Biology subjects

Davis, E.

Publications and source records attributed to Davis, E..

26 records · Page 2Linked to original sources

bioRxiv2022

A multi-pronged human microglia response to Alzheimer's disease Aβ pathology

Microglial activation and neuroinflammation are initial steps in the pathogenesis of Alzheimers disease (AD). However, studies in mouse models and human postmortem samples have yielded divergent results regarding microglia cell states relevant to AD. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for early AD. While human microglia adopt a disease-associated (DAM) profile, they display a much more pronounced HLA-cell state related to antigen presentation in response to amyloid plaques. In parallel, a distinctive pro-inflammatory cytokine and chemokine CRM response is mounted against oligomeric amyloid-{beta}. TREM2 and, to a lesser extent, APOE polymorphisms, modulate the response of microglia to amyloid-{beta} plaques, in contrast with the response to oligomeric A{beta}. Specific polygenic risk genes are enriched in each branch of these multi-pronged response of human microglia to amyloid pathology (ARM). ARM responses can be captured in post-mortem studies when reanalyzed in light of this novel, comprehensive data set. In conclusion, therapeutic strategies targeting microglia in AD need to carefully assess how they affect the different cell states, as the overall balance between distinct microglial profiles might determine a protective or damaging outcome.

neuroscience↗

bioRxiv2022

Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent integrated stress response in C9orf72 FTD/ALS

GGGGCC (G4C2) hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C4G2) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9orf72 (C4G2) antisense repeat expanded RNAs trigger the activation of the PKR/eIF2-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG initiated translation, leading to global translation inhibition and stress granule formation. Increased phosphorylation of PKR/eIF2 is also observed in the frontal cortex of C9orf72 FTD/ALS patients. Finally, only antisense (C4G2), but not sense (G4C2), repeat expanded RNAs can activate the PKR/eIF2 pathway. These results provide a mechanism by which antisense repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9orf72 repeat expansions.

neuroscience↗

bioRxiv2021

A community-developed extension to Darwin Core for reporting the chronometric age of specimens

Darwin Core, the data standard used for sharing modern biodiversity and paleodiversity occurrence records, has previously lacked proper mechanisms for reporting what is known about the estimated age range of specimens from deep time. This has led to data providers putting these data in fields where they cannot easily be found by users, which impedes the reuse and improvement of these data by other researchers. Here we describe the development of the Chronometric Age Extension to Darwin Core, a ratified, community-developed extension that enables the reporting of ages of specimens from deeper time and the evidence supporting these estimates. The extension standardizes reporting about the methods or assays used to determine an age and other critical information like uncertainty. It gives data providers flexibility about the level of detail reported, focusing on the minimum information needed for reuse while still allowing for significant detail if providers have it. Providing a standardized format for reporting these data will make them easier to find and search and enable researchers to pinpoint specimens of interest for data improvement or accumulate more data for broad temporal studies. The Chronometric Age Extension was also the first community-managed vocabulary to undergo the new Biodiversity Informatics Standards (TDWG) review and ratification process, thus providing a blueprint for future Darwin Core extension development.

paleontology↗

bioRxiv2020

Concurrent assessment of gait kinematics using marker-based and markerless motion capture

Kinematic analysis is a useful and widespread tool used in research and clinical biomechanics for the estimation of human pose and the quantification of human movement. Common marker-based optical motion capture systems are expensive, time intensive, and require highly trained operators to obtain kinematic data. Markerless motion capture systems offer an alternative method for the measurement of kinematic data with several practical benefits. This work compared the kinematics of human gait measured using a deep learning algorithm-based markerless motion capture system to those of a common marker-based motion capture system. Thirty healthy adult participants walked on a treadmill while data were simultaneously recorded using eight video cameras (markerless) and seven infrared optical motion capture cameras (marker-based). Video data were processed using markerless motion capture software, marker-based data were processed using marker-based capture software, and both sets of data were compared. The average root mean square distance (RMSD) between corresponding joints was less than 2.5 cm for all joints except the hip, which was 3.6 cm. Lower limb segment angles indicated pose estimates from both systems were very similar, with RMSD of less than 5.5{degrees} for all segment angles except those that represent rotations about the long axis of the segment. Lower limb joint angles captured similar patterns for flexion/extension at all joints, ab/adduction at the knee and hip, and toe-in/toe-out at the ankle. These findings demonstrate markerless motion capture can measure similar 3D kinematics to those from marker-based systems.

bioengineering↗

bioRxiv2019

Tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

A disintegrin and metalloprotease 10 (ADAM10) is essential for embryonic development and impacts on diseases such as cancer, Alzheimers and inflammatory diseases. ADAM10 is a molecular scissor that proteolytically cleaves the extracellular region from over 100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors and chemokines. ADAM10 was recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function is critically dependent on a TspanC8 partner. To address this, we generated the first monoclonal antibodies to Tspan15 as a model TspanC8. These were used to show that ADAM10 is the principal Tspan15-interacting protein, that Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Together these findings suggest that ADAM10 exists as an intimate ADAM10/TspanC8 scissor complex.

cell biology↗

bioRxiv2019

CoralP: Flexible visualization of the human phosphatome

Protein phosphatases and kinases play critical roles in a host of biological processes and diseases via the removal and addition of phosphoryl groups. While kinases have been extensively studied for decades, recent findings regarding the specificity and activities of phosphatases have generated an increased interest in targeting phosphatases for pharmaceutical development. This increased focus has created a need for methods to visualize this important class of proteins within the context of the entire phosphatase protein family. Here, we present CoralP, an interactive web application for the generation of customizable, publication-quality representations of human phosphatome data. Phosphatase attributes can be encoded through edge colors, node colors, and node sizes. CoralP is the first and currently the only tool designed for phosphatome visualization and should be of great use to the signaling community. The source code and web application are available at https://github.com/PhanstielLab/coralp and http://phanstiel-lab.med.unc.edu/coralp respectively.

bioinformatics↗

bioRxiv2018

A metapopulation model for the 2018 Ebola outbreak in Equateur province in the Democratic Republic of the Congo

Ebola virus disease (EVD) is a viral haemorrhagic fever with high mortality that has caused a number of severe outbreaks in Central and West Africa. Although the majority previous outbreaks have been relatively small, the result of managing outbreaks places huge strains on already limited resources. Mathematical models matched to early case reporting data can be used to identify outbreaks that are at high risk of spreading. Here we consider the EVD outbreak in Equateur Province in the Democratic Republic of the Congo, which was declared on 8 May 2018. We use a simple stochastic metapopulation model to capture the dynamics in the three affected health zones: Bikoro, Iboko and Wangata. We are able to rapidly simulate a large number of realisations and use approximate Bayesian computation, a likelihood-free method, to determine parameters by matching between reported and simulated cases. This method has a number of advantages over more traditional likelihood-based methods as it is less sensitive to errors in the data and is a natural extension to the prediction framework. Using data from 8 to 25 May 2018 we are able to capture the exponential increases in the number of cases in three locations (Bikoro, Iboko and Wangata), although our estimated basic reproductive ratio is higher than for previous outbreaks. Using additional data until 08 July 2018 we are able to detect a decrease in transmission such that the reproductive ratio falls below one. We also estimate the probability of transmission to Kinshasa. We believe this method of fitting models to data offers a generic approach that can deliver rapid results in real time during a range of future outbreaks.

epidemiology↗

bioRxiv2018

Comprehensive analysis of retinal development at single cell resolution identifies NFI factors as essential for mitotic exit and specification of late-born cells.

Precise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the extensive cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single cell RNA-sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each of the major retinal cell types. These data identify transitions in gene expression between early and late-stage retinal progenitors, as well as a classification of neurogenic progenitors. We identify here the NFI family of transcription factors (Nfia, Nfib, and Nfix) as genes with enriched expression within late RPCs, and show they are regulators of bipolar interneuron and Muller glia specification and the control of proliferative quiescence.

developmental biology↗