Biology subjects

Wilson, R.

Publications and source records attributed to Wilson, R..

At least 73 records · Page 4Linked to original sources

bioRxiv2021

Quantifying the Inhibitory Impact of Soluble Phenolics on Carbon Mineralization from Sphagnum-rich Peatlands

The mechanisms controlling the extraordinarily slow carbon (C) mineralization rates characteristic of Sphagnum-rich peatlands ("bogs") remain somewhat elusive, despite decades of research on this topic. Soluble phenolic compounds have been invoked as potentially significant contributors to bog peat recalcitrance due to their affinity to slow microbial metabolism and cell growth. Despite this potentially significant role, the effects of soluble phenolic compounds on bog peat C mineralization remain unclear. We analyzed this effect by manipulating the concentration of free soluble phenolics in anaerobic bog peat incubations using water-soluble polyvinylpyrrolidone (PVP), a compound that binds with and inactivates phenolics, preventing phenolic-enzyme interactions. CO2 and CH4 production rates (end-products of C mineralization) correlated positively with PVP concentration following Michaelis-Menten (M.M.) saturation functions. Using M.M. parameters, we determined that soluble phenolics inhibit, at minimum, 57 {+/-} 16% of total C (CO2+CH4) mineralization in the anaerobic incubation conditions studied. These findings are consistent with other studies that have indicated that soluble phenolics play a significant role in regulating bog peat stability in the face of decomposition.

ecology↗

bioRxiv2021

Microinductor-Fused Atomic Force Microscopy Cantilevers for Dynamic Imaging and Multimodal Manipulation

Recent advances in atomic force microscopy (AFM) imaging and force spectroscopy have demonstrated improvements in rapid acquisition of quantitative data for applications in materials science, surface characterization, and biology. However, conventional AFM technology is limited in detection sensitivity and the ability to excite at off-resonance frequencies restricting broad utility of the technology. Here we demonstrate new AFM cantilevers fabricated with a planar microcoil at the tip region, which can be used to generate or sense highly-localized magnetic fields. Torsion/bending actuation of the cantilevers is accomplished with simple experimental configurations, enabling quantitative and simultaneous mapping of both stiffness and friction at the sample surface with more than one order of magnitude improvement in compositional contrast. Our method is compatible with commercial AFM systems, allowing us to clearly resolve small stiffness and friction variations in copolymer and biological samples that were difficult to detect by conventional AFM methods. In combination with fluorescence microscopy, we also generated localized fields to selectively stimulate and monitor structural changes in viable cells with nm-scale detail. Hybrid AFM cantilevers may be useful to characterize a broad range of complex material surfaces, in addition to combined physical and chemical analyses of single cells and biological microenvironments.

biophysics↗

bioRxiv2021

Animal lifestyle changes acceptable mass limits for attached tags

O_LIAnimal-attached devices have transformed our understanding of vertebrate ecology. To minimize tag-related harm for these studies, researchers have long advocated that tag masses should not exceed 3% of the animals body mass. However, this proposition ignores tag forces generated as a result of animal movement. C_LIO_LIUsing data from collar-attached accelerometers on diverse free-ranging terrestrial animals, we detail a tag-based acceleration method (TbAM) in which we quantify animal athleticism in terms of fractions of animal movement time devoted to different collar-recorded accelerations. The varying accelerations are converted to forces imposed on the animals based on the acceleration and tag mass and allow derivation of defined force limits, including those amounting to 3% of the animals mass, for specified fractions of any animals active time. C_LIO_LIWe demonstrate how species athleticism is the principal determinant of tag forces, whereas body mass is of little importance. Forces exerted by 3% tags were mostly equivalent to 4-19% of the animals masses during moving, with a maximum of 54% in a hunting cheetah. Cumulative frequency curves of tag acceleration for periods when animals were active, all showed a characteristic sigmoid pattern, which was displaced further to the right as higher acceleration activities accounted for an increasing proportion of any animals time. Specifying that tags should exert forces that are less than 3% of the animals body mass for 95% of the time led to corrected tag masses constituting between 1.6% and 2.98% of our study animals masses, with values depending on animal athleticism. C_LIO_LIRecognition that animal athleticism affects tag forces of their carriers fundamentally changes how acceptable tag mass limits should be determined by ethics bodies. In order to have a scientifically robust acceptable threshold to limit the forces experienced by an animal carrier, we suggest practitioners derive a similar cumulative acceleration profile for their study species and use a minimum of the 95% limits on the plot (although higher limits may be more appropriate). C_LI

zoology↗

bioRxiv2020

Tasmanian devil facial tumour-derived extracellular vesicles reveal mesenchymal transition markers and adhesion molecules related to metastasis.

Tasmanian devils are threatened with extinction by Devil Facial Tumor Disease (DFTD), which consists of two genetically independent transmissible cancers (DFT1 and DFT2). Both cancers typically cause death due to metastases. However, the mechanisms underpinning DFTD metastasis are not well understood. The nano-sized, membrane-enclosed extracellular vesicles (EVs) released by cancer cells have been implicated in metastasis, thus EVs may yield insights into DFTD metastasis. Here, we characterized EVs derived from cultured DFT1, DFT2, and devil fibroblast cells. The proteome of EVs was determined using data independent acquisition mass spectrometry and an in-house spectral library of >1,500 proteins. Relative to EVs from fibroblast cells, EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with cell adhesion and focal adhesion functions. Furthermore, hallmark proteins of epithelial mesenchymal transition, which are associated with increased metastatic features in some cancers, were enriched in DFT2 EVs relative to DFT1 EVs, suggesting differential aggressiveness between the cancers and a target for novel differential diagnosis biomarkers. This first EV-based investigation of DFTD increases our understanding of the cancers EVs and their possible involvement in the metastatic process. As EVs are found in body fluids, these results offer potential for non-invasive biomarkers for DFTD.

cancer biology↗

bioRxiv2020

Path tortuosity changes the transport cost paradigm in terrestrial animals

Animal movement paths are variously tortuous, with high turn rates predicted to be energetically costly, especially at high speeds. Animals travel most efficiently at the speed that gives the lowest cost of transport (COT), a well-defined point for movement in fluid media. However, theoretically, land animals should travel at their maximum speed to minimize COT, which they do not, instead travelling at walking pace. We measured oxygen consumption in humans to demonstrate that the energetic costs of turning increase disproportionately with both speed and angular velocity. This resulted in the minimum COT speed occurring at very low speeds, which reduced with increased path tortuosity. Data on turn rates from six free-ranging terrestrial species underpinned this because all individuals turned faster at the slowest speeds across the full speed range. The optimum movement speed for minimum COT in land animals thus depends on the environment and behavior since both affect track tortuosity.

ecology↗

bioRxiv2020

Time mating guinea pigs by monitoring changes to the vaginal membrane throughout the estrus cycle and with ultrasound confirmation

Guinea pig development in utero is more similar to humans than any other rodent species. As such, their importance to reproductive studies is evident, particularly those studies focused on therapeutic interventions to improve human pregnancy outcome. Tracking the guinea pig estrus cycle is imperative to ensuring appropriately timed mating and can be performed by monitoring the guinea pig vaginal membrane. Here, we describe, and provide picture representation, of changes to the guinea pig vaginal membrane throughout the estrus cycle. Utilization of this monitoring enabled a 100% pregnancy success rate on the first mating attempt in a cohort of five guinea pigs. This approach, along with early pregnancy ultrasounds as a secondary method to confirm pregnancy, offers a cost effective and reliable approach to timed-mating in the guinea pig.

physiology↗

bioRxiv2020

Mapping social reward and punishment processing in the human brain: A voxel-based meta-analysis of neuroimaging findings using the Social Incentive Delay task

Social incentives (rewards or punishments) motivate human learning and behaviour, and alterations in the brain circuits involved in the processing social incentives have been linked with several neuropsychiatric disorders. However, questions still remain about the exact neural substrates implicated in social incentive processing. Here, we conducted four Anisotropic Effect Size Signed Differential Mapping voxel-based meta-analyses of fMRI studies investigating the neural correlates of the anticipation and receipt of social rewards and punishments using the Social Incentive Delay task. We map the regions involved in each of these four processes in the human brain, identify decreases in the BOLD signal during the anticipation of both social reward and punishment avoidance that were missed in individual studies due to a lack of power, and characterise the effect size and direction of changes in the BOLD signal for each brain area. Our results provide a better understanding of the brain circuitry involved in social incentive processing and can inform hypotheses about potentially disrupted brain areas linked with dysfunctional social incentive processing during disease. HighlightsO_LIVoxel-based meta-analysis of the neural underpinnings of social incentive processing C_LIO_LIWe map the brain regions involved in the processing of social incentives in humans C_LIO_LIWe identify new regions missed in individual studies as a result of lack of power C_LIO_LIOur work can inform research on pathological brain processing of social incentives C_LI

neuroscience↗

bioRxiv2020

Stretched-Exponential Modeling of Anomalous T1{rho} and T2 Relaxation in the Intervertebral Disc In Vivo

PurposeIntervertebral disc degeneration (IVDD), resulting in the depletion of hydrophilic glycosaminoglycans (GAGs) located in the nucleus pulposus (NP), can lead to debilitating neck and back pain. Magnetic Resonance Imaging (MRI) is a promising means of IVD assessment due to the sensitivity of MRI tissue relaxation properties to matrix composition. Furthermore, anomalous (i.e. non-monoexponential) relaxation models have shown higher sensitivity to specific matrix components compared to conventional monoexponential models. Here, we extend the use of the stretched exponential model, an anomalous relaxation model, to IVD relaxometry data. Theory and MethodsT1{rho} and T2 relaxation data were measured in the cervical IVDs of healthy volunteers and IVDs adjacent to cervical fusion, and analyzed using both conventional and stretched-exponential (SE) models. Model differences were evaluated via goodness of fit in the healthy data. Normalized histograms of the resultant quantitative MRI (qMRI) maps were described using stable distributions, and data were compared across adjacent disc segments. ResultsIn the healthy IVDs, we found lower mean squared error in the SE relaxation model fitting behavior compared to monoexponential models, supporting anomalous relaxation behavior in healthy IVDs. SE model parameter T1{rho} increased level-wise in the caudal direction, especially in the nucleus pulposus, while conventional T1{rho} and T2 monoexponential measures did not vary. For IVDs adjacent to cervical fusion, SE parameters deviated near the fusion site compared with those in the healthy population. ConclusionSE modeling of T1{rho} relaxation provides greater sensitivity to level-wise variation in IVD matrix properties compared with conventional relaxation modeling, and could provide improved sensitivity to early stages of IVD degeneration. The improved model fit and correlation between the SE T1{rho} parameter with IVD level suggests SE modeling may be a more sensitive method for detection of GAG content variation.

biophysics↗

bioRxiv2019

Automatic Detection of Synaptic Partners in a Whole-Brain Drosophila EM Dataset

The study of neural circuits requires the reconstruction of neurons and the identification of synaptic connections between them. To scale the reconstruction to the size of whole-brain datasets, semi-automatic methods are needed to solve those tasks. Here, we present an automatic method for synaptic partner identification in insect brains, which uses convolutional neural networks to identify post-synaptic sites and their pre-synaptic partners. The networks can be trained from human generated point annotations alone and require only simple post-processing to obtain final predictions. We used our method to extract 244 million putative synaptic partners in the fifty-teravoxel full adult fly brain (FAFB) electron microscopy (EM) dataset and evaluated its accuracy on 146,643 synapses from 702 neurons with a total cable length of 312 mm in four different brain regions. The predicted synaptic connections can be used together with a neuron segmentation to infer a connectivity graph with high accuracy: between 92% and 96% of edges linking connected neurons are correctly classified as weakly connected (less than five synapses) and strongly connected (at least five synapses). Our synaptic partner predictions for the FAFB dataset are publicly available, together with a query library allowing automatic retrieval of up- and downstream neurons.

neuroscience↗

bioRxiv2019

A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter

Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n=2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n=7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p=1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 153 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. In summary, our data supports a functional role of rs76735376 in the regulation of LPA expression.

genetics↗

bioRxiv2019

A heme-binding protein produced by Haemophilus haemolyticus inhibits non-typeable Haemophilus influenzae

Many commensal bacteria and opportunistic pathogens scavenge heme from their environment. Pathogens and host are engaged in an arms race to control access to heme, but similar conflicts between bacterial species that might regulate pathogen colonisation are largely unknown. We show here that a commensal bacterium, Haemophilus haemolyticus, makes hemophilin, a heme-binding protein that not only allows the bacterium to effectively scavenge heme for its own growth, but also inhibits co-culture of the opportunistic pathogen, non-typeable Haemophilus influenzae (NTHi), by heme starvation. Knockout of the hemophilin gene abrogates the ability of H. haemolyticus to inhibit NTHi and an x-ray crystal structure shows that hemophilin has a previously unreported heme-binding structure. The bound heme molecule is deeply buried and the heme iron atom is coordinated through a single histidine side chain. Biochemical characterization shows that this arrangement allows heme to be captured in the ferrous or ferric state, and with small ferrous or ferric heme-ligands bound, suggesting hemophilin could function over in a wide range of physiological conditions. Our data raise the possibility that competition for heme between commensal and pathogenic bacteria can influence bacterial colonisation, and therefore disease likelihood, and suggest that strains of H. haemolyticus that overproduce hemophilin might have therapeutic uses in reducing colonisation and subsequent opportunistic infection by NTHi.

biochemistry↗

bioRxiv2018

Alcohol consumption is associated with widespread changes in blood DNA methylation: analysis of cross-sectional and longitudinal data

BackgroundDNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart.\n\nMethodsUsing the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined using baseline peripheral blood samples from 5,606 adult Melbourne Collaborative Cohort Study (MCCS) participants. For a subset of 1,088 of them, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. Independent data from the LOLIPOP (N=4,042) and KORA (N=1,662) cohorts were used to replicate associations discovered in the MCCS.\n\nResultsCross-sectional analyses identified 1,414 CpGs associated with alcohol intake at P<10-7, 1,243 of which had not been reported previously. Of these 1,243 novel associations, 1,078 were replicated (P<0.05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated (P<0.05) 403 of 518 associations that had been reported previously. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1,414 CpGs, 530 were differentially methylated (P<0.05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1,414 cross-sectional associations.\n\nConclusionOur study indicates that, for middle-aged and older adults, alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with changes in alcohol consumption.

epidemiology↗

bioRxiv2018

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

Changes in gene expression are key for the cells to adapt and response to intrinsic and extrinsic stimulus. It has been shown that genotoxic stress induces global hypomethylation as a result of decreased expression of DNA methyl transferases (DNMT). We hypothesized that DNA damage suppresses long non-coding RNA expression in the vasculature via DNA methylation leading to more robust DNA repair/survival or cellular senescence/death cell fate decisions. We show here that ionizing radiation reduces the expression of DNMTs in the vascular endothelium and this leads to increased expression of the anti-apoptotic lncRNA MEG9. MEG9 is a lncRNA from the DLK1-DIO3 ncRNA cluster. Loss-of-function studies using RNA gapmers indicate that MEG9 protects endothelial cells from DNA damage induced cell death. Consistent with this phenotype, knockdown of MEG9 decreases growth factor dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Mechanistically, we observed that MEG9 knockdown decreased the expression of cell survival genes including survivin and induced the expression of pro-apoptotic genes such as Bad/Bax. Taken together, our findings illustrate how DNA methylation at selective lncRNA loci can regulate their expression and drive endothelial cell fate decisions.

cell biology↗

bioRxiv2018

Two spatially distinct posterior alpha sources fulfill different functional roles in attention

Directing attention helps to extract relevant information and suppress distracters. Alpha brain oscillations (8-12Hz) play a fundamental role in this process, with a power decrease facilitating processing of important information and power increase inhibiting brain regions processing irrelevant information. Evidence for this phenomenon arises from visual attention studies (Worden et al., 2000), however, the effect also exists in other modalities, including the somatosensory system (Haegens et al., 2011) and inter-sensory attention tasks (Foxe and Snyder, 2011). We investigated what happens when attention is divided between two modalities using both a multi- and unimodal attention paradigm while recording EEG over 128 scalp electrodes in two separate experiments. In Experiment 1 participants divided their attention between the visual and somatosensory modality to determine the temporal or spatial frequency of a target stimulus (vibrotactile stimulus or Gabor grating). In Experiment 2, participants divided attention between two visual hemifields to identify the orientation of a target Gabor grating. In both experiments, pre-stimulus alpha power in visual areas decreased linearly with increasing attention to visual stimuli. In contrast, alpha power in parietal areas showed lower pre-stimulus alpha power when attention was divided between modalities, compared to unimodal attention. These results suggest that there are two different alpha sources, where one reflects the visual spotlight of attention and the other reflects attentional effort. To our knowledge, this is the first study to show that attention recruits two spatially distinct alpha sources in occipital and parietal brain regions, which act simultaneously but serve different functions in attention.\n\nSIGNIFICANCE STATEMENTAttention to one spatial location/sensory modality leads to power changes of alpha oscillations (~10Hz) with decreased power over regions processing relevant information and power increases to actively inhibit areas processing to-be-ignored information. Here, we used detailed source modelling to investigate EEG data recorded during separate uni-modal (visual) and multi- (visual and somatosensory) attention tasks. Participants either focused their attention on one modality/spatial location or directed it to both. We show for the first time two distinct alpha sources are active simultaneously but play different roles. A sensory (visual) alpha source was linearly modulated by attention representing the visual spotlight of attention. In contrast, a parietal alpha source was modulated by attentional effort, showing lowest alpha power when attention was divided.

neuroscience↗

bioRxiv2018

MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.

cancer biology↗

bioRxiv2018

Modelling genotypes in their physical microenvironment to predict single- and multi-cellular behaviour

A cells phenotype is the set of observable characteristics resulting from the interaction of the genotype with the surrounding environment, determining cell behaviour. Deciphering genotype-phenotype relationships has been crucial to understand normal and disease biology. Analysis of molecular pathways has provided an invaluable tool to such understanding; however, it does typically not consider the physical microenvironment, which is a key determinant of phenotype.\n\nIn this study, we present a novel modelling framework that enables to study the link between genotype, signalling networks and cell behaviour in a 3D microenvironment. To achieve this we bring together Agent Based Modelling, a powerful computational modelling technique, and gene networks. This combination allows biological hypotheses to be tested in a controlled stepwise fashion, and it lends itself naturally to model a heterogeneous population of cells acting and evolving in a dynamic microenvironment, which is needed to predict the evolution of complex multi-cellular dynamics. Importantly, this enables modelling co-occurring intrinsic perturbations, such as mutations, and extrinsic perturbations, such as nutrients availability, and their interactions.\n\nUsing cancer as a model system, we illustrate the how this framework delivers a unique opportunity to identify determinants of single-cell behaviour, while uncovering emerging properties of multi-cellular growth.\n\nAvailability and ImplementationFreely available on the web at http://www.microc.org. Research Resource Identification Initiative ID (https://scicrunch.org/): SCR 016672

bioinformatics↗

bioRxiv2017

Blazing Signature Filter: a library for fast pairwise similarity comparisons

Identifying similarities between datasets is a fundamental task in data mining and has become an integral part of modern scientific investigation. Whether the task is to identify co-expressed genes in large-scale expression surveys or to predict combinations of gene knockouts which would elicit a similar phenotype, the underlying computational task is often a multi-dimensional similarity test. As datasets continue to grow, improvements to the efficiency, sensitivity or specificity of such computation will have broad impacts as it allows scientists to more completely explore the wealth of scientific data. A significant practical drawback of large-scale data mining is that the vast majority of pairwise comparisons are unlikely to be relevant, meaning that they do not share a signature of interest. It is therefore essential to efficiently identify these unproductive comparisons as rapidly as possible and exclude them from more time-intensive similarity calculations. The Blazing Signature Filter (BSF) is a highly efficient pairwise similarity algorithm which enables extensive data mining within a reasonable amount of time. The algorithm transforms datasets into binary metrics, allowing it to utilize the computationally efficient bit operators and provide a coarse measure of similarity. As a result, the BSF can scale to high dimensionality and rapidly filter unproductive pairwise comparison. Two bioinformatics applications of the tool are presented to demonstrate the ability to scale to billions of pairwise comparisons and the usefulness of this approach.

bioinformatics↗

bioRxiv2017

MicroRNA perturbation of the MRN complex buffers DNA damage response from VEGF signaling

MicroRNAs contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, gain and loss of function experiments show that miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sprouting in vitro and in vivo. Genetic and pharmacological disruption of VEGFR-2 signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Mechanistically, disruption of the MRN complex induced CD44, a known driver of senescence and regulator of VEGF signaling in addition to suppressing IL-13 a stimulator of VEGF signaling. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.

cancer biology↗