bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strong gene activation with genome-wide specificity using a new orthogonal CRISPR/Cas9-based Programmable Transcriptional Activator
Authors: Selma S , Bernabé-Orts J , Vazquez-Vilar M , Diego B , Ajenjo M , García-Carpintero V , Granell A , Orzaez D 
Published: December 2018

ABSTRACTSynthetic Biology (SynBio) aims at rewiring plant metabolic and developmental programs with orthogonal regulatory circuits. This endeavour requires new molecular tools able to interact with endogenous factors in a potent yet at the same time highly specific manner. A promising new class of SynBio tools that could play this function are the synthetic transcriptional activators based on CRISPR/Cas9 architecture, which combine autonomous activation domains (ADs) capable of recruiting the cell’s transcription machinery, with the easily customizable DNA-binding activity of nuclease-inactivated Cas9 protein (dCas9), creating so-called Programmable Transcriptional Activators (PTAs). In search for optimized dCas9-PTAs we performed a combinatorial analysis with seven different ADs arranged in four different protein/RNA architectures. This analysis resulted in the selection of a new dCas9-PTA with improved features as compared with previously reported activators. The new synthetic riboprotein, named dCasEV2.1, combines EDLL and VPR ADs using a multiplexable mutated version (v2.1) of the previously described aptamer-containing guide RNA2.0. We show here that dCasEV2.1 is a strong and wide spectrum activator, displaying variable activation levels depending on the basal activity of the target promoter. Maximum activation rates reaching up to 10000 fold were observed when targeting the NbDFR gene. Most remarkably, RNAseq analysis of dCasEV2.1-transformed N. benthamiana leaves revealed that the topmost activation capacity of dCasEV2.1 on target genes is accompanied with strict genome-wide specificity, making dCasEV2.1 an attractive tool for rewiring plant metabolism and regulatory networks.
A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood
Authors: Mordaunt Charles E. , Park Bo Y. , Bakulski Kelly M. , Feinberg Jason I. , Croen Lisa A. , Ladd-Acosta Christine , Newschaffer Craig J. , Volk Heather E. , Ozonoff Sally , Hertz-Picciotto Irva , LaSalle Janine M. , Schmidt Rebecca J. , Fallin M. Daniele 
Published: December 2018

AbstractBackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the United States. ASD risk is thought to arise from a combination of genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers and treatments. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing (Non-TD) or neurotypical children.MethodsGenome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from umbilical cord blood samples from both the Markers of Autism Risk in Babies--Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. An algorithm-based diagnosis from 36 month assessments categorized the younger sibling as either ASD, typically developing (TD), or not ASD but non-typically developing (Non-TD). 59 ASD, 92 Non-TD, and 120 TD subjects were included and differences were identified in ASD versus TD subjects, with Non-TD versus TD as a specificity control. Meta-analysis was used to combine the results from both studies. Functional enrichments of differentially-expressed genes were examined across diagnostic groups.ResultsWhile cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance when adjusting for multiple comparisons, 172 genes were nominally differentially-expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for toxic substance response and xenobiotic metabolism functions, and gene sets involved in chromatin regulation and systemic lupus erythematosus were significantly upregulated (FDR q < 0.05). In contrast, 66 genes were differentially-expressed between Non-TD and TD cord blood, including only 8 genes that were also differentially-expressed in ASD.ConclusionsThis is the first study to identify perinatal gene expression differences in umbilical cord blood specific to ASD. The results of this meta-analysis across two prospective ASD cohorts support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.
RNase L reprograms translation by widespread mRNA turnover escaped by antiviral mRNAs
Authors: Burke James M , Moon Stephanie L , Lester Evan T , Matheny Tyler , Parker Roy 
Published: December 2018

SUMMARYIn response to foreign and endogenous double-stranded RNA (dsRNA), protein kinase R (PKR) and ribonuclease L (RNase L) reprogram translation in mammalian cells. PKR inhibits translation initiation through eIF2α phosphorylation, which triggers stress granule (SG) formation and promotes translation of stress responsive mRNAs. The mechanisms of RNase L-driven translation repression, its contribution to SG assembly, and its regulation of dsRNA stress-induced mRNAs are unknown. We demonstrate that RNase L drives translational shut-off in response to dsRNA by promoting widespread turnover of mRNAs. This alters stress granule assembly and reprograms translation by only allowing for the translation of mRNAs resistant to RNase L degradation, including numerous antiviral mRNAs such asIFN-β. Individual cells differentially activate dsRNA responses revealing variation that can affect cellular outcomes. This identifies bulk mRNA degradation and the resistance of antiviral mRNAs as the mechanism by which RNaseL reprograms translation in response to dsRNA.
Conserved tau microtubule-binding repeat histidines confer pH-dependent tau-microtubule association
Authors: Charafeddine Rabab A. , Cortopassi Wilian A. , Lak Parnian , Jacobson Matthew P. , Barber Diane L. , Wittmann Torsten 
Published: December 2018

ABSTRACTTau, a member of the MAP2/tau family of microtubule-associated proteins, functions to stabilize and organize axonal microtubules in healthy neurons. In contrast, tau dissociates from microtubules and forms neurotoxic extracellular aggregates in neurodegenerative tauopathies. MAP2/tau family proteins are characterized by three to five conserved, intrinsically disordered repeat regions that mediate electrostatic interactions with the microtubule surface. We use molecular dynamics, microtubule-binding experiments and live cell microscopy to show that highly conserved histidine residues near the C terminus of each MT-binding repeat are pH sensors that can modulate tau-MT interaction strength within the physiological intracellular pH range. At lower pH, these histidines are positively charged and form cation-π interactions with phenylalanine residues in a hydrophobic cleft between adjacent tubulin dimers. At higher pH, tau deprotonation decreases microtubule-binding both in vitro and in cells. However, electrostatic and hydrophobic characteristics of histidine are required for tau-MT-binding as substitution with constitutively positively charged, non-aromatic lysine or uncharged alanine greatly reduces or abolishes tau-MT binding. Consistent with these findings, tau-MT binding is reduced in a cancer cell model with increased intracellular pH but is rapidly rescued by decreasing pH to normal levels. Thus, these data add a new dimension to the intracellular regulation of tau activity and could be relevant in normal and pathological conditions.
Evolution of pathogenic and nonpathogenic yeasts mitochondrial genomes inferred by supertrees and supermatrices with divergence estimates based on relaxed molecular clocks
Authors: Lopes Luciano R. , Ferreira Renata C. , Antoneli Fernando , Paiva Paulo B. , Briones Marcelo R. S. 
Published: December 2018

AbstractThe evolution of mitochondrial genomes is essential for the adaptation of yeasts to the variation of environmental levels of oxygen. AlthoughSaccharomyces cerevisiaemitochondrial DNA lacks all complex I genes, respiration is possible because alternative NADH dehydrogenases are encoded byNDE1andNDI1nuclear genes. The proposed whole genome duplication (WGD) in the yeast ancestor at 150-100 million years ago caused nuclear gene duplications and secondary losses, although its relation to the loss of complex I mitocondrial is unknown. Here we present phylogenomic supertrees and supermatrix tree of 46 mitochondrial genomes showing that the loss of complex I predates WGD and occurred independently in theS. cerevisiaegroup and the fission yeastSchizosaccharomyces pombe. We also show that the branching patterns do not differ dramatically in supertrees and supermatrix phylogenies. Our inferences indicated consistent relations between conserved mitochondrial chromosomal gene order (synteny) in closely related yeasts. Correlation of mitochondrial molecular clock estimates and atmospheric oxygen variation in the Phanerozoic suggests that theSaccharomyceslineage might have lost the complex I during hypoxic periods near Perminian-Triassic or Triassic-Jurassic mass extinction events, while theSchizosaccharomyceslineage possibly lost the complex I during hypoxic environment periods during Middle Cambrian until Lower Devonian. The loss of mitochondrial complex I during low oxygen might not affect yeast metabolism due to fermentative switch. The return to increased oxygen periods might have favored adaptations to aerobic metabolism. Additionally, we also showed thatNDE1andNDI1phylogenies indicate evolutionary convergence in yeasts where mitochondrial complex I is absent.
Spatiotemporal neural correlates of brain-computer interface learning
Authors: Corsi Marie-Constance , Chavez Mario , Schwartz Denis , George Nathalie , Hugueville Laurent , Khan Ari E. , Dupont Sophie , Bassett Danielle S. , De Vico Fallani Fabrizio 
Published: December 2018

AbstractBrain-computer interfaces have been largely developed to allow communication, control, and neurofeedback in human beings. Despite their great potential, BCIs perform inconsistently across individuals. Moreover, the neural processes activated by training that enable humans to achieve good control remain poorly understood. In this study, we show that BCI skill acquisition is paralleled by a progressive reinforcement of task-related activity and by the reduction of connectivity between regions beyond those primarily targeted during the experiments. Notably, these patterns of activity and connectivity reflect growing automaticity and predict future BCI performance. Altogether, our findings provide new insights in the neural mechanisms underlying BCI learning, which have implications for the use of this technology in a broad range of real-life applications.
Exploring contributors to variability in estimates of SNP-heritability and genetic correlations from the iPSYCH case-cohort and published meta-studies of major psychiatric disorders
Authors: Schork Andrew J. , Werge Thomas ,   iPSYCH Consortium
Published: December 2018

AbstractAs more and more large psychiatric genetic cohorts are becoming available, more and more independent investigations into the underlying genetic architecture are performed, and an expanding set of replicates for estimates of key genetic parameters, namely, liability scale SNP heritability and genetic correlations – is amassing in the literature. In recent work, we published a set of SNP-heritability and genetic correlation estimates for major psychiatric disorders using data from the iPSYCH case-cohort study, and presented them alongside estimates gleaned from large, independently collected, analyzed and published meta-studies of the same disorders. Although in the broadest sense the estimates from iPSYCH and external meta-studies were concordant, and requiring strict statistical significance could reject the null hypothesis for few pairs, there were enough subtle trends in the differences to warrant further investigation. In this work, we consider a set of factors related to sample ascertainment, including the lifetime risks for disorders for the sampled populations, the use of age censored or partially screened controls, the sampling of extreme cases and controls, and diagnostic error rates, and attempt to assess their potential contributions to estimates of genetic parameters in the context of the difference trends observed in our previous work.
Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan
Authors: Ruth Katherine S. , Soares Ana Luiza G. , Borges Maria-Carolina , Eliassen A. Heather , Hankinson Susan E. , Jones Michael E. , Kraft Peter , Nichols Hazel B. , Sandler Dale P. , Schoemaker Minouk J. , Taylor Jack A. , Zeleniuch-Jacquotte Anne , Lawlor Deborah A. , Swerdlow Anthony J. , Murray Anna 
Published: December 2018

AbstractAnti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3,344 pre-menopausal women from five cohorts (median age 44–48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P=3.48×10−10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 SD (95% CI [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings support the hypothesis that AMH is a valid measure of ovarian reserve in pre-menopausal women and suggest that the underlying biology of ovarian reserve results in a causal link between pre-menopausal AMH levels and menopause timing.
Roost selection by male northern long-eared bats (Myotis septentrionalis) in a managed fire-adapted forest
Authors: Alston Jesse M. , Abernethy Ian M. , Keinath Douglas A. , Goheen Jacob R. 
Published: December 2018

AbstractWildlife conservation in multi-use landscapes requires identifying and conserving critical resources that may otherwise be destroyed or degraded by human activity. Summer day-roost sites are critical resources for bats, so conserving roost sites is thus a focus of many bat conservation plans. Studies quantifying day-roost characteristics typically focus on female bats due to their relative importance for reproduction, but large areas of species’ ranges can be occupied predominantly by male bats due to sexual segregation. We used VHF telemetry to identify and characterize summer day-roost selection by male northern long-eared bats (Myotis septentrionalis) in a ponderosa pine (Pinus ponderosa) forest in South Dakota, USA. We tracked 18 bats to 43 tree roosts and used an information theoretic approach to determine the relative importance of tree- and plot-level characteristics on roost site selection. Bats selected roost trees that were larger in diameter, more decayed, and under denser canopy than other trees available on the landscape. Much like studies of female northern long-eared bats have shown, protecting large-diameter snags within intact forest is important for the conservation of male northern longeared bats. Unlike female-specific studies, however, many roosts in our study (39.5%) were located in short (≤ 3 m) snags. Protecting short snags may be a low-risk, high-reward strategy for conservation of resources important to male northern long-eared bats. Other tree-roosting bat species in fire-prone forests are likely to benefit from forest management practices that promote these tree characteristics, particularly in high-elevation areas where populations largely consist of males.
Auditory deviance detection in the human insula: An intracranial EEG study
Authors: Blenkmann Alejandro O. , Collavini Santiago , Lubell James , Llorens Anaïs , Funderud Ingrid , Ivanovic Jugoslav , Larsson Pål G. , Meling Torstein R. , Bekinschtein Tristan , Kochen Silvia , Endestad Tor , Knight Robert T. , Solbakk Anne-Kristin 
Published: December 2018

ABSTRACTWhile the human insula is known to be involved in auditory processing, knowledge about its precise functional role and the underlying electrophysiology is limited. To assess its role in automatic auditory deviance detection we analyzed the high frequency EEG activity (75-145 Hz) from 90 intracranial insular electrodes across 16 patients who were candidates for resective epilepsy surgery while they passively listened to a stream of standard and deviant tones. Deviant and standard tones differed in four physical dimensions: intensity, frequency, location and time. Auditory responses were found in the short and long gyri, and the anterior, superior, and inferior segments of the circular sulcus of the insular cortex, but only a subset of electrodes in the inferior segment showed deviance detection responses, i.e. a greater and later response to deviants relative to standards. Altogether, our results indicate that the human insula is engaged during auditory deviance detection.
Arkadia via SNON enables NODAL-SMAD2/3 signaling effectors to transcribe different genes depending on their levels
Authors: Carthy Jonathon M. , Ioannou Marilia , Episkopou Vasso 
Published: December 2018

AbstractHow cells assess levels of signaling and select to transcribe different target genes depending on the levels of activated effectors remains elusive. High NODAL-signalling levels specify anterior/head, lower specify posterior, and complete loss abolishes anterior-posterior patterning in the mammalian embryo. Here we show that cells assess NODAL-activated SMAD2 and SMAD3 (SMAD2/3) effector-levels by complex formation and pairing each effector with the co-repressor SNON, which is present in the cell before signaling. These complexes enable the E3-ubiquitin ligase Arkadia (RNF111) to degrade SNON. High SMAD2/3 levels can saturate and remove SNON, leading to derepression and activation of a subset of targets (high targets) that are highly susceptible to SNON repression. However, low SMAD2/3 levels can only reduce SNON preventing derepression/activation of high targets. Arkadia degrades SNON transiently only upon signaling exposure, leading to dynamic signaling-responses, which most likely initiate level-specific cell-fate decisions. Arkadia-null mouse embryos and Embryonic Stem Cells (ESC) cannot develop anterior tissues and head. However, SnoN/Arkadia, double-null embryos and ESCs are rescued confirming that Arkadia removes SNON, to achieve level-dependent cell-fatesOne Sentence SummarySignaling intensity induces equivalent degradation of a transcriptional repressor leading to level-dependent responses.
A comparison of gene expression and DNA methylation patterns across tissues and species
Authors: Blake Lauren E. , Roux Julien , Hernando-Herraez Irene , Banovich Nicholas E. , Perez Raquel Garcia , Hsiao Chiaowen Joyce , Eres Ittai , Chavarria Claudia , Marques-Bonet Tomas , Gilad Yoav 
Published: December 2018

AbstractPreviously published comparative functional genomic data sets from primates using frozen tissue samples, including many data sets from our own group, were collected and analyzed using non-optimal study designs and analysis approaches. In addition, when samples from multiple tissues were studied in a comparative framework, individual and tissue were confounded. We designed a multi-tissue comparative study of gene expression and DNA methylation in primates that minimizes confounding effects by using a balanced design with respect to species, tissues, and individuals. We also developed a comparative analysis pipeline that minimizes biases due to sequence divergence. We thus present the most comprehensive catalog of similarities and differences in gene expression and methylation levels between livers, kidneys, hearts, and lungs, in humans, chimpanzees, and rhesus macaques. We estimate that overall, only between 7 to 11% (depending on the tissue) of inter-species differences in gene expression levels can be accounted for by corresponding differences in promoter DNA methylation. However, gene expression divergence in conserved tissue-specific genes can be explained by corresponding inter-species methylation changes more often. We end the paper by providing recommendations for effective study design and best practices for meta-data recording for comparative functional genomic studies in primates.
Decreased grey matter volume in mTBI patients with post-traumatic headache compared to headache-free mTBI patients and healthy controls: a longitudinal MRI study
Authors: Burrowes Shana A.B. , Sours Rhodes Chandler , Meeker Timothy J. , Greenspan Joel D. , Gullapalli Rao P. , Seminowicz David A. 
Published: December 2018

AbstractBackgroundTraumatic brain injury (TBI) occurs in 1.7 million people annually and many patients go on to develop persistent disorders including post-traumatic headache (PTH). PTH is considered chronic if it continues past 3 months. In this study we aimed to identify changes in cerebral grey matter volume (GMV) associated with PTH in mild TBI patients.Methods50 mTBI patients (31 Non-PTH; 19 PTH) underwent MRI scans: within 10 days post-injury, 1 month, 6 months and 18 months. PTH was assessed at visit 4 by a post-TBI headache questionnaire. Healthy controls (n=21) were scanned twice 6 months apart.ResultsCompared to non-PTH, PTH patients had decreased GMV across two large clusters described as the right anterior-parietal (p=0.012) and left temporal-opercular (p=0.027). Compared to healthy controls non-PTH patients had decreased GMV in the left thalamus (p=0.047); PTH patients had decreased GMV in several extensive clusters: left temporal-opercular (p=0.003), temporal-parietal (p=0.041), superior frontal gyrus (p=0.008) and right middle frontal/superior frontal gyrus (0.004) and anterior-parietal (p=0.003).ConclusionDifferences between PTH and non-PTH patients were most striking at early time points. These early changes may be associated with an increased risk of PTH. Patients with these changes should be monitored for chronic PTH.