bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping sequences can bias population receptive field estimates
Authors: Infanti Elisa , Schwarzkopf D. Samuel
Published: October 2019

Population receptive field (pRF) modelling is a common technique for estimating the stimulus-selectivity of populations of neurons using neuroimaging. Here, we aimed to address if pRF properties estimated with this method depend on the spatio-temporal structure and the predictability of the mapping stimulus. We mapped the polar angle preference and tuning width of voxels in visual cortex (V1-V4) of healthy, adult volunteers. We compared sequences orderly sweeping through the visual field or jumping from location to location employing stimuli of different width (45° vs 6°) and cycles of variable duration (8s vs 60s). While we did not observe any systematic influence of stimulus predictability, the temporal structure of the sequences significantly affected tuning width estimates. Ordered designs with large wedges and short cycles produced systematically smaller estimates than random sequences. Interestingly, when we used small wedges and long cycles, we obtained larger tuning width estimates for ordered than random sequences. We suggest that, ordered and random mapping protocols show different susceptibility to other design choices such as stimulus type and duration of the mapping cycle and can produce significantly different pRF results.
A complex virome that includes two distinct emaraviruses is associated to virus-like symptoms in Camellia japonica
Authors: Peracchio C. , Forgia M. , Chiapello M. , Vallino M. , Turina M. , Ciuffo M.
Published: October 2019

Camellia japonica plants manifesting a complex and variable spectrum of viral symptoms like chlorotic ringspots, necrotic rings, yellowing with necrotic rings, yellow mottle, leaves and petals deformations, flower color-breaking were studied since 1940 essentially through electron microscopic analyses; however, a strong correlation between symptoms and one or more well characterized viruses was never verified. In this work samples collected from symptomatic plants were analyzed by NGS technique and a complex virome composed by viruses members of the Betaflexiviridae and Fimoviridae families was identified. In particular, the genomic fragments typical of the emaravirus group were organized in the genomes of two new emaraviruses species, tentatively named Camellia japonica associated emaravirus 1 and 2. They are the first emaraviruses described in camellia plants and were always found solely in symptomatic plants. On the contrary, in both symptomatic and asymptomatic plants, we detected five betaflexiviruses isolates that, based on aa identitiy comparisons, can be classified in two new putative species called Camellia japonica associated betaflexivirus 1 and Camellia japonica associated betaflexivirus 2. Together with other recently identified betaflexiviruses associated to Camellia japonica disease, the betaflexiviruses characterized in this study show an unusual hyper-conservation of the coat protein at aminoacidic level.
Chromatin-based techniques map DNA interaction landscapes in psoriasis susceptibility loci and highlightKLF4as a target gene in 9q31
Authors: Ray-Jones Helen , Duffus Kate , McGovern Amanda , Martin Paul , Shi Chenfu , Hankinson Jenny , Gough Oliver , Yarwood Annie , Morris Andrew P , Adamson Antony , Taylor Christopher , Ding James , Gaddi Vasanthi Priyadarshini , Fu Yao , Gaffney Patrick , Orozco Gisela , Warren Richard B , Eyre Steve
Published: October 2019

Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. Here, we use a disease-focused Capture Hi-C experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. In the 9q31 risk locus we combine further epigenomic evidence to demonstrate how the psoriasis association forms a functional interaction with the distant (>500 kb)KLF4gene. We use CRISPR activation coupled with RNA-seq to demonstrate how activation of psoriasis-associated enhancers upregulatesKLF4in HaCaT cells. Our study design provides a robust pipeline for following up on GWAS disease-associated variants, paving the way for functional translation of genetic findings into clinical benefit.
Tissue- and population-level microbiome analysis of the wasp spiderArgiope bruennichiidentifies a novel dominant bacterial symbiont
Authors: Sheffer Monica M. , Uhl Gabriele , Prost Stefan , Lueders Tillmann , Urich Tim , Bengtsson Mia M.
Published: October 2019

Many ecological and evolutionary processes in animals depend upon microbial symbioses. In spiders, the role of the microbiome in these processes remains mostly unknown. We compared the microbiome between populations, individuals, and tissue types of a range-expanding spider, using 16S rRNA gene sequencing. Our study is one of the first to go beyond targeting known endosymbionts in spiders, and characterizes the total microbiome across different body compartments (leg, prosoma, hemolymph, book lungs, ovaries, silk glands, midgut, and fecal pellets). Overall, the microbiome differs significantly between populations and individuals, but not between tissue types. The microbiome of the wasp spiderArgiope bruennichifeatures a novel dominant bacterial symbiont, which is abundant in every tissue type in spiders from geographically distinct populations, and present in offspring. The novel symbiont is affiliated with theTenericutes, but has low sequence identity (<85%) to all previously named taxa, suggesting that the novel symbiont represents a new bacterial clade. Its presence in offspring implies that it is vertically transmitted. Our results shed light on the processes which shape microbiome differentiation in this species, and raise several questions about the implications of the novel dominant bacterial symbiont on the biology and evolution of its host.
mRNA structural dynamics shape Argonaute-target interactions
Authors: Ruijtenberg Suzan , Sonneveld Stijn , Cui Tao Ju , Logister Ive , de Steenwinkel Dion , Xiao Yao , MacRae Ian J. , Joo Chirlmin , Tanenbaum Marvin E.
Published: October 2019

Small RNAs (such as miRNAs, siRNAs and piRNAs) regulate protein expression in a wide variety of biological processes and play an important role in cellular function, development and disease. Association of small RNAs with Argonaute (AGO) family proteins guide AGO to target RNAs, generally resulting in target silencing through transcriptional silencing, translational repression or mRNA degradation. Here we develop a live-cell single-molecule imaging assay to simultaneously visualize translation of individual mRNA molecules and their silencing by human AGO2-siRNA complexes. We find that siRNA target sites are commonly maskedin vivoby RNA secondary structures, which inhibit AGO2-target interactions. Translating ribosomes unmask AGO2 binding sites, stimulating AGO2-target interactions and promoting mRNA degradation. Using a combination of mathematical modeling and experiments, we find that mRNA structures are highly heterogeneous and continuously refolding. We show that structural dynamics of mRNAs shape AGO2-target recognition, which may be a common feature controlling mRNA-protein interactions.
The circadian clock and darkness control natural competence in cyanobacteria
Authors: Taton Arnaud , Erikson Christian , Yang Yiling , Rubin Benjamin E. , Rifkin Scott A. , Golden James W. , Golden Susan S.
Published: October 2019

Natural genetic competence-based transformation contributed to the evolution of prokaryotes, including the cyanobacterial phylum that established oxygenic photosynthesis. The cyanobacteriumSynechococcus elongatusis noted both as a model system for analyzing a prokaryotic circadian clock and for its facile, but poorly understood, natural competence. Here a genome-wide screen aimed at determining the genetic basis of competence in cyanobacteria identified all genes required for natural transformation inS. elongatus, including conserved Type IV pilus, competence-associated, and newly described genes, and revealed that the circadian clock controls the process. The findings uncover a daily program that determines the state of competence inS. elongatusand adapts to seasonal changes of day-length. Pilus biogenesis occurs daily in the morning, but competence is maximal upon the coincidence of circadian dusk and the onset of darkness. As in heterotrophic bacteria, where natural competence is conditionally regulated by nutritional or other stress, cyanobacterial competence is conditional and is tied to the daily cycle set by the cell’s most critical nutritional source, the Sun.
Whole-genome duplication and host genotype affect rhizosphere microbial communities
Authors: Ponsford Julian C. B. , Hubbard Charley J. , Harrison Joshua G. , Maignien Lois , Buerkle C. Alex , Weinig Cynthia
Published: October 2019

The composition of complex microbial communities found in association with plants is influenced in part by host phenotype. Yet, the salient genetic architecture is often unknown. Genome duplication events are common in the evolutionary history of plants, influence many important plant traits, and may affect associated microbial communities. Using experimentally induced whole genome duplication (WGD), we tested the effect of WGD on rhizosphere bacterial communities in Arabidopsis thaliana. Specifically, we performed 16S rRNA amplicon sequencing to characterize differences between microbiomes associated with specific host genotypes (Columbia vs. Landsberg) and ploidy levels (diploid vs. tetraploid). We modeled abundances of individual bacterial taxa by utilizing a hierarchical Bayesian framework, based on the Dirichlet and multinomial distributions. We found that host genotype and host ploidy level affected rhizosphere community composition, for instance, the microbiome of the tetraploid Columbia genotype differed from that of other host genotypes. We then tested to what extent microbiomes derived from a given host genotype or ploidy level affected plant performance by inoculating sterile seedlings of each genotype with microbial communities harvested from a prior generation. We found a negative effect of the tetraploid Columbia microbiome on growth of all four plant genotypes. The findings suggest that while both host genotype and ploidy affect microbial community assembly, bacterial communities found in association with only some host genotypes may affect growth of subsequent plant generations.

Importance

Plants influence the composition of their associated microbial communities; yet the underlying host genetic factors are often unknown. Genome duplication events are common in the evolutionary history of plants and affect many plant traits, including the quality and quantity of compounds exuded into the root zone, which can affect root-bound microbes. In Arabidopsis thaliana, we characterized how whole-genome duplication affected the composition of rhizosphere bacterial communities, and how bacterial communities associated with two host plant genotypes and ploidy levels affected subsequent plant growth. We observed an interaction in which ploidy level within one host genotype affected both bacterial community composition and function. This research reveals how genome duplication, a widespread genetic feature of both wild and crop plant species, influences the coexistence of bacterial taxa and affects plant growth.
HD Spot: Interpretable Deep Learning Classification of Single Cell Transcript Data
Authors: Prince Eric , Hankinson Todd C.
Published: October 2019

High throughput data is commonplace in biomedical research as seen with technologies such as single-cell RNA sequencing (scRNA-seq) and other Next Generation Sequencing technologies. As these techniques continue to be increasingly utilized it is critical to have analysis tools that can identify meaningful complex relationships between variables (i.e., in the case of scRNA-seq: genes) in a way such that human bias is absent. Moreover, it is equally paramount that both linear and non-linear (i.e., one-to-many) variable relationships be considered when contrasting datasets. HD Spot is a deep learning-based framework that generates an optimal interpretable classifier a given high-throughput dataset using a simple genetic algorithm as well as an autoencoder to classifier transfer learning approach. Using four unique publicly available scRNA-seq datasets with published ground truth, we demonstrate the robustness of HD Spot and the ability to identify ontologically accurate gene lists for a given data subset. HD Spot serves as a bioinformatic tool to allow novice and advanced analysts to gain complex insight into their respective datasets enabling novel hypotheses development.
Resveratrol attenuates high-fat diet-induced obesity and the aging-related sarcopenia mitochondrial dysfunction in skeletal muscle
Authors: Bai Chyi-Huey , Alizargar Javad , Wu Jia-Ping
Published: October 2019

Sarcopenic obesity is a progressive loss of skeletal muscle mass and strength with increases in adiposity. The aim of this study was to investigate the effects of resveratrol on obesity or sarcopenia to potential therapy risk for skeletal muscle declines in physical function. C57BL/6J male mice were fed either a high-fat diet for 4 weeks and resveratrol (low-, middle-, and high-dose) for 8 weeks to express the obesity effect. Samp8 mice sarcopenia skeletal muscle functional deterioration expressed an age-associated decline. Resveratrol (150 mg/Kg BW, daily) was administered by oral gavage two times a week one month of the experimental period. Exercise training based on adaptations in the muscle is training twice a week for 4 weeks. The skeletal muscles from mice in each group were analyzed by H&E staining, TUNEL and western blot analysis to determine mitochondrial function expression, apoptosis and relative fibrosis signaling. Results of the present study indicate that resveratrol in obesity skeletal muscle is linked to an increase in the expression of mitochondrial function involved in Bcl-2 and PI3K/AKT. On the other hand, resveratrol attenuates sarcopenia Samp8 mice, the age-related loss of skeletal muscle mass and mitochondrial function involved in Bad, caspase 3 and IL-6/ERK1. However, exercise training not find a significant difference in sarcopenia skeletal muscles SAMP8 mice. Exercise training didn’t induce sarcopenia skeletal muscle hypertrophy in sarcopenic SAMP8 mice. Therefore, we suggest that resveratrol as a therapeutic potential in the combination of sarcopenia and obesity, the state called sarcopenic obesity.
NHR-8 regulated P-glycoproteins uncouple xenobiotic stress resistance from longevity in chemosensory C. elegans mutants
Authors: Guerrero Gabriel A. , Derisbourg Maxime J. , Wester Laura E. , Gordia Marco , Dinort J. Eike , Alonso María J. , Hartman Matías D. , Schilling Klara , Mayr Felix A.M.C. , Lu Ryan J. , Benayoun Bérénice A. , Denzel Martin S.
Published: October 2019

Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 was necessary to regulate PGPs and tunicamycin resistance in a cholesterol-dependent fashion. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants.
HIV-1 Vpr Degrades TET2 to Suppress IRF7 and Interferon Expression in Plasmacytoid Dendritic Cells
Authors: Wang Qi , Tsao Li-Chung , Lv Lei , Xu Yanping , Cheng Liang , Yu Haisheng , Zhang Liguo , Xiong Yue , Su Lishan
Published: October 2019

Plasmacytoid dendritic cells (pDCs) are the major source of type I interferons (IFN-I) in rapid response to viral infections, with constitutive expression of interferon regulatory factor 7 (IRF7). HIV-1 expresses several accessory proteins to counteract specific IFN-induced host restriction factors. As one abundant virion-associated protein, HIV-1 Vpr remains enigmatic in enhancing HIV-1 infection via unclear mechanisms. Here we report that Vpr impaired IFN-I induction in pDCs to enhance HIV-1 replication in CD4+ T cells. Blockade of IFN-I signaling abrogated the effect of Vpr on HIV-1 replication. Virion-associated Vpr suppressed IFN-I induction in pDC by TLR7 agonists. Modulation of IFN-I induction by Vpr was genetically dependent on its activity of TET2 degradation. We further demonstrate that Vpr-mediated TET2 degradation reduced expression of IRF7 in pDCs. Finally, degradation of TET2 in pDCs by Vpr reduced the demethylation level of the IRF7 promoter via CXXC5-dependent recruitment. We conclude that HIV-1 Vpr functions to promote HIV-1 replication by suppressing TET2-dependent IRF7 expression and IFN-I induction in pDCs. The Vpr-TET2-IRF7 axis provides a novel therapeutic target to control HIV-1 infection.
Dimensionality, information and learning in prefrontal cortex
Authors: Bartolo Ramon , Saunders Richard C. , Mitz Andrew , Averbeck Bruno B.
Published: October 2019

Learning leads to changes in population patterns of neural activity. In this study we wanted to examine how these changes in patterns of activity affect the dimensionality of neural responses and information about choices. We addressed these questions by carrying out high channel count recordings in dorsal-lateral prefrontal cortex (dlPFC; 768 electrodes) while monkeys performed a two-armed bandit reinforcement learning task. The high channel count recordings allowed us to study population coding while monkeys learned choices between actions or objects. We found that the dimensionality of neural population activity was higher across blocks in which animals learned the values of novel pairs of objects, than across blocks in which they learned the values of actions. The increase in dimensionality with learning in object blocks was related to less shared information across blocks, and therefore patterns of neural activity that were less similar, when compared to learning in action blocks. Furthermore, these differences emerged with learning, and were not a simple function of the choice of a visual image or action. Therefore, learning the values of novel objects increases the dimensionality of neural representations in dlPFC.
Monkeys and Humans Implement Causal Inference to Simultaneously Localize Auditory and Visual Stimuli
Authors: Mohl Jeff T. , Pearson John M. , Groh Jennifer M.
Published: October 2019

The environment is sampled by multiple senses, which are woven together to produce a unified perceptual state. However, optimally unifying such signals requires assigning particular signals to the same or different underlying objects or events. Many prior studies (especially in animals) have assumed fusion of cross-modal information, whereas recent work in humans has begun to probe the appropriateness of this assumption. Here we present results from a novel behavioral task in which both monkeys and humans localized visual and auditory stimuli and reported their perceived sources through saccadic eye movements. When the locations of visual and auditory stimuli were widely separated, subjects made two saccades, while when the two stimuli were presented at the same location they made only a single saccade. Intermediate levels of separation produced mixed response patterns: a single saccade to an intermediate position on some trials or separate saccades to both locations on others. The distribution of responses was well described by a hierarchical causal inference model that accurately predicted both the explicit “same vs. different” source judgements as well as biases in localization of the source(s) under each of these conditions. The results from this task are broadly consistent with prior work in humans across a wide variety of analogous tasks, extending the study of multisensory causal inference to non-human primates and to a natural behavioral task with both a categorical assay of the number of perceived sources and a continuous report of the perceived position of the stimuli.

Author Summary

We experience the world through multiple sensory systems, which interact to shape perception. To do so, the brain must first determine which pieces of sensory input arise from the same source and which have nothing to do with one another. To probe how the brain accomplishes this causal inference, we developed a naturalistic paradigm that provides a behavioral report both of the number of perceived stimuli and their locations. We tested performance on this task in both humans and monkeys, and we found that both species perform causal inference in a similar manner. By providing this cross-species comparison at the behavioral level, our paradigm lays the groundwork for future experiments using neuronal recording techniques that may be impractical or impossible in human subjects.
Replacing murine insulin 1 with human insulin protects NOD mice from diabetes
Authors: Elso Colleen M. , Scott Nicholas A. , Mariana Lina , Masterman Emma I. , Sutherland Andrew P.R. , Thomas Helen E. , Mannering Stuart I.
Published: October 2019

Type 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse modelandthe clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.
Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells
Authors: Zhang Jiye , Xu Bangfa , Chen Xinping , Zhao Liqiang , Zhang Pei , Wang Fei , Li Xiaojuan , Wang Meiling , Xu Weihua , Zhang Wenwen , Fu Shengmiao
Published: October 2019

Germ cell 1 spermatogonial (GC-1spg) cells are multipotent progenitor cells. We previously confirmed that bone morphogenetic protein (BMP) 9 is among the most osteogenic BMPs. However, whether GC-1spg cells are driven toward osteogenic differentiation under proper stimuli is uncertain. Additionally, the molecular mechanism of BMP9 remains unclear. In the present study, we aimed to determine whether BMP9 can induce osteogenic differentiation of GC-1spg cells. Recombinant adenoviruses were generated by the AdEasy system to regulate the BMP9 expression in GC-1spg cells. We identified osteogenic markers by real-time PCR and staining techniquesin vitro. Ectopic ossification assays and histological analysis were also performed to verify thein vivoactivity of BMP9. Finally, potential signaling pathways of BMP9 were assessed by transcriptome sequencing and KEGG enrichment analysis. Using recombinant adenoviruses, we demonstrate that BMP9 upregulates osteogenic markers including Runx2, osteocalcin, osteopontin, and Sox9. BMP9 also activates alkaline phosphatase activity and calcium deposition in GC-1spg cells.In vivoresults show that BMP9 overexpression in GC-1spg cells promotes ectopic bone formation and chondrogenesis. In addition, RNA-sequencing and KEGG pathway analysis demonstrate that several signaling pathways are involved in BMP9-mediated osteogenesis. GC-1spg cells not only maintain spermatogenesis but also retain the ability to form bone tissue. Therefore, BMP9 activity in GC-1spg cells may help identify signaling pathways implicated in bone formation and could be of use in regenerative medicine.
Pooled CRISPRi screening of the cyanobacteriumSynechocystissp. PCC 6803 for enhanced growth, tolerance, and chemical production
Authors: Yao Lun , Shabestary Kiyan , Björk Sara M. , Asplund-Samuelsson Johannes , Joensson Haakan N. , Jahn Michael , Hudson Elton P.
Published: October 2019

We developed an inducible CRISPRi gene repression library in the cyanobacteriumSynechocystissp. PCC 6803, where all annotated genes are targeted for repression. We used the library to estimate gene fitness in multiple conditions. The library revealed several mutants with increased specific growth rates (up to 17%), and transcriptomics of these mutants revealed common upregulation of genes within photosynthetic electron flow. We challenged the library with L-lactate stress to find more tolerant mutants. Repression of the peroxiredoxin Bcp2 increased growth rate by 49% in the presence of 0.1 M L-lactate. Finally, the library was transformed into a L-lactate-secreting strain, and droplet microfluidics sorting of top producers enriched sgRNAs targeting nutrient assimilation, redox modulation, and cyclic-electron flow. Several clones showed increased productivity in batch cultivations (up to 75%). In some cases, tolerance or productivity was enhanced by partial repression of essential genes, which are difficult to access by transposon insertion.
Non-selective response inhibition in equiprobable Go/NoGo task: Bayesian analysis of fMRI data
Authors: Masharipov Ruslan , Korotkov Alexander , Medvedev Svyatoslav , Kireev Maxim
Published: October 2019

Response inhibition is typically considered a brain mechanism selectively triggered by particular “inhibitory” stimuli or events. Based on recent research, an alternative non-selective mechanism was proposed by several authors. Presumably, the inhibitory brain activity may be triggered not only by the presentation of “inhibitory” stimuli but also by any imperative stimuli, including Go stimuli, when the context is uncertain. Earlier support for this notion was mainly based on the absence of a significant difference between neural activity evoked by equiprobable Go and NoGo stimuli. Equiprobable Go/NoGo design with a simple response time task limits potential confounds between response inhibition and accompanying cognitive processes while not preventing prepotent automaticity. However, previous neuroimaging studies utilized classical null hypothesis significance testing, making it impossible to accept the null hypothesis. Therefore, the current research aimed to provide evidence for practical equivalence of neuronal activity in Go and NoGo trials using Bayesian analysis of functional magnetic resonance imaging (fMRI) data. Thirty-four healthy participants performed a cued Go/NoGo task with an equiprobable presentation of Go and NoGo stimuli. To independently localize brain areas associated with response inhibition in similar experimental conditions, we performed a meta-analysis of fMRI studies using equal probability Go/NoGo tasks. As a result, we observed overlap between response inhibition areas and areas demonstrating the practical equivalence of neuronal activity located in the right dorsolateral prefrontal cortex, parietal cortex, premotor cortex, and left inferior frontal gyrus. Thus, obtained results favour the existence of non-selective response inhibition, which can act in settings of contextual uncertainty induced by the equal probability of Go and NoGo stimuli.

Highlights

Non-selective response inhibition was assessed by equiprobable Go/NoGo task

Bayesian analysis of fMRI data was combined with a meta-analysis of fMRI studies

Several nodes of response inhibition system were equally involved in Go and NoGo trials

Evidence for non-selective response inhibition in uncertain context was found
Trem-2 promotes emergence of restorative macrophages and endothelial cells during recovery from hepatic tissue damage
Authors: Coelho Inês , Duarte Nádia , Barros André , Macedo Maria Paula , Penha-Gonçalves Carlos
Published: October 2019

Macrophages are pivotal in mounting liver inflammatory and tissue repair reactions upon hepatic injury showing remarkable functional plasticity. Nevertheless, the molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) or chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts in liver macrophages and impacts endothelial cell differentiation during tissue recovery.

Trem-2 gene ablation led to delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. We found that during tissue recovery macrophages in transition to the Kupffer cell compartment expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with an unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2.

During tissue recovery lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs) engaged in a transcriptional program compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and striking in vitro morphological changes towards typical endothelial cells.

In conclusion, we found that the dynamics of liver macrophages in response to liver injury is critically controlled by Trem-2 and is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from the pro-inflammatory to the tissue repair phase by driving the acquisition of restorative properties of phagocytic macrophages.
Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex
Authors: Perzel Mandell Kira A. , Price Amanda J. , Wilton Richard , Collado-Torres Leonardo , Tao Ran , Eagles Nicholas J. , Szalay Alexander S. , Hyde Thomas M. , Weinberger Daniel R. , Kleinman Joel E. , Jaffe Andrew E.
Published: October 2019

DNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain is a highly dynamic tissue, but our understanding of key drivers of epigenetic variability across development is limited. We therefore assessed genomic methylation at over 39 million sites in the prenatal cortex using whole genome bisulfite sequencing and found loci and regions in which methylation levels are dynamic across development. We saw that DNAm at these loci was associated with nearby gene expression and enriched for enhancer chromatin states in prenatal brain tissue. Additionally, these loci were enriched for genes associated with psychiatric disorders and genes involved with neurogenesis. We also found autosomal differences in DNAm between the sexes during prenatal development, though these have less clear functional consequences. We lastly confirmed that the dynamic methylation at this critical period is specifically CpG methylation, with very low levels of CpH methylation. Our findings provide detailed insight into prenatal brain development as well as clues to the pathogenesis of psychiatric traits seen later in life.
Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference
Authors: Hop Paul J. , Luijk René , Daxinger Lucia , van Iterson Maarten , Dekkers Koen F. , Jansen Rick ,   BIOS Consortium, van Meurs Joyce B.J. , ’t Hoen Peter A.C. , Ikram M. Arfan , van Greevenbroek Marleen M.J. , Boomsma Dorret I. , Slagboom P. Eline , Veldink Jan H. , van Zwet Erik W. , Heijmans Bastiaan T.
Published: October 2019

DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identified 818 genes that influence DNA methylation patterns in blood using large-scale population genomics data. By employing genetic instruments as causal anchors, we identified directed associations between gene expression and distant DNA methylation levels, whilst ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. We found that DNA methylation patterns are commonly shaped by transcription factors that consistently increase or decrease DNA methylation levels. However, we also observed genes encoding proteins without DNA binding activity with widespread effects on DNA methylation (e.g.NFKBIE, CDCA7(L)andNLRC5) and we suggest plausible mechanisms underlying these findings. Many of the reported genes were unknown to influence DNA methylation, resulting in a comprehensive resource providing insights in the principles underlying epigenetic regulation.
Soluble cyanobacterial carotenoprotein as a robust antioxidant nanocarrier and delivery module
Authors: Maksimov Eugene G. , Zamaraev Alexey V. , Parshina Evgenia Yu. , Slonimskiy Yury B. , Slastnikova Tatiana A. , Abdrakhmanov Alibek A. , Babaev Pavel A. , Efimova Svetlana S. , Ostroumova Olga S. , Stepanov Alexey V. , Ryabova Anastasia V. , Friedrich Thomas , Sluchanko Nikolai N.
Published: October 2019

To counteract oxidative stress, antioxidants including carotenoids are highly promising, yet their exploitation is drastically limited by the poor bioavailability and fast photodestruction, whereas current delivery systems are far from being efficient. Here we demonstrate that the recently discovered nanometer-sized water-soluble carotenoprotein fromAnabaena(termed CTDH) transiently interacts with liposomes to efficiently extract carotenoids via carotenoid-mediated homodimerization, yielding violet-purple protein samples amenable to lyophilization and long-term storage. We characterize spectroscopic properties of the pigment-protein complexes and thermodynamics of liposome-protein carotenoid transfer and demonstrate the highly efficient delivery of echinenone form CTDH into liposomes. Most importantly, we show carotenoid delivery to membranes of mammalian cells, which provides protection from reactive oxygen species. The described carotenoprotein may be considered as part of modular systems for the targeted antioxidant delivery.

Significance statement

Carotenoids are excellent natural antioxidants but their delivery to vulnerable cells is challenging due to their hydrophobic nature and susceptibility to degradation. Thus, systems securing antioxidant stability and facilitating targeted delivery are of great interest for the design of medical agents. In this work, we have demonstrated that soluble cyanobacterial carotenoprotein can deliver echinenone into membranes of liposomes and mammalian cells with almost 70 % efficiency, which alleviates the induced oxidative stress. Our findings warrant the robustness of the protein-based carotenoid delivery for studies of carotenoid activities and effects on cell models.
Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1
Authors: Guo Yajuan , Leacock Krystynne A. , Redmond Catherine , Jaskula-Ranga Vinod , Coulombe Pierre A.
Published: October 2019

The type I intermediate filament (IF) keratin 14 (K14) provides vital structural support in basal keratinocytes of epidermis. Recent studies evidenced a role for K14-dependent disulfide bonding in the organization and dynamics of keratin IFs in skin keratinocytes. Here we report that knock-in mice harboring a cysteine-to-alanine substitution at codon 373 (C373A) inKrt14exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in the epidermis. A proteomics screen identified 14-3-3 as major K14 interacting proteins. Follow-up studies showed that YAP1, a transcriptional effector of Hippo signaling regulated by 14-3-3sigma in skin keratinocytes, shows aberrant subcellular partitioning and function in differentiatingKrt14C373A keratinocytes. Residue C373 in K14, which is conserved in several other type I IFs, is thus revealed as a novel regulator of keratin organization and YAP function in early differentiating keratinocytes, with an impact on cell mechanics, homeostasis and barrier function in the epidermis.
Targeting Viperin to the Mitochondrion Inhibits the Thiolase Activity of the Trifunctional Enzyme Complex
Authors: Dumbrepatil Arti B. , Zegalia Kelcie A. , Sajja Keerthi , Kennedy Robert T. , Marsh E. Neil. G.
Published: October 2019

Understanding the mechanisms by which viruses evade host cell immune defenses is important for developing improved antiviral therapies. In an unusual twist, human cytomegalovirus (HCMV) co-opts the antiviral radical SAM enzyme, viperin (Virusinhibitoryprotein,endoplasmicreticulum-associated,interferon-inducible), to enhance viral infectivity. This process involves translocation of viperin to the mitochondrion where it binds the β-subunit (HADHB) of the mitochondrial trifunctional enzyme complex that catalyzes the thiolysis of β-ketoacyl-CoA esters as part of fatty acid β-oxidation. We have investigated how the interaction between these two enzymes alters their activities and their effect on cellular ATP levels. Studies with purified enzymes demonstrated that viperin inhibits the thiolase activity of HADHB, but, unexpectedly, HADHB activates viperin to synthesize the antiviral nucleotide 3’-deoxy-3’,4’-didehydro-CTP. Enzyme activities were also measured in lysates prepared from transfected HEK 293T cells transiently expressing these enzymes. Mirroring the studies on purified enzymes, localizing viperin to the mitochondria decreased thiolase activity whereas co-expression of HADHB significantly increased viperin activity. Furthermore, targeting viperin to mitochondria also increased the rate at which HADHB was retro-translocated out of mitochondria and degraded, providing an additional mechanism for reducing HADHB activity. Targeting viperin to the mitochondria decreased cellular ATP levels by over 50 %, consistent with the enzyme disrupting fatty acid catabolism. These results provide biochemical insight into the mechanism by which HCMV subjugates viperin; they also provide a biochemical rational for viperin’s recently discovered role in regulating thermogenesis in adipose tissues.
The Interaction of Viperin with Hepatitis C Virus Non-Structural Protein 5A Inhibits the Catalytic Activity of Viperin
Authors: Ghosh Soumi , Patel Ayesha M. , Grunkemeyer Timothy J. , Dumbrepatil Arti B. , Zegalia Kelcie , Kennedy Robert T. , Marsh E. Neil G.
Published: October 2019

The radical SAM enzyme viperin exerts a wide range of antiviral effects through both the synthesis of the antiviral nucleotide 3’-deoxy-3’, 4’-didehydro-CTP (ddhCTP) and through its interactions with various cellular and viral proteins. Here we investigate the interaction of viperin with hepatitis C virus non-structural protein 5A (NS5A) and the host sterol regulatory protein, vesicle-associated membrane protein A (VAP-33). NS5A and VAP-33 form part of the viral replication complex that is essential for copying the RNA genome of the virus. Using transfected enzymes in HEK293T cells, we show that viperin binds to both NS5A and VAP-33 independently and that this interaction is dependent on all three proteins being localized to the ER membrane. Co-expression of viperin with VAP-33 and NS5A was found to reduce NS5A levels, most likely by increasing the rate of proteasomal degradation. However, co-expression of viperin with VAP-33 and NS5A also reduces the specific activity of viperin by ~ 3-fold. This observation suggests that NS5A may have evolved to bind viperin as a strategy to reduce ddhCTP synthesis, thereby reducing possibility of the replication complex introducing this chain-terminating nucleotide during genome synthesis.
Prevalence of beta-lactam drug-resistance genes in commensal Escherichia coli contaminating ready-to-eat lettuce
Authors: Liao Ningbo , Rubin Julia , Hu Yuan , Ramirez Hector A. , Borges Clarissa Araújo , Zhou Biao , Zhang Yanjun , Zhang Ronghua , Jiang Jianmin , Riley Lee W.
Published: October 2019

The objective of this study was to evaluate the prevalence of antibiotic resistance and beta-lactam drug resistance genes in Escherichia coli isolated from ready-to-eat lettuce, obtained from local supermarkets in Northern California. Bags of lettuce were purchased from 4 chain supermarkets during three different periods—Oct 2018–Jan 2019, Feb 2019–Apr 2019 and May 2019–July 2019. From 91 packages of lettuce, we recovered 34 E. coli isolates from 22 (24%) lettuce samples. All E. coli isolates were genotyped by multilocus sequence typing (MLST), and we found 15 distinct sequence types (STs). Five of these genotypes (ST2819, ST4600, ST2432, ST1198 and ST5143) have been reported to cause infection in humans. Twenty (59%) E. coli isolates were found resistant to at least one of the antibacterial drugs. They included resistance to ampicillin (AMP, 85%) and ampicillin/sulbactam (SAM, 50%), cefoxitin (FOX, 40%) and cefuroxime (CXM, 35%). We found 8 (40%) of 20 beta-lactam resistant E. coli isolates to carry blaCTX-M; 5 (25%) tested positive for blaSHV, while only 4 (20%) tested positive for blaTEM. Additionally, we identified a class A broad-spectrum beta-lactamase SED-1 gene, blaSED, reported by others in Citrobacter sedlakii isolated from bile of a patient. This study found that a large proportion of fresh lettuce carry beta-lactam drug-resistant E. coli, which could serve as a reservoir for drug resistance genes that could potentially enter pathogens to cause human infections.
Dopamine modulates prediction error forwarding in the nonlemniscal inferior colliculus
Authors: Valdés-Baizabal Catalina , Carbajal Guillermo V. , Pérez-González David , Malmierca Manuel S.
Published: October 2019

The predictive processing framework describes perception as a hierarchical predictive model of sensation. Higher-level neural structures constrain the processing at lower-level structures by suppressing synaptic activity induced by predictable sensory input. But when predictions fail, deviant input is forwarded bottom-up as ‘prediction error’ to update the perceptual model. The earliest prediction error signals identified in the auditory pathway emerge from the nonlemniscal inferior colliculus (IC). The drive that these feedback signals exert on the perceptual model depends on their ‘expected precision’, which determines the postsynaptic gain applied in prediction error forwarding. Expected precision is theoretically encoded by the neuromodulatory (e.g., dopaminergic) systems. To test this empirically, we recorded extracellular responses from the rat nonlemniscal IC to oddball and cascade sequences before, during and after the microiontophoretic application of dopamine or eticlopride (a D2-like receptor antagonist). Hence, we studied dopaminergic modulation on the subcortical processing of unpredictable and predictable auditory changes. Results demonstrate that dopamine reduces the net neuronal responsiveness exclusively to unexpected input, without significantly altering the processing of expected auditory events at population level. We propose that, in natural conditions, dopaminergic projections from the thalamic subparafascicular nucleus to the nonlemniscal IC could serve as a precision-weighting mechanism mediated by D2-like receptors. Thereby, the levels of dopamine release in the nonlemniscal IC could modulate the early bottom-up flow of prediction error signals in the auditory system by encoding their expected precision.
Synchronous chromosome segregation in mouse oocytes is ensured by biphasic securin destruction and cyclin B1-Cdk1
Authors: Thomas Christopher , Levasseur Mark D. , Harris Rebecca J. , Davies Owen R. , Madgwick Suzanne
Published: October 2019

Successful cell division relies on the faithful segregation of chromosomes. If chromosomes segregate prematurely the cell is at risk of aneuploidy. Alternatively, if cell division is attempted in the absence of complete chromosome segregation, non-segregated chromosomes can become trapped within the cleavage furrow and the cell can lose viability. Securin plays a key role in this process, acting as a pseudosubstrate to inhibit the protease separase that functions to cleave the cohesin rings that hold chromosomes together. Consequently, securin must be depleted ahead of anaphase, ensuring chromosome segregation occurs in time with the anaphase trigger. Here we find that MI mouse oocytes contain a large excess of securin over separase and reveal the existence of a novel mechanism that functions to promote the destruction of excess securin in prometaphase. Critically, this mechanism relies on key residues that are only exposed when securin is not bound to separase. We suggest that the majority of non-separase bound securin is removed by this mechanism, allowing for separase activity to be protected until just before anaphase. In addition, we further demonstrate the importance of complementary mechanisms of separase inhibition by directly measuring cleavage activity in live oocytes, confirming that both securin and inhibition by cyclin B1-Cdk1 are independently sufficient to prevent premature separase activation.