ResearchPad - Ecology, Evolution, Behavior and Systematics https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Do avian blood parasites influence hypoxia physiology in a high elevation environment?]]> https://www.researchpad.co/product?articleinfo=5b59c3e7463d7e7b3acb09a9

Background

Montane birds which engage in elevational movements have evolved to cope with fluctuations in environmental hypoxia, through changes in physiological parameters associated with blood oxygen-carrying capacity such as haemoglobin concentration (Hb) and haematocrit (Hct). In particular, elevational migrants which winter at low elevations, encounter varying intensities of avian haemosporidian parasites as they traverse heterogeneous environments. Whilst high intensity parasite infections lead to anaemia, one can expect that the ability to cope with haemosporidian infections should be a key trait for elevational migrants that must be balanced against reducing the oxygen-carrying capacity of blood in response to high elevation. In this study, we explored the links between environmental hypoxia, migration, and disease ecology by examining natural variation in infections status and intensity of avian haemoporidians across a suite of Himalayan birds with different migratory strategies while controlling for host phylogeny.

Results

We found predictably large variation in haemoglobin levels across the elevational gradient and this pattern was strongly influenced by season and whether birds are elevational migrants. The overall malaria infection intensity declined with elevation whereas Hb and Hct decreased with increase in parasite intensity, suggesting an important role of malaria parasites on hypoxia stressed birds in high elevation environments.

Conclusions

Our results provide a key insight into how physiological measures and sub-clinical infections might affect dynamics of high-elevation bird populations. We suggest a potential impact of avian elevational migration on disease dynamics and exposure to high intensity infections with disease spread in the face of climate change, which will exacerbate hypoxic stress and negative effects of chronic avian malaria infection on survival and reproductive success in wild birds. Future work on chronic parasite infections must consider parasite intensity, rather than relying on infection status alone.

Electronic supplementary material

The online version of this article (10.1186/s12898-018-0171-2) contains supplementary material, which is available to authorized users.

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<![CDATA[Network inference reveals novel connections in pathways regulating growth and defense in the yeast salt response]]> https://www.researchpad.co/product?articleinfo=5afd46d0463d7e6ee57105d0

Cells respond to stressful conditions by coordinating a complex, multi-faceted response that spans many levels of physiology. Much of the response is coordinated by changes in protein phosphorylation. Although the regulators of transcriptome changes during stress are well characterized in Saccharomyces cerevisiae, the upstream regulatory network controlling protein phosphorylation is less well dissected. Here, we developed a computational approach to infer the signaling network that regulates phosphorylation changes in response to salt stress. We developed an approach to link predicted regulators to groups of likely co-regulated phospho-peptides responding to stress, thereby creating new edges in a background protein interaction network. We then use integer linear programming (ILP) to integrate wild type and mutant phospho-proteomic data and predict the network controlling stress-activated phospho-proteomic changes. The network we inferred predicted new regulatory connections between stress-activated and growth-regulating pathways and suggested mechanisms coordinating metabolism, cell-cycle progression, and growth during stress. We confirmed several network predictions with co-immunoprecipitations coupled with mass-spectrometry protein identification and mutant phospho-proteomic analysis. Results show that the cAMP-phosphodiesterase Pde2 physically interacts with many stress-regulated transcription factors targeted by PKA, and that reduced phosphorylation of those factors during stress requires the Rck2 kinase that we show physically interacts with Pde2. Together, our work shows how a high-quality computational network model can facilitate discovery of new pathway interactions during osmotic stress.

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<![CDATA[Supervised machine learning reveals introgressed loci in the genomes of Drosophila simulans and D. sechellia]]> https://www.researchpad.co/product?articleinfo=5ae95a39463d7e06f246c067

Hybridization and gene flow between species appears to be common. Even though it is clear that hybridization is widespread across all surveyed taxonomic groups, the magnitude and consequences of introgression are still largely unknown. Thus it is crucial to develop the statistical machinery required to uncover which genomic regions have recently acquired haplotypes via introgression from a sister population. We developed a novel machine learning framework, called FILET (Finding Introgressed Loci via Extra-Trees) capable of revealing genomic introgression with far greater power than competing methods. FILET works by combining information from a number of population genetic summary statistics, including several new statistics that we introduce, that capture patterns of variation across two populations. We show that FILET is able to identify loci that have experienced gene flow between related species with high accuracy, and in most situations can correctly infer which population was the donor and which was the recipient. Here we describe a data set of outbred diploid Drosophila sechellia genomes, and combine them with data from D. simulans to examine recent introgression between these species using FILET. Although we find that these populations may have split more recently than previously appreciated, FILET confirms that there has indeed been appreciable recent introgression (some of which might have been adaptive) between these species, and reveals that this gene flow is primarily in the direction of D. simulans to D. sechellia.

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<![CDATA[Switchable slow cellular conductances determine robustness and tunability of network states]]> https://www.researchpad.co/product?articleinfo=5ae95a42463d7e06f246c06c

Neuronal information processing is regulated by fast and localized fluctuations of brain states. Brain states reliably switch between distinct spatiotemporal signatures at a network scale even though they are composed of heterogeneous and variable rhythms at a cellular scale. We investigated the mechanisms of this network control in a conductance-based population model that reliably switches between active and oscillatory mean-fields. Robust control of the mean-field properties relies critically on a switchable negative intrinsic conductance at the cellular level. This conductance endows circuits with a shared cellular positive feedback that can switch population rhythms on and off at a cellular resolution. The switch is largely independent from other intrinsic neuronal properties, network size and synaptic connectivity. It is therefore compatible with the temporal variability and spatial heterogeneity induced by slower regulatory functions such as neuromodulation, synaptic plasticity and homeostasis. Strikingly, the required cellular mechanism is available in all cell types that possess T-type calcium channels but unavailable in computational models that neglect the slow kinetics of their activation.

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<![CDATA[Patterning mechanisms diversify neuroepithelial domains in the Drosophila optic placode]]> https://www.researchpad.co/product?articleinfo=5ae67869463d7e517897cd3e

The central nervous system develops from monolayered neuroepithelial sheets. In a first step patterning mechanisms subdivide the seemingly uniform epithelia into domains allowing an increase of neuronal diversity in a tightly controlled spatial and temporal manner. In Drosophila, neuroepithelial patterning of the embryonic optic placode gives rise to the larval eye primordium, consisting of two photoreceptor (PR) precursor types (primary and secondary), as well as the optic lobe primordium, which during larval and pupal stages develops into the prominent optic ganglia. Here, we characterize a genetic network that regulates the balance between larval eye and optic lobe precursors, as well as between primary and secondary PR precursors. In a first step the proneural factor Atonal (Ato) specifies larval eye precursors, while the orphan nuclear receptor Tailless (Tll) is crucial for the specification of optic lobe precursors. The Hedgehog and Notch signaling pathways act upstream of Ato and Tll to coordinate neural precursor specification in a timely manner. The correct spatial placement of the boundary between Ato and Tll in turn is required to control the precise number of primary and secondary PR precursors. In a second step, Notch signaling also controls a binary cell fate decision, thus, acts at the top of a cascade of transcription factor interactions to define PR subtype identity. Our model serves as an example of how combinatorial action of cell extrinsic and cell intrinsic factors control neural tissue patterning.

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<![CDATA[Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5’ splice site]]> https://www.researchpad.co/product?articleinfo=5ae95a3a463d7e06f246c068

Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3’ splice site, with different exonic mutations affecting exon 11 splicing through disruption of exonic splicing regulatory elements. In this study, we report a novel intron 11 regulatory element, which is involved in exon 11 splicing, as revealed by the investigated pathogenic effect of variants c.1199+17G>A and c.1199+20G>C, identified in PKU patients. Both mutations cause exon 11 skipping in a minigene system. RNA binding assays indicate that binding of U1snRNP70 to this intronic region is disrupted, concomitant with a slightly increased binding of inhibitors hnRNPA1/2. We have investigated the effect of deletions and point mutations, as well as overexpression of adapted U1snRNA to show that this splicing regulatory motif is important for regulation of correct splicing at the natural 5’ splice site. The results indicate that U1snRNP binding downstream of the natural 5’ splice site determines efficient exon 11 splicing, thus providing a basis for development of therapeutic strategies to correct PAH exon 11 splicing mutations. In this work, we expand the functional effects of non-canonical intronic U1 snRNP binding by showing that it may enhance exon definition and that, consequently, intronic mutations may cause exon skipping by a novel mechanism, where they disrupt stimulatory U1 snRNP binding close to the 5’ splice site. Notably, our results provide further understanding of the reported therapeutic effect of exon specific U1 snRNA for splicing mutations in disease.

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<![CDATA[Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations]]> https://www.researchpad.co/product?articleinfo=5ae95a37463d7e06f246c066

Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143–35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5–3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.

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<![CDATA[Machine learning identifies signatures of host adaptation in the bacterial pathogen Salmonella enterica]]> https://www.researchpad.co/product?articleinfo=5afd46cb463d7e6ee57105cd

Emerging pathogens are a major threat to public health, however understanding how pathogens adapt to new niches remains a challenge. New methods are urgently required to provide functional insights into pathogens from the massive genomic data sets now being generated from routine pathogen surveillance for epidemiological purposes. Here, we measure the burden of atypical mutations in protein coding genes across independently evolved Salmonella enterica lineages, and use these as input to train a random forest classifier to identify strains associated with extraintestinal disease. Members of the species fall along a continuum, from pathovars which cause gastrointestinal infection and low mortality, associated with a broad host-range, to those that cause invasive infection and high mortality, associated with a narrowed host range. Our random forest classifier learned to perfectly discriminate long-established gastrointestinal and invasive serovars of Salmonella. Additionally, it was able to discriminate recently emerged Salmonella Enteritidis and Typhimurium lineages associated with invasive disease in immunocompromised populations in sub-Saharan Africa, and within-host adaptation to invasive infection. We dissect the architecture of the model to identify the genes that were most informative of phenotype, revealing a common theme of degradation of metabolic pathways in extraintestinal lineages. This approach accurately identifies patterns of gene degradation and diversifying selection specific to invasive serovars that have been captured by more labour-intensive investigations, but can be readily scaled to larger analyses.

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<![CDATA[Computational mechanisms underlying cortical responses to the affordance properties of visual scenes]]> https://www.researchpad.co/product?articleinfo=5ae95a44463d7e06f246c06d

Biologically inspired deep convolutional neural networks (CNNs), trained for computer vision tasks, have been found to predict cortical responses with remarkable accuracy. However, the internal operations of these models remain poorly understood, and the factors that account for their success are unknown. Here we develop a set of techniques for using CNNs to gain insights into the computational mechanisms underlying cortical responses. We focused on responses in the occipital place area (OPA), a scene-selective region of dorsal occipitoparietal cortex. In a previous study, we showed that fMRI activation patterns in the OPA contain information about the navigational affordances of scenes; that is, information about where one can and cannot move within the immediate environment. We hypothesized that this affordance information could be extracted using a set of purely feedforward computations. To test this idea, we examined a deep CNN with a feedforward architecture that had been previously trained for scene classification. We found that responses in the CNN to scene images were highly predictive of fMRI responses in the OPA. Moreover the CNN accounted for the portion of OPA variance relating to the navigational affordances of scenes. The CNN could thus serve as an image-computable candidate model of affordance-related responses in the OPA. We then ran a series of in silico experiments on this model to gain insights into its internal operations. These analyses showed that the computation of affordance-related features relied heavily on visual information at high-spatial frequencies and cardinal orientations, both of which have previously been identified as low-level stimulus preferences of scene-selective visual cortex. These computations also exhibited a strong preference for information in the lower visual field, which is consistent with known retinotopic biases in the OPA. Visualizations of feature selectivity within the CNN suggested that affordance-based responses encoded features that define the layout of the spatial environment, such as boundary-defining junctions and large extended surfaces. Together, these results map the sensory functions of the OPA onto a fully quantitative model that provides insights into its visual computations. More broadly, they advance integrative techniques for understanding visual cortex across multiple level of analysis: from the identification of cortical sensory functions to the modeling of their underlying algorithms.

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<![CDATA[RIT1 controls actin dynamics via complex formation with RAC1/CDC42 and PAK1]]> https://www.researchpad.co/product?articleinfo=5afd1336463d7e52e3d2f953

RIT1 belongs to the RAS family of small GTPases. Germline and somatic RIT1 mutations have been identified in Noonan syndrome (NS) and cancer, respectively. By using heterologous expression systems and purified recombinant proteins, we identified the p21-activated kinase 1 (PAK1) as novel direct effector of RIT1. We found RIT1 also to directly interact with the RHO GTPases CDC42 and RAC1, both of which are crucial regulators of actin dynamics upstream of PAK1. These interactions are independent of the guanine nucleotide bound to RIT1. Disease-causing RIT1 mutations enhance protein-protein interaction between RIT1 and PAK1, CDC42 or RAC1 and uncouple complex formation from serum and growth factors. We show that the RIT1-PAK1 complex regulates cytoskeletal rearrangements as expression of wild-type RIT1 and its mutant forms resulted in dissolution of stress fibers and reduction of mature paxillin-containing focal adhesions in COS7 cells. This effect was prevented by co-expression of RIT1 with dominant-negative CDC42 or RAC1 and kinase-dead PAK1. By using a transwell migration assay, we show that RIT1 wildtype and the disease-associated variants enhance cell motility. Our work demonstrates a new function for RIT1 in controlling actin dynamics via acting in a signaling module containing PAK1 and RAC1/CDC42, and highlights defects in cell adhesion and migration as possible disease mechanism underlying NS.

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<![CDATA[Genomic expansion of magnetotactic bacteria reveals an early common origin of magnetotaxis with lineage-specific evolution]]> https://www.researchpad.co/product?articleinfo=5b59b126463d7e792f6190a8

The origin and evolution of magnetoreception, which in diverse prokaryotes and protozoa is known as magnetotaxis and enables these microorganisms to detect Earth’s magnetic field for orientation and navigation, is not well understood in evolutionary biology. The only known prokaryotes capable of sensing the geomagnetic field are magnetotactic bacteria (MTB), motile microorganisms that biomineralize intracellular, membrane-bounded magnetic single-domain crystals of either magnetite (Fe3O4) or greigite (Fe3S4) called magnetosomes. Magnetosomes are responsible for magnetotaxis in MTB. Here we report the first large-scale metagenomic survey of MTB from both northern and southern hemispheres combined with 28 genomes from uncultivated MTB. These genomes expand greatly the coverage of MTB in the Proteobacteria, Nitrospirae, and Omnitrophica phyla, and provide the first genomic evidence of MTB belonging to the Zetaproteobacteria and “Candidatus Lambdaproteobacteria” classes. The gene content and organization of magnetosome gene clusters, which are physically grouped genes that encode proteins for magnetosome biosynthesis and organization, are more conserved within phylogenetically similar groups than between different taxonomic lineages. Moreover, the phylogenies of core magnetosome proteins form monophyletic clades. Together, these results suggest a common ancient origin of iron-based (Fe3O4 and Fe3S4) magnetotaxis in the domain Bacteria that underwent lineage-specific evolution, shedding new light on the origin and evolution of biomineralization and magnetotaxis, and expanding significantly the phylogenomic representation of MTB.

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<![CDATA[On the role of extrinsic noise in microRNA-mediated bimodal gene expression]]> https://www.researchpad.co/product?articleinfo=5ae6147c463d7e4331d54a11

Several studies highlighted the relevance of extrinsic noise in shaping cell decision making and differentiation in molecular networks. Bimodal distributions of gene expression levels provide experimental evidence of phenotypic differentiation, where the modes of the distribution often correspond to different physiological states of the system. We theoretically address the presence of bimodal phenotypes in the context of microRNA (miRNA)-mediated regulation. MiRNAs are small noncoding RNA molecules that downregulate the expression of their target mRNAs. The nature of this interaction is titrative and induces a threshold effect: below a given target transcription rate almost no mRNAs are free and available for translation. We investigate the effect of extrinsic noise on the system by introducing a fluctuating miRNA-transcription rate. We find that the presence of extrinsic noise favours the presence of bimodal target distributions which can be observed for a wider range of parameters compared to the case with intrinsic noise only and for lower miRNA-target interaction strength. Our results suggest that combining threshold-inducing interactions with extrinsic noise provides a simple and robust mechanism for obtaining bimodal populations without requiring fine tuning. Furthermore, we characterise the protein distribution’s dependence on protein half-life.

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<![CDATA[A computational model of shared fine-scale structure in the human connectome]]> https://www.researchpad.co/product?articleinfo=5ae6147b463d7e4331d54a10

Variation in cortical connectivity profiles is typically modeled as having a coarse spatial scale parcellated into interconnected brain areas. We created a high-dimensional common model of the human connectome to search for fine-scale structure that is shared across brains. Projecting individual connectivity data into this new common model connectome accounts for substantially more variance in the human connectome than do previous models. This newly discovered shared structure is closely related to fine-scale distinctions in representations of information. These results reveal a shared fine-scale structure that is a major component of the human connectome that coexists with coarse-scale, areal structure. This shared fine-scale structure was not captured in previous models and was, therefore, inaccessible to analysis and study.

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<![CDATA[A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability]]> https://www.researchpad.co/product?articleinfo=5ae5cb76463d7e39eef05add

The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed to provide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessity of a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.

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<![CDATA[Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations]]> https://www.researchpad.co/product?articleinfo=5ae5cb77463d7e39eef05ade

The C-terminus domain of non-structural 3 (NS3) protein of the Flaviviridae viruses (e.g. HCV, dengue, West Nile, Zika) is a nucleotide triphosphatase (NTPase) -dependent superfamily 2 (SF2) helicase that unwinds double-stranded RNA while translocating along the nucleic polymer. Due to these functions, NS3 is an important target for antiviral development yet the biophysics of this enzyme are poorly understood. Microsecond-long molecular dynamic simulations of the dengue NS3 helicase domain are reported from which allosteric effects of RNA and NTPase substrates are observed. The presence of a bound single-stranded RNA catalytically enhances the phosphate hydrolysis reaction by affecting the dynamics and positioning of waters within the hydrolysis active site. Coupled with results from the simulations, electronic structure calculations of the reaction are used to quantify this enhancement to be a 150-fold increase, in qualitative agreement with the experimental enhancement factor of 10–100. Additionally, protein-RNA interactions exhibit NTPase substrate-induced allostery, where the presence of a nucleotide (e.g. ATP or ADP) structurally perturbs residues in direct contact with the phosphodiester backbone of the RNA. Residue-residue network analyses highlight pathways of short ranged interactions that connect the two active sites. These analyses identify motif V as a highly connected region of protein structure through which energy released from either active site is hypothesized to move, thereby inducing the observed allosteric effects. These results lay the foundation for the design of novel allosteric inhibitors of NS3.

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<![CDATA[Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases]]> https://www.researchpad.co/product?articleinfo=5ae5cb79463d7e39eef05adf

The origin of the machinery that realizes protein biosynthesis in all organisms is still unclear. One key component of this machinery are aminoacyl tRNA synthetases (aaRS), which ligate tRNAs to amino acids while consuming ATP. Sequence analyses revealed that these enzymes can be divided into two complementary classes. Both classes differ significantly on a sequence and structural level, feature different reaction mechanisms, and occur in diverse oligomerization states. The one unifying aspect of both classes is their function of binding ATP. We identified Backbone Brackets and Arginine Tweezers as most compact ATP binding motifs characteristic for each Class. Geometric analysis shows a structural rearrangement of the Backbone Brackets upon ATP binding, indicating a general mechanism of all Class I structures. Regarding the origin of aaRS, the Rodin-Ohno hypothesis states that the peculiar nature of the two aaRS classes is the result of their primordial forms, called Protozymes, being encoded on opposite strands of the same gene. Backbone Brackets and Arginine Tweezers were traced back to the proposed Protozymes and their more efficient successors, the Urzymes. Both structural motifs can be observed as pairs of residues in contemporary structures and it seems that the time of their addition, indicated by their placement in the ancient aaRS, coincides with the evolutionary trace of Proto- and Urzymes.

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<![CDATA[Effector gene birth in plant parasitic nematodes: Neofunctionalization of a housekeeping glutathione synthetase gene]]> https://www.researchpad.co/product?articleinfo=5ae55380463d7e27f9ddbe06

Plant pathogens and parasites are a major threat to global food security. Plant parasitism has arisen four times independently within the phylum Nematoda, resulting in at least one parasite of every major food crop in the world. Some species within the most economically important order (Tylenchida) secrete proteins termed effectors into their host during infection to re-programme host development and immunity. The precise detail of how nematodes evolve new effectors is not clear. Here we reconstruct the evolutionary history of a novel effector gene family. We show that during the evolution of plant parasitism in the Tylenchida, the housekeeping glutathione synthetase (GS) gene was extensively replicated. New GS paralogues acquired multiple dorsal gland promoter elements, altered spatial expression to the secretory dorsal gland, altered temporal expression to primarily parasitic stages, and gained a signal peptide for secretion. The gene products are delivered into the host plant cell during infection, giving rise to “GS-like effectors”. Remarkably, by solving the structure of GS-like effectors we show that during this process they have also diversified in biochemical activity, and likely represent the founding members of a novel class of GS-like enzyme. Our results demonstrate the re-purposing of an endogenous housekeeping gene to form a family of effectors with modified functions. We anticipate that our discovery will be a blueprint to understand the evolution of other plant-parasitic nematode effectors, and the foundation to uncover a novel enzymatic function.

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<![CDATA[Multiscale modelization in a small virus: Mechanism of proton channeling and its role in triggering capsid disassembly]]> https://www.researchpad.co/product?articleinfo=5ae5cb7a463d7e39eef05ae0

In this work, we assess a previously advanced hypothesis that predicts the existence of ion channels in the capsid of small and non-enveloped icosahedral viruses. With this purpose we examine Triatoma Virus (TrV) as a case study. This virus has a stable capsid under highly acidic conditions but disassembles and releases the genome in alkaline environments. Our calculations range from a subtle sub-atomic proton interchange to the dismantling of a large-scale system representing several million of atoms. Our results provide structure-based explanations for the three roles played by the capsid to enable genome release. First, we observe, for the first time, the formation of a hydrophobic gate in the cavity along the five-fold axis of the wild-type virus capsid, which can be disrupted by an ion located in the pore. Second, the channel enables protons to permeate the capsid through a unidirectional Grotthuss-like mechanism, which is the most likely process through which the capsid senses pH. Finally, assuming that the proton leak promotes a charge imbalance in the interior of the capsid, we model an internal pressure that forces shell cracking using coarse-grained simulations. Although qualitatively, this last step could represent the mechanism of capsid opening that allows RNA release. All of our calculations are in agreement with current experimental data obtained using TrV and describe a cascade of events that could explain the destabilization and disassembly of similar icosahedral viruses.

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<![CDATA[Cytokinin stabilizes WUSCHEL by acting on the protein domains required for nuclear enrichment and transcription]]> https://www.researchpad.co/product?articleinfo=5ae5cb7c463d7e39eef05ae2

Concentration-dependent transcriptional regulation and the spatial regulation of transcription factor levels are poorly studied in plant development. WUSCHEL, a stem cell-promoting homeodomain transcription factor, accumulates at a higher level in the rib meristem than in the overlying central zone, which harbors stem cells in the shoot apical meristems of Arabidopsis thaliana. The differential accumulation of WUSCHEL in adjacent cells is critical for the spatial regulation and levels of CLAVATA3, a negative regulator of WUSCHEL transcription. Earlier studies have revealed that DNA-dependent dimerization, subcellular partitioning and protein destabilization control WUSCHEL protein levels and spatial accumulation. Moreover, the destabilization of WUSCHEL may also depend on the protein concentration. However, the roles of extrinsic spatial cues in maintaining differential accumulation of WUS are not understood. Through transient manipulation of hormone levels, hormone response patterns and analysis of the receptor mutants, we show that cytokinin signaling in the rib meristem acts through the transcriptional regulatory domains, the acidic domain and the WUSCHEL-box, to stabilize the WUS protein. Furthermore, we show that the same WUSCHEL-box functions as a degron sequence in cytokinin deficient regions in the central zone, leading to the destabilization of WUSCHEL. The coupled functions of the WUSCHEL-box in nuclear retention as described earlier, together with cytokinin sensing, reinforce higher nuclear accumulation of WUSCHEL in the rib meristem. In contrast a sub-threshold level may expose the WUSCHEL-box to destabilizing signals in the central zone. Thus, the cytokinin signaling acts as an asymmetric spatial cue in stabilizing the WUSCHEL protein to lead to its differential accumulation in neighboring cells, which is critical for concentration-dependent spatial regulation of CLAVATA3 transcription and meristem maintenance. Furthermore, our work shows that cytokinin response is regulated independently of the WUSCHEL function which may provide robustness to the regulation of WUSCHEL concentration.

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<![CDATA[Origins of scale invariance in vocalization sequences and speech]]> https://www.researchpad.co/product?articleinfo=5ae5cb75463d7e39eef05adc

To communicate effectively animals need to detect temporal vocalization cues that vary over several orders of magnitude in their amplitude and frequency content. This large range of temporal cues is evident in the power-law scale-invariant relationship between the power of temporal fluctuations in sounds and the sound modulation frequency (f). Though various forms of scale invariance have been described for natural sounds, the origins and implications of scale invariant phenomenon remain unknown. Using animal vocalization sequences, including continuous human speech, and a stochastic model of temporal amplitude fluctuations we demonstrate that temporal acoustic edges are the primary acoustic cue accounting for the scale invariant phenomenon. The modulation spectrum of vocalization sequences and the model both exhibit a dual regime lowpass structure with a flat region at low modulation frequencies and scale invariant 1/f2 trend for high modulation frequencies. Moreover, we find a time-frequency tradeoff between the average vocalization duration of each vocalization sequence and the cutoff frequency beyond which scale invariant behavior is observed. These results indicate that temporal edges are universal features responsible for scale invariance in vocalized sounds. This is significant since temporal acoustic edges are salient perceptually and the auditory system could exploit such statistical regularities to minimize redundancies and generate compact neural representations of vocalized sounds.

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