bluuebunny/crossref_metadata_2025 huggingface dataset:
β-cyclocitric acid: a new apocarotenoid eliciting drought tolerance in plants
Authors: D’Alessandro Stefano , Mizokami Yusuke , Legeret Bertrand , Havaux Michel
Published: December 2018

β-Cyclocitral (β-CC) is a volatile compound deriving from1O2oxidation of β-carotene in plant leaves. β-CC elicits a retrograde signaling, modulating1O2-responsive genes and enhancing tolerance to photooxidative stress. Here, we show that β-CC is largely converted into β-cyclocitric acid (β-CCA) in leaves and that this metabolite is a signal involved in stress tolerance. Treatment of Arabidopsis plants with β-CCA markedly enhanced plant tolerance to drought by a mechanism different from known responses such as stomatal closure, changes in osmotic potential and jasmonate signaling. Furthermore, we show that the response to β-CCA does not fully overlap with the β-CC-dependent signaling, indicating that β-CCA induces only a branch of the β-CC signaling pathway. In addition, the protective effect of β-CCA is a conserved mechanism, being observed in a variety of plant species. This study provides a new bioactive agent with promising agronomic applications for protecting plants against drought.
Pathogenic Budding Yeasts Isolated outside of Clinical Settings
Authors: Opulente Dana , Langdon Quinn , Buh Kelly , Haase Max , Sylvester Kayla , Moriarty Ryan V. , Jarzyna Martin , Considine Samantha , Schneider Rachel , Hittinger Chris Todd
Published: December 2018

Budding yeasts are distributed across a wide range of habitats, including as human commensals. However, under some conditions, these commensals can cause superficial, invasive, and even lethal infections. Despite their importance to human health, little is known about the ecology of these opportunistic pathogens, aside from their associations with mammals and clinical environments. During a survey of approximately 1000 non-clinical samples across the United States of America, we isolated 54 strains of budding yeast species considered opportunistic pathogens, including Candida albicans and Candida (Nakaseomyces) glabrata. We found that, as a group, pathogenic yeasts were positively associated with fruits and soil environments, while the species Pichia kudriavzevii (syn. Candida krusei syn. Issatchenkia orientalis) had a significant association with plants. These results suggest that pathogenic yeast ecology is more complex and diverse than is currently appreciated and raises the possibility that these additional environments could be a point of contact for human infections.
Posture controls mechanical tuning in the black widow spider mechanosensory system
Authors: Mhatre Natasha , Sivalinghem Senthurran , Mason Andrew C
Published: December 2018

Spiders rely on mechanical vibration sensing for sexual signalling, prey capture and predator evasion. The sensory organs underlying vibration detection, called slit sensilla, resemble cracks in the spider's exoskeleton, and are distributed all over the spider body. Those crucial to sensing web- and other substrate-borne vibrations are called lyriform organs and are densely distributed around leg joints. It has been shown that forces that cause bending at leg joints also activate these lyriform organs. Little is known of how the biomechanics of the body of a freely-suspended spider in its natural posture interact with vibrations introduced into the body and how this affects vibration perception. Female black widow spiders, in particular, have a striking body-form; their long thin legs support a large pendulous abdomen. Here, we show that in their natural posture, the large abdominal mass of black widow females, interacts with the spring-like behaviour of their leg joints and determines the mechanical behaviour of different leg joints. Furthermore, we find that adopting different body postures enables females to alter both the level and tuning of the mechanical input to lyriform organs. Therefore, we suggest that posture may be used to flexibly and reversibly focus attention to different classes or components of web vibration. Postural effects thus emphasize the dynamic loop of interactions between behaviour and perception, i.e. between 'brain' and body.
Engineering a decoy substrate in soybean to enable recognition of the Soybean Mosaic Virus NIa protease
Authors: Helm Matthew , Qi Mingsheng , Sarkar Shayan , Yu Haiyue , Whitham Steven A. , Innes Roger W.
Published: December 2018

In Arabidopsis, recognition of the AvrPphB effector protease from Pseudomonas syringae is mediated by the disease resistance (R) protein RPS5, which is activated by AvrPphB-induced cleavage of the Arabidopsis protein kinase PBS1. The recognition specificity of RPS5 can be altered by substituting the AvrPphB cleavage site within PBS1 with cleavage sequences for other proteases, including proteases from viruses. AvrPphB also activates defense responses in soybean (Glycine max), suggesting that soybean may contain an R protein analogous to RPS5. It was unknown, however, whether this response is mediated by cleavage of a soybean PBS1-like protein. Here we show that soybean contains three PBS1 orthologs and that their products are cleaved by AvrPphB. Further, transient expression of soybean PBS1 derivatives containing a five-alanine insertion at their AvrPphB cleavage sites activated cell death in soybean protoplasts, demonstrating that soybean likely contains an AvrPphB-specific resistance protein that is activated by a conformational change in soybean PBS1 proteins. Significantly, we show that a soybean PBS1 decoy protein modified to contain a cleavage site for the Soybean mosaic virus (SMV) NIa protease triggers cell death in soybean protoplasts when cleaved by this protease, indicating that the PBS1 decoy approach will work in soybean using endogenous PBS1 genes. Lastly, we show that activation of the AvrPphB-dependent cell death response effectively inhibits systemic spread of SMV in soybean. These data also indicate that decoy engineering may be feasible in other crop plant species that recognize AvrPphB protease activity.
Stress-induced phospho-ubiquitin formation causes parkin degradation
Authors: Kovalchuke Lyudmila , Mosharov Eugene V. , Levy Oren A. , Greene Lloyd A.
Published: December 2018

Mutations in the E3 ubiquitin ligase parkin are the most common known cause of autosomal recessive parkinsonism. Multiple types of stress decrease parkin protein levels, an effect that may be relevant to sporadic Parkinson's disease (PD), but the mechanism(s) involved in this loss remain largely unclear. We sought to elucidate these mechanisms using a PD-relevant stressor, L-DOPA, the precursor to dopamine, which forms reactive oxygen species (ROS) as well as toxic quinones via auto-oxidation. We find that L-DOPA causes parkin loss through both an oxidative stress-independent and an oxidative stress-dependent pathway. Characterization of the latter reveals that it requires both the kinase PINK1 and parkin's interaction with phosphorylated ubiquitin (phospho-Ub) and is mediated by proteasomal degradation. Surprisingly, mitochondrial parkin activity and autoubiquitination as well as mitophagy are not required for such loss. During stress induced by the oxidative stressor hydrogen peroxide or the metabolic uncoupler CCCP, parkin degradation also requires its association with phospho-Ub, indicating that this mechanism is broadly generalizable. As oxidative stress, metabolic dysfunction and phospho-Ub levels are all elevated in PD patients, we suggest that these changes may lead to the loss of parkin expression in PD.
GA-repeats on mammalian X chromosomes support Ohno’s hypothesis of dosage compensation by transcriptional upregulation
Authors: D’Souza Edridge , Hosage Elizaveta , Weinand Kathryn , Gisselbrecht Steve , Markstein Vicky , Markstein Peter , Bulyk Martha L. , Markstein Michele
Published: December 2018

Over 50 years ago, Susumo Ohno proposed that dosage compensation in mammals would require upregulation of gene expression on the single active X chromosome, a mechanism which to date is best understood in the fruit fly Drosophila melanogaster. Here, we report that the GA-repeat sequences that recruit the conserved MSL dosage compensation complex to the Drosophila X chromosome are also enriched across mammalian X chromosomes, providing genomic support for the Ohno hypothesis. We show that mammalian GA-repeats derive in part from transposable elements, suggesting a mechanism whereby unrelated X chromosomes from dipterans to mammals accumulate binding sites for the MSL dosage compensation complex through convergent evolution, driven by their propensity to accumulate transposable elements.
Co-opted transposons help perpetuate conserved higher-order chromosomal structures
Authors: Choudhary Mayank NK , Friedman Ryan Z , Wang Julia T , Jang Hyo Sik , Zhuo Xiaoyu , Wang Ting
Published: December 2018

Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include architectural proteins—such as CTCF, RAD21 and SMC3—that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed. Here we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice via deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species via CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to a collapse of such conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time. TEs have long been considered a source of genetic innovation; by examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.

One-sentence summary

Co-option of transposable elements maintains conserved 3D genome structures via CTCF binding site turnover in human and mouse.
Evolutionary history of phycoerythrin pigmentation in the water bloom-forming cyanobacteriumMicrocystis aeruginosa
Authors: Tanabe Yuuhiko , Yamaguchi Haruyo
Published: December 2018

Microcystis aeruginosais a bloom-forming cyanobacterium found in eutrophic fresh-and brackish water bodies worldwide. As typical for cyanobacteria, mostM. aeruginosastrains are blue-green in color owing to the concomitance of two photosynthetic pigments, phycocyanin (PC) and chlorophylla. Although less common,M. aeruginosastrains that are brownish in color owing to the presence of another pigment phycoerythrin (PE) have been documented. However, the genomic basis, phylogeny, and evolutionary origin of PE pigmentation inM. aeruginosahave only been poorly characterized until date. In the present study, we sequenced and characterized the genomes of five PE-containingM. aeruginosastrains. Putative PE synthesis and regulation genes (thecpecluster) were identified in all five sequenced genomes as well as in three previously publishedM. aeruginosagenomes. Of note, Absorption spectra indicated that the PE content, but not PC content, was markedly altered in response to availability of red/green light in all PE-containing strains. This was consistent with the presence ofccaS/ccaR, a hallmark of type II chromatic adapter, in thecpecluster. Phylogenetic analyses of core genome genes indicated that PE-containing genotypes were located in three different phylogenetic groups. In contrast, the genomic organization of thecpecluster was mostly conserved regardless of genomic background. Additionally, the phylogenies of PE genes were found to be congruent, consistent with the core genome phylogeny. A comparison of core genome and PE genes showed a similar level of genetic divergence between two PE-containing groups. These results suggest that genes responsible for PE pigmentation were introduced intoM. aeruginosaearly during evolution and were repeatedly lost thereafter possibly due to ecological adaptation. Additional horizontal gene transfer (HGT) later during evolution also contributed to the present phylogenetic distribution of PE inM. aeruginosa.
Plant-derived coumarins shape the composition of an Arabidopsis synthetic root microbiome
Authors: Voges Mathias J.E.E.E. , Bai Yang , Schulze-Lefert Paul , Sattely Elizabeth S.
Published: December 2018

Significance

The root microbiome composition is largely determined by the soil inoculum, with a distinct contribution from the host. Yet, the molecular mechanisms with which the host influences its rhizobiome are only beginning to be discovered. Using a hydroponics-based synthetic community approach, we probe the impact of root-exuded specialized metabolites in shaping the root microbiome. We uncover a role for coumarins in structuring the rhizobiome, particularly by limiting the growth of a Pseudomonas strain, for which we propose a mechanism of action. Our findings support the exciting possibility that root-exuded coumarins form a part of the plant’s adaptive response to iron deficiency that goes beyond iron mobilization to modulate the rhizobiome, and highlights avenues towards engineering the rhizosphere for plant health.

The factors that dictate the composition of the root microbiome and its role in plant fitness has been a long-standing question. Recent work has highlighted a major contribution of the soil inoculum in determining the composition of the root microbiome. However, plants are known to conditionally exude a diverse array of unique secondary metabolites, largely varying between species and environmental conditions. Here, we explore the role of specialized metabolites in dictating which bacteria reside in the rhizosphere. We employed a reduced synthetic community (SynCom) of Arabidopsis thaliana root-isolated bacteria to detect community shifts that occur in the absence of the secreted small molecule phytoalexins, flavonoids, and coumarins. We find that lack of coumarin biosynthesis in f6’h1 mutant plant lines causes a shift in the root microbial community specifically under iron deficiency. We demonstrate a potential role for iron-mobilizing coumarins in sculpting the A. thaliana root bacterial community by inhibiting the proliferation of a relatively abundant Pseudomonas species via a redox-mediated mechanism. This work establishes a systematic approach enabling elucidation of specific mechanisms by which plant-derived molecules mediate microbial community composition. Our findings expand on the function of conditionally-exuded specialized metabolites and lead to new avenues to effectively engineer the rhizosphere for improving crop growth in alkaline soils, which make up a third of total arable soils.
Extreme genetic signatures of local adaptation during plant colonization
Authors: Shah Niraj , Wakabayashi Tomomi , Kawamura Yasuko , Skovbjerg Cathrine Kiel , Wang Ming-Zhuo , Mustamin Yusdar , Isomura Yoshiko , Gupta Vikas , Jin Haojie , Mun Terry , Sandal Niels , Azuma Fuyuki , Fukai Eigo , Seren Ümit , Kusakabe Shohei , Kikuchi Yuki , Nitanda Shogo , Kumaki Takashi , Sønderkær Mads , Nielsen Kaare Lehmann , Schneeberger Korbinian , Stougaard Jens , Sato Shusei , Schierup Mikkel Heide , Andersen Stig Uggerhøj
Published: December 2018

Colonization of new habitats is expected to require genetic adaptations to overcome environmental challenges. Here we use full genome re-sequencing and extensive common garden experiments to investigate demographic and selective processes associated with the recent colonization of Japan byLotus japonicus. We carefully track the colonization process whereL. japonicusgradually spread from subtropical conditions to much colder climates in northern Japan. We characterize the loss of diversity during this process and identify genomic regions with extreme genetic differentiation. Next, we perform population structure-corrected association mapping of phenotypic traits measured in a common garden and discover a number of genome-wide significant associations. Contrasting these analyses, we find that there is a strong concordance between phenotypic variation and extreme differentiation for overwintering and flowering time traits. Our results provide evidence that these traits were direct targets of selection by local adaptation during the colonization process and point to associated candidate genes.
Gene augmentation and read-through rescue channelopathy in an iPSC-RPE model of congenital blindness
Authors: Shahi Pawan K. , Hermans Dalton , Sinha Divya , Brar Simran , Moulton Hannah , Stulo Sabrina , Borys Katarzyna D. , Capowski Elizabeth , Pillers De-Ann M. , Gamm David M. , Pattnaik Bikash. R.
Published: December 2018

Purpose

Mutations in the KCNJ13 gene are known to cause Leber’s Congenital Amaurosis (LCA16), an inherited pediatric blindness. KCNJ13 gene encodes the Kir7.1 subunit protein which acts as a tetrameric inwardly rectifying potassium ion channel in the retinal pigment epithelium to maintain ionic homeostasis thereby allowing photoreceptors to encode visual information. We sought to determine if genetic approaches might be effective in treating blindness due to mutations in KCNJ13.

Methods

We developed patient-derived hiPSC-RPE carrying an autosomal recessive nonsense mutation in the KCNJ13 gene (c.158G>A, p.Trp53*). We performed biochemical and electrophysiology assays of Kir7.1 function. Both small molecule read-through drug and gene-therapy approaches were tested using this disease-in-a-dish approach.

Results

We found that the LCA16 hiPSC-RPE had normal morphology but did not express a functional Kir7.1 channel and was unable to demonstrate normal physiology. Following read-through drug treatment, the LCA16 hiPSC cells were hyperpolarized by 30 mV and Kir7.1 current was restored. Similarly, loss-of-function of Kir7.1 channel was circumvented by lentiviral gene delivery to the hiPSC-RPE cells. In either approach, Kir7.1 protein was expressing normally with restoration of membrane potential and Kir7.1 current.

Conclusion

Loss-of-function mutation in Kir7.1 is a cause of LCA. Using either read-through therapy or gene augmentation, we rescued Kir7.1 channel function in patient-derived iPSC-RPE cells via a precision medicine approach.
Decomposing the causes for niche differentiation between species using hypervolumes
Authors: Carvalho Jose Carlos , Cardoso Pedro
Published: December 2018

Hutchinson's n-dimensional hypervolume concept holds a central role across different fields of ecology and evolution. The question of the amount of hypervolume overlap and differentiation between species is of great interest to understand the processes that drive niche dynamics, competitive interactions and, ultimately, community assembly. A novel framework is proposed to decompose overall differentiation among hypervolumes into two distinct components: niche shifts and niche contraction / expansion processes. Niche shift corresponds to the replacement of space between the hypervolumes occupied by two species, whereas niche contraction / expansion processes correspond to net differences between the amount of space enclosed by each hypervolume. Hypervolumes were constructed for two Darwin' finches, Geospiza conirostris and Geospiza magnirostris, using intraspecific trait data from Genovesa Island, where they live in sympatry. Results showed that significant niche shifts, not niche contraction, occurred between these species. This means that Geospiza conirostris occupied a different niche space and not a reduced space on Genovesa. The proposed framework allows disentangling different processes and understand the drivers of niche partitioning between coexisting species. Niche displacement due to competition can this way be separated from niche contraction due to specialization or expansion due to lower pressure on newly occupied ecological settings.
Accurate sub-population detection and mapping across single cell experiments with PopCorn
Authors: Wang Yijie , Hoinka Jan , Przytycka Teresa M
Published: December 2018

The identification of sub-populations of cells present in a sample and the comparison of such sub-populations across samples are among the most frequently performed analyzes of single-cell data. Current tools for these kinds of data, however, fall short in their ability to adequately perform these tasks. We introduce a novel method, PopCorn (single cell sub-Populations Comparison), allowing for the identification of sub-populations of cells present within individual experiments while simultaneously performing sub-populations mapping across these experiments. PopCorn utilizes several novel algorithmic solutions enabling the execution of these tasks with unprecedented precision. As such, PopCorn provides a much-needed tool for comparative analysis of populations of single cells.
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

Synthetic 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.
CompStor Novos: a low cost yet fast assembly-based variant calling for personal genomes
Authors: Oenning Travis , Bae Taejeong , Iyengar Aravind , Brickner Barrett , Soysa Madushanka , Wright Nicholas , Kumar Prasanth , Indupuru Suneel , Abyzov Alexej , Coker Jonathan
Published: December 2018

Application of assembly methods for personal genome analysis from next generation sequencing data has been limited by the requirement for an expensive supercomputer hardware or long computation times when using ordinary resources. We describe CompStor Novos, achieving supercomputer-class performance in de novo assembly computation time on standard server hardware, based on a tiered-memory algorithm. Run on commercial off-the-shelf servers, Novos assembly is more precise and 10-20 times faster than that of existing assembly algorithms. Furthermore, we integrated Novos into a variant calling pipeline and demonstrate that both compute times and precision of calling point variants and indels compare well with standard alignment-based pipelines. Additionally, assembly eliminates bias in the estimation of allele frequency for indels and naturally enables discovery of breakpoints for structural variants with base pair resolution. Thus, Novos bridges the gap between alignment-based and assembly-based genome analyses. Extension and adaption of its underlying algorithm will help quickly and fully harvest information in sequencing reads for personal genome reconstruction.
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

Background

Autism 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.

Methods

Genome-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.

Results

While 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.

Conclusions

This 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

In 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

Tau, 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.
Prospects of using Avocado oil for attenuating quorum sensing regulated virulence, bio-filming formation and its antibacterial and antioxidant activities
Authors: Hanan Muhammad M. , Amina Musarat , Ahamad Syed Rizwan , Hassan Wafaa H. B.
Published: December 2018

Background: Quorum sensing inhibition (QSI) is considered as an attractive strategy for the development of anti-pathogenic agents, mainly for drug resistant bacteria.
Methods: The anti-quorum sensing activity was investigated by biosensor bioassay using Chromobacterium violaceum CVO26 and Pseudomonas aeruginosa PAO1. Quorum sensing is a key regulator of virulence factors of Pseudomonas aeruginosa such as bio-film formation, motility, productions of proteases, hemolysin, and Pyocyanin production. Additionally, the GC/MS technique was employed to detect the essential components of avocado oil.
Results: Avocado oil inhibits quorum system-mediated virulence factor production such as violacein in C. Violaceum CVO26 and elastase, Pyocyanin production in Pseudomonas aeruginosa PAO1. Additionally, the use of sub-minimum inhibitory concentrations (sub-MICs) of avocado oil signiﬁcantly inhibits the quorum system-mediated biofilm formation, exopolysaccride production (EPS) and swarming motility. Furthermore, this study concerned the potent activity of avocado oil antibacterial and antioxidant agent. Moreover, a total of 23 components was identified in avocado oil by GC/MS.
Conclusion: Avocado oil could be exploited as a natural source of anti-pathogenic, where the pathogenicity is mediated through quorum sensing, antibacterial as well as antioxidant agents.
Topological Data Analysis of Single-cell Hi-C Contact Maps
Authors: Carriere Mathieu , Rabadan Raul
Published: December 2018

In this article, we show how the recent statistical techniques developed in Topological Data Analysis for the Mapper algorithm can be extended and leveraged to formally define and statistically quantify the presence of topological structures coming from biological phenomena in datasets of CCC contact maps.
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

The 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

Brain-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

As 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

Anti-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

Wildlife 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

While 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

How 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-fates

One Sentence Summary

Signaling 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

Previously 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.
Intertwined canonical and non-canonical initiation in dual promoters are pervasive and differentially regulate Polymerase II transcription
Authors: Nepal Chirag , Hadzhiev Yavor , Tarifeno-Saldivia Estefania , Cardenas Ryan , Suzuki Ana-Maria , Carninci Piero , Peers Bernard , Lenhard Boris , Andersen Jesper B , Mueller Ferenc
Published: December 2018

The diversity and complexity of transcription start site (TSS) selection reflects variation of preinitiation complexes, divergent function of promoter-binding proteins and underlies not only transcriptional dynamics but may also impact on post-transcriptional fates of RNAs. The majority of metazoan genes are transcribed by RNA polymerase II from a canonical initiation motif having an YR dinucleotide at their TSSs. In contrast, translation machinery-associated genes carry promoters with polypyrimidine initiator (known as 5′-TOP or TCT) with cytosine replacing the R nucleotide. The functional significance of start site choice in promoter architectures is little understood. To get insight into the developmental regulation of start site selection we profiled 5′ ends of transcripts during zebrafish embryogenesis. We uncovered a novel class of dual-initiation (DI) promoters utilized by thousands of genes. In DI promoters non-canonical YC-initiation representing 5′-TOP/TCT initiators is intertwined with canonical YR-initiation. During maternal to zygotic transition, the two initiation types are divergently used in hundreds of DI promoters, demonstrating that the two initiation systems are distinctly regulated. We show via the example of snoRNA host genes and translation interference experiments that dual-initiation from shared promoters can lead to divergent spatio-temporal expression dynamics generating distinct sets of RNAs with different post-transcriptional fates. Thus utilization of DI promoters in large number of genes suggests two transcription initiation mechanisms targeting these promoters. DI promoters are conserved within human and fruit fly and reflect an evolutionary conserved mechanism for switching transcription initiation to adapt to the changing developmental context. Thus, our findings highlight a novel level of complexity of core promoter regulation in metazoans and broaden the scope for identification and characterization of alternative RNA products generated at shared core promoters.