Biology subjects

Jones, D.

Publications and source records attributed to Jones, D..

8 recordsLinked to original sources

bioRxiv2018

Uncovering a role for the dorsal hippocampal commissure in episodic memory

The dorsal hippocampal commissure (DHC) is a white matter tract that provides inter-hemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted MRI (DW-MRI) and white matter tractography to reconstruct the DHC across both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived Diffusion Tensor MRI (DT-MRI) metrics from the DHC in a large sample of human subjects to investigate whether inter-individual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC was correlated with performance in a standardised episodic memory task; an effect that was not reproduced in a comparison commissure tract - the anterior commissure. These findings highlight a role for the DHC in episodic memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

neuroscience↗

bioRxiv2018

Gene-Specific Predictability of Protein Levels from mRNA Data in Humans

Transcriptomic data are widely available, and the extent to which they are predictive of protein abundances remains debated. Using multiple public databases, we calculate mRNA and mRNA-to-protein ratio variability across human tissues to quantify and classify genes for protein abundance predictability confidence. We propose that such predictability is best understood as a spectrum. A gene-specific, tissue-independent mRNA-to-protein ratio plus mRNA levels explains [~]80% of protein abundance variance for more predictable genes, as compared to [~]55% for less predictable genes. Protein abundance predictability is consistent with independent mRNA and protein data from two disparate cell lines, and mRNA-to-protein ratios estimated from publicly-available databases have predictive power in these independent datasets. Genes with higher predictability are enriched for metabolic function, tissue development/cell differentiation roles, and transmembrane transporter activity. Genes with lower predictability are associated with cell adhesion, motility and organization, the immune system, and the cytoskeleton. Surprisingly, many genes that regulate mRNA-to-protein ratios are constitutively expressed but also exhibit ratio variability, suggesting a general autoregulation mechanism whereby protein expression profile changes can be implemented quickly, or homeostatic sensing stabilizes protein abundances under fluctuating conditions. Gene classifications and their mRNA-to-protein ratios are provided as a resource to facilitate protein abundance predictions by others.

systems biology↗

bioRxiv2018

Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine-resistance in breast cancer

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor- (ER) positive breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer and it is regulated by HIF1 both in-vitro and in-vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ER but it became predominantly a HIF-1-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1 and ER overlap in SNAT2s cis-regulatory elements. In addition, the downregulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia.\n\nOverexpression of SNAT2 in-vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ER inhibition, in hypoxia, or when glutamine levels were low. SNAT2 upregulation in-vivo caused complete resistance to anti-estrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlate with HIF-1 and worse outcome in patients given anti-estrogen therapy. Our findings show a switch in regulation of SNAT2 between ER and HIF-1, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.

cancer biology↗

bioRxiv2018

Precision measurement of cis-regulatory energetics in living cells

Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of \"allelic manifolds\", a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP and {sigma}70 RNA polymerase. Doing so, we consistently obtained energetic measurements precise to ~ 0.1 kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.

biophysics↗

bioRxiv2018

Draft Genome Sequence of the Asian Pear Scab Pathogen, Venturia nashicola

Venturia nashicola, which causes scab disease of Asian pear, is a host-specific, biotrophic fungus, with a sexual stage that occurs during saprobic growth. V. nashicola is endemic to Asia and is regarded as a quarantine threat to Asian pear production outside of this continent. Currently, fungicide applications are routinely used to control scab disease. However, fungicide resistance in V. nashicola, as in other fungal pathogens, is an ongoing challenge and alternative control or prevention measures that include, for example, the deployment of durable host resistance, are required. A close relative of V. nashicola, V. pirina, causes scab disease of European pear. European pear displays non-host resistance (NHR) to V. nashicola and Asian pears are non-hosts of V. pirina. It is anticipated that the host specificity of these two fungi is governed by differences in their effector arsenals, with a subset responsible for activating NHR. The Pyrus-Venturia pathosystems provide a unique opportunity to dissect the underlying genetics of non-host interactions and to understand coevolution in relation to this potentially more durable form of resistance. Here, we present the first V. nashicola draft whole genome sequence (WGS), which is made up of 40,800 scaffolds (totalling 45 Mb) and 11,094 predicted genes. Of these genes, 1,232 are predicted to encode a secreted protein by SignalP, with 273 of these predicted to be effectors by EffectorP. The V. nashicola WGS will enable comparison to the WGSs of other Venturia spp. to identify effectors that potentially activate NHR in the pear scab pathosystems.

genomics↗

bioRxiv2018

Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice

BACKGROUNDCadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Many individuals exposed to dietary Cd are also infected by seasonal influenza virus. The H1N1 strain causes mild to severe pneumonia which can be fatal.\n\nOBJECTIVESTo determine the influence of low-dose Cd exposure on inflammatory responses to H1N1 influenza A virus.\n\nMETHODSWe exposed mice to low-dose (1 mg CdCl2/l) Cd or vehicle (water) for 16 weeks prior to infection with a sub-lethal dose of H1N1. Lung inflammation was assessed by histopathology and flow cytometry. We used a combination of transcriptomics, metabolomics and bioinformatics to determine the molecular associations of inflammatory cells important in Cd-exacerbated responses.\n\nRESULTSCd-treated mice had increased lung tissue inflammatory cells, including neutrophils, monocytes, T lymphocytes and dendritic cells, following H1N1 infection. Lung genetic responses to infection (increasing TNF-a, interferon and complement, and decreasing myogenesis) were also exacerbated. Global correlations with immune cell counts, leading edge gene transcripts and metabolites revealed that Cd increased correlation of myeloid immune cells with pro-inflammatory genes, particularly interferon-{gamma}, and metabolites in amino acid, nucleobase, glycerophospholipid and vitamin B3 pathways.\n\nDISCUSSIONCd burden in mice increased inflammation in response to sub-lethal H1N1 challenge, which was coordinated by genetic and metabolic responses, and could provide new targets for intervention against lethal inflammatory pathology of clinical H1N1 infection.

pharmacology and toxicology↗

bioRxiv2018

Viromic analysis of wastewater input to a river catchment reveals a diverse assemblage of RNA viruses

Detection of viruses in the environment is heavily dependent on PCR-based approaches that require reference sequences for primer design. While this strategy can accurately detect known viruses, it will not find novel genotypes, nor emerging and invasive viral species. In this study, we investigated the use of viromics, i.e. high-throughput sequencing of the biosphere viral fraction, to detect human/animal pathogenic RNA viruses in the Conwy river catchment area in Wales, UK. Using a combination of filtering and nuclease treatment, we extracted the viral fraction from wastewater, estuarine river water and sediment, followed by RNASeq analysis on the Illumina HiSeq platform for the discovery of RNA virus genomes. We found a higher richness of RNA viruses in wastewater samples than in river water and sediment, and assembled a complete norovirus GI.2 genome from wastewater effluent, which was not contemporaneously detected by conventional qRT-PCR. To our knowledge, this is the first environmentally-derived norovirus genome sequence to be available from a public database. The simultaneous presence of diverse rotavirus signatures in wastewater indicated the potential for zoonotic infections in the area and suggested run-off from pig farms as a possible origin of these viruses. Our results show that viromics can be an important tool in the discovery of pathogenic viruses in the environment and can be used to inform and optimize reference-based detection methods provided appropriate and rigorous controls are included.\n\nImportanceEnteric viruses cause gastro-intestinal illness and are commonly transmitted through the faecal-oral route. When wastewater is released into river systems, these viruses can contaminate the environment. Our results show that we can use viromics to find the range of potentially pathogenic viruses that are present in the environment and identify prevalent genotypes. The ultimate goal is to trace the fate of these pathogenic viruses from origin to the point where they are a threat to human health, informing reference-based detection methods and water quality management.

microbiology↗

bioRxiv2017

Treatment-resistant depression and peripheral C-reactive protein

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDysregulation of the peripheral innate immune system has been implicated in the pathophysiology of major depressive disorder (MDD), and may partly account for why many patients do not experience symptomatic improvement. Elevated CRP has been demonstrated in meta-analysis for MDD compared to healthy volunteers, but little is known about whether this is the case for particular clinical phenotypes of the disorder, as opposed to MDD in general.\n\nAdded value of this studyThis study recruited a large cohort of MDD patients, stratified by prior exposure to monoamine reuptake inhibitor treatment. MDD participants were carefully screened for physical comorbidity, and were compared to healthy volunteers matched for age, sex, body mass indices, and cigarette smoking status. Using group-wise comparisons and the innovative statistical approach of partial least squares, we demonstrated that elevated CRP was associated with treatment-resistance, childhood adversity, and specific depressive and anxious symptoms.\n\nImplications of all the available evidenceCRP is significantly increased \"on average\" in MDD patients, However, CRP was most abnormally increased in the subgroup of patients with treatment-resistant depression. High BMI, high scores on vegetative symptoms of depression, low scores on calmness, and a history of childhood adversity, were all predictive of increased CRP. In future, stratification of MDD patients using pro-inflammatory biomarkers, like CRP, may be valuable for sample enrichment and targeted treatment interventions.\n\nAbstractO_ST_ABSBackgroundC_ST_ABSC-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.\n\nMethodsWe recruited 102 treatment-resistant, depressed MDD patients, 48 treatment-responsive, non-depressed MDD patients, 48 depressed but un-medicated patients, and 54 healthy volunteers. High sensitivity CRP in peripheral venous blood, body mass index (BMI), and questionnaire assessments of depression, anxiety, and childhood trauma, were measured. Group differences in CRP were estimated, before and after correction for BMI. Partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.\n\nOutcomesCompared to healthy volunteers, BMI-corrected CRP was significantly elevated in treatment-resistant patients (P = 0.007; Cohens d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two factor solution that accounted for 34.7% of variation in clinical measures, and for 36.0% of variation in CRP. The clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were: vegetative depressive symptoms, BMI, state anxiety, and feeling unloved as a child or wishing for a different childhood.\n\nInterpretationPeripheral CRP was elevated in MDD, especially in treatment-resistant cases. Other phenotypes associated with elevated CRP included childhood adversity, and specific depressive and anxious symptoms. We suggest that MDD patients stratified for pro-inflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.\n\nFundingWellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimers Disease (NIMA) Consortium.

neuroscience↗