Biology subjects

Roy, M.

Publications and source records attributed to Roy, M..

45 records · Page 3Linked to original sources

bioRxiv2019

Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity

Using single-cell transcriptional profiling we mapped the immune system of the naked mole-rat (Heterocephalus glaber), a small but long-lived and cancer-resistant subterranean rodent. Both splenic and circulating immune cells were examined in healthy young animals and following an infection-mimicking lipopolysaccharide challenge. Our study revealed that the naked mole-rat immune system is characterized by a high myeloid to lymphoid cell ratio that includes a novel, lipopolysaccharide responsive, granulocyte cell subset not found in the mouse. Conversely, we find that naked mole-rats do not have a cell subset that corresponds to natural killer cells as defined in other well-characterized mammalian species. Supporting this finding, we show that the naked mole-rat genome has not expanded any of the gene families encoding diverse natural killer cell receptors, which are the genomic hallmarks of species in which natural killer cells have been described. These unusual features suggest an atypical mode of immunosurveillance and a greater reliance on myeloid-biased innate immunity.

immunology↗

bioRxiv2019

Studying ecosystems with DNA metabarcoding: lessons from aquatic biomonitoring

An ongoing challenge for ecological studies has been the collection of data with high precision and accuracy at a sufficient scale to detect effects relevant to management of critical global change processes. A major hurdle for many workflows has been the time-consuming and challenging process of sorting and identification of organisms, but the rapid development of DNA metabarcoding as a biodiversity observation tool provides a potential solution. As high-throughput sequencing becomes more rapid and cost-effective, a big data revolution is anticipated, based on higher and more accurate taxonomic resolution, more efficient detection, and greater sample processing capacity. These advances have the potential to amplify the power of ecological studies to detect change and diagnose its cause, through a methodology termed Biomonitoring 2.0.\n\nDespite its promise, the unfamiliar terminology and pace of development in high-throughput sequencing technologies has contributed to a growing concern that an unproven technology is supplanting tried and tested approaches, lowering trust among potential users, and reducing uptake by ecologists and environmental management practitioners. While it is reasonable to exercise caution, we argue that any criticism of new methods must also acknowledge the shortcomings and lower capacity of current observation methods. Broader understanding of the statistical properties of metabarcoding data will help ecologists to design, test and review evidence for new hypotheses.\n\nWe highlight the uncertainties and challenges underlying DNA metabarcoding and traditional methods for compositional analysis, focusing on issues of taxonomic resolution, sample similarity, taxon misidentification, sample contamination, and taxon abundance. Using the example of freshwater benthic ecosystems, one of the most widely-applied non-microbial applications of DNA metabarcoding to date, we explore the ability of this new technology to improve the quality and utility of ecological data, recognising that the issues raised have widespread applicability across all ecosystem types.

ecology↗

bioRxiv2019

Free water in white matter differentiates MCI and AD from control subjects

Recent evidence show that neuroinflammation plays a role in many neurological diseases including mild cognitive impairment (MCI) and Alzheimers disease (AD), and that free water (FW) modeling from clinically acquired diffusion MRI (DTI-like acquisitions) can be sensitive to this phenomenon. This FW index measures the fraction of the diffusion signal explained by isotropically unconstrained water, as estimated from a bi-tensor model. In this study, we developed a simple FW processing pipeline that uses a safe white matter (WM) mask without gray matter (GM)/CSF partial volume contamination (WMsafe) near ventricles and sulci. We investigated if FW inside the WMsafe mask, including and excluding areas of white matter damage such as white matter hyperintensities (WMHs) as shown on T2 FLAIR, computed across the whole white matter could be indicative of diagnostic grouping along the AD continuum. After careful quality control, 81 cognitively normal controls (NC), 103 subjects with MCI and 42 with AD were selected from the ADNIGO and ADNI2 databases. We show that MCI and AD have significantly higher FW measures even after removing all partial volume contamination. We also show, for the first time, that when WMHs are removed from the masks, the significant results are maintained, which demonstrates that the FW measures are not just a byproduct of WMHs. Our new and simple FW measures can be used to increase our understanding of the role of inflammation-associated edema in AD and may aid in the differentiation of healthy subjects from MCI and AD patients.

neuroscience↗

bioRxiv2019

Nod2 protects remote small intestinal sites in case of colonic inflammation.

NOD2 mutations are key risk factors for Crohns disease (CD). NOD2 contributes to intestinal homeostasis by regulating innate and adaptive immunity together with intestinal epithelial function. However, the roles of NOD2 during gut inflammation is not known. We initially observed that NOD2 expression was increased in epithelial cells remote from inflamed areas in CD patients. To explore this finding, Nod2 mRNA expression, inflammation and gut permeability were examined in the small bowel of wild-type (WT), Nod2 knockout and Nod2 mutant mice after rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). In WT mice, Nod2 upregulation remote to rectal injury was associated with pro-inflammatory cytokine expression, recirculating CD4+ T-cells, increased paracellular permeability and myosin like chain kinase activity. Nod2 knockout or mutation led to duodenitis and ileitis demonstrating the remote protective role of Nod2. Bone morrow stem cell (BMSC) transplantations indicated that the small intestinal inflammation was due to NOD2 loss in both hematopoietic and non-hematopoietic compartments. As a whole, WT but not mutant NOD2 prevents disease extension at sites remote from the initial intestinal injury.

immunology↗

bioRxiv2018

Metabolic reprogramming dynamics in tumor spheroids: Insights from a multicellular, multiscale model

Mathematical modeling provides the predictive ability to understand the metabolic reprogramming and complex pathways that mediate cancer cells proliferation. We present a mathematical model using a multiscale, multicellular approach to simulate avascular tumor growth, applied to pancreatic cancer. The model spans three distinct spatial and temporal scales. At the extracellular level, reaction diffusion equations describe nutrient concentrations over a span of seconds. At the cellular level, a lattice-based energy driven stochastic approach describes cellular phenomena including adhesion, proliferation, viability and cell state transitions, occurring on the timescale of hours. At the sub-cellular level, we incorporate a detailed kinetic model of intracellular metabolite dynamics on the timescale of minutes, which enables the cells to uptake and excrete metabolites and use the metabolites to generate energy and building blocks for cell growth. This is a particularly novel aspect of the model. Certain defined criteria for the concentrations of intracellular metabolites lead to cancer cell growth, proliferation and necrosis. Overall, we model the evolution of the tumor in both time and space. Starting with a cluster of tumor cells, the model produces an avascular tumor that quantitatively and qualitatively mimics experimental measurements of multicellular tumor spheroids. Through our model simulations, we can investigate the response of individual intracellular species under a metabolic perturbation and investigate how that response contributes to the response of the tumor as a whole. The predicted response of intracellular metabolites under various targeted strategies are difficult to resolve with experimental techniques. Thus, the model can give novel predictions as to the response of the tumor as a whole, identifies potential therapies to impede tumor growth, and predicts the effects of those therapeutic strategies. In particular, the model provides quantitative insight into the dynamic reprogramming of tumor cells at the intracellular level in response to specific metabolic perturbations. Overall, the model is a useful framework to study targeted metabolic strategies for inhibiting tumor growth.

systems biology↗

bioRxiv2018

Bundle-specific fornix reconstruction for dual-tracer PET-tractometry

Tractography is known to have problems reconstructing white matter bundles that are narrow, have high curvature, or go through partial volume voxels contaminated by CSF or gray matter. One such bundle is the fornix, the major output tract of the hippocampus, which is especially problematic with aging. Hippocampal atrophy and ventricular expansion make the fornix even harder (often impossible) to track with current state-of-the-art techniques. In this work, a bundle-specific tractography algorithm is proposed to fully reconstruct the fornix. By injecting shape, position, and orientation priors, fornix reconstruction is markedly is improved. We report an increase in spatial coverage and better reproducibility across test-retest. These improvements over classical tractography algorithms also enable tractometry of the fornix to be combined with dual-tracer positron emission tomography (PET) data in participants with mild cognitive impairment (MCI). MCI participants underwent a multi-modal brain imaging before and after a 6-month daily ketogenic supplement. We report, for the first time, significant diffusion measures and 18F-fluorodeoxyglucose (FDG) uptake differences in specific sub-sections of the fornix after the ketogenic supplement.

neuroscience↗

bioRxiv2018

Regional diversity in the postsynaptic proteome of the mouse brain

The proteome of the postsynaptic terminal of excitatory synapses comprises over one thousand proteins in vertebrate species and plays a central role in behavior and brain disease. The brain is organized into anatomically distinct regions and whether the synapse proteome differs across these regions is poorly understood. Postsynaptic proteomes were isolated from seven forebrain and hindbrain regions in mice and their composition determined using proteomic mass spectrometry. Seventy-four percent of proteins showed differential expression and each region displayed a unique compositional signature. These signatures correlated with the anatomical divisions of the brain and their embryological origins. Biochemical pathways controlling plasticity and disease, protein interaction networks and individual proteins involved with cognition all showed differential regional expression. Combining proteomic and connectomic data shows that interconnected regions have specific proteome signatures. Diversity in synapse proteome composition is key feature of mouse and human brain structure.

neuroscience↗

bioRxiv2018

Pins & Needles: Towards Limb Disownership in Augmented Reality

The seemingly stable construct of our bodily self depends on the continued, successful integration of multisensory feedback about our body, rather than its purely physical composition. Accordingly, pathological disruption of such neural processing is linked to striking alterations of the bodily self, ranging from limb misidentification to disownership, and even the desire to amputate a healthy limb. While previous embodiment research has relied on experimental setups using supernumerary limbs in variants of the Rubber Hand Illusion, we here used Augmented Reality to directly manipulate the feeling of ownership for ones own, biological limb. Using a Head-Mounted Display, participants received visual feedback about their own arm, from an embodied first-person perspective. In a series of three studies, in independent cohorts, we altered embodiment by providing visuotactile feedback that could be synchronous (control condition) or asynchronous (400ms delay, Real Hand Illusion). During the illusion, participants reported a significant decrease in ownership of their own limb, along with a lowered sense of agency. Supporting the right-parietal body network, we found an increased illusion strength for the left upper limb as well as a modulation of the feeling of ownership during anodal transcranial direct current stimulation. Extending previous research, these findings demonstrate that a controlled, visuotactile conflict about ones own limb can be used to directly and systematically modulate ownership - without a proxy. This not only corroborates the malleability of body representation but questions its permanence. These findings warrant further exploration of combined VR and neuromodulation therapies for disorders of the bodily self.

neuroscience↗

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↗