Biology subjects

Krishnan, A.

Publications and source records attributed to Krishnan, A..

105 records · Page 6Linked to original sources

bioRxiv2019

Conversion of a defensive toxin-antitoxin system into an offensive T6SS effector in Burkholderia

Bacteria use various kinds of toxins to either inhibit the growth of co-habiting bacteria or when needed control their own growth. Here we report that Burkholderia and certain other bacteria have altered the potential defensive function of Tox-REase-5 domain containing toxins into offensive function. The Burkholderia gladioli strain NGJ1 encodes such toxins as type VI secretion system (T6SS) effectors (Tse) and potentially deploys them to kill co-habiting rice endophytic bacteria. Notably, the immunity (Tsi) proteins associated with Tse effectors demonstrate functional similarity with the antitoxin of type II toxin-antitoxin (TA) system. Genome analysis of diverse bacteria revealed that various Tse orthologs are either encoded as TA or T6SS effectors. In addition, potential evolutionary events associated with conversion of TA into T6SS effectors have been delineated. Our results indicate that the transposition of IS3 elements has led to the operonic fusion of certain T6SS related genes with TA genes resulting in their conversion into T6SS effectors. Such a genetic change has enabled bacteria to utilize novel toxins to precisely target co-habiting bacteria.

microbiology↗

bioRxiv2019

Simultaneously vocalizing Asian barbets adopt different frequencies without coordinating temporal rhythms

Sound stream segregation is an important challenge faced by simultaneously vocalizing animals. Chorusing birds, for instance, coordinate vocal timing to minimize overlap. Alternatively, other birds may use frequency differences to segregate sound streams, and vocalizing at different frequencies may enable them to remain distinct from each other. Here, I show that conspecific Asian barbets vocalize at distinctly different peak frequencies from each other. Additionally, they also differ in repetition rate, as measured by the inter-phrase interval. However, conspecific individuals across species do not temporally coordinate with each other during vocal interactions, maintaining independent and highly stereotyped individual rhythms together with different peak frequencies. Frequency differences between individuals may facilitate sound stream segregation when calls overlap in time. I propose that frequency differences between conspecifics may be widespread among birds possessing stereotyped, repetitive calls such as those found in barbets. This may enable segregation of competing sound streams both during cooperative duets and competitive singing during territorial interactions.

animal behavior and cognition↗

bioRxiv2019

Sympatric wren-warblers partition acoustic signal space and song perch height

By evolving divergent acoustic signals, sympatric assemblages of animals may minimize potentially costly masking interference. Acoustic signal space may be multidimensional, with coexisting species also vocalizing from different regions of physical space. Here, we demonstrate acoustic signal space partitioning in four sympatric species of wren-warbler (Cisticolidae, Prinia), in an Indian dry deciduous scrub habitat. We find that the breeding songs of wren-warblers are divergent from each other in multivariate parameter space, with only minimal interspecific overlap. Partitioning of signal space exerts constraints on the intraspecific diversity of acoustic signals, and each species exhibits different strategies to overcome these constraints. Two species partition intraspecific signal space into multiple note types, whereas a third exhibits intraspecific variation in repetition rate, thus supporting song diversity within a constrained acoustic space. Finally, we find that the four species also partition song perch heights, thus exhibiting separation along multiple axes of acoustic signal space. We hypothesize that divergent song perch heights may be driven by competition for higher singing perches or other ecological factors rather than signal propagation. Acoustic signal partitioning along multiple axes may therefore, we propose, arise from a combination of diverse ecological processes.

animal behavior and cognition↗

bioRxiv2019

Supervised-learning is an accurate method for network-based gene classification

BackgroundAssigning every human gene to specific functions, diseases, and traits is a grand challenge in modern genetics. Key to addressing this challenge are computational methods such as supervised-learning and label-propagation that can leverage molecular interaction networks to predict gene attributes. In spite of being a popular machine learning technique across fields, supervised-learning has been applied only in a few network-based studies for predicting pathway-, phenotype-, or disease-associated genes. It is unknown how supervised-learning broadly performs across different networks and diverse gene classification tasks, and how it compares to label-propagation, the widely-benchmarked canonical approach for this problem.\n\nResultsIn this study, we present a comprehensive benchmarking of supervised-learning for network-based gene classification, evaluating this approach and a state-of-the-art label-propagation technique on hundreds of diverse prediction tasks and multiple networks using stringent evaluation schemes. We demonstrate that supervised-learning on a genes full network connectivity outperforms label-propagation and achieves high prediction accuracy by efficiently capturing local network properties, rivaling label-propagations appeal for naturally using network topology. We further show that supervised-learning on the full network is also superior to learning on node-embeddings (derived using node2vec), an increasingly popular approach for concisely representing network connectivity.\n\nConclusionThese results show that supervised-learning is an accurate approach for prioritizing genes associated with diverse functions, diseases, and traits and should be considered a staple of network-based gene classification workflows. The datasets and the code used to reproduce the results and add new gene classification methods have been made freely available.\n\nContactarjun@msu.edu

bioinformatics↗

bioRxiv2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1-3. Changes to DNA methylation patterns over time form the basis of an ageing clock4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns dont just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

molecular biology↗

bioRxiv2019

11β-Hydroxysteroid Dehydrogenase Type 1 inhibition in Idiopathic Intracranial Hypertension: a double-blind randomized controlled trial.

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11{beta}-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability, and investigate indicators of in vivo efficacy of the 11{beta}-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared to placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-weeks treatment with AZD4017 or placebo was conducted. Women aged 18 to 55 years with active idiopathic intracranial hypertension (>25cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400mg twice daily of oral AZD4017 compared to matching placebo over 12-weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropological measures. In vivo efficacy was evaluated in the central nervous system and systemically. 31 subjects (mean age 31.2 (SD=6.9) years and BMI 39.2 (SD=12.6) kg/m2) were randomized to AZD4017 (n=17) or placebo (n=14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1-1.5; p=0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group (mean change: -4.3 cmH2O (SD=5.7); p=0.009) but not in the placebo group (mean change: -0.3 cmH2O (SD=5.9); p=0.8). AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11{beta}-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation and CSF cortisone to cortisol ratios) demonstrated significant enzyme inhibition. This is the first phase 2 randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe, well-tolerated and inhibited 11{beta}-hydroxysteroid dehydrogenase type 1 activity in vivo. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

clinical trials↗

bioRxiv2019

Acoustic community structure and seasonal turnover in tropical South Asian birds

Birds produce diverse acoustic signals, with coexisting species occupying distinct acoustic niches to minimize masking, resulting in overdispersion within acoustic space. In tropical regions of the world, an influx of migrants from temperate regions occurs during winter. The effects of these migrants on acoustic community structure and dynamics remain unstudied. Here, I show that in a tropical urban bird community, the influx of winter migrants is accompanied by a turnover of the acoustic community. However, in spite of this turnover, the acoustic community remains overdispersed in acoustic niche space. The winter acoustic community additionally exhibits lower frequency-band diversity, consistent with species singing less continuously, as well as lower phylogenetic diversity. My data thus suggests that acoustic niches and community structure are stable across seasons in spite of species turnover. Migrants occupy similar regions of acoustic space as residents, and are relatively closely related to some of these species. Their arrival therefore leads to greater phylogenetic clustering in the winter, and thus lower phylogenetic diversity, although the acoustic community remains overdispersed. Studying seasonal dynamics of acoustic communities thus provides valuable insight into assembly processes, as well as a potential framework for long-term monitoring of urban ecosystems.

ecology↗

bioRxiv2019

Visual signal evolution along complementary color axes in four bird lineages

Animal color patterns function in varied behavioral contexts including recognition, camouflage and even thermoregulation. The diversity of visual signals may be constrained by various factors, for example, dietary factors, and the composition of ambient environmental light (sensory drive). How have high-contrast and diverse signals evolved within these constraints? In four bird lineages, we present evidence that plumage colors cluster along a line in tetrachromatic color space. Additionally, we present evidence that this line represents complementary colors, which are defined as opposite sides of a line passing through the achromatic point (putatively for higher chromatic contrast). Finally, we present evidence that interspecific color variation over at least some regions of the body is not constrained by phylogenetic relatedness. Thus, we hypothesize that species-specific plumage patterns within these bird lineages evolve by swapping the distributions of a complementary color pair (or dark and light patches in one group, putatively representing an achromatic complementary axis). The relative role of chromatic and achromatic contrasts in discrimination may depend on the environment that each species inhabits.

ecology↗

bioRxiv2018

Developmental Effects of the Pesticide Imidacloprid on Zebrafish Body Length and Mortality

The pesticide imidacloprid, a Neonicotinoid, is widely used and commercially available. Neonicotinoids are antagonists at nicotinic acetylcholine receptors, which can cause neurobehavioral effects in developing organisms. While the effects of other insecticides such as Malathion and Fipronil on zebrafish Danio rerio development have been studied, few studies describe the morphological effects of imidacloprid during zebrafish development. To test the hypothesis that imidacloprid concentration positively correlates to increased mortality and decreased body length, we exposed zebrafish to imidacloprid for five days post fertilization. Body length and embryo mortality were recorded at 1, 2, 3, 4, and 5 days post fertilization in 0 ug/L, 100 ug/L, 1,000 ug/L, and 10,000 ug/L imidacloprid concentrations. These concentrations were chosen to mimic levels that could be reached in the environment especially soon after application. Our results demonstrate statistically increased embryo mortality, with a f crit value of 3.193 and a f value of 3.098 from an ANOVA test, and impaired body length with a dose dependent correlation to the concentration of imidacloprid and a P value of less than 0.01 from a T test. Given the pesticides high prevalence, future studies should be considered to determine if this effect may impact livestock and human development.

developmental biology↗

bioRxiv2018

The unexpected provenance of components in eukaryotic nucleotide-excision-repair and kinetoplast DNA-dynamics from bacterial mobile elements

BackgroundProtein weaponry deployed in biological conflicts between selfish elements and their hosts are increasingly recognized as being re-purposed for diverse molecular adaptations in the evolution of several uniquely eukaryotic systems. The anti-restriction protein ArdC, transmitted along with the DNA during invasion, is one such factor deployed by plasmids and conjugative transposons against their bacterial hosts.\n\nResultsUsing sensitive computational methods we unify the N-terminal single-stranded DNA-binding domain of ArdC (ArdC-N) with the DNA-binding domains of the nucleotide excision repair (NER) XPC/Rad4 protein and Trypanosoma Tc-38 (p38) protein implicated in kinetoplast(k) DNA replication and dynamics. We show that the ArdC-N domain was independently acquired twice by eukaryotes from bacterial mobile elements. One gave rise to the beta-hairpin domains of XPC/Rad4 and the other to the Tc-38-like proteins in the stem kinetoplastid. Eukaryotic ArdC-N domains underwent tandem duplications to form an extensive DNA-binding interface. In XPC/Rad4, the ArdC-N domain combined with the inactive transglutaminase domain of a peptide-N-glycanase originally derived from an active archaeal version, often incorporated in systems countering invasive DNA. We also show that parallel acquisitions from conjugative elements and bacteriophages gave rise to the Topoisomerase IA, DNA polymerases IB-Ds, and DNA ligases involved in kDNA dynamics.\n\nConclusionsWe resolve two outstanding questions in eukaryote-biology: 1) origin of the unique DNA lesion-recognition component of NER; 2) origin of the unusual, plasmid-like features of kDNA. These represent a more general trend in the origin of distinctive components of systems involved in DNA dynamics and their links to the ubiquitin system.

genomics↗

bioRxiv2018

Multiple brain networks mediating stimulus-pain relationships in humans

The brain transforms nociceptive input into a complex pain experience comprised of sensory, affective, motivational, and cognitive components. However, it is still unclear how pain arises from nociceptive input, and which brain networks coordinate to generate pain experiences. We introduce a new high-dimensional mediation analysis technique to estimate distributed, network-level patterns mediating the relationship between stimulus intensity and pain. In a large-scale analysis of functional magnetic resonance imaging data (N=284), we identify both traditional mediators in somatosensory brain regions and additional mediators located in prefrontal, midbrain, striatal, and default-mode regions unrelated to nociception in standard analyses. The whole brain mediators are specific for pain vs. aversive sounds and are organized in five functional networks. Brain mediators explain 32% more within-subject variance of single-trial pain ratings than previous brain-based models. Our results provide a new, broader view of the networks underlying pain experience, as well as distinct targets for interventions.

neuroscience↗

bioRxiv2018

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

PurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.\n\nMethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.\n\nResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.\n\nConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

genomics↗

bioRxiv2017

Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of autism-associated 16p11.2 deletion

As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identified a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We tested 565 pairwise knockdowns in the developing eye, and identified 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppressed or enhanced cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways were also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for genetic interactions within CNVs and identifies potential therapeutic targets for neurodevelopmental disorders.

genomics↗

bioRxiv2017

RECoN: Rice Environment Coexpression Network for Systems Level Analysis of Abiotic-Stress Response

Transcriptional profiling is a prevalent and powerful approach for capturing the response of crop plants to environmental stresses, e.g. response of rice to drought. However, functionally interpreting the resulting genome-wide gene expression changes is severely hampered by the large gaps in our genomic knowledge about which genes work together in cellular pathways/processes in rice. Here, we present a new web resource - RECoN - that relies on a network-based approach to go beyond currently limited annotations in delineating functional and regulatory perturbations in new rice stress transcriptome datasets generated by a researcher. To build RECoN, we first enumerated 1,744 stress-specific gene modules covering 28,421 rice genes (>72% of the genes in the genome). Each module contains a group of genes tightly coexpressed across a large number of environmental conditions and, thus, is likely to be functionally coherent. When a user provides a new differential expression profile, RECoN identifies modules substantially perturbed in their experiment and further suggests deregulated functional and regulatory mechanisms based on the enrichment of current annotations within the predefined modules. We demonstrate the utility of this resource by analyzing new drought transcriptomes of rice in three developmental stages, which revealed large-scale insights into the cellular processes and regulatory mechanisms involved in common and stage-specific drought responses. RECoN enables biologists to functionally explore new data from all abiotic stresses on a genome-scale and to uncover gene candidates, including those that are currently functionally uncharacterized, for engineering stress tolerance.

systems biology↗

bioRxiv2017

SANe: The Seed Active Network For Mining Transcriptional Regulatory Programs of Seed Development

Developing seeds undergo coordinated physiological and morphological changes crucial for development of the embryo, dormancy and germination. The metabolic changes that occur during seed development are regulated by interconnected network of Transcription Factors (TFs) that regulate gene expression in a spatiotemporal manner. The complexity of these networks is such that the TFs that play key regulatory roles during seed development are largely unknown. In this study, we created a genome-scale regulatory network dedicated to describing regulation of biological processes within various compartments and developmental stages of Arabidopsis seeds. Differential network analysis revealed key TFs that rewire their targeting patterns specifically during seed development, many of which were already known, and a few novel ones that we verified experimentally. Our method shows that a high-resolution tissue-specific transcriptome dataset can be accurately modeled as a functional regulatory network predictive of related TFs. We provide an easy to use webtool using which researchers can upload a newly generated transcriptome and identify key TFs important to their dataset as well as gauge their regulatory effect on phenotypes observed in the experiment. We refer to this network as Seed Active Network (SANe) and made it accessible at https://plantstress-pereira.uark.edu/SANe/. We anticipate SANe will facilitate the discovery of TFs yet unknown for their involvement in seed related metabolic pathways and provide an interface to generate new hypothesis for experimentation.

bioinformatics↗