Biology subjects

Jones, A.

Publications and source records attributed to Jones, A..

At least 109 records · Page 6Linked to original sources

bioRxiv2020

Septins disruption controls tumor growth and enhances efficacy of Herceptin

Septin expressions are altered in cancer cells and exhibit poor prognoses in malignancies. As the first approach to develop a septin filament targeting agent, we optimized the structure of Forchlorfenuron (FCF), a known plant cytokinin to generate UR214-9, which contrary to FCF, causes septin-2/9 filamental structural catastrophe in cancer cells without altering cellular septin protein levels. In-silico docking using septin-2/septin-2 dimer complex showed that UR214-9 displaced the guanine carbonyl oxygen from the GDP binding domain and showed increased binding energy than FCF(-8.59vs-7.21). UR214-9 reduced cancer cell growth, downregulated HER2/STAT-3 axis and controlled growth of HER2+ pancreatic, breast and ovarian cancer xenografts in NSG mice and enhanced response of Herceptin against HER2+breast cancer xenograft. Transcriptome analysis of UR214-9 exposed cells demonstrated significant perturbation of <20 genes compared to afatinib which impacted >1200 genes in JIMT-1 breast cancer cells indicating target specificity and non-transcriptional functions of UR214-9. In summary, disrupting septins via UR214-9 is a new approach to control the growth of HER2+ malignancies.

cancer biology↗

bioRxiv2019

Multiplexed single-cell profiling of post-perturbation transcriptional responses to define cancer vulnerabilities and therapeutic mechanism of action

Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate or the expression of a marker gene. Information-rich assays, such as gene-expression profiling, are generally not amenable to efficient profiling of a given perturbation across multiple cellular contexts. Here, we developed MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines, and combine it with Cell Hashing to further multiplex additional experimental conditions, such as multiple post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and can be used to predict long-term cell viability from short-term transcriptional responses to treatment.

cancer biology↗

bioRxiv2019

Systematic profiling of full-length immunoglobulin and T-cell receptor repertoire diversity in rhesus macaque through long read transcriptome sequencing

The diversity of immunoglobulin (Ig) and T-cell receptor (TCR) repertoires is a focal point of immunological studies. Rhesus macaques are key for modeling human immune responses, placing critical importance on the accurate annotation and quantification of their Ig and TCR repertoires. However, due to incomplete reference resources, the coverage and accuracy of the traditional targeted amplification strategies for profiling rhesus Ig and TCR repertoires are largely unknown. Here, using long read sequencing, we sequenced four Indian-origin rhesus macaque tissues and obtained high quality, full-length sequences for over 6,000 unique Ig and TCR transcripts, without the need for sequence assembly. We constructed the first complete reference set for the constant regions of all known isotypes and chain types of rhesus Ig and TCR repertoires. We show that sequence diversity exists across the entire variable regions of rhesus Ig and TCR transcripts. Consequently, existing strategies using targeted amplification of rearranged variable regions comprised of V(D)J gene segments miss a significant fraction (27% to 53% and 42% to 49%) of rhesus Ig/TCR diversity. To overcome these limitations, we designed new rhesus-specific assays that remove the need for primers conventionally targeting variable regions and allow single cell-level Ig and TCR repertoire analysis. Our improved approach will enable future studies to fully capture rhesus Ig and TCR repertoire diversity and is applicable for improving annotations in any model organism.

immunology↗

bioRxiv2019

Novel mechanisms for phosphate acquisition in abundant rhizosphere-dwelling Bacteroidetes

Global food production is reliant on the application of finite phosphorus (P) fertilisers. Numerous negative consequences associated with intensive P fertilisation have resulted in a high demand to find alternative sustainable methods that will enhance crop P uptake. Bacteroidetes, primarily from the genus Flavobacterium, have recently been shown to be abundant members of the plant microbiome, but their general ecological role and potential to mobilise P in the rhizosphere remains very poorly characterised. Here, we sought to determine the P mobilisation potential of Flavobacterium strains isolated from the rhizosphere of oilseed rape (Brassica napus L.). We show that these Flavobacterium strains possess novel mechanisms for P mobilisation and subsequent acquisition. These include the constitutive and inducible expression of completely novel and phylogenetically distinct phosphatases, the phosphate starvation inducible expression of uncharacterised and hypothetical genes and gene clusters and, for the first time, the involvement of outer membrane SusCD transport complexes (usually associated with carbohydrate transport) in P acquisition. The genes encoding these unusual phosphate starvation inducible proteins were enriched in plant-associated Flavobacterium strains suggesting that this machinery represents niche-adaptive strategies for overcoming P scarcity in this genus. We propose that abundant rhizosphere-dwelling Flavobacterium spp. have evolved unique mechanisms for coping with Pi-stress which may provide novel solutions for future sustainable agricultural practices.

microbiology↗

bioRxiv2019

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins play an essential role in the adaptive immune response for the presentation of self and non-self peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug induced agranulocytosis (severe lower white blood cell count) in patients with B*27:05, B*38:02 and DRB1*08:03 alleles in different populations: Taiwanese, Vietnamese, Han Chinese and Caucasian.\n\nIn this study, informatics methods were used to investigate if any sequence or structural similarities exist between the two associated HLA-B alleles, compared with a set of \"control\" alleles assumed not be associated, which could help explain the molecular basis of the adverse drug reaction. We demonstrated using MHC Motif Viewer and MHCcluster that the two alleles do not have a propensity to bind similar peptides, and thus at a gross level the structure of the antigen presentation region of the two alleles are not similar. We also performed multiple sequence alignment to identify polymorphisms shared by the risk but not by the control alleles and molecular docking to compare the predicted binding positions of the drug-allele combinations.\n\nTwo residues, Cys67 and Thr80, were identified from the multiple sequence alignments to be unique to these risk alleles alone. The molecular docking showed the poses of the risk alleles to favour the F-pocket of the peptide binding groove, close to the Thr80 residue, with the control alleles generally favouring a different pocket. The data are thus suggestive that Thr80 may be a critical residue in HLA-mediated anti-thyroid drug induced agranulocytosis, and thus can guide future research and risk assessment.

bioinformatics↗

bioRxiv2019

Determinants of anemia among pregnant women in northern Ghana

Anemia is a global public health issue affecting half of all pregnant women in developing countries. In 2014, 42% of Ghanaian pregnant women aged 15-49 years were anemic (<11.0g/dl) but information on the determinants of anemia, particularly dietary diversity during the critical third trimester of pregnancy is limited. We assessed the association between determinants and anemia among pregnant women in northern Ghana.\n\nWe employed a cross-sectional design involving 624 pregnant women ([≥]20 weeks of gestation) attending four antenatal care (ANC) health facilities ~25 kilometres north of Tamale, Ghana between July and August 2017. Hemoglobin concentration (measured using Hemocue HB 301) was classified as severe, moderate, or mild. Other data included socio-demographic characteristics, malaria prevention, deworming, and iron/folate tablet use. The FAO Minimum Dietary Diversity (MDD-W) metric was used to categorize women into \"inadequate\" (MDD-W <5 food groups) and \"adequate\" (MDD-W [≥]5). Logistic regression models were used to determine the association between moderate/severe anemia (Hb<9.0g/dl) and mild anemia (9.0-10.9g/dl), or with no anemia ([≥]11.0g/dl) using STATA 14 software.\n\nOf 624 women sampled, hemoglobin data were available for 601. The mean age was 27.81{+/-}0.25 years, gestational age was 31.93{+/-}0.13 weeks, ANC attendance was 3.89{+/-}0.07; Hb concentration was 9.73g/dl{+/-}0.07, and MDD-W index for ten food groups was 5.33{+/-}0.04. Anemia (Hb<11.0g/dl) was observed in 74.8% of women (moderate/severe anemia=33.4% and mild anemia=41.4%). Using adjusted logistic regression, women who received deworming medication had lesser odds of being moderate/severe anemic (aOR=0.51, P=0.021). While women who were engaged in other occupation (herdsmen) and no previous parity had higher odds of being moderate/severe anemic (aOR=2.90, P=0.042) and (aOR=2.13, P=0.004) respectively. Moderate/severe anemia was not statistically associated with MDD-W, nor with socioeconomic status/wealth index. Conclusion, anemia in pregnancy was nearly twice that of Ghana as a whole. Deworming medication was found to be protective intervention for anemia during pregnancy.

scientific communication and education↗

bioRxiv2019

Biased Signaling: Distinct Ligand-directed Plasma Membrane Signalsomes Using a Common RGS/G Protein Core

Biased signaling occurs when different ligands that are directed at the same receptor launch different cellular outcomes. Because of their pharmacological importance, we know the most about biased ligands and little is known about other mechanisms to achieve signaling bias. In the canonical animal G protein system, endocytosis of a 7-transmembrane GPCR is mediated by arrestins to propagate or arrest cytoplasmic signaling depending on the bias. In Arabidopsis, GPCRs are not required for G protein coupled signaling because the heterotrimeric G protein complex spontaneously exchanges nucleotide. Instead, the prototype 7-transmembrane Regulator of G Signaling 1 protein AtRGS1 modulates G signaling and through ligand-dependent endocytosis, de-repression of signaling is initiated but canonical arrestins are not involved. Endocytosis initiates from two separate pools of plasma membrane: sterol-dependent domains, possibly lipid rafts, and a clathrin-accessible neighborhood, each with a select set of discriminators, activators, and newly-discovered arrestin-like adaptors. Different trafficking origins and trajectories lead to different cellular outcomes. Thus, compartmentation with its attendant signalosome architecture is a previously unknown mechanism to drive biased signaling.

plant biology↗

bioRxiv2019

FAIRshake: toolkit to evaluate the findability, accessibility, interoperability, and reusability of research digital resources

As more datasets, tools, workflows, APIs, and other digital resources are produced by the research community, it is becoming increasingly difficult to harmonize and organize these efforts for maximal synergistic integrated utilization. The Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles have prompted many stakeholders to consider strategies for tackling this challenge by making these digital resources follow common standards and best practices so that they can become more integrated and organized. Faced with the question of how to make digital resources more FAIR, it has become imperative to measure what it means to be FAIR. The diversity of resources, communities, and stakeholders have different goals and use cases and this makes assessment of FAIRness particularly challenging. To begin resolving this challenge, the FAIRshake toolkit was developed to enable the establishment of community-driven FAIR metrics and rubrics paired with manual, semi- and fully-automated FAIR assessment capabilities. The FAIRshake toolkit contains a database that lists registered digital resources, with their associated metrics, rubrics, and assessments. The FAIRshake toolkit also has a browser extension and a bookmarklet that enables viewing and submitting assessments from any website. The FAIR assessment results are visualized as an insignia that can be viewed on the FAIRshake website, or embedded within hosting websites. Using FAIRshake, a variety of bioinformatics tools, datasets listed on dbGaP, APIs registered in SmartAPI, workflows in Dockstore, and other biomedical digital resources were manually and automatically assessed for FAIRness. In each case, the assessments revealed room for improvement, which prompted enhancements that significantly upgraded FAIRness scores of several digital resources.

bioinformatics↗

bioRxiv2019

Atg8a interacts with transcription factor Sequoia to control the expression of autophagy genes in Drosophila

Autophagy is a fundamental, evolutionarily conserved, process in which cytoplasmic material is degraded through the lysosomal pathway [1-7]. One of the most important and well-studied autophagy-related proteins is LC3 [Microtubule-associated protein 1 light chain 3, (called Atg8 in yeast and Drosophila)], which participates in autophagosome formation and autophagy cargo selection in the cytoplasm, and is one of the most widely utilized markers of autophagy [8, 9]. Despite growing evidence that LC3 is enriched in the nucleus, little is known about the mechanisms involved in targeting LC3 to the nucleus and the nuclear components it interacts with [10-13]. Here we show that Drosophila Atg8a protein, homologous to mammalian LC3 and yeast Atg8, interacts with the transcription factor Sequoia in a LIR-motif dependent manner. We show that Sequoia depletion induces autophagy in nutrient rich conditions through enhanced expression of autophagy genes. We also show that Atg8a interacts with YL-1, a component of a nuclear acetyltransferase complex, and is acetylated at position K46. Additionally, we show that Atg8a interacts with the deacetylase Sir2, which deacetylates Atg8a during starvation in order to activate autophagy. Our results suggest a mechanism of regulation of expression of autophagy genes by Atg8a, which is linked to its acetylation status and its interaction with Sequoia, YL-1 and Sir2.

cell biology↗

bioRxiv2019

Landscape drivers of genomic diversity and divergence in woodland Eucalyptus

Spatial genetic patterns are influenced by numerous factors, and they can vary even among coexisting, closely related species due to differences in dispersal and selection. Eucalyptus (LHeritier 1789; the \"eucalypts\") are foundation tree species that provide essential habitat and modulate ecosystem services throughout Australia. Here we present a study of landscape genomic variation in two woodland eucalypt species, using whole genome sequencing of 388 individuals of Eucalyptus albens and Eucalyptus sideroxylon. We found exceptionally high genetic diversity ({pi} {approx} 0.05) and low genome-wide, inter-specific differentiation (FST = 0.15). We found no support for strong, discrete population structure, but found substantial support for isolation by geographic distance (IBD) in both species. Using generalised dissimilarity modelling, we identified additional isolation by environment (IBE). Eucalyptus albens showed moderate IBD, and environmental variables have a small but significant amount of additional predictive power (i.e., IBE). Eucalyptus sideroxylon showed much stronger IBD, and moderate IBE. These results highlight the vast adaptive potential of these species, and set the stage for testing evolutionary hypotheses of interspecific adaptive differentiation across environments.

evolutionary biology↗

bioRxiv2018

Mapping the human kinome in response to DNA damage

We provide a catalog for the effects of the human kinome on cell survival in response to DNA damaging agents, selected to cover all major DNA repair pathways. By treating 313 kinase-deficient cell lines with ten diverse DNA damaging agents, including seven commonly used chemotherapeutics, we were able to identify kinase specific vulnerabilities and resistances. In order to identify novel synthetic lethal interactions, we investigate the cellular response to carmustine for 25 cell lines, by establishing a phenotypic FACS assay designed to mechanistically investigate and validate gene-drug interactions. We show apoptosis, cell cycle, DNA damage and proliferation after alkylation or crosslink-induced damage for selected cell lines and rescue the cellular sensitivity of DYRK4, EPHB6, MARK3, PNCK as a proof of principle for our study. Our data suggest that some cancers with inactivated DYRK4, EPHB6, MARK3 or PNCK gene could be particularly vulnerable to treatment by alkylating chemotherapeutic agents carmustine or temozolomide.

systems biology↗

bioRxiv2018

EREFinder: Genome-wide detection of estrogen response elements

MotivationEstrogen response elements (EREs) are specific DNA sequences to which ligand-bound estrogen receptors (ERs) physically bind, allowing them to act as transcription factors for target genes. Locating EREs and ER responsive regions is therefore a potentially important component of the study of estrogen-regulated pathways.\n\nResultsWe tested and demonstrated the ability of EREFinder, a novel algorithm we developed, to locate regions of ER-binding across the human genome and show that these regions designated by the program occur more frequently near estrogen responsive genes. EREFinder can handle large input files, has settings to allow for broad and narrow searches, and provides the full output to allow for greater data manipulation. These features facilitate a wide range of hypothesis testing for researchers and make EREFinder an excellent tool to aid in estrogen-related research.\n\nAvailability and ImplementationSource code and binaries freely available for download at https://github.com/JonesLabIdaho/EREfinder, implemented in C++ and supported on Linux and MS Windows.\n\nContactaanderson@bio.tamu.edu\n\nSupplemental MaterialsR scripts can be found at https://github.com/JonesLabIdaho/EREfinder

bioinformatics↗

bioRxiv2018

DNAscan: a fast, computationally and memory efficient bioinformatics pipeline for the analysis of DNA next-generation-sequencing data

The generation of DNA Next Generation Sequencing (NGS) data is a commonly applied approach for studying the genetic basis of biological processes, including diseases, and underpins the aspirations of precision medicine. However, there are significant challenges when dealing with NGS data. A huge number of bioinformatics tools exist and it is therefore challenging to design an analysis pipeline; NGS analysis is computationally intensive, requiring expensive infrastructure which can be problematic given that many medical and research centres do not have adequate high performance computing facilities and the use of cloud computing facilities is not always possible due to privacy and ownership issues. We have therefore developed a fast and efficient bioinformatics pipeline that allows for the analysis of DNA sequencing data, while requiring little computational effort and memory usage. We achieved this by exploiting state-of-the-art bioinformatics tools. DNAscan can analyse raw, 40x whole genome NGS data in 8 hours, using as little as 8 threads and 16 Gbs of RAM, while guaranteeing a high performance. DNAscan can look for SNVs, small indels, SVs, repeat expansions and viral genetic material (or any other organism). Its results are annotated using a customisable variety of databases including ClinVar, Exac and dbSNP, and a local deployment of the gene.iobio platform is available for an on-the-fly result visualisation.

bioinformatics↗

bioRxiv2018

Active Function Learning

How do people actively explore to learn about functional relationships, that is, how continuous inputs map onto continuous outputs? We introduce a novel paradigm to investigate information search in continuous, multi-feature function learning scenarios. Participants either actively selected or passively observed information to learn about an underlying linear function. We develop and compare different variants of rule-based (linear regression) and non-parametric (Gaussian process regression) active learning approaches to model participants active learning behavior. Our results show that participants performance is best described by a rule-based model that attempts to efficiently learn linear functions with a focus on high and uncertain outcomes. These results advance our understanding of how people actively search for information to learn about functional relations in the environment.

animal behavior and cognition↗

bioRxiv2017

Comparative Qualitative Phosphoproteomics Analysis Identifies Shared Phosphorylation Motifs and Associated Biological Processes in Flowering Plants

Phosphorylation is regarded as one of the most prevalent post-translational modifications and plays a key role in regulating cellular processes. In this work we carried out a comparative bioinformatics analysis of phosphoproteomics data, to profile two model species representing the largest subclasses in flowering plants the dicot Arabidopsis thaliana and the monocot Oryza sativa, to understand the extent to which phosphorylation signaling and function is conserved across evolutionary divergent plants. Using pre-existing mass spectrometry phosphoproteomics datasets and bioinformatic tools and resources, we identified 6,537 phosphopeptides from 3,189 phosphoproteins in Arabidopsis and 2,307 phosphopeptides from 1,613 phosphoproteins in rice. The relative abundance ratio of serine, threonine, and tyrosine phosphorylation sites in rice and Arabidopsis were highly similar: 88.3: 11.4: 0.4 and 86.7: 12.8: 0.5, respectively. Tyrosine phosphorylation shows features different from serine and threonine phosphorylation and was found to be more frequent in doubly-phosphorylated peptides in Arabidopsis. We identified phosphorylation sequence motifs in the two species to explore the similarities, finding nineteen pS motifs and two pT motifs that are shared in rice and Arabidopsis; among them are five novel motifs that have not previously been described in both species. The majority of shared motif-containing proteins were mapped to the same biological processes with similar patterns of fold enrichment, indicating high functional conservation. We also identified shared patterns of crosstalk between phosphoserines with motifs pSXpS, pSXXpS and pSXXXpS, where X is any amino acid, in both species indicating this is an evolutionary conserved signaling mechanism in flowering plants. However, our results are suggestive that there is greater co-occurrence of crosstalk between phosphorylation sites in Arabidopsis, and we were able to identify several pairs of motifs that are statistically significantly enriched to co-occur in Arabidopsis proteins, but not in rice.

bioinformatics↗

bioRxiv2017

Temporal dissociation of salience and prediction error responses to appetitive and aversive taste

The feedback-related negativity, a frontocentral event-related potential (ERP) occurring 200350 milliseconds (ms) after emotionally-valued outcomes, has been posited as the neural correlate of reward prediction error, a key component of associative learning. Recent evidence challenged this interpretation and has led to the suggestion that this ERP expresses salience, instead. Here we distinguish between utility prediction error and salience by delivering or withholding hedonistically matched appetitive and aversive tastes, and measure ERPs to cues signalling each taste. We observed a typical FRN (computed as the loss-minus-gain difference wave) to appetitive taste, but a reverse-FRN to aversive taste. When tested axiomatically, frontocentral ERPs showed a salience response across tastes, with a particularly early response to outcome delivery, supporting recent propositions of a fast, unsigned and unspecific response to salient stimuli. ERPs also expressed aversive prediction error peaking at 285ms, which conformed to the logic of an axiomatic model of prediction error. With stimuli that most resemble those used in animal models we did not detect any frontocentral ERP signal for utility prediction error, in contrast with dominant views of the functional role of the feedback-related negativity ERP. We link the animal and human literature and present a challenge for current perspectives on associative learning research using ERPs.

neuroscience↗

bioRxiv2017

Surgically disconnected temporal pole exhibits resting functional connectivity with remote brain regions

Functional connectivity, as measured by resting-state fMRI, has proven a powerful method for studying brain systems in the context of behavior, development, and disease states. However, the relationship of functional connectivity to structural connectivity remains unclear. If functional connectivity relies on structural connectivity, then anatomical isolation of a brain region should eliminate functional connectivity with other brain regions. We tested this by measuring functional connectivity of the surgically disconnected temporal pole in resection patients (N=5; mean age 37; 2F, 3M). Functional connectivity was evaluated based on coactivation of whole-brain fMRI data with the average low-frequency BOLD signal from disconnected tissue in each patient. In sharp contrast to our prediction, we observed significant functional connectivity between the disconnected temporal pole and remote brain regions in each disconnection case. These findings raise important questions about the neural bases of functional connectivity measures derived from the fMRI BOLD signal.

neuroscience↗

bioRxiv2017

Population Genomics And The Evolution Of Virulence In The Fungal Pathogen Cryptococcus neoformans

Cryptococcus neoformans is an opportunistic fungal pathogen that causes approximately 625,000 deaths per year from nervous system infections. Here, we leveraged a unique, genetically diverse population of C. neoformans from sub-Saharan Africa, commonly isolated from mopane trees, to determine how selective pressures in the environment coincidentally adapted C. neoformans for human virulence. Genome sequencing and phylogenetic analysis of 387 isolates, representing the global VNI and African VNB lineages, highlighted a deep, non-recombining split in VNB (herein VNBI and VNBII). VNBII was enriched for clinical samples relative to VNBI, while phenotypic profiling of 183 isolates demonstrated that VNBI isolates were significantly more resistant to oxidative stress and more heavily melanized than VNBII isolates. Lack of melanization in both lineages was associated with loss-of-function mutations in the BZP4 transcription factor. A genome-wide association study across all VNB isolates revealed sequence differences between clinical and environmental isolates in virulence factors and stress response genes. Inositol transporters and catabolism genes, which process sugars present in plants and the human nervous system, were identified as targets of selection in all three lineages. Further phylogenetic and population genomic analyses revealed extensive loss of genetic diversity in VNBI, suggestive of a history of population bottlenecks, along with unique evolutionary trajectories for mating type loci. These data highlight the complex evolutionary interplay between adaptation to natural environments and opportunistic infections, and that selection on specific pathways may predispose isolates to human virulence.

genomics↗