bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibrotic scar after experimental autoimmune encephalomyelitis inhibits oligodendrocyte differentiation
Authors: Yahn Stephanie L. , Li Jiajun , Goo Irene , Gao Han , Brambilla Roberta , Lee Jae K.
Published: October 2019

Remyelination failure is a crucial component of disease progression in the autoimmune demyelinating disease Multiple Sclerosis (MS). The regenerative capacity of oligodendrocyte progenitor cells (OPCs) to replace myelinating oligodendrocytes is likely influenced by many aspects of the lesion environment including inflammatory signaling and extracellular matrix (ECM) deposition. These features of MS lesions are typically attributed to infiltrating leukocytes and reactive astrocytes. Here we demonstrate that fibroblasts also contribute to the inhibitory environment in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Using Col1α1GFPtransgenic mice, we show that perivascular fibroblasts are activated in the spinal cord at EAE onset, and infiltrate the parenchyma by the peak of behavioral deficits where they are closely associated with areas of demyelination, myeloid cell accumulation, and ECM deposition. We further show that both fibroblast conditioned media and fibroblast ECM inhibit the differentiation of OPCs into mature oligodendrocytes. Taken together, our results indicate that the fibrotic scar is a major component of EAE pathology that leads to an inhibitory environment for remyelination, thus raising the possibility that anti-fibrotic mechanisms may serve as novel therapeutic targets for MS.
Synthetic biogenesis of chromoplasts from leaf chloroplasts
Authors: Llorente Briardo , Torres-Montilla Salvador , Morelli Luca , Florez-Sarasa Igor , Ezquerro Miguel , D’andrea Lucio , Majer Eszter , Troncoso Adrian , Fernie Alisdair R. , Daròs José A. , Rodriguez-Concepcion Manuel
Published: October 2019

Plastids, the defining organelles of plant cells, undergo physiological and morphological changes to fulfill distinct biological functions. In particular, the differentiation of chloroplasts into chromoplasts results in an enhanced storage capacity for carotenoids with industrial and nutritional value such as beta-carotene (pro-vitamin A). Here, we show that synthetically inducing a burst in the production of phytoene, the first committed intermediate of the carotenoid pathway, elicits an artificial chloroplast-to-chromoplast differentiation in leaves. Phytoene overproduction initially interferes with photosynthesis, acting as a metabolic threshold switch mechanism that weakens chloroplast identity. In a second stage, phytoene conversion into downstream carotenoids is required for the differentiation of chromoplasts. Our findings reveal that lowering the photosynthetic capacity of chloroplasts and increasing the production of carotenoids are not just the consequence but an absolute requirement for chromoplast differentiation, which additionally involves a concurrent reprogramming of nuclear gene expression and plastid morphology for improved carotenoid storage.
Behaviour and cold hardiness of the purple stem borer in winter, colonizing more northerly latitudes
Authors: Huang Jianrong , Li Guoping , Lei Haixia , Fan Chunbin , Tian Caihong , Chen Qi , Huang Bo , Li Huilong , Lu Zhaocheng , Feng Hongqiang
Published: October 2019

To escape or alleviate low temperatures in winter, insects have evolved many behavioral and physiological strategies. The rice pest insect, the purple stem borer, Sesamia inferens (Walker) is currently reported to be expanding their northern distributions and causing damage to summer maize in Xinxiang, China. However, their method of coping with the lower temperature in the new northern breeding area in winter is largely unknown. This paper investigates the overwinter site of S. inferens, and identifies the cold hardiness of larvae collected from a new breeding area in winter and explores a potential distribution based on low temperature threshold and on species distribution model, MaxEnt. The results show that the overwintering location of the S. inferens population is more likely to be underground with increasing latitude and,in the north, with the temperature decreasing, the larvae gradually moved down the corn stalk and drilled completely underground by February 18th. Those who were still above ground were all winterkilled. The cold hardiness test shows the species is a moderate freeze-tolerant one, and Supercooling Points (SCP), Freezing Points (FP) and mortality rate during the middle of winter (January, SCP: −7.653, FP: −6.596) were significantly lower than early winter (October) or late winter (March). Distribution in the new expansion area was predicted and the survival probability area was below N 35° for the Air Lower Lethal Temperature (ALLT50) and below N 40° for the Underground Lower Lethal Temperature (ULLT50), The suitable habitat areas for S. inferens with MaxEnt were also below N 40°. This study suggests the overwinter strategies have led to the colonization of up to a five degree more northerly overwintering latitude. This behavior of S. inferens could help maize producers to propose a control method to increase pest mortality by extracting the maize stubble after harvest.
Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1
Authors: Nishi Masamitsu , Kimura Takashi , Furuta Mitsuru , Suenaga Koichi , Matsumura Tsuyoshi , Fujimura Harutoshi , Jinnai Kenji , Yoshikawa Hiroo
Published: October 2019

Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to sequestration of the splicing factor, muscleblind-like 2 (MBNL2), and aberrant splicing, mainly in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with the control, the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and control. The level of change in PSI between DM1 and control was higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain. We hypothesize that in DM1, aberrantly spliced isoforms in the neuronal cell body of the GM may not be transported to the axon. This might affect the WM as a consequence of Wallerian degeneration secondary to cell body damage. Our findings may have implications for analysis of the pathological mechanisms and exploring potential therapeutic targets.
Alcohol Effects on Globus Pallidus Connectivity: Role of Impulsivity and Binge Drinking
Authors: Fede Samantha J. , Abrahao Karina P. , Cortes Carlos R. , Grodin Erica N. , Schwandt Melanie L. , George David T. , Diazgranados Nancy , Ramchandani Vijay A. , Lovinger David M. , Momenan Reza
Published: October 2019

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe – frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors.
Bayesian modelling of high-throughput sequencing assays with malacoda
Authors: Ghazi Andrew R. , Kong Xianguo , Chen Ed , Edelstein Leonard C. , Shaw Chad A.
Published: October 2019

NGS studies have uncovered an ever-growing catalog of human variation while leaving an enormous gap between observed variation and experimental characterization of variant function. High-throughput screens powered by NGS have greatly increased the rate of variant functionalization, but the development of comprehensive statistical methods to analyze screen data has lagged behind. In the massively parallel reporter assay (MPRA), short barcodes are counted by sequencing DNA libraries transfected into cells and output RNA in order to simultaneously measure the shifts in transcription induced by thousands of genetic variants. These counts present many statistical challenges, including over-dispersion, depth dependence, and uncertain DNA concentrations. So far, the statistical methods used have been rudimentary, employing transformations on count level data and disregarding experimental and technical structure while failing to quantify uncertainty in the statistical model.
GSMN-ML- a genome scale metabolic network reconstruction of the obligate human pathogenMycobacterium leprae
Authors: Borah Khushboo , Kearney Jacque-Lucca , Banerjee Ruma , Vats Pankaj , Wu Huihai , Dahale Sonal , Sunitha Manjari K , Joshi Rajendra , Bonde Bhushan , Ojo Olabisi , Lahiri Ramanuj , Williams Diana L. , McFadden Johnjoe
Published: October 2019

Leprosy, caused byMycobacterium leprae, has plagued humanity for thousands of years and continues to cause morbidity, disability and stigmatization in two to three million people today. Although effective treatment is available, the disease incidence has remained approximately constant for decades so new approaches, such as vaccine or new drugs, are urgently needed for control. Research is however hampered by the pathogen’s obligate intracellular lifestyle and the fact that it has never been grownin vitro. Consequently, despite the availability of its complete genome sequence, fundamental questions regarding the biology of the pathogen, such as its metabolism, remain largely unexplored. In order to explore the metabolism of the leprosy bacillus with a long-term aim of developing a medium to grow the pathogenin vitro, we reconstructed anin silicogenome scale metabolic model of the bacillus, GSMN-ML. The model was used to explore the growth and biomass production capabilities of the pathogen with a range of nutrient sources, such as amino acids, glucose, glycerol and metabolic intermediates. We also used the model to analyze RNA-seq data fromM. lepraegrown in mouse foot pads, and performed Differential Producibility Analysis (DPA) to identify metabolic pathways that appear to be active during intracellular growth of the pathogen, which included pathways for central carbon metabolism, co-factor, lipids, amino acids, nucleotides and cell wall synthesis. The GSMN-ML model is thereby a usefulin silicotool that can be used to explore the metabolism of the leprosy bacillus, analyze functional genomic experimental data, generate predictions of nutrients required for growth of the bacillusin vitroand identify novel drug targets.

Author Summary

Mycobacterium leprae, the obligate human pathogen is uncultivable in axenic growth medium, and this hinders research on this pathogen, and the pathogenesis of leprosy. The development of novel therapeutics relies on the understanding of growth, survival and metabolism of this bacterium in the host, the knowledge of which is currently very limited. Here we reconstructed a metabolic network ofM. leprae-GSMN-ML, a powerfulin silicotool to study growth and metabolism of the leprosy bacillus. We demonstrate the application of GSMN-ML to identify the metabolic pathways, and metabolite classes thatM. lepraeutilizes during intracellular growth.
Common alleles ofCMT2andNRPE1are major determinants ofde novoDNA methylation variation inArabidopsis thaliana
Authors: Sasaki Eriko , Kawakatsu Taiji , Ecker Joseph , Nordborg Magnus
Published: October 2019

DNA cytosine methylation is an epigenetic mark associated with silencing of transposable elements (TEs) and heterochromatin formation. In plants, it occurs in three sequence contexts: CG, CHG, and CHH (where H is A, T, or C). The latter does not allow direct inheritance of methylation during DNA replication due to lack of symmetry, and methylation must therefore be re-established every cell generation. Genome-wide association studies (GWAS) have previously shown thatCMT2andNRPE1are major determinants of genome-wide patterns of TE CHH-methylation. Here we instead focus on CHH-methylation of individual TEs and TE-families, allowing us to identify the pathways involved in CHH-methylation simply from natural variation and confirm the associations by comparing them with mutant phenotypes. Methylation at TEs targeted by the RNA-directed DNA methylation (RdDM) pathway is unaffected byCMT2variation, but is strongly affected by variation atNRPE1, which is largely responsible for the longitudinal cline in this phenotype. In contrast, CMT2-targeted TEs are affected by both loci, which jointly explain 7.3% of the phenotypic variation (13.2% of total genetic effects). There is no longitudinal pattern for this phenotype, however, because the geographic patterns appear to compensate for each other in a pattern suggestive of stabilizing selection.

Author Summary

DNA methylation is a major component of transposon silencing, and essential for genomic integrity. Recent studies revealed large-scale geographic variation as well as the existence of majortrans-acting polymorphisms that partly explained this variation. In this study, we re-analyze previously published data (The 1001 Epigenomes), focusing onde novoDNA methylation patterns of individual TEs and TE families rather than on genome-wide averages (as was done in previous studies). GWAS of the patterns reveals the underlying regulatory networks, and allowed us to comprehensively characterizetrans-regulation ofde novoDNA methylation and its role in the striking geographic pattern for this phenotype.
Plasmodiophora brassicae in its environment-effects of temperature and light on resting spore survival in soil
Authors: Zahr Kher , Sarkes Alian , Yang Yalong , Zhou Qixing , Feindel David , Harding Michael W. , Feng Jie
Published: October 2019

Clubroot caused by Plasmodiophora brassicae is an important disease on cruciferous crops worldwide. Management of clubroot has been challenging, due largely to the millions of resting spores produced within an infected root that can survive dormant in the soil for many years. This study was conducted to investigate some of the environmental conditions that may affect the survival of resting spores in the soil. Soil samples containing clubroot resting spores (1 × 107 spores g-1 soil) were stored at various temperatures for two years. Additionally, other samples were buried in soil, or kept on the soil surface in the field. The content of P. brassicae DNA and the numbers of viable spores in the samples were assessed by quantitative polymerase chain reaction (qPCR) and pathogenicity bioassays, respectively. The results indicated that 4°C, 20°C and being buried in the soil were better conditions for spore survival than were −20°C, 30°C and at the soil surface. Most of the spores kept on the soil surface were killed, suggesting the negative effect of light on spore viability. Additional experiments confirmed that ultraviolet (UV) light contributed a large negative effect on spore viability as lower pathogenicity and less DNA content were observed from the 2-and 3-hour UV light treated spores compared to the untreated control. Finally, this work demonstrated that DNA-based quantification methods such as qPCR can be poor predictors of P. brassicae disease potential due to the presence and persistence of DNA from dead spores.
Phylogeography of two Andean frogs: Test of vicariance versus elevational gradient models of diversification
Authors: Koscinski Daria , Handford Paul , Tubaro Pablo L. , Li Peiwen , Lougheed Stephen C.
Published: October 2019

The tropical and subtropical Andes have among the highest levels of biodiversity in the world. Understanding the forces that underlie speciation and diversification in the Andes is a major focus of research. Here we tested two hypotheses of species origins in the Andes: 1. Vicariance mediated by orogenesis or shifting habitat distribution. 2. Parapatric diversification along elevational environmental gradients. We also sought insights on the factors that impacted the phylogeography of co-distributed taxa, and the influences of divergent species ecology on population genetic structure. We used phylogeographic and coalescent analyses of nuclear and mitochondrial DNA sequence data to compare genetic diversity and evolutionary history of two frog species:Pleurodema borellii(Family: Leiuperidae, 130 individuals; 20 sites), andHypsiboas riojanus(Family: Hyllidae, 258 individuals; 23 sites) across their shared range in northwestern Argentina. The two showed concordant phylogeographic structuring, and our analyses support the vicariance model over the elevational gradient model. However,Pleurodema borelliiexhibited markedly deeper temporal divergence (≥4 Ma) thanH. riojanus(1-2 Ma). The three main mtDNA lineages ofP. borelliiwere nearly allopatric and diverged between 4-10 Ma. At similar spatial scales, differentiation was less in the putatively more habitat-specializedH. riojanusthan in the more generalistP. borellii. Similar allopatric distributions of major lineages for both species implies common causes of historical range fragmentation and vicariance. However, different divergence times among clades presumably reflect different demographic histories, permeability of different historical barriers at different times, and/or difference in life history attributes and sensitivities to historical environmental change. Our research enriches our understanding of the phylogeography of the Andes in northwestern Argentina.
Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz
Authors: Bisso Andrea , Filipuzzi Marco , Gamarra Figueroa Gianni Paolo , Brumana Giulia , Biagioni Francesca , Doni Mirko , Ceccotti Giorgia , Tanaskovic Nina , Morelli Marco Jacopo , Pendino Vera , Chiacchiera Fulvio , Pasini Diego , Olivero Daniela , Campaner Stefano , Sabò Arianna , Amati Bruno
Published: October 2019

Background & Aims

Activation of MYC and CTNNB1 (encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.

Approach & Results

We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Conditional activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the mouse liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a “Myc/β-catenin signature”, composed of a discrete set of Myc-activated genes whose expression increased in presence of active β-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/β-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

Conclusions

Yap and Taz mediate the cooperative action of Myc and β-catenin in liver tumorigenesis. This warrants efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.
Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling
Authors: Barysch Sina V. , Stankovic-Valentin Nicolas , Karaca Samir , Doppel Judith , Nait Achour Thiziri , Sticht Carsten , Urlaub Henning , Melchior Frauke
Published: October 2019

Molecular switches are essential modules in signaling networks and transcriptional reprogramming. Here, we describe a role for small ubiquitin-related-modifier SUMO as a molecular switch in epidermal growth factor receptor (EGFR) signaling. Using quantitative mass spectrometry, we compared the endogenous SUMO-proteomes of Hela cells before and after EGF-stimulation. Thereby, we identified a small group of transcriptional co-regulators including IRF2BP1, IRF2BP2 and IRF2BPL as novel players in EGFR signaling. Comparison of cells expressing wildtype or SUMOylation deficient IRF2BP1 indicated that transient deSUMOylation of IRF2BP1 is important for appropriate expression of immediate early genes including Dual specificity phosphatase 1 (DUSP1, MKP-1), an important feedback regulator of EGFR signaling. We find that IRF2BP1 is a SUMO-dependent repressor, whose transient deSUMOylation on the DUSP1 promotor allows - and whose timely reSUMOylation restricts - DUSP1 expression. Our work thus provides a paradigm how comparative SUMO proteome analyses serve to reveal novel regulators in signal transduction and transcription.
SECAT: Quantifying differential protein-protein interaction states by network-centric analysis
Authors: Rosenberger George , Heusel Moritz , Bludau Isabell , Collins Ben , Martelli Claudia , Williams Evan , Xue Peng , Liu Yansheng , Aebersold Ruedi , Califano Andrea
Published: October 2019

Protein-protein interactions (PPIs) play critical functional and regulatory roles in virtually all cellular processes. They are essential for the formation of macromolecular complexes, which in turn constitute the basis for extended protein interaction networks that determine the functional state of a cell. We and others have previously shown that chromatographic fractionation of native protein complexes in combination with bottom-up mass spectrometric analysis of consecutive fractions supports the multiplexed characterization and detection of state-specific changes of protein complexes.

In this study, we describe a computational approach that extends the analysis of data from the co-fractionation / mass spectrometric analysis of native complexes to the level of PPI networks, thus enabling a qualitative and quantitative comparison of the proteome organization between samples and states. The Size-Exclusion Chromatography Algorithmic Toolkit (SECAT) implements a novel, network-centric strategy for the scalable and robust differential analysis of PPI networks. SECAT and its underlying statistical framework elucidate differential quantitative abundance and stoichiometry attributes of proteins in the context of their PPIs. We validate algorithm predictions using publicly available datasets and demonstrate that SECAT represents a more scalable and effective methodology to assess protein-network state and that our approach thus obviates the need to explicitly infer individual protein complexes. Further, by differential analysis of PPI networks of HeLa cells in interphase and mitotic state, respectively, we demonstrate the ability of the algorithm to detect PPI network differences and to thus suggest molecular mechanisms that differentiate cellular states.
Haptic assistance that restricts use of redundant solutions is detrimental to motor learning
Authors: Lokesh Rakshith , Ranganathan Rajiv
Published: October 2019

Understanding the use of haptic assistance to facilitate motor learning is a critical issue, especially in the context of tasks requiring control of motor variability. However, the question of how haptic assistance should be designed in tasks with redundancy, where multiple solutions are available, is currently unknown. Here we examined the effect of haptic assistance that either allowed or restricted the use of redundant solutions on the learning of a bimanual steering task. 60 college-aged participants practiced steered a single cursor placed in between their hands along a smooth W-shaped track of a certain width as quickly as possible. Haptic assistance was either applied at the ‘task’ level using a force channel that only constrained the cursor to the track, allowing for the use of different hand trajectories, or (ii) the ‘individual effector’ level using a force channel that constrained each hand to a specific trajectory. In addition, we also examined the effect of ‘fading’ – i.e., decreasing assistance with practice to reduce dependence on haptic assistance. Results showed all groups improved with practice - however, groups with haptic assistance at the individual effector level performed worse than those at the task level. Moreover, fading of assistance did not offer learning benefits over constant assistance. Overall, the results suggest that haptic assistance is not effective for motor learning when it restricts the use of redundant solutions.
The Electrophysiological Signature of Mind Wandering
Authors: Arnau Stefan , Löffler Christoph , Rummel Jan , Hagemann Dirk , Wascher Edmund , Schubert Anna-Lena
Published: October 2019

Mind wandering during ongoing tasks can impede task performance and increase the risk of failure in laboratory as well as in daily-life tasks and work environments. Neurocognitive measures like the electroencephalography (EEG) offer the opportunity to assess mind wandering non-invasively without interfering with the primary task. However, the literature on electrophysiological correlates of mind wandering is rather inconsistent. The present study aims towards clarifying this picture by breaking down the temporal dynamics of mind-wandering encounters using a cluster-based permutation approach. Participants performed a switching task during which mind wandering was occasionally assessed via thought probes applied after trial completion at random time points. In line with previous studies, response accuracy was reduced during mind wandering. Moreover, alpha power during the inter-trial interval was significantly increased on those trials on which participants reported that they had been mind-wandering. This spatially widely distributed effect is theoretically well in line with recent findings linking an increased alpha power to an internally oriented state of attention. Measurements of alpha power may therefore be used to detect mind wandering online during critical tasks in traffic and industry in order to prevent failures.
Colibactin DNA damage signature indicates causative role in colorectal cancer
Authors: Dziubańska-Kusibab Paulina J. , Berger Hilmar , Battistini Federica , Bouwman Britta A. M. , Iftekhar Amina , Katainen Riku , Crosetto Nicola , Orozco Modesto , Aaltonen Lauri A. , Meyer Thomas F.
Published: October 2019

Colibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs) in human cells. We investigated if colibactin creates a particular DNA damage signature in infected cells by identifying DSBs in colon cells after infection with pks+ E.coli. Interestingly, genomic contexts of DSBs were enriched for AT-rich penta-/hexameric sequence motifs, exhibiting a particularly narrow minor groove width and extremely negative electrostatic potential. This corresponded with the binding characteristics of colibactin to double-stranded DNA, as elucidated by docking and molecular dynamics simulations. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the identified motifs in colorectal cancers. Our work provides direct evidence for a role of colibactin in the etiology of human cancer.

One sentence summary

We identify a mutational signature of colibactin, which is significantly enriched in human colorectal cancers.
Ant cuticular hydrocarbons are heritable and associated with variation in colony productivity
Authors: Walsh Justin , Pontieri Luigi , d’Ettorre Patrizia , Linksvayer Timothy A.
Published: October 2019

In social insects, cuticular hydrocarbons function in nestmate recognition and also provide a waxy barrier against desiccation, but basic evolutionary genetic features, including the heritability of hydrocarbon profiles and how they are shaped by natural selection are largely unknown. We used a new pharaoh ant (Monomorium pharaonis) laboratory mapping population to estimate the heritability of individual cuticular hydrocarbons, genetic correlations between hydrocarbons, and fitness consequences of phenotypic variation in the hydrocarbons. Individual hydrocarbons had low to moderate estimated heritability, indicating that some compounds provide more information about genetic relatedness and can also better respond to natural selection. Strong genetic correlations between compounds are likely to constrain independent evolutionary trajectories, which is expected given that many hydrocarbons share biosynthetic pathways. Variation in cuticular hydrocarbons was associated with variation in colony productivity, with some hydrocarbons experiencing strong directional selection. Altogether, our study builds on our knowledge of the genetic architecture of the social insect hydrocarbon profile and demonstrates that hydrocarbon variation is shaped by natural selection.
Identification and biochemical characterization of a novel eukaryotic-like Ser/Thr kinase inE. coli
Authors: Rajagopalan Krithika , Dworkin Jonathan
Published: October 2019

In bacteria, signaling phosphorylation is thought to occur primarily on His and Asp residues. However, phosphoproteomic surveys in phylogenetically diverse bacteria over the past decade have identified numerous proteins that are phosphorylated on Ser and/or Thr residues. Consistently, genes encoding Ser/Thr kinases are present in many bacterial genomes such asE. coli, which encodes at least three Ser/Thr kinases. Here we identify a previously uncharacterized ORF,yegI, and demonstrate that it encodes a novel Ser/Thr kinase. YegI lacks several conserved residues including those important for Mg2+binding seen in other bacterial Ser/Thr kinases, suggesting that the consensus may be too stringent. We further find that YegI is a two-pass membrane protein with both N- and C-termini located intracellularly.
The role of environment, local adaptation and past climate fluctuation on the amount and distribution of genetic diversity in the teosinte in Mexico
Authors: Gasca-Pineda Jaime , Gutiérrez-Guerrero Yocelyn T. , Aguirre-Planter Erika , Eguiarte Luis E.
Published: October 2019

Wild maize, commonly known as teosinte, has a wide distribution in central Mexico and inhabits a wide range of environmental conditions. According to previous studies, the environment is a determinant factor for the amount and distribution of genetic diversity. In this study, we used a set of neutral markers to explore the influence of contemporary factors and historical environmental shifts on genetic diversity, including present and three historical periods. Using a set of 22 nuclear microsatellite loci, we genotyped 527 individuals from 29 localities. We found highly variable levels of genetic diversity (Z. m. parviglumis HE= 0.3646–0.7699;Z. m. mexicana HE= 0.5885–0.7671) and significant genetic structure among localities (averageDEST= 0.4332). Also, we recovered significant values of heterozygote deficiency (averageFIS= 0.1796) and variable levels of selfing (sg2=0.0–0.3090). The Bayesian assignment analysis yielded four genetic clusters dividing the sample into subspecies, that in turn, were separated into two clusters. Environmental conditions played a strong influence in the distribution of genetic diversity, as demographic analysis and changes in species range revealed by modeling analyses were consistent. We conclude that current genetic diversity in teosinte is the result of a mixture of local adaptation and genetic isolation along with historical environmental fluctuations.
Comprehensive analysis of antiviral adaptive immunity formation and reactivation down to single-cell level
Authors: Minervina Anastasia A. , Pogorelyy Mikhail V. , Komech Ekaterina A. , Karnaukhov Vadim K. , Bacher Petra , Rosati Elisa , Franke Andre , Chudakov Dmitriy M. , Mamedov Ilgar Z. , Lebedev Yuri B. , Mora Thierry , Walczak Aleksandra M.
Published: October 2019

The diverse repertoire of T-cell receptors (TCR) plays a key role in the adaptive immune response to infections. Previous studies show that secondary responses to the yellow fever vaccine — the model for acute infection in humans — are weaker than primary ones, but only quantitative measurements can describe the concentration changes and lineage fates for distinct T-cell clones in vivo over time. Using TCR alpha and beta repertoire sequencing for T-cell subsets, as well as single-cell RNAseq and TCRseq, we track the concentrations and phenotypes of individual T-cell clones in response to primary and secondary yellow fever immunization showing their large diversity. We confirm the secondary response is an order of magnitude weaker, albeit 10 days faster than the primary one. Estimating the fraction of the T-cell response directed against the single immunodominant epitope, we identify the sequence features of TCRs that define the high precursor frequency of the two major TCR motifs specific for this particular epitope. We also show the consistency of clonal expansion dynamics between bulk alpha and beta repertoires, using a new methodology to reconstruct alpha-beta pairings from clonal trajectories.
MitoPlex: A Targeted Multiple Reaction Monitoring Assay for Quantification of a Curated Set of Mitochondrial Proteins
Authors: Stotland Aleksandr B. , Spivia Weston , Orosco Amanda , Andres Allen M. , Gottlieb Roberta A. , Van Eyk Jennifer E. , Parker Sarah J.
Published: October 2019

Mitochondria are the major source of cellular energy (ATP), as well as critical mediators of widespread functions such as cellular redox balance, apoptosis, and metabolic flux. Methods to quantify mitochondrial content are limited to low throughput immunoassays, measurement of mitochondrial DNA, or relative quantification by untargeted mass spectrometry. Here, we present a high throughput, reproducible and quantitative mass spectrometry multiple reaction monitoring based assay of 37 proteins critical to central carbon chain metabolism and overall mitochondrial function termed ‘MitoPlex’. We coupled this protein multiplex with a parallel analysis of the central carbon chain metabolites (218 metabolite assay) extracted in tandem from the same sample, be it cells or tissue. In tests of its biological applicability in cells and tissues, ‘MitoPlex plus metabolites’ indicated profound effects of HMG-CoA Reductase inhibition (e.g., statin treatment) on mitochondria of i) differentiating C2C12 skeletal myoblasts, as well as a clear opposite trend of statins to promote mitochondrial protein expression and metabolism in heart and liver, while suppressing mitochondrial protein and ii) aspects of metabolism in the skeletal muscle obtained from C57Bl6 mice. Our results not only reveal new insights into the metabolic effect of statins in skeletal muscle, but present a new high throughput, reliable MS-based tool to study mitochondrial dynamics in both cell culture and in vivo models.
Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure
Authors: Criscione June , Ji Weizhen , Jeffries Lauren , McGrath James M. , Soloway Scott , Pusztai Lajos , Lakhani Saquib
Published: October 2019

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide. Most cases are multifactorial in etiology, but some are associated with variants in the myocilin gene, MYOC. Here, we report the identification of a novel MYOC variant, c.1153G>A, in a 24-yr-old female patient with a personal and family history of juvenile/early-onset POAG. Further genetic testing within her family demonstrated that this variant segregates with the POAG phenotype in an autosomal dominant pattern. Identification of this MYOC variant in multiple affected relatives provides evidence for its pathogenicity, supporting previous findings linking MYOC mutations, in particular in the third exon's olfactomedin domain, to juvenile-onset POAG. This case also emphasizes the potential value of genetic testing in families with histories of eye disorders.
A uniparental isodisomy event introducing homozygous pathogenic variants drives a multisystem metabolic disorder
Authors: Daniels Eileen G. , Alders Marielle , Lezzerini Marco , McDonald Andrew , Peters Marjolein , Kuijpers Taco W. , Lakeman Phillis , Houtkooper Riekelt H. , MacInnes Alyson W.
Published: October 2019

Uniparental isodisomy (UPiD) is a rare genetic event that occurs when two identical copies of a single chromosome are inherited from one parent. Here we report a patient with a severe, multisystem metabolic disorder who inherited two copies of Chromosome 12 from her father. He was a heterozygous carrier of a variant in the muscle-specific enzyme 6-phosphofructokinase (PFKM) gene and of a truncating variant in the pseudouridine synthase 1 (PUS1) gene (both on Chromosome 12), resulting in a homozygous state of these mutations in his daughter. The PFKM gene functions in glycolysis and is linked to Tarui syndrome. The PUS1 gene functions in mitochondrial tRNA processing and is linked to myopathy, lactic acidosis, and sideroblastic anemia (MLASA). Analysis of human dermal fibroblasts, which do not express PFKM, revealed a loss of PUS1 mRNA and PUS1 protein only in the patient cells compared to healthy controls. The patient cells also revealed a reduction of the mitochondrial-encoded protein MTCO1, whereas levels of the nuclear-encoded SDHA remained unchanged, suggesting a specific impairment of mitochondrial translation. Further destabilization of these cells is suggested by the altered levels of BAX, BCL-2, and TP53 proteins, alterations that become augmented upon exposure of the cells to DNA damage. The results illustrate the efficacy of UPiD events to reveal rare pathogenic variants in human disease and demonstrate how these events can lead to cellular destabilization.
The interplay between host community structure and pathogen life‐history constraints in driving the evolution of host‐range shifts
Authors: Okamoto Kenichi W. , Amarasekare Priyanga , Post David M. , Vasseur David A. , Turner Paul E.
Published: October 2019

The ability of pathogens and parasites to adaptively exploit novel hosts has contributed to their unparalleled diversification along the tree of life. Moreover, evolved host‐range shifts are of particular applied interest – for instance, zoonotic ‘spillovers’ towards humans motivate growing concern about emerging infectious diseases. Thus, identifying the constraints upon, and conditions conducive to, host switching by pathogens is critical to addressing pressing public health and agricultural problems, as well as to understand a major driver of biodiversity.

How do processes that structure host communities (such as among‐host competition) set the selective context for the evolution of pathogen host ranges, and how do these processes interact with trade‐offs constraining the evolution of a pathogen's ability to exploit its host?

Here, we develop a theoretical framework to understand how resource competition among hosts interacts with constraints on pathogen biology in driving host shifts. We characterize how antagonistic pleiotropy in the pathogen's ability to exploit hosts can counteract ecological selection towards host‐range shifts.

We find that although the effects of apparent competition on host‐range shifts are mediated through the ancestral pathogen's direct and indirect effects on the entire host community, the effects of exploitative competition on host‐range shifts are mediated through exploitative competition's effect on the previously unexploited host.

Finally, we show that even when changes in host community structure create conditions conducive to host switching, a general trade‐off between pathogen virulence and burst size can prevent pathogens from evolving seemingly adaptive patterns of host use. We illustrate how these constraints faced by pathogens shape the eco‐evolutionary interaction between pathogen evolution and host communities.

We discuss how our results inform predictions about the kinds of pathogen lineages likely to exhibit host‐range shifts, and the role of apparent versus direct competition in structuring host—pathogen communities over evolutionary time.

A free Plain Language Summary can be found within the Supporting Information of this article.
Distribution maps of cetacean and seabird populations in the North‐East Atlantic
Authors: Waggitt James J. , Evans Peter G. H. , Andrade Joana , Banks Alex N. , Boisseau Oliver , Bolton Mark , Bradbury Gareth , Brereton Tom , Camphuysen Cornelis Jan , Durinck Jan , Felce Tom , Fijn Ruben Christiaan , Garcia‐Baron Isabel , Garthe Stefan , Geelhoed Steve C. V. , Gilles Anita , Goodall Martin , Haelters Jan , Hamilton Sally , Hartny‐Mills Lauren , Hodgins Nicola , James Kathy , Jessopp Mark , Kavanagh Ailbhe S. , Leopold Mardik , Lohrengel Katrin , Louzao Maite , Markones Nele , Martínez-Cedeira Jose , Ó Cadhla Oliver , Perry Sarah L. , Pierce Graham J. , Ridoux Vincent , Robinson Kevin P. , Santos M. Begoña , Saavedra Camilo , Skov Henrik , Stienen Eric W. M. , Sveegaard Signe , Thompson Paul , Vanermen Nicolas , Wall Dave , Webb Andy , Wilson Jared , Wanless Sarah , Hiddink Jan Geert
Published: October 2019

Distribution maps of cetaceans and seabirds at basin and monthly scales are needed for conservation and marine management. These are usually created from standardized and systematic aerial and vessel surveys, with recorded animal densities interpolated across study areas. However, distribution maps at basin and monthly scales have previously not been possible because individual surveys have restricted spatial and temporal coverage.

This study develops an alternative approach consisting of: (a) collating diverse survey data to maximize spatial and temporal coverage, (b) using detection functions to estimate variation in the surface area covered (km2) among these surveys, standardizing measurements of effort and animal densities, and (c) developing species distribution models (SDM) that overcome issues with heterogeneous and uneven coverage.

2.68 million km of survey data in the North‐East Atlantic between 1980 and 2018 were collated and standardized. SDM using Generalized Linear Models and General Estimating Equations in a hurdle approach were developed. Distribution maps were then created for 12 cetacean and 12 seabird species at 10 km and monthly resolution. Qualitative and quantitative assessment indicated good model performance.

Synthesis and applications. This study provides the largest ever collation and standardization of diverse survey data for cetaceans and seabirds, and the most comprehensive distribution maps of these taxa in the North‐East Atlantic. These distribution maps have numerous applications including the identification of important areas needing protection, and the quantification of overlap between vulnerable species and anthropogenic activities. This study demonstrates how the analysis of existing and diverse survey data can meet conservation and marine management needs.
Exposure to Asian dust within a few days of delivery is associated with placental abruption in Japan: a case‐crossover study
Authors: Michikawa T , Yamazaki S , Shimizu A , Nitta H , Kato K , Nishiwaki Y , Morokuma S
Published: October 2019

Objective

Asian dust is a natural phenomenon in which dust particles are transported from desert areas in China and Mongolia to East Asia. Short‐term exposure to Asian dust has been associated with cardiovascular disease through mechanisms such as systemic inflammation. Because inflammation is a potential trigger of placental abruption, exposure may also lead to abruption. We examined whether exposure to Asian dust was associated with abruption.

Design

A bi‐directional, time‐stratified case‐crossover design.

Setting and population

From the Japan Perinatal Registry Network database, we identified 3014 patients who delivered singleton births in hospitals in nine Japanese prefectures from 2009 to 2014 with a diagnosis of placental abruption.

Methods

Asian dust levels were measured at Light Detection and Ranging monitoring stations, and these measurements were used to define the Asian dust days. As there was no information on the onset day of abruption, we assumed this day was the day before delivery (lag1).

Main outcome measures

Placental abruption.

Results

During the study period, the Asian dust days ranged from 15 to 71 days, depending on the prefecture. The adjusted odds ratio of placental abruption associated with exposure to Asian dust was 1.4 (95% confidence interval = 1.0, 2.0) for cumulative lags of 1–2 days. Even after adjustment for co‐pollutant exposures, this association did not change substantially.

Conclusions

In this Japanese multi‐area study, exposure to Asian dust was associated with an increased risk of placental abruption.

Tweetable abstract

Exposure to environmental factors such as Asian dust may be a trigger of placental abruption.