. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could be a therapeutic strategy.
Suppressing peatland methane production by electron snorkeling through pyrogenic carbon
Authors: Sun Tianran , Guzman Juan J. L. , Seward James D. , Enders Akio , Yavitt Joseph B. , Lehmann Johannes , Angenent Largus T.
Published: February 2020

Northern peatlands are experiencing more frequent fire events as a result of changing climate conditions. Forest fires naturally result in a direct and negative climate impact by emitting large amounts of carbon into the atmosphere. Recent studies show that this extensive emission may shift the soil carbon regime from a sink to a source. However, the fires also convert parts of the burnt biomass into pyrogenic carbon. Here, we show an indirect, but positive, climate impact induced by fire-derived pyrogenic carbon. We found that the accumulation of pyrogenic carbon reduced post-fire methane production from peatland soils by 13-24%. The conductive, capacitive, and redox-cycling electron transfer mechanisms enabled pyrogenic carbon to function as an electron snorkel, which redirected soil electron fluxes to facilitate alternative microbial respiration and reduced the rate of methane production by 50%. Given the fact that methane has a 34-fold greater warming potential than carbon dioxide, we estimate that global greenhouse gas emissions are reduced by 35 Tg CO2e annually through the electron snorkeling of pyrogenic carbon in peatlands. Our results highlight an important, but overlooked, function of pyrogenic carbon in neutralizing forest fire emissions and call for its consideration in the global carbon budget estimation.
Skeletonization of Plant Point Cloud Data in Stochastic Optimization Framework
Authors: Chaudhury Ayan , Godin Christophe
Published: February 2020

Skeleton extraction from 3D plant point cloud data is an essential prior for myriads of phenotyping studies. Although skeleton extraction from 3D shapes have been studied extensively in the computer vision and graphics literature, handling the case of plants is still an open problem. Drawbacks of the existing approaches include the zigzag structure of the skeleton, nonuniform density of skeleton points, lack of points in the areas having complex geometry structure, and most importantly the lack of biological relevance. With the aim to improve existing skeleton structures of state-of-the-art, we propose a stochastic framework which is supported by the biological structure of the original plant (we consider plants without any leaves). Initially we estimate the branching structure of the plant by the notion of β-splines to form acurve treedefined as a finite set of curves joined in a tree topology with certain level of smoothness. In the next phase, we force the discrete points in the curve tree to move towards the original point cloud by treating each point in the curve tree as a center of Gaussian, and points in the input cloud data as observations from the Gaussians. The task is to find the correct locations of the Gaussian centroids by maximizing a likelihood. The optimization technique is iterative and is based on the Expectation Maximization (EM) algorithm. The E-step estimates which Gaussian the observed point cloud was sampled from, and the M-step maximizes the negative log-likelihood that the observed points were sampled from the Gaussian Mixture Model (GMM) with respect to the model parameters. We experiment with several real world and synthetic datasets and demonstrate the robustness of the approach over the state-of-the-art.
Infrared heater warming system markedly reduces dew formation: An overlooked factor in arid ecosystems
Authors: Feng Tianjiao , Zhang Lixu , Chen Qian , Ma Zhiyuan , Wang Hao , Shangguan Zijian , Wang Lixin , He Jin-Sheng
Published: February 2020

Dew plays a vital role in ecosystem processes in arid and semi-arid regions and is expected to be affected by climate warming. Infrared heater warming systems have been widely used to simulate climate warming effects on ecosystem. However, how this warming system affects dew formation has been long ignored and rarely addressed. In a typical alpine grassland ecosystem on the Northeast of the Tibetan Plateau, we measured dew amount and duration by artificial condensing surfaces, leaf wetness sensors andin situdew formation on plants from 2012 to 2017. We also measured plant traits related to dew conditions. The results showed that (1) warming reduced the dew amount by 41.6%-91.1% depending on the measurement method, and reduced dew duration by 32.1 days compared to the ambient condition. (2) Different plant functional groups differed in dew formation. (3) Under the infrared warming treatment, the dew amount decreased with plant height, while under the ambient conditions, the dew amount showed the opposite trend. We concluded that warming with an infrared heater system greatly reduces dew formation, and if ignored, it may lead to overestimation of the effects of climate warming on ecosystem processes in climate change simulation studies.
Faster than thought: Detecting sub-second activation sequences with sequential fMRI pattern analysis
Authors: Wittkuhn Lennart , Schuck Nicolas W.
Published: February 2020

Neural computations are often anatomically localized and executed on sub-second time scales. Understanding the brain therefore requires methods that offer sufficient spatial and temporal resolution. This poses a particular challenge for the study of the human brain because non-invasive methods have either high temporalorspatial resolution, but not both. Here, we introduce a novel multivariate analysis method for conventional blood-oxygen-level dependent functional magnetic resonance imaging (BOLD fMRI) that allows to study sequentially activated neural patterns separated by less than 100 ms with anatomical precision. Human participants underwent fMRI and were presented with sequences of visual stimuli separated by 32 to 2048 ms. Probabilistic pattern classifiers were trained on fMRI data to detect the presence of image-specific activation patterns in early visual and ventral temporal cortex. The classifiers were then applied to data recorded during sequences of the same images presented at increasing speeds. Our results show that probabilistic classifier time courses allowed to detect neural representations and their order, even when images were separated by only 32 ms. Moreover, the frequency spectrum of the statistical sequentiality metric distinguished between sequence speeds on sub-second versus supra-second time scales. These results survived when data with high levels of noise and rare sequence events at unknown times were analyzed. Our method promises to lay the groundwork for novel investigations of fast neural computations in the human brain, such as hippocampal replay.
Hierarchical coupling between ATP hydrolysis and Hsp90’s client binding site
Authors: Wolf Steffen , Sohmen Benedikt , Hellenkamp Björn , Thurn Johann , Stock Gerhard , Hugel Thorsten
Published: February 2020

I.

Several indicators for a signal propagation from a binding site to a distant functional site have been found in the Hsp90 dimer. Here we determined a time-resolved pathway from ATP hydrolysis to changes in a distant folding substrate binding site. This was possible by combining single-molecule fluorescence-based methods with extensive atomistic nonequilibrium molecular dynamics simulations. We find that hydrolysis of one ATP effects a structural asymmetry in the full Hsp90 dimer that leads to the collapse of a central folding substrate binding site. Arg380 is the major mediator in transferring structural information from the nucleotide to the substrate binding site. This allosteric process occurs via hierarchical dynamics that involve timescales from picoto milliseconds and length scales from Ångstroms to several nanometers. We presume that similar hierarchical mechanisms are fundamental for information transfer through many other proteins.
Parkinson’s disease determinants, prediction and gene-environment interactions in the UK Biobank
Authors: Jacobs Benjamin M. , Belete Daniel , Bestwick Jonathan P , Blauwendraat Cornelis , Bandres-Ciga Sara , Heilbron Karl , Dobson Ruth , Nalls Mike A. , Singleton Andrew B. , Hardy John , Giovannoni Gavin , Lees Andrew J. , Schrag Anette , Noyce Alastair J ,   for The International Parkinson’s Disease Genomics Consortium (IPDGC)
Published: February 2020

Objective

To systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate existing risk prediction algorithms and the impact of including addition genetic risk on the performance of prediction.

Methods

We identified individuals with incident PD diagnoses (n=1276) and unmatched controls (n=500,406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. A polygenic risk score (PRS) was constructed and used to examine gene-environment interactions. The PRS was also incorporated into a previously-developed prediction algorithm for finding incident cases.

Results

Strong evidence of association (Pcorr<0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, and daytime somnolence, and novel associations with epilepsy and earlier menarche. Individuals with the highest 10% of PRS scores had increased risk of PD (OR=3.30, 95% CI 2.57-4.24) compared to the lowest risk decile. Higher PRS scores were associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm improved model performance (Nagelkerke pseudo-R20.0053, p=6.87×10−14). We found evidence of interaction between the PRS and diabetes.

Interpretation

Here we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity and predictive power of a polygenic risk score, and to demonstrate a novel gene-environment interaction, whereby the effect of diabetes on PD risk appears to depend on prior genetic risk for PD.
Oecophyllibacter saccharovoransgen. nov. sp. nov., a bacterial symbiont of the weaver antOecophylla smaragdina
Authors: Chua Kah-Ooi , See-Too Wah-Seng , Tan Jia-Yi , Song Sze-Looi , Yong Hoi-Sen , Yin Wai-Fong , Chan Kok-Gan
Published: February 2020

In this study, bacterial strains Ha5T, Ta1 and Jb2 were isolated from different colonies of weaver antOecophylla smaragdina. They were distinguished as different strains based on matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry and distinctive random-amplified polymorphic DNA (RAPD) fingerprints. Cells of these bacterial strains were Gram-negative, rod-shaped, aerobic, non-motile, catalase-positive and oxidase-negative. They were able to grow at 15–37°C (optimum, 28–30°C) and in the presence of 0–1.5 % (w/v) NaCl (optimum 0%). Their predominant cellular fatty acids were C18:1ω7c, C16:0, C19:0ω8ccyclo, C14:0and C16:02-OH. Strains Ha5T, Ta1 and Jb2 shared highest 16S rRNA gene sequence similarity (94.56–94.63%) withNeokomagataea tanensisNBRC106556Tbut were phylogenetically closer toBombellaspp. andSaccharibacterfloricolaDSM15669T. Both 16S rRNA gene sequence-based phylogenetic analysis and core gene-based phylogenomic analysis placed them in a distinct lineage in familyAcetobacteraceae. These bacterial strains shared higher than species level thresholds in multiple overall genome-relatedness indices which indicated that they belonged to the same species. In addition, they did not belong to any of the current taxa ofAcetobacteraceaeas they had low pairwise average nucleotide identity (≤70.7%),in silicoDNA-DNA hybridization (≤39.5%) and average amino acid identity (≤66.ü%) values with all the type members of the family. Based on these results, bacterial strains Ha5T, Ta1 and Jb2 represent a novel species of a novel genus in familyAcetobacteraceae,for which we propose the nameOecophyllibacter saccharovoransgen. nov. sp. nov., and strain Ha5Tas the type strain.
LC/MS-QToF Profiling, Anti-Diabetic and Anti-Adipogenic potential of Divya MadhuKalp: A Novel Herbo-mineral Formulation
Authors: Balkrishna Acharya , Joshi Alpana , Das Subrata K. , Bisht Laxmi , Sakat Sachin , Sharma Vinamra , Sharma Niti , Joshi Khemraj , Verma Sudeep , Sharma Vinay K , Joshi CS
Published: February 2020

The incidence rate of diabetes mellitus is increasing worldwide. Herbal formulations have recently gained importance as an alternative therapeutic option in controlling diabetes without causing any side effects. In the present study, we have demonstrated maintenance of glycemic homeostasis and anti-adipogenic potential of a herbo-mineral formulation Divya MadhuKalp (DMK). Initially, we evaluated the presence of bioactive compounds in DMK using LC/MS-QToF analysis. In-vitro analysis of DMK in L6 (skeletal muscle) cells showed a significant increase in cellular glucose uptake. Similarly, a human equivalent dose of DMK significantly reduced blood glucose level in normoglycemic and oral glucose tolerance rat model. DMK extract also inhibited formation of advanced glycation end product and showed anti-α-glucosidase activity. Further analysis of DMK in 3T3 L1 pre-adipocytes demonstrated anti-adipogenic activity through reduction in intracellular lipid accumulation and triglyceride contents along with downregulation of major adipogenic transcriptional factors (PPAR-γ and C/EBPα) and, adipocytes marker genes (LPL, AP2 and adiponectin). In conclusion, DMK exhibited anti-diabetic and anti-adipogenic activities by synergistic effect of its bioactive compounds and can be considered as a potent herbo-mineral formulation for treating metabolic diseases.
A Bayesian nonparametric approach to super-resolution single-molecule localization
Authors: Gabitto Mariano I. , Marie-Nelly Herve , Pakman Ari , Pataki Andras , Darzacq Xavier , Jordan Michael I.
Published: February 2020

We consider the problem of single-molecule identification in super-resolution microscopy. Super-resolution microscopy overcomes the diffraction limit by localizing individual fluorescing molecules in a field of view. This is particularly difficult since each individual molecule appears and disappears randomly across time and because the total number of molecules in the field of view is unknown. Additionally, data sets acquired with super-resolution microscopes can contain a large number of spurious fluorescent fluctuations caused by background noise.

To address these problems, we present a Bayesian nonparametric framework capable of identifying individual emitting molecules in super-resolved time series. We tackle the localization problem in the case in which each individual molecule is already localized in space. First, we collapse observations in time and develop a fast algorithm that builds upon the Dirichlet process. Next, we augment the model to account for the temporal aspect of fluorophore photo-physics. Finally, we assess the performance of our methods with ground-truth data sets having known biological structure.
Signal propagation via cortical hierarchies
Authors: Vázquez-Rodríguez Bertha , Liu Zhen-Qi , Hagmann Patric , Mišić Bratislav
Published: February 2020

The wiring of the brain is organized around a putative unimodal-transmodal hierarchy. Here we investigate how this intrinsic hierarchical organization of the brain shapes the transmission of information among regions. The hierarchical positioning of individual regions was quantified by applying diffusion map embedding to resting state functional MRI networks. Structural networks were reconstructed from diffusion spectrum imaging and topological shortest paths among all brain regions were computed. Sequences of nodes encountered along a path were labelled by their hierarchical position, tracing out path motifs. We find that the cortical hierarchy guides communication in the network. Specifically, nodes are more likely to forward signals to nodes closer in the hierarchy and cover a range of unimodal and transmodal regions, potentially enriching or diversifying signals en route. We also find evidence of systematic detours, particularly in attention networks, where communication is re-routed. Altogether, the present work highlights how the cortical hierarchy shapes signal exchange and imparts behaviourally-relevant communication patterns in brain networks.
A novel voltage clamp/dye uptake assay reveals saturable transport of molecules through CALHM1 and connexin channels
Authors: Gaete Pablo S. , Lillo Mauricio A. , López William , Liu Yu , Harris Andrew L. , Contreras Jorge E.
Published: February 2020

Channels that are permeable to small molecules such as ATP, in addition to atomic ions, are emerging as important regulators in health and disease. Nonetheless, mechanisms of molecular permeation and selectivity of these channels remain mostly unexplored due to the lack of quantitative methodologies. To address this need, we developed a novel two-electrode voltage clamp (TEVC)/dye uptake assay to examine the kinetics of molecular permeation of channels formed by human connexins (hCx), and the calcium homeostasis modulator (hCALHM1). We expressed hCx26, hCx30, and hCALHM1 individually inXenopus laevisoocytes. To quantify the uptake of small molecular dyes through these channels, we developed a protocol that renders oocytes translucent – thereby amenable to optical detection techniques – without affecting the functional properties of the expressed channels. To control membrane potential and to determine functional channel expression accurately, dye uptake was evaluated in conjunction with TEVC. Using this methodology, we found that: (1) CALHM1 and Cx30 hemichannels display saturable transport of molecules that could be described by Michaelis-Menten kinetics, with apparent KMand Vmax; (2) Kinetic parameters for molecular transport through CALHM1 are sensitive to voltage and extracellular calcium; (3) Significant transport of molecules occurs through CALHM1 when there are little or no ionic currents through the channels; (4) Cx mutations in the N-terminal region significantly affect kinetics of transport and permselectivity. Our results reveal that molecular flux through these channels has a rate-limiting step, that the kinetic parameters of molecular transport are sensitive to modulators of channel gating and that molecular transport and ionic currents can be differentially affected. Our methodology allows the analysis of how human mutations causing diseases affect kinetic properties and permselectivity of molecular signaling and enables the study of molecular mechanisms, including selectivity and saturability, associated with molecular transport in large-pore channels.
North-westward range expansion of the bumblebeeBombus haematurusinto Central Europe is associated with warmer winters and niche conservatism
Authors: Biella Paolo , Ćetković Aleksandar , Gogala Andrej , Neumayer Johann , Sárospataki Miklós , Šima Peter , Smetana Vladimir
Published: February 2020

Range expansions of naturally spreading species are crucial for understanding how species interact with the environment and build their niche. Here, we studied the bumblebeeBombus haematurusKriechbaumer, 1870, a species historically distributed in the eastern Mediterranean area which has very recently started expanding northwards into Central Europe. After updating the global distribution of this species, we investigated if niche shifts took place during this range expansion between colonized and historical areas. In addition, we have explored which climatic factors have favoured the natural range expansion of the species. Our results indicated thatBombus haematurushas colonized large territories in 7 European countries outside the historical area in the period from the 1980s to 2018, a natural expansion over an area that equals the 20% of the historical distribution. In addition, this bumblebee performs generalism in flower visitation and habitat use, although a preference for forested areas emerges. The land-use associated with the species in the colonized areas is similar to the historical distribution, indicating that no major niche shifts occurred during the spread. Furthermore, the component of climate change that favoured this colonization is the warming of winter temperatures and similar warming rates took place during both overwintering and queen’s emergence phases. These findings document a case of natural range expansion due to environmental change rather than due to niche shifts, and specifically they indicate that warmer winters are playing a major role in the process of natural colonization of new areas.
Analysis of variance when both input and output sets are high-dimensional
Authors: de los Campos Gustavo , Pook Torsten , Gonzalez-Raymundez Agustin , Simianer Henner , Mias George , Vazquez Ana I.
Published: February 2020

Motivation

Modern genomic data sets often involve multiple data-layers (e.g., DNA-sequence, gene expression), each of which itself can be high-dimensional. The biological processes underlying these data-layers can lead to intricate multivariate association patterns.

Results

We propose and evaluate two methods for analysis variance when both input and output sets are high-dimensional. Our approach uses random effects models to estimate the proportion of variance of vectors in the linear span of the output set that can be explained by regression on the input set. We consider a method based on orthogonal basis (Eigen-ANOVA) and one that uses random vectors (Monte Carlo ANOVA, MC-ANOVA) in the linear span of the output set. We used simulations to assess the bias and variance of each of the methods, and to compare it with that of the Partial Least Squares (PLS)–an approach commonly used in multivariate-high-dimensional regressions. The MC-ANOVA method gave nearly unbiased estimates in all the simulation scenarios considered. Estimates produced by Eigen-ANOVA and PLS had noticeable biases. Finally, we demonstrate insight that can be obtained with the of MC-ANOVA and Eigen-ANOVA by applying these two methods to the study of multi-locus linkage disequilibrium in chicken genomes and to the assessment of inter-dependencies between gene expression, methylation and copy-number-variants in data from breast cancer tumors.

Availability

The Supplementary data includes an R-implementation of each of the proposed methods as well as the scripts used in simulations and in the real-data analyses.

Contact

gustavoc@msu.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
Authors: Sun Chunyun , Chen Long , Yang Ji , Luo Chunxia , Zhang Yanjing , Li Jing , Yang Jiahui , Zhang Jie , Xie Liangzhi
Published: February 2020

SARS-CoV-2 and SARS-CoV share a common human receptor ACE2. Protein-protein interaction structure modeling indicates that spike-RBD of the two viruses also has similar overall binding conformation and binding free energy to ACE2.In vitroassays using recombinant ACE2 proteins and ACE2 expressing cells confirmed the two coronaviruses’ similar binding affinities to ACE2. The above studies provide experimental supporting evidences and possible explanation for the high transmissibility observed in the SARS-CoV-2 outbreak. Potent ACE2-blocking SARS-CoV neutralizing antibodies showed limited cross-binding and neutralizing activities to SARS-CoV-2. ACE2-non-blocking SARS-CoV RBD antibodies, though with weaker neutralizing activities against SARS-CoV, showed positive cross-neutralizing activities to SARS-CoV-2 with an unknown mechanism. These findings suggest a trade-off between the efficacy and spectrum for therapeutic antibodies to different coronaviruses, and hence highlight the possibilities and challenges in developing broadly protecting antibodies and vaccines against SARS-CoV-2 and its future mutants.
Full cell infiltration and thick tissue formationin vivoin tailored electrospun scaffolds
Authors: Zonderland Jip , Rezzola Silvia , Gomes David , Espinosa Sandra Camarero , Lourenço Ana Henriques Ferreira , Serafim Andrada , Stancu Izabela Cristina , Koper David , Liu Hong , Habibovic Pamela , Kessler Peter , Peters Marloes , Emans Peter , Bouvy Nicole , Wieringa Paul , Moroni Lorenzo
Published: February 2020

Electrospun (ESP) scaffolds are a promising type of tissue engineering constructs for large defects with limited depth. To form new functional tissue, the scaffolds need to be infiltrated with cells, which will deposit extracellular matrix. However, due to dense fiber packing and small pores, cell and tissue infiltration of ESP scaffolds is limited. Here, we combine two established methods, increasing fiber diameter and co-spinning sacrificial fibers, to create a porous ESP scaffold that allows robust tissue infiltration. Full cell infiltration across 2 mm thick scaffolds is seen 3 weeks after subcutaneous implantation in rats. After 6 weeks, the ESP scaffolds are almost fully filled withde novotissue. Cell infiltration and tissue formationin vivoin this thickness has not been previously achieved. In addition, we propose a novel method forin vitrocell seeding to improve cell infiltration and a model to study 3D migration through a fibrous mesh. This easy approach to facilitate cell infiltration further improves previous efforts and could greatly aid tissue engineering approaches utilizing ESP scaffolds.

Statement of significance

Electrospinning creates highly porous scaffolds with nano- to micrometer sized fibers and are a promising candidate for a variety of tissue engineering applications. However, smaller fibers also create small pores which are difficult for cells to penetrate, restricting cells to the top layers of the scaffolds. Here, we have improved the cell infiltration by optimizing fiber diameter and by co-spinning a sacrificial polymer. We developed novel culture technique that can be used to improve cell seeding and to study cytokine driven 3D migration through fibrous meshes. After subcutaneous implantation, infiltration of tissue and cells was observed up to throughout up to 2 mm thick scaffolds. This depth of infiltrationin vivohad not yet been reported for electrospun scaffolds. The scaffolds we present here can be used forin vitrostudies of migration, and for tissue engineering in defects with a large surface area and limited depth.
Circadian Rhythm Analysis Using Wearable Device Data: A Novel Penalized Machine Learning Approach
Authors: Li Xinyue , Kane Michael , Zhang Yunting , Sun Wanqi , Song Yuanjin , Dong Shumei , Lin Qingmin , Zhu Qi , Jiang Fan , Zhao Hongyu
Published: February 2020

Background

Wearable devices have been widely used in clinical studies to study daily activity patterns, but the analysis remains the major obstacle for researchers.

Study Objective

This study proposed a novel method to characterize sleep-activity rhythms using actigraphy and further used it to describe early childhood daily rhythm formation and examine its association with physical development.

Methods

We developed a machine learning-based Penalized Multi-band Learning (PML) algorithm to sequentially infer dominant periodicities based on Fast Fourier Transform (FFT) and further characterize daily rhythms. We implemented and applied the algorithm to Actiwatch data collected from a 262 healthy infant cohort at 6-, 12-, 18-, and 24-month old, with 159, 101, 111, and 141 subjects participating at each time point respectively. Autocorrelation analysis and Fisher’s test for harmonic analysis with Bonferroni correction were applied to compare with PML. The association between activity rhythm features and early childhood motor development, assessed by Peabody Developmental Motor Scales-Second Edition (PDMS-2), was studied through linear regression.

Results

PML results showed that 1-day periodicity is most dominant at 6 and 12 months, whereas 1-day, 1/3-day, and 1/2-day periodicities are most dominant at 18 and 24 months. These periodicities are all significant in Fisher’s test, with 1/4-day periodicity also significant at 12 months. Autocorrelation effectively detected 1-day periodicity but not others. At 6 months, PDMS-2 is associated with assessment seasons. At 12 months, PDMS-2 is associated with seasons and FFT signals at 1/3-day periodicity (P<.001) and 1/2-day periodicity (P=.04). In particular, subcategories of stationary, locomotion, and gross motor are associated with FFT signals at 1/3-day periodicity (P<.001).

Conclusions

The proposed PML algorithm can effectively conduct circadian rhythm analysis using time-series wearable device data. Application of the method effectively characterized sleep-wake rhythm development and identified the association between daily rhythm formation and motor development during early childhood.
Evolution of multicellularity by collective integration of spatial information
Authors: Colizzi Enrico Sandro , Vroomans Renske M.A. , Merks Roeland M.H.
Published: February 2020

At the origin of multicellularity, cells may have evolved aggregation in response to predation, for functional specialisation or to allow large-scale integration of environmental cues. These group-level properties emerged from the interactions between cells in a group, and determined the selection pressures experienced by these cells.

We investigate the evolution of multicellularity with an evolutionary model where cells search for resources by chemotaxis in a shallow, noisy gradient. Cells can evolve their adhesion to others in a periodically changing environment, where a cell’s fitness solely depends on its distance from the gradient source.

We show that multicellular aggregates evolve because they perform chemo-taxis more efficiently than single cells. Only when the environment changes too frequently, a unicellular state evolves which relies on cell dispersal. Both strategies prevent the invasion of the other through interference competition, creating evolutionary bi-stability. Therefore, collective behaviour can be an emergent selective driver for undifferentiated multicellularity.
Control of Systemic Iron Homeostasis by the 3’ Iron-Responsive Element of Divalent Metal Transporter 1 in Mice
Authors: Tybl Elisabeth , Gunshin Hiromi , Gupta Sanjay , Barrientos Tomasa , Bonadonna Michael , Nos Ferran Celma , Palais Gael , Karim Zoubida , Sanchez Mayka , Andrews Nancy C. , Galy Bruno
Published: February 2020

Divalent metal transporter 1 (DMT1) is essential for dietary iron assimilation and erythroid iron acquisition. The 3’ untranslated region of the murine DMT1 mRNA contains an iron responsive element (IRE) that is conserved in humans but whose functional role remains unclear. We generated and analyzed mice with targeted disruption of the DMT1 3’IRE. These animals display hypoferremia during the suckling period, associated with a reduction of DMT1 mRNA and protein in the intestine. In contrast, adult mice exhibit hyperferremia, accompanied by enlargement of hepatic and splenic iron stores. Intriguingly, disruption of the DMT1 3’IRE in adult animals augments intestinal DMT1 expression, in part due to increased mRNA translation. Hence, during postnatal growth, the DMT1 3’IRE promotes intestinal DMT1 expression and secures iron sufficiency; in adulthood, it suppresses DMT1 and prevents systemic iron loading. This work demonstrates that the 3’IRE of DMT1 plays a role in the control of DMT1 expression and systemic iron homeostasis, and reveals an age-dependent switch in its activity.

Key points

Targeted mutagenesis of the 3’IRE of DMT1 in mice reveals its importance for maintenance of systemic iron homeostasis.

The 3’IRE stimulates intestinal DMT1 expression and prevents hypoferremia during early life, but exerts opposite effects in adulthood
Tasting the differences: microbiota analysis of different insect-based novel food
Authors: Frigerio Jessica , Agostinetto Giulia , Galimberti Andrea , De Mattia Fabrizio , Labra Massimo , Bruno Antonia
Published: February 2020

Traceability, quality and safety of edible insects are important both for the producers and the consumers. Today, alongside the burst of edible insects in western countries, we are facing a gap of knowledge of insect microbiota associated with the microbial ecosystems of insect-based products. Recent studies suggest that the insect microbiota can vary between insect species and that can be shaped by additional factors, such as rearing conditions. Also, the production processes of raw materials (i.e. insect flour) into final food products can affect the insect microbiota too. This has consequences for the evaluation of food safety and food traceability. In this context, High-Throughput DNA Sequencing (HTS) techniques can give insight into the carryover of insect microbiota into final food products. In this study, we investigated the microbiota composition of insect-based commercial food products, applying HTS techniques coupled with bioinformatic analysis. The aim of this work was to analyse the microbiota variability of different categories of insect-based products made ofA. domesticus(house cricket),T. molitor(mealworm beetle), andA. diaperinus(lesser mealworm or litter beetle), including commercial raw materials and processed food items, purchased via e-commerce from different companies. Our data revealed that samples cluster per insect species based on microbiota profile and preliminary results suggested that a small number of prevalent bacteria formed a “core microbiota” characterizing the products depending on the insect, suggesting that a resident microbiota is conserved. This microbial signature can be recognized despite the different food processing levels, rearing conditions selling companies. We showed that differences exist when comparing raw vs processed food made of the same insect, or similar products produced by different companies as well, laying the groundwork for further analyses. These results support the application of HTS analysis for studying the composition of processed insect food in a wider perspective, for food traceability and food quality control.
Comprehensive cell surface proteomics defines markers of classical, intermediate and non-classical monocytes
Authors: Ravenhill Benjamin J. , Soday Lior , Houghton Jack , Antrobus Robin , Weekes Michael P.
Published: February 2020

Monocytes are a critical component of the cellular innate immune system, and can be subdivided into classical, intermediate and non-classical subsets on the basis of surface CD14 and CD16 expression. Classical monocytes play the canonical role of phagocytosis, and account for the majority of circulating cells. Intermediate and non-classical cells are known to exhibit varying levels of phagocytosis and cytokine secretion, and are differentially expanded in certain pathological states. Characterisation of cell surface proteins expressed by each subset is informative not only to improve understanding of phenotype, but may also provide biological insights into function. Here we use highly multiplexed Tandem-Mass-Tag (TMT)-based mass spectrometry with selective cell surface biotinylation to characterise the classical monocyte surface proteome, then interrogate the phenotypic differences between each monocyte subset to identify novel protein markers.