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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Coupled active systems encode emergent behavioral dynamics of the unicellular predator Lacrymaria olor

Multiple active systems in a cell work together to produce sophisticated cellular behaviors such as motility and search. However, it is often unclear how this coupling specifies the complex emergent dynamics that define such behaviors. As a model system, we analyzed the hunting strategy of Lacrymaria olor, a unicellular predatory ciliate that uses extreme morphological changes to extend, contract and whip an apparent \"cell neck\" over many body lengths to capture prey. Tracking millions of unique subcellular morphologies over time revealed that these fast dynamics encode a comprehensive local search behavior apparent only at longer timescales. This hunting behavior emerges as a tug-of-war between active sub-cellular structures that use surface cilia and cortex contractility to deform the structure of the neck. The resulting search space can be described mathematically using a small number of normal shape modes that change amplitude rapidly during hunts. The distribution of these shape modes in space and time reveals a transition point between tense and compressed neck morphologies at the mean neck length, such that new shapes are readily sampled by repeatedly extending and retracting across this critical length. Molecular perturbations to the cell-signaling controller show that coupling between ciliary and contractile programs is needed to maintain this length/shape relationship; neither system alone provides the dynamic repertoire of shapes necessary for comprehensive search. Our results highlight the utility of coupling antagonistic active systems as a strategy for encoding or engineering complex behaviors in molecular machines.\n\nOne Sentence Summary: Analysis of millions of unique cellular morphologies of the highly dynamic single-celled predator Lacrymaria olor reveals that it programs a comprehensive search space and emergent hunting behavior through coupling surface based active cilia and cortex based contractile molecular systems together.

systems biology↗
bioRxiv2018

Learning Gene Networks Underlying Clinical Phenotypes Using SNP Perturbations

Recent technologies are generating an abundance of genome sequence data and molecular and clinical phenotype data, providing an opportunity to understand the genetic architecture and molecular mechanisms underlying diseases. Previous approaches have largely focused on the co-localization of single-nucleotide polymorphisms (SNPs) associated with clinical and expression traits, each identified from genome-wide association studies and expression quantitative trait locus (eQTL) mapping, and thus have provided only limited capabilities for uncovering the molecular mechanisms behind the SNPs influencing clinical phenotypes. Here we aim to extract rich information on the functional role of trait-perturbing SNPs that goes far beyond this simple co-localization. We introduce a computational framework called Perturb-Net for learning the gene network that modulates the influence of SNPs on phenotypes, using SNPs as naturally occurring perturbation of a biological system. Perturb-Net uses a probabilistic graphical model to directly model both the cascade of perturbation from SNPs to the gene network to the phenotype network and the network at each layer of molecular and clinical phenotypes. Perturb-Net learns the entire model by solving a single optimization problem with an extremely fast algorithm that can analyze human genome-wide data within a few hours. In our analysis of asthma data, for a locus that was previously implicated in asthma susceptibility but for which little is known about the molecular mechanism underlying the association, Perturb-Net revealed the gene network modules that mediate the influence of the SNP on asthma phenotypes. Many genes in this network module were well supported in the literature as asthma-related.

bioinformatics↗
bioRxiv2018

Widespread alteration of protein autoinhibition in human cancers

Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

cancer biology↗
bioRxiv2018

Genome wide screen reveals a specific interaction between autosome and X that is essential for hybrid male sterility

Hybrid male progeny from interspecies cross are more prone to sterility or inviability than hybrid female progeny, and the male sterility and inviability often demonstrate a parent-of-origin asymmetry. However, the underlying mechanism of asymmetric sterility or inviability remains elusive. We previously established a genome-wide hybrid incompatibility (HI) landscape between Caenorhabditis briggsae and C. nigoni by phenotyping a large collection of C. nigoni strains each carrying a C. briggsae introgression. In this study, we investigate the genetic mechanism of asymmetric sterility and inviability in both hybrid male and female progeny between the two species. Specifically, we performed reciprocal crosses between C. briggsae and different C. nigoni strains that each carries a GFP-labeled C. briggsae genomic fragment referred to as introgression, and scored the HI phenotypes in the F1 progeny. The aggregated introgressions cover 94.6% of the C. briggsae genome, including 100% of the X chromosome. Surprisingly, we observed that two C. briggsae X fragments that produce C. nigoni male sterility as an introgression rescued hybrid F1 sterility in males fathered by C. briggsae, indicating that at least two separate X-autosome interactions are involved in the hybrid male sterility. In addition, we identified another two C. briggsae genomic intervals on the Chromosome II or IV, respectively, which can rescue the inviability, but not the sterility, of hybrid F1 males fathered by C. nigoni, suggesting the involvement of differential epistatic interactions in the asymmetric hybrid male fertility and inviability. Importantly, backcrossing of the rescued sterile males with C. nigoni led to isolation of a 1.1-Mb genomic interval that specifically interacts with an X-linked introgression, which is essential for hybrid male fertility. We further identified three C. briggsae genomic intervals on the Chromosome I, II and III, respectively that produce inviability in all F1 progeny dependent or independent of the parent-of-origin. Taken together, we identified multiple independent interacting loci that are responsible for asymmetric hybrid male and female sterility and inviability, which provides important insights into the asymmetric HI and lays a foundation for their molecular characterization.\n\nAuthor summaryIt is common that closely related species can mate with each other, but their hybrid progeny are often sterile or inviable, especially in the male progeny. The mechanism underlying the asymmetric sterility or inviability remains poorly understood. We previously addressed this question between two nematodes, Caenorhabditis briggsae and C. nigoni, by systematic substitution of various parts of the C. nigoni genome with its C. briggsaes equivalent followed by phenotypic examination. Here we investigate the genetic mechanism of the asymmetric sterility and inviability in the hybrid F1 male and female progeny between the two species. We achieved this through crossing a cohort of C. nigoni strains each carrying a substitution with C. briggsae, which led to differential homozygosity of the C. briggsae substitution in the hybrid progeny. The aggregated substitutions cover 94.6% of the C. briggsae genome, including 100% of the X chromosome. Surprisingly, we identified two C. briggsae X fragments that produced C. nigoni male sterility as a substitution but rescued hybrid F1 sterility in males fathered by C. briggsae, indicating that at least two separate X-autosome interactions are involved in the hybrid male sterility. In addition, we identified multiple genomic intervals on C. briggsae autosomes that can rescue the inviability, but not the sterility, of hybrid F1 males fathered by C. nigoni. Importantly, we isolated a 1.1-Mb genomic interval that specifically interacts with an X-linked introgression, which is essential for hybrid male fertility. We further identified three C. briggsae genomic intervals on the Chromosome I, II and III, respectively that produce inviability in all F1 progeny dependent or independent of the parent-of-origin. The identified interacting loci lays a foundation for their molecular characterization.

evolutionary biology↗
bioRxiv2018

Graphene Oxide as 2D Platform for Complexation and Intracellular Delivery of siRNA

The development of efficient and safe nucleic acid delivery vectors remains an unmet need holding back translation of gene therapy approaches into bedside. Graphene oxide (GO) could help bypass such bottleneck thanks to its large surface area, versatile chemistry and biocompatibility, which could overall enhance transfection efficiency while abolishing some of the limitations linked to the use of viral vectors. Here, we aimed to assess the capacity of bare GO, without any further surface modification, to complex a short double-stranded nucleic acid of biological relevance (siRNA) and mediate its intracellular delivery. GO formed stable complexes with siRNA at 10:1, 20:1 and 50:1 GO:siRNA mass ratios. Complexation was further corroborated by atomistic molecular dynamics simulations. GO:siRNA complexes were promptly internalized in a primary mouse cell culture, as early as 4 h after exposure. At this time point, intracellular siRNA levels were comparable to those provided by a lipid-based transfection reagent that achieved significant gene silencing. Time-lapse tracking of internalized GO and siRNA evidenced a sharp decrease of intracellular siRNA from 4 to 12 h, while GO was sequestered in large vesicles, which may explain the lack of biological effect (i.e. gene silencing) achieved by GO:siRNA complexes. This study underlines the potential of non-surface modified GO flakes to act as 2D siRNA delivery platforms, without the need for cationic functionalization, but warrants further vector optimization to allow effective release of the nucleic acid and achieve efficient gene silencing.

bioengineering↗
bioRxiv2018

A mosaic of independent innovations involving eyes shut are critical for the evolutionary transition from closed to open rhabdoms

A fundamental question in evolutionary biology is how developmental processes are modified to produce morphological innovations while abiding by functional constraints. Here we address this question by investigating the cellular mechanism responsible for the transition between fused and open rhabdoms in ommatidia of apposition compound eyes; a critical step required for the development of visual systems based on neural superposition. Utilizing Drosophila and Tribolium as representatives of fused and open rhabdom morphology respectively, we identified three changes required for this innovation to occur. First, the expression pattern of the extracellular matrix protein Eyes Shut (EYS) was co-opted and expanded from mechanosensory neurons to the photoreceptor cells in taxa with open rhabdoms. Second, EYS homologs in these taxa obtained a novel extension of the amino terminus leading to the internalization of a cleaved signal sequence. This amino terminus extension does not interfere with cleavage or function in mechanosensory neurons, but it does permit specific targeting of the EYS protein to the apical photoreceptor membrane. Finally, a specific interaction evolved between EYS and a subset of Prominin homologs that is required for the development of open, but not fused, rhabdoms. Together, our findings portray a case study wherein the evolution of a set of molecular novelties has precipitated the origin of an adaptive photoreceptor cell arrangement.\n\nAuthor SummaryUnderstanding how adaptive morphologies originate is a central question in evolutionary developmental biology. Once confined largely to arguments about the relative frequencies of protein coding vs. regulatory mutations, numerous studies have since revealed more complex interactions involving alterations in gene expression and novel protein-protein interactions as drivers of novel trait evolution. Our study exploits the genetic amenability of Drosophila and utilizes direct comparisons with Tribolium to define a set of cellular mechanisms necessary for the evolutionary transition from a fused (Tribolium) to an open (Drosophila) rhabdom. Our results depict an evolutionary transition involving both non-coding and coding changes that resulted in a novel visual architecture, permitting a subset of diurnal insects to diversify into niches characterized by low light.

evolutionary biology↗
bioRxiv2017

A convergent depression vulnerability pathway encoded by emergent spatiotemporal dynamics

Fluctuations in brain local field potential (LFP) oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these LFP oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional processes at the network level. Here we use machine learning to integrate LFP activity acquired concurrently from seven cortical and subcortical brain regions into an analytical model that predicts the emergence of depression-related behavioral dysfunction across individual mice subjected to chronic social defeat stress. We uncover a spatiotemporal dynamic network in which activity originates in prefrontal cortex (PFC) and nucleus accumbens (NAc, ventral striatum), relays through amygdala and ventral tegmental area (VTA), and converges in ventral hippocampus (VHip). The activity of this network correlates with acute threat responses and brain-wide cellular firing, and it is enhanced in three independent molecular-, physiological-, and behavioral-based models of depression vulnerability. Finally, we use two antidepressant manipulations to demonstrate that this vulnerability network is biologically distinct from the networks that signal behavioral dysfunction after stress. Thus, corticostriatal to VHip-directed spatiotemporal dynamics organized at the network level are a novel convergent depression vulnerability pathway.

neuroscience↗
bioRxiv2017

Improving Phenotypic Measurements in High-Content Imaging Screens

Image-based screening is a powerful technique to reveal how chemical, genetic, and environmental perturbations affect cellular state. Its potential is restricted by the current analysis algorithms that target a small number of cellular phenotypes and rely on expert-engineered image features. Newer algorithms that learn how to represent an image are limited by the small amount of labeled data for ground-truth, a common problem for scientific projects. We demonstrate a sensitive and robust method for distinguishing cellular phenotypes that requires no additional ground-truth data or training. It achieves state-of-the-art performance classifying drugs by similar molecular mechanism, using a Deep Metric Network that has been pre-trained on consumer images and a transformation that improves sensitivity to biological variation. However, our method is not limited to classification into predefined categories. It provides a continuous measure of the similarity between cellular phenotypes that can also detect subtle differences such as from increasing dose. The rich, biologically-meaningful image representation that our method provides can help therapy development by supporting high-throughput investigations, even exploratory ones, with more sophisticated and disease-relevant models.

cell biology↗
bioRxiv2018

De novo assembly of the Pasteuria penetrans genome reveals high plasticity, host dependency, and BclA-like collagens.

1.Pasteuria penetrans is a gram-positive endospore forming bacterial parasite of Meloidogyne spp. the most economically damaging genus of plant parasitic nematodes globally. The obligate antagonistic nature of P. penetrans makes it an attractive candidate biological control agent. However, deployment of P. penetrans for this purpose is inhibited by a lack of understanding of its metabolism and the molecular mechanics underpinning parasitism of the host, in particular the initial attachment of the endospore to the nematode cuticle. Several attempts to assemble the genomes of species within this genus have been unsuccessful. Primarily this is due to the obligate parasitic nature of the bacterium which makes obtaining genomic DNA of sufficient quantity and quality which is free from contamination challenging. Taking advantage of recent developments in whole genome amplification, long read sequencing platforms, and assembly algorithms, we have developed a protocol to generate large quantities of high molecular weight genomic DNA from a small number of purified endospores. We demonstrate this method via genomic assembly of P. penetrans. This assembly reveals a reduced genome of 2.64Mbp estimated to represent 86% of the complete sequence; its reduced metabolism reflects widespread reliance on the host and possibly associated organisms. Additionally, apparent expansion of transposases and prediction of partial competence pathways suggest a high degree of genomic plasticity. Phylogenetic analysis places our sequence within the Bacilli, and most closely related to Thermoactinomyces species. Seventeen predicted BclA-like proteins are identified which may be involved in the determination of attachment specificity. This resource may be used to develop in vitro culture methods and to investigate the genetic and molecular basis of attachment specificity.

microbiology↗
bioRxiv2018

The intimate knowledge of DNA crystals revealed by molecular dynamics simulations

X-ray crystallography has been traditionally considered as the primary tool for the determination of biomolecular structures and its derived models are taken as the gold standard in structural biology. However, contacts formed through the crystal lattice are known to affect the structures, especially in the case of small and flexible molecules, like DNA oligos, introducing drastic changes in the structure with respect to the solution phase. Furthermore, it is still unknown why molecules crystallize in certain symmetry groups and how the associated lattice impacts their structure. The role of crystallization additives and whether they are just innocuous and unspecific catalyzers of the crystallization process also remains unclear. On account of a massive computational effort and the use of the latest generation force field, we were able to describe with unprecedented level of detail the nature of intermolecular forces that participate in the stabilization of B-DNA crystals in various symmetry groups and in different solvent environments. We showed that the stability of the crystal lattice and the type of crystallization additives are tightly coupled, and certain symmetry groups are only stable in the presence of a specific crystallization additive (i.e., spermine). Additives and crystal contacts induce small but non-negligible changes in the physical properties of DNA.

biophysics↗
bioRxiv2018

Three-dimensional nanostructure of an intact microglia cell

Microglia are non-neuronal cells of the myeloid lineage that invade and take up long-term residence in the brain during development (Ginhoux et al. 2010) and are increasingly implicated in neuronal maturation, homeostasis, and pathology (Bessis et al. 2007; Paolicelli et al. 2011; Li et al. 2012; Aguzzi et al. 2013, Cunningham 2013, Cunningham et al. 2013). Since the early twentieth century several methods for staining and visualizing microglia have been developed. Scientists in Ramon y Cajals group (Achucarro 1913, Rio-Hortega 1919) pioneered these methods and their work led to the christening of microglia as the third element of the nervous system, distinct from astrocytes and neurons. More recently, a combination of imaging, genetic, and immunological tools has been used to visualize microglia in living brain (Davalos et al. 2005; Nimmerjahn et al. 2005). It was found that microglia are highly motile under resting conditions and rapidly respond to injuries (Kettenmann et al. 2011) suggesting a role for microglia in both brain homeostasis and pathology. Transmission Electron microscopy (TEM) has provided crucial complementary information on microglia morphology and physiology but until recently EM analyses have been limited to single or limited serial section studies (Tremblay et al. 2010; Paolicelli et al. 2011; Schafer et al. 2012; Tremblay et al. 2012; Sipe et al. 2016). TEM studies were successful in defining a set of morphological criteria for microglia: a polygonal nucleus with peripheral condensed chromatin, a relatively small cytoplasm with abundant presence of rough endoplasmic reticulum (RER), and a large volume of lysosomes and inclusions in the perikaryon. Recent advances in volumetric electron microscopy techniques allow for 3D reconstruction of large samples at nanometer-resolution, thus opening up new avenues for the understanding of cell biology and architecture in intact tissues. At the same time, correlative light and electron microscopy (CLEM) techniques have been extended to 3D brain samples to help navigate and identify critical molecular landmarks within large EM volumes (Briggman and Denk 2006; Maco et al. 2013; Blazquez-Llorca et al. 2015, Bosch et al. 2015). Here we present the first volumetric ultrastructural reconstruction of an entire mouse hippocampal microglia using serial block face scanning electron microscopy (SBEM). Using CLEM we have ensured the inclusion of both large, small, and filopodial microglia processes. Segmentation of the dataset allowed us to carry out a comprehensive inventory of microglia cell structures, including vesicles, organelles, membrane protrusions, and processes. This study provides a reference that can serve as a data mining resource for investigating microglia cell biology.

neuroscience↗
bioRxiv2018

Proteomic Profile of TGF-β1 treated Lung Fibroblasts identifies Novel Markers of Activated Fibroblasts in the Silica Exposed Rat Lung

We performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) on control and TGF-{beta}1-exposed rat lung fibroblasts to identify proteins differentially expressed between cell populations. A total of 1648 proteins were found to be differentially expressed in response to TGF-{beta}1 treatment and 196 proteins were expressed at [≥] 1.2 fold relative to control. Guided by these results, we next determined whether similar changes in protein expression were detectable in the rat lung after chronic exposure to silica dust. Of the five proteins selected for further analysis, we found that levels of all proteins were markedly increased in the silica-exposed rat lung, including the proteins for the very low density lipoprotein receptor (VLDLR) and the transmembrane (type I) heparin sulfate proteoglycan called syndecan 2 (SDC2). Because VLDLR and SDC2 have not, to our knowledge, been previously linked to the pathobiology of silicosis, we next examined whether knockdown of either gene altered responses to TGF-{beta}1 in MRC-5 lung fibroblasts. Interestingly, we found knockdown of either VLDLR or SDC2 dramatically reduced collagen production to TGF-{beta}1, suggesting that both proteins might play a novel role in myofibroblast biology and pathogenesis of silica-induced pulmonary fibrosis. In summary, our findings suggest that performing LC-MS/MS on TGF-{beta}1 stimulated lung fibroblasts can uncover novel molecular targets of activated myofibroblasts in silica-exposed lung.\n\nHighlightsWe identified 196 proteins differentially expressed between control and TGF-{beta}1 treated fibroblastsby LC-MS/MS.\n\nSeveral proteins identified by LC-MS/MS were also found to be differentially expressed in whole lung tissues and isolated fibroblasts after chronic exposure to silica dust, including the very low density lipoprotein receptor (VLDLR) and the transmembrane type I heparan sulfate proteoglycan called syndecan 2\n\nKnockdown of SDC2 or VLDLR markedly inhibited collagen production in MRC-5 fibroblasts, suggesting a novel pathogenic role for these proteins in myofibroblast biology.

pharmacology and toxicology↗
bioRxiv2017

Between semelparity and iteroparity: empirical evidence for a continuum of modes of parity

The number of times an organism reproduces (i.e. its mode of parity) is a fundamental life-history character, and evolutionary and ecological models that compare the relative fitness of strategies are common in life history theory and theoretical biology. Despite the success of mathematical models designed to compare intrinsic rates of increase between annual-semelparous and perennial-iteroparous reproductive schedules, there is widespread evidence that variation in reproductive allocation among semelparous and iteroparous organisms alike is continuous. This paper reviews the ecological and molecular evidence for the continuity and plasticity of modes of parity--that is, the idea that annual-semelparous and perennial-iteroparous life histories are better understood as endpoints along a continuum of possible strategies. I conclude that parity should be understood as a continuum of different modes of parity, which differ by the degree to which they disperse or concentrate reproductive effort in time. I further argue that there are three main implications of this conclusion: (1) That seasonality should not be conflated with parity; (2) that mathematical models purporting to explain the evolution of semelparous life histories from iteroparous ones (or vice versa) should not assume that organisms can only display either an annual-semelparous life history or a perennial-iteroparous one; and (3) that evolutionary ecologists should examine the physiological or molecular basis of traits underlying different modes of parity, in order to obtain a general understanding of how different life history strategies can evolve from one another.

evolutionary biology↗
bioRxiv2018

Binary transcriptional control of pattern formation in development

Predicting developmental outcomes from regulatory DNA sequence and transcription factor patterns remains an open challenge in physical biology. Using stripe 2 of the even-skipped gene in Drosophila embryos as a case study, we dissect the regulatory forces underpinning a key step along the developmental decision-making cascade: the generation of cytoplasmic mRNA patterns via the control of transcription in individual cells. Using live imaging and computational approaches, we found that the transcriptional burst frequency is modulated across the stripe to control the mRNA production rate. However, we discovered that bursting alone cannot quantitatively recapitulate the formation of the stripe, and that control of the window of time over which each nucleus transcribes even-skipped plays a critical role in stripe formation. Theoretical modeling revealed that these regulatory strategies--bursting and the time window--obey different kinds of regulatory logic, suggesting that the stripe is shaped by the interplay of two distinct underlying molecular processes.

developmental biology↗
bioRxiv2018

Adhesion of active cytoskeletal vesicles

Regulation of adhesion is a ubiquitous feature of living cells, observed during processes such as motility, antigen recognition or rigidity sensing. At the molecular scale, a myriad of mechanisms are necessary to recruit and activate the essential proteins, while at the cellular scale efficient regulation of adhesion relies on the cells ability to adapt its global shape. To understand the role of shape remodeling during adhesion, we use a synthetic biology approach to design a minimal model, starting with a limited number of building blocks. We assemble cytoskeletal vesicles whose size, reduced volume, and cytoskeleton contractility can be independently tuned. We are able to show that these cytoskeletal vesicles can sustain strong adhesion to solid substrates only if molecular motors are able to actively remodel the actin cortex. When the cytoskeletal vesicles are deformed under hypertonic osmotic pressure, they develop a crumpled geometry with huge deformations. In the presence of molecular motors, these deformations are dynamic in nature and can compensate for an absence of excess membrane area needed for adhesion to take place. When the cytoskeletal deformations are able to compensate for lack of excess membrane area, the cytoskeletal vesicles are able to attach to the rigid glass surfaces even under strong adhesive forces. The balance of deformability and adhesion strength is identified to be key to enable cytoskeletal vesicles to adhere to solid substrates.

biophysics↗
bioRxiv2017

Nitrogen-Fixing Populations Of Planctomycetes And Proteobacteria Are Abundant In The Surface Ocean

Nitrogen fixation in the surface ocean impacts the global climate by regulating the microbial primary productivity and the sequestration of carbon through the biological pump. Cyanobacterial populations have long been thought to represent the main suppliers of the bio-available nitrogen in this habitat. However, recent molecular surveys of nitrogenase reductase gene revealed the existence of rare non-cyanobacterial populations that can also fix nitrogen. Here, we characterize for the first time the genomic content of some of these heterotrophic bacterial diazotrophs (HBDs) inhabiting the open surface ocean waters. They represent new lineages within Planctomycetes and Proteobacteria, a phylum never linked to nitrogen fixation prior to this study. HBDs were surprisingly abundant in the Pacific Ocean and the Atlantic Ocean northwest, conflicting with decades of PCR surveys. The abundance and widespread occurrence of non-cyanobacterial diazotrophs in the surface ocean emphasizes the need to re-evaluate their role in the nitrogen cycle and primary productivity.

microbiology↗
bioRxiv2017

Discovery Of Drought-Responsive Transposable Element-Related Peach miRNAs

MicroRNAs (miRNA) are small non-coding regulatory RNAs that suppress their specific target transcripts either by cleavage or inhibition of translation. Transposable element related miRNAs (TE-miRNA) have been subjected to various studies so far, and some of them were found to be involved in stress response in plants. Here, small RNA (sRNA) sequencing libraries generated from drought stress treated peach tissues were utilized to identify TE-miRNAs. Our computational analysis led to the identification of 63 TE-miRNAs, which were either locating nearby of any TE (TE-related), or overlapping with a TE (TE-derived). Furthermore, 13 out of 63 TE-miRNAs were designated as drought-responsive. Expression pattern of the identified drought-responsive TE-miRNAs are observed as tissue-specific manner, and their specific target transcripts are mostly related to transcription factors and growth-associated genes. Our findings suggest that miRNAs in relation with transposable elements might be key molecular players in the regulation of drought response.

plant biology↗
bioRxiv2018

Label propagation defines signaling networks associated with recurrently mutated cancer genes

Each different tumor type has a distinct profile of genomic perturbations and each of these alterations causes unique changes to cellular homeostasis. Detailed analyses of these changes would reveal downstream effects of genomic alterations, contributing to our understanding of their roles in tumor development and progression. Across a range of tumor types, including bladder, lung, and endometrial carcinoma, we determined genes that are frequently altered in The Cancer Genome Atlas patient populations to study the effects of these alterations on signaling and regulatory pathways. To achieve this, we used a label propagation-based methodology to generate networks from gene expression signatures of mutations. Individual networks offered a comprehensive view of signaling changes represented by gene signatures, which in turn reflect the scope of molecular events that are perturbed in the presence of a given genomic alteration. Comparing different networks to each other revealed commonalities between them and biological pathways distinct genomic alterations converge on, highlighting the critical signaling events tumor dysregulate through multiple mechanisms. Finally, mutations inducing common changes to the signaling network were used to search for genomic markers of drug response, connecting shared perturbations to differential drug response.

bioinformatics↗