Journals

Correction: Brain-Computer Interface-Based Communication in the Completely Locked-In State

PLOS Biology (new articles) - 7 hours 55 min ago

by Ujwal Chaudhary, Bin Xia, Stefano Silvoni, Leonardo G. Cohen, Niels Birbaumer

Categories: Biology, Journals

Integrative network-centric approach reveals signaling pathways associated with plant resistance and susceptibility to <i>Pseudomonas syringae</i>

PLOS Biology (new articles) - 7 hours 55 min ago

by Elizabeth K. Brauer, George V. Popescu, Dharmendra K. Singh, Mauricio Calviño, Kamala Gupta, Bhaskar Gupta, Suma Chakravarthy, Sorina C. Popescu

Plant protein kinases form redundant signaling pathways to perceive microbial pathogens and activate immunity. Bacterial pathogens repress cellular immune responses by secreting effectors, some of which bind and inhibit multiple host kinases. To understand how broadly bacterial effectors may bind protein kinases and the function of these kinase interactors, we first tested kinase–effector (K-E) interactions using the Pseudomonas syringae pv. tomato–tomato pathosystem. We tested interactions between five individual effectors (HopAI1, AvrPto, HopA1, HopM1, and HopAF1) and 279 tomato kinases in tomato cells. Over half of the tested kinases interacted with at least one effector, and 48% of these kinases interacted with more than three effectors, suggesting a role in the defense. Next, we characterized the role of select multi-effector–interacting kinases and revealed their roles in basal resistance, effector-triggered immunity (ETI), or programmed cell death (PCD). The immune function of several of these kinases was only detectable in the presence of effectors, suggesting that these kinases are critical when particular cell functions are perturbed or that their role is typically masked. To visualize the kinase networks underlying the cellular responses, we derived signal-specific networks. A comparison of the networks revealed a limited overlap between ETI and basal immunity networks. In addition, the basal immune network complexity increased when exposed to some of the effectors. The networks were used to successfully predict the role of a new set of kinases in basal immunity. Our work indicates the complexity of the larger kinase-based defense network and demonstrates how virulence- and avirulence-associated bacterial effectors alter sectors of the defense network.
Categories: Biology, Journals

Genome-wide functional analyses of plant coiled–coil NLR-type pathogen receptors reveal essential roles of their N-terminal domain in oligomerization, networking, and immunity

PLOS Biology (new articles) - 7 hours 55 min ago

by Tadeusz Wróblewski, Laurentiu Spiridon, Eliza Cristina Martin, Andrei-Jose Petrescu, Keri Cavanaugh, Maria Jose-Truco, Huaqin Xu, Dariusz Gozdowski, Krzysztof Pawłowski, Richard W. Michelmore, Frank L.W. Takken

The ability to induce a defense response after pathogen attack is a critical feature of the immune system of any organism. Nucleotide-binding leucine-rich repeat receptors (NLRs) are key players in this process and perceive the occurrence of nonself-activities or foreign molecules. In plants, coevolution with a variety of pests and pathogens has resulted in repertoires of several hundred diverse NLRs in single individuals and many more in populations as a whole. However, the mechanism by which defense signaling is triggered by these NLRs in plants is poorly understood. Here, we show that upon pathogen perception, NLRs use their N-terminal domains to transactivate other receptors. Their N-terminal domains homo- and heterodimerize, suggesting that plant NLRs oligomerize upon activation, similar to the vertebrate NLRs; however, consistent with their large number in plants, the complexes are highly heterometric. Also, in contrast to metazoan NLRs, the N-terminus, rather than their centrally located nucleotide-binding (NB) domain, can mediate initial partner selection. The highly redundant network of NLR interactions in plants is proposed to provide resilience to perturbation by pathogens.
Categories: Biology, Journals

Heterochromatin delays CRISPR-Cas9 mutagenesis but does not influence the outcome of mutagenic DNA repair

PLOS Biology (new articles) - 7 hours 55 min ago

by Eirini M. Kallimasioti-Pazi, Keerthi Thelakkad Chathoth, Gillian C. Taylor, Alison Meynert, Tracy Ballinger, Martijn J. E. Kelder, Sébastien Lalevée, Ildem Sanli, Robert Feil, Andrew J. Wood

Genome editing occurs in the context of chromatin, which is heterogeneous in structure and function across the genome. Chromatin heterogeneity is thought to affect genome editing efficiency, but this has been challenging to quantify due to the presence of confounding variables. Here, we develop a method that exploits the allele-specific chromatin status of imprinted genes in order to address this problem in cycling mouse embryonic stem cells (mESCs). Because maternal and paternal alleles of imprinted genes have identical DNA sequence and are situated in the same nucleus, allele-specific differences in the frequency and spectrum of mutations induced by CRISPR-Cas9 can be unequivocally attributed to epigenetic mechanisms. We found that heterochromatin can impede mutagenesis, but to a degree that depends on other key experimental parameters. Mutagenesis was impeded by up to 7-fold when Cas9 exposure was brief and when intracellular Cas9 expression was low. In contrast, the outcome of mutagenic DNA repair was unaffected by chromatin state, with similar efficiencies of homology-directed repair (HDR) and deletion spectra on maternal and paternal chromosomes. Combined, our data show that heterochromatin imposes a permeable barrier that influences the kinetics, but not the endpoint, of CRISPR-Cas9 genome editing and suggest that therapeutic applications involving low-level Cas9 exposure will be particularly affected by chromatin status.
Categories: Biology, Journals

Reply to “Far away from the lamppost”

PLOS Biology (new articles) - Wed, 2018-12-12 00:00

by Thomas Stoeger, Martin Gerlach, Richard I. Morimoto, Luís A. Nunes Amaral

In this Formal Comment, the authors of the recent publication "Large-scale investigation of the reasons why potentially important genes are ignored" maintain that it can be read as an opportunity to explore the unknown.
Categories: Biology, Journals

Far away from the lamppost

PLOS Biology (new articles) - Wed, 2018-12-12 00:00

by Tudor I. Oprea, Lily Jan, Gary L. Johnson, Bryan L. Roth, Avi Ma’ayan, Stephan Schürer, Brian K. Shoichet, Larry A. Sklar, Michael T. McManus

This Formal Comment responds to a recent Meta-Research Article by identifying initiatives that are already in place for funding risky exploratory research that illuminate mysteries of the dark genome.
Categories: Biology, Journals

Sex-specific dominance reversal of genetic variation for fitness

PLOS Biology (new articles) - Wed, 2018-12-12 00:00

by Karl Grieshop, Göran Arnqvist

The maintenance of genetic variance in fitness represents one of the most longstanding enigmas in evolutionary biology. Sexually antagonistic (SA) selection may contribute substantially to maintaining genetic variance in fitness by maintaining alternative alleles with opposite fitness effects in the two sexes. This is especially likely if such SA loci exhibit sex-specific dominance reversal (SSDR)—wherein the allele that benefits a given sex is also dominant in that sex—which would generate balancing selection and maintain stable SA polymorphisms for fitness. However, direct empirical tests of SSDR for fitness are currently lacking. Here, we performed a full diallel cross among isogenic strains derived from a natural population of the seed beetle Callosobruchus maculatus that is known to exhibit SA genetic variance in fitness. We measured sex-specific competitive lifetime reproductive success (i.e., fitness) in >500 sex-by-genotype F1 combinations and found that segregating genetic variation in fitness exhibited pronounced contributions from dominance variance and sex-specific dominance variance. A closer inspection of the nature of dominance variance revealed that the fixed allelic variation captured within each strain tended to be dominant in one sex but recessive in the other, revealing genome-wide SSDR for SA polymorphisms underlying fitness. Our findings suggest that SA balancing selection could play an underappreciated role in maintaining fitness variance in natural populations.
Categories: Biology, Journals

Analysis validation has been neglected in the Age of Reproducibility

PLOS Biology (new articles) - Tue, 2018-12-11 00:00

by Kathleen E. Lotterhos, Jason H. Moore, Ann E. Stapleton

Increasingly complex statistical models are being used for the analysis of biological data. Recent commentary has focused on the ability to compute the same outcome for a given dataset (reproducibility). We argue that a reproducible statistical analysis is not necessarily valid because of unique patterns of nonindependence in every biological dataset. We advocate that analyses should be evaluated with known-truth simulations that capture biological reality, a process we call “analysis validation.” We review the process of validation and suggest criteria that a validation project should meet. We find that different fields of science have historically failed to meet all criteria, and we suggest ways to implement meaningful validation in training and practice.
Categories: Biology, Journals

Experimental bacterial adaptation to the zebrafish gut reveals a primary role for immigration

PLOS Biology (new articles) - Tue, 2018-12-11 00:00

by Catherine D. Robinson, Helena S. Klein, Kyleah D. Murphy, Raghuveer Parthasarathy, Karen Guillemin, Brendan J. M. Bohannan

All animals live in intimate association with microorganisms that profoundly influence their health and development, yet the traits that allow microorganisms to establish and maintain host associations are not well understood. To date, most investigations aimed at identifying traits required for host association have focused on intrahost niches. Consequently, little is known about the relative contribution of extrahost factors such as environmental growth and survival and immigration into hosts from the external environment, as promoters of host association. To address this, we developed a tractable experimental evolution system that investigates both intra- and extrahost factors contributing to bacterial adaptation to the vertebrate gut. We passaged replicate lines of a zebrafish bacterial isolate, Aeromonas veronii, through populations of germ-free larval zebrafish (Danio rerio), each time using gut-associated Aeromonas populations to inoculate the aquatic environment of the next zebrafish population. We observed rapid increased adaptation to the host in all replicate lines. The initial adaptations present in early-evolved isolates did not increase intrahost fitness but rather enhanced both immigration from the environment and interhost transmission. Only in later-evolved isolates did we find evidence for intrahost-specific adaptations, as demonstrated by comparing their competitive fitness in the host genotype to which they evolved to that in a different genotype. Our results show how selection for bacterial transmission between hosts and their environment can shape bacterial-host association. This work illuminates the nature of selective forces present in host–microbe systems and reveals specific mechanisms of increased host association. Furthermore, our findings demonstrate that the entire host–microbe–environment system must be considered when identifying microbial traits that contribute to host adaptation.
Categories: Biology, Journals

Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver

PLOS Biology (new articles) - Tue, 2018-12-11 00:00

by Adrija Kalvisa, Majken S. Siersbæk, Stine M. Præstholm, Line J. L. Christensen, Ronni Nielsen, Oliver Stohr, Sabine Vettorazzi, Jan Tuckermann, Morris White, Susanne Mandrup, Lars Grøntved

Hepatic circadian gene transcription is tightly coupled to feeding behavior, which has a profound impact on metabolic disorders associated with diet-induced obesity. Here, we describe a genomics approach to uncover mechanisms controlling hepatic postprandial gene expression. Combined transcriptomic and cistromic analysis identified hundreds of circadian-regulated genes and enhancers controlled by feeding. Postprandial suppression of enhancer activity was associated with reduced glucocorticoid receptor (GR) and Forkhead box O1 (FOXO1) occupancy of chromatin correlating with reduced serum corticosterone levels and increased serum insulin levels. Despite substantial co-occupancy of feeding-regulated enhancers by GR and FOXO1, selective disruption of corticosteroid and/or insulin signaling resulted in dysregulation of specific postprandial regulated gene programs. In combination, these signaling pathways operate a major part of the genes suppressed by feeding. Importantly, the feeding response was disrupted in diet-induced obese animals, which was associated with dysregulation of several corticosteroid- and insulin-regulated genes, providing mechanistic insights to dysregulated circadian gene transcription associated with obesity.
Categories: Biology, Journals

More diversity in epithelial cell polarity: A fruit flies’ gut feeling

PLOS Biology (new articles) - Thu, 2018-12-06 00:00

by H-Arno J. Müller

Multicellular animals face the principle challenge to deal with two distinct compartments: the internal organismal compartment and the external environment. This challenge is met by the differentiation of cell sheets into epithelia, which provide a dynamic barrier in tissues, organs, and organisms. Cell polarity is key to all functions of epithelia, and compromising polarity causes many severe diseases. Within the past 20 years, research on Drosophila melanogaster discovered a conserved molecular machinery that controls epithelial polarity. Recent findings suggest that the textbook Drosophila-based paradigm of the control of epithelial polarity may not be as universal as previously assumed.
Categories: Biology, Journals

Plant epithelia: What is the role of the mortar in the wall?

PLOS Biology (new articles) - Thu, 2018-12-06 00:00

by Michael Palmgren

In a growing plant root, the inner vascular system is sealed off by an epithelium, the endodermis. The space between all of the cells in the endodermal layer is filled with an impermeable mass called the Casparian strip, which closes the spaces between cells in the endodermal layer. The role of the Casparian strip has been proposed to prevent backflow of water and nutrients into the soil, but as mutant plants lacking the Casparian strip only have weak phenotypes, the view that it serves an essential function in plants has been challenged. In an accompanying paper, it is shown that loss of the Casparian strip impacts the ability of the plant to take up ammonium and allocate it to the shoots.
Categories: Biology, Journals

Gut microbiota diversity across ethnicities in the United States

PLOS Biology (new articles) - Wed, 2018-12-05 00:00

by Andrew W. Brooks, Sambhawa Priya, Ran Blekhman, Seth R. Bordenstein

Composed of hundreds of microbial species, the composition of the human gut microbiota can vary with chronic diseases underlying health disparities that disproportionally affect ethnic minorities. However, the influence of ethnicity on the gut microbiota remains largely unexplored and lacks reproducible generalizations across studies. By distilling associations between ethnicity and differences in two US-based 16S gut microbiota data sets including 1,673 individuals, we report 12 microbial genera and families that reproducibly vary by ethnicity. Interestingly, a majority of these microbial taxa, including the most heritable bacterial family, Christensenellaceae, overlap with genetically associated taxa and form co-occurring clusters linked by similar fermentative and methanogenic metabolic processes. These results demonstrate recurrent associations between specific taxa in the gut microbiota and ethnicity, providing hypotheses for examining specific members of the gut microbiota as mediators of health disparities.
Categories: Biology, Journals

Widespread winners and narrow-ranged losers: Land use homogenizes biodiversity in local assemblages worldwide

PLOS Biology (new articles) - Wed, 2018-12-05 00:00

by Tim Newbold, Lawrence N. Hudson, Sara Contu, Samantha L. L. Hill, Jan Beck, Yunhui Liu, Carsten Meyer, Helen R. P. Phillips, Jörn P. W. Scharlemann, Andy Purvis

Human use of the land (for agriculture and settlements) has a substantial negative effect on biodiversity globally. However, not all species are adversely affected by land use, and indeed, some benefit from the creation of novel habitat. Geographically rare species may be more negatively affected by land use than widespread species, but data limitations have so far prevented global multi-clade assessments of land-use effects on narrow-ranged and widespread species. We analyse a large, global database to show consistent differences in assemblage composition. Compared with natural habitat, assemblages in disturbed habitats have more widespread species on average, especially in urban areas and the tropics. All else being equal, this result means that human land use is homogenizing assemblage composition across space. Disturbed habitats show both reduced abundances of narrow-ranged species and increased abundances of widespread species. Our results are very important for biodiversity conservation because narrow-ranged species are typically at higher risk of extinction than widespread species. Furthermore, the shift to more widespread species may also affect ecosystem functioning by reducing both the contribution of rare species and the diversity of species’ responses to environmental changes among local assemblages.
Categories: Biology, Journals

Neural responses to natural and model-matched stimuli reveal distinct computations in primary and nonprimary auditory cortex

PLOS Biology (new articles) - Tue, 2018-12-04 00:00

by Sam V. Norman-Haignere, Josh H. McDermott

A central goal of sensory neuroscience is to construct models that can explain neural responses to natural stimuli. As a consequence, sensory models are often tested by comparing neural responses to natural stimuli with model responses to those stimuli. One challenge is that distinct model features are often correlated across natural stimuli, and thus model features can predict neural responses even if they do not in fact drive them. Here, we propose a simple alternative for testing a sensory model: we synthesize a stimulus that yields the same model response as each of a set of natural stimuli, and test whether the natural and “model-matched” stimuli elicit the same neural responses. We used this approach to test whether a common model of auditory cortex—in which spectrogram-like peripheral input is processed by linear spectrotemporal filters—can explain fMRI responses in humans to natural sounds. Prior studies have that shown that this model has good predictive power throughout auditory cortex, but this finding could reflect feature correlations in natural stimuli. We observed that fMRI responses to natural and model-matched stimuli were nearly equivalent in primary auditory cortex (PAC) but that nonprimary regions, including those selective for music or speech, showed highly divergent responses to the two sound sets. This dissociation between primary and nonprimary regions was less clear from model predictions due to the influence of feature correlations across natural stimuli. Our results provide a signature of hierarchical organization in human auditory cortex, and suggest that nonprimary regions compute higher-order stimulus properties that are not well captured by traditional models. Our methodology enables stronger tests of sensory models and could be broadly applied in other domains.
Categories: Biology, Journals

Vibrant symbiosis: Achieving reciprocal science outreach through biological art

PLOS Biology (new articles) - Sat, 2018-12-01 00:00

by Lindsey E. Lopes, Sarah J. Waldis, Stephanie M. Terrell, Kristin A. Lindgren, Louise K. Charkoudian

Scientific outreach efforts traditionally involve formally trained scientists teaching the general public about the methods, significance, and excitement of science. We recently experimented with an alternative “symbiotic outreach” model that prioritizes building a reciprocal relationship between formally trained and “outsider” scientists to facilitate active two-way communication. Herein, we present the results of our outreach effort involving college students and adults with intellectual and developmental disabilities working together to make biological and multimedia art. By discussing the steps others can take to cultivate reciprocal outreach within their local communities, we hope to lower the barrier for widespread adoption of similar approaches and ultimately to decrease the gap between formally trained scientists and the general public.
Categories: Biology, Journals

JMJD5 links CRY1 function and proteasomal degradation

PLOS Biology (new articles) - Sat, 2018-12-01 00:00

by Anand R. Saran, Diana Kalinowska, Sangphil Oh, Ralf Janknecht, Luciano DiTacchio

The circadian oscillator is a molecular feedback circuit whose orchestration involves posttranslational control of the activity and protein levels of its components. Although controlled proteolysis of circadian proteins is critical for oscillator function, our understanding of the underlying mechanisms remains incomplete. Here, we report that JmjC domain–containing protein 5 (JMJD5) interacts with CRYPTOCHROME 1 (CRY1) in an F-box/leucine-rich repeat protein 3 (FBXL3)-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. We also report that in the absence of JMJD5, AMP-regulated protein kinase (AMPK)-induced CRY1 degradation is impaired, establishing JMJD5 as a key player in this mechanism. JMJD5 cooperates with CRY1 to repress circadian locomotor output cycles protein kaput (CLOCK)–brain and muscle ARNT-like protein 1 (BMAL1), thus linking CRY1 destabilization to repressive function. Finally, we find that ablation of JMJD5 impacts FBXL3- and CRY1-related functions beyond the oscillator.
Categories: Biology, Journals

Adolescent development of cortical oscillations: Power, phase, and support of cognitive maturation

PLOS Biology (new articles) - Sat, 2018-12-01 00:00

by Scott Marek, Brenden Tervo-Clemmens, Natalie Klein, William Foran, Avniel Singh Ghuman, Beatriz Luna

During adolescence, the integration of specialized functional brain networks related to cognitive control continues to increase. Slow frequency oscillations (4–10 Hz) have been shown to support cognitive control processes, especially within prefrontal regions. However, it is unclear how neural oscillations contribute to functional brain network development and improvements in cognitive control during adolescence. To bridge this gap, we employed magnetoencephalography (MEG) to explore changes in oscillatory power and phase coupling across cortical networks in a sample of 68 adolescents and young adults. We found a redistribution of power from lower to higher frequencies throughout adolescence, such that delta band (1–3 Hz) power decreased, whereas beta band power (14–16 and 22–26 Hz) increased. Delta band power decreased with age most strongly in association networks within the frontal lobe and operculum. Conversely, beta band power increased throughout development, most strongly in processing networks and the posterior cingulate cortex, a hub of the default mode (DM) network. In terms of phase, theta band (5–9 Hz) phase-locking robustly decreased with development, following an anterior-to-posterior gradient, with the greatest decoupling occurring between association networks. Additionally, decreased slow frequency phase-locking between frontolimbic regions was related to decreased impulsivity with age. Thus, greater decoupling of slow frequency oscillations may afford functional networks greater flexibility during the resting state to instantiate control when required.
Categories: Biology, Journals

Extensive editing of cellular and viral double-stranded RNA structures accounts for innate immunity suppression and the proviral activity of ADAR1<sup>p150</sup>

PLOS Biology (new articles) - Fri, 2018-11-30 00:00

by Christian K. Pfaller, Ryan C. Donohue, Stepan Nersisyan, Leonid Brodsky, Roberto Cattaneo

The interferon (IFN)-mediated innate immune response is the first line of defense against viruses. However, an IFN-stimulated gene, the adenosine deaminase acting on RNA 1 (ADAR1), favors the replication of several viruses. ADAR1 binds double-stranded RNA and converts adenosine to inosine by deamination. This form of editing makes duplex RNA unstable, thereby preventing IFN induction. To better understand how ADAR1 works at the cellular level, we generated cell lines that express exclusively either the IFN-inducible, cytoplasmic isoform ADAR1p150, the constitutively expressed nuclear isoform ADAR1p110, or no isoform. By comparing the transcriptome of these cell lines, we identified more than 150 polymerase II transcripts that are extensively edited, and we attributed most editing events to ADAR1p150. Editing is focused on inverted transposable elements, located mainly within introns and untranslated regions, and predicted to form duplex RNA structures. Editing of these elements occurs also in primary human samples, and there is evidence for cross-species evolutionary conservation of editing patterns in primates and, to a lesser extent, in rodents. Whereas ADAR1p150 rarely edits tightly encapsidated standard measles virus (MeV) genomes, it efficiently edits genomes with inverted repeats accidentally generated by a mutant MeV. We also show that immune activation occurs in fully ADAR1-deficient (ADAR1KO) cells, restricting virus growth, and that complementation of these cells with ADAR1p150 rescues virus growth and suppresses innate immunity activation. Finally, by knocking out either protein kinase R (PKR) or mitochondrial antiviral signaling protein (MAVS)—another protein controlling the response to duplex RNA—in ADAR1KO cells, we show that PKR activation elicits a stronger antiviral response. Thus, ADAR1 prevents innate immunity activation by cellular transcripts that include extensive duplex RNA structures. The trade-off is that viruses take advantage of ADAR1 to elude innate immunity control.
Categories: Biology, Journals

Building a local community of practice in scientific programming for life scientists

PLOS Biology (new articles) - Thu, 2018-11-29 00:00

by Sarah L. R. Stevens, Mateusz Kuzak, Carlos Martinez, Aurelia Moser, Petra Bleeker, Marc Galland

In this paper, we describe why and how to build a local community of practice in scientific programming for life scientists who use computers and programming in their research. A community of practice is a small group of scientists who meet regularly to help each other and promote good practices in scientific programming. While most life scientists are well trained in the laboratory to conduct experiments, good practices with (big) data sets and their analysis are often missing. We propose a model on how to build such a community of practice at a local academic institution, present two real-life examples, and introduce challenges and implemented solutions. We believe that the current data deluge that life scientists face can benefit from the implementation of these small communities. Good practices spread among experimental scientists will foster open, transparent, and sound scientific results beneficial to society.
Categories: Biology, Journals