Biology subjects

O'Connor, J.

Publications and source records attributed to O'Connor, J..

14 recordsLinked to original sources

bioRxiv2025

The impact of western versus agrarian diet consumption on gut microbiome composition and immune dysfunction in people living with HIV in rural and urban Zimbabwe

BackgroundPeople living with HIV (PLWH) suffer from chronic inflammation even with effective antiretroviral therapy (ART). A high-fat, low-fiber western-type diet has been linked with inflammation, in part through gut microbiome changes. In sub-Saharan Africa (SSA), a region with high HIV burden, urbanization has been linked with a shift from traditional agrarian towards westernized diets, and with changes in food security. To explore the relationship between diet, inflammation, and the gut microbiome in PLWH, we enrolled 1) ART Naive PLWH who provided samples before and after 24 weeks of ART, 2) PLWH on ART at both timepoints and 3) HIV-seronegative controls. Individuals were evenly recruited from rural and urban Zimbabwe (locations were 145 kilometers/90 miles apart). Using a food frequency survey designed to measure intake of agrarian versus western-type food items in Zimbabwe, we determined how diet differs with urbanization, HIV-infection and treatment, and is related to inflammation and the gut microbiome. ResultsIndividuals residing in a rural area of Zimbabwe less frequently consumed high-fat, low-fiber western type food items and had lower consumption of diverse food items overall, except for sadza-a subsistence staple-processed from home-grown grains. Consumption of a more western-type diet correlated with lower CD4+ T cell percentage in untreated and treated PLWH and with increased T cell exhaustion in PLWH on ART. PLWH on ART at time of enrollment also consumed diverse food items at a lower frequency and more often were underweight. Low food consumption correlated with muted improvements in T cell exhaustion after 24 weeks of ART. Individuals residing in the rural area had more Prevotella-rich/Bacteroides-poor microbiomes, but this did was not significantly mediated by diet. western diet consumption reduced the diversity of carbohydrate substrate degradation capabilities in the microbiome, based on predictions made using metagenomic polysaccharide utilization loci. ConclusionsTaken together, this work supports that consumption of more high-fat/low-fiber type food items has the potential to exacerbate HIV pathogenesis in a sub-Saharan setting where HIV burden is high and reinforces the importance of nutritional support for promoting immunologic response to ART in PLWH in SSA.

microbiology↗

bioRxiv2024

Quinolinic acid links kidney injury to brain toxicity

Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a novel connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells adjacent to the ventricle in the setting of kidney failure. These findings were associated with brain inflammation and cell death. A separate mouse model of acute kidney injury also had an increase in circulating toxic tryptophan metabolites along with altered brain inflammation. Patients with advanced CKD similarly demonstrated elevated plasma kynurenine metabolites and quinolinic acid was uniquely correlated with fatigue and reduced quality of life in humans. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.

molecular biology↗

bioRxiv2024

inSequio: A Programmable 3D CAD Application for Designing DNA Nanostructures

DNA nanotechnology is evolving rapidly, paralleling the historic trajectory of the 1970s electronics industry. However, current DNA nanostructure (DN) design software limits users to either manual design with minimal automation or a constrained range of automated designs. inS[e]quio Design Studio, developed by Parabon(R) NanoLabs, bridges this gap as a programmable 3D computer-aided design (CAD) application, integrating a domain-specific graphical editor with a Python API for versatile DN design. Developed in C++ for Windows(R) and Macintosh(R) systems, inS[e]quio features a user-friendly GUI with extensive CAD tools, capable of managing complex designs and offloading computational tasks to the cloud. It supports various DNA design formats, PDB molecule integration, residue modifications, and includes preloaded designs and thorough documentation. With its combination of features, inS[e]quio enables a code-centric design (CCD) approach, enhancing DN construction with improved precision, scalability, and efficiency. This approach is elucidated through a streptavidin barrel cage designed via Python notebook and a spheroid origami case study. Marking a significant advance in DN design automation, inS[e]quio, the first fully programmable 3D CAD tool for DN design, enables both manual and programmatic 3D editing. This fusion of features establishes inS[e]quio as a transformative tool, poised to significantly enhance designer productivity and expand the scope of possible designs. Extended AbstractAdvances in DNA nanotechnology have positioned the field at a juncture reminiscent of the pivotal growth phase of the electronics industry in the 1970s. The evolution of software for designing DNA nanostructures (DNs) is following a similar historical trajectory and dozens of software packages have been developed for creating them. Existing software options, however, require users to choose between manual design with minimal automation support or selecting from a limited set of designs, typically wireframe, that can be generated from a high-level structural description. Here, we introduce the inS[e]quio Design Studio, a programmable 3D computer-aided design (CAD) application that effectively bridges this gap. By integrating a domain-specific, freeform graphical editor with a Python application programming interface (API), inS[e]quio provides a comprehensive and extensible platform for designing complex nucleic acid (NA) nanostructures. The inS[e]quio desktop application, developed in C++, runs on Windows(R) and Macintosh(R) operating systems. Its graphical user interface (GUI) features multiple synchronized view panels and a diverse set of CAD and NA-specific editing tools. Its optimized graphics pipeline enables editing of designs with >2M nucleotides, and it includes an integrated service infrastructure for offloading heavy computations to cloud servers. The software also supports import and export of various DNA design file formats, integration of arbitrary PDB molecules, and specification of residue modifications. Additionally, it includes preloaded sample designs, scripts, and comprehensive documentation. Parabon has used evolving versions of inS[e]quio for over a decade to design a variety of proprietary DNs and have now transitioned it into a commercially available product. This paper summarizes inS[e]quios features, discusses its strengths and limitations, and outlines planned enhancements. Although freeform 3D design is well supported in inS[e]quio, the integration of its CAD environment with its API facilitates a code-centric design (CCD) approach for DN construction that offers notable productivity advantages over traditional methods, including enhanced precision, scalability, and efficiency. Here we describe CCD, outline its benefits and demonstrate its use through a well-documented Python notebook, included with the product, which generates a sample design within the inS[e]quio application. A spheroid origami created using CCD is also presented. As the first commercial fully programmable 3D CAD application specifically created for DN design, the release of inS[e]quio represents a milestone in the field of DN design automation. It introduces a new dimension to the discipline by enabling both manual and programmatic 3D editing, thereby facilitating an innovative CCD approach. The availability of extensive documentation and technical support enables designers to efficiently adopt and utilize these capabilities. This combination of features establishes inS[e]quio as a noteworthy addition to the tools available for DN design, with the potential to significantly increase designer productivity and broaden the scope of designs that can be developed by practitioners of all skill levels. Windows and Mac versions of the inS[e]quio desktop application are available for download at https://parabon.com/insequio. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/586810v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@16a2714org.highwire.dtl.DTLVardef@2bc610org.highwire.dtl.DTLVardef@1d852e2org.highwire.dtl.DTLVardef@129b3fa_HPS_FORMAT_FIGEXP M_FIG C_FIG An illustration of the inS[e]quio Design Studio desktop application interoperating with a Python Jupyter notebook and molecular dynamics (MD) simulation tools to support an iterative code-centric design (CCD) process. The design cycle includes (a) programmatic and/or manual creation of objects in the inS[e]quio editors; (b) visual inspection and manipulation of objects via user interface; (c) in silico evaluation of designs via MD simulation using native or external tools; repeating a-c as necessary; and (d) procurement of strands and synthesis of DNA nanostructures (DNs).

bioengineering↗

bioRxiv2024

EXPLANA: A user-friendly workflow for EXPLoratory ANAlysis and feature selection in cross-sectional and longitudinal microbiome studies

MotivationLongitudinal microbiome studies (LMS) are increasingly common but have analytic challenges including non-independent data requiring mixed-effects models and large amounts of data that motivate exploratory analysis to identify factors related to outcome variables. Although change analysis (i.e. calculating deltas between values at different timepoints) can be powerful, how to best conduct these analyses is not always clear. For example, observational LMS measurements show natural fluctuations, so baseline might not be a reference of primary interest; whereas, for interventional LMS, baseline is a key reference point, often indicating the start of treatment. ResultsTo address these challenges, we developed a feature selection workflow for cross-sectional and LMS that supports numerical and categorical data called EXPLANA (EXPLoratory ANAlysis). Machine-learning methods were combined with different types of change calculations and downstream interpretation methods to identify statistically meaningful variables and explain their relationship to outcomes. EXPLANA generates an interactive report that textually and graphically summarizes methods and results. EXPLANA had good performance on simulated data, with an average area under the curve (AUC) of 0.91 (range: 0.79-1.0, SD = 0.05), outperformed an existing tool (AUC: 0.95 vs. 0.56), and identified novel order-dependent categorical feature changes. EXPLANA is broadly applicable and simplifies analytics for identifying features related to outcomes of interest.

bioinformatics↗

bioRxiv2022

Deep neural network automated segmentation of cellular structures in volume electron microscopy

Recent advances in automated segmentation using deep neural network models allow identification of intracellular structures. This study describes a new pipeline to train a convolutional neural network for rapid and efficient detection of structures of wide range in size and complexity. AbstractThree-dimensional electron microscopy is an important imaging modality in contemporary cell biology. Identification of intracellular structures is laborious and time-consuming, however, and impairs effective use of a potentially powerful tool. Resolving this bottleneck is therefore a critical next step in frontier biomedical imaging. We describe Automated Segmentation of intracellular substructures in Electron Microscopy (ASEM), a new pipeline to train a convolutional neural network to detect structures of wide range in size and complexity. We obtain for each structure a dedicated model based on a small number of sparsely annotated ground truth annotations from only one or two cells. To improve model generalization to different imaging conditions, we developed a rapid, computationally effective strategy to refine an already trained model by including a few additional annotations. We show the successful automated identification of mitochondria, Golgi apparatus, endoplasmic reticulum, nuclear pore complexes, caveolae, clathrin coated pits and coated vesicles in cells imaged by focused ion beam scanning electron microscopy with quasi-isotropic resolution. ASEM enabled us to uncover a wide range of membrane-nuclear pore diameters within a single cell and to derive morphological metrics from clathrin coated pits and vesicles at all stages of maturation consistent with the classical constant-growth assembly model.

cell biology↗

bioRxiv2022

Insight into the evolutionary assemblage of cranial kinesis from a Cretaceous bird

The independent movements and flexibility of various parts of the skull, called cranial kinesis, is an evolutionary innovation that is found in living vertebrates only in some squamates and crown birds, and considered to be a major factor underpinning much of the enormous phenotypic and ecological diversity of living birds, the most diverse group of extant amniotes. Compared to the postcranium, our understanding of the evolutionary assemblage of the characteristic modern bird skull has been hampered by sparse fossil records of early cranial materials, with competing hypotheses regarding the evolutionary development of cranial kinesis among early members of the avialans. Here, a detailed three-dimensional reconstruction of the skull of the Early Cretaceous enantiornithine Yuanchuavis kompsosoura allows for its in depth description, including elements that are poorly known among early diverging avialans but are central to deciphering the mosaic assembly of features required for modern avian cranial kinesis. Our reconstruction of the skull shows evolutionary and functional conservation of the temporal and palatal regions by retaining the ancestral theropod dinosaurian configuration within the skull of this otherwise derived and volant bird. Geometric morphometric analysis of the palatine suggests that loss of the jugal process represents the first step in the structural modifications of this element leading to the kinetic crown bird condition. The mixture of plesiomorphic temporal and palatal structures together with a derived avialan rostrum and postcranial skeleton encapsulated in Yuanchuavis manifests the key role of evolutionary mosaicism and experimentation in early bird diversification.

paleontology↗

bioRxiv2022

Increasing computational protein design literacy through cohort-based learning for undergraduate students

Undergraduate research experiences can improve student success in graduate education and STEM careers. During the COVID-19 pandemic, undergraduate researchers at our institution and many others lost their work-study research positions due to interruption of in-person research activities. This imposed a financial burden on the students and eliminated an important learning opportunity. To address these challenges, we created a paid, fully-remote, cohort-based research curriculum in computational protein design. Our curriculum used existing protein design methods as a platform to first educate and train undergraduate students and then to test research hypotheses. In the first phase, students learned computational methods to assess the stability of designed protein assemblies. In the second phase, students used a larger dataset to identify factors that could improve the accuracy of current protein design algorithms. This cohort-based program created valuable new research opportunities for undergraduates at our institute and enhanced the undergraduates feeling of connection with the lab. Students learned transferable and useful skills such as literature review, programming basics, data analysis, hypothesis testing, and scientific communication. Our program provides a model of structured computational research training opportunities for undergraduate researchers in any field for organizations looking to expand educational access. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

scientific communication and education↗

bioRxiv2022

Sinking a giant: quantitative macroevolutionary comparative methods debunk qualitative assumptions

Myhrvold et al.1 suggest that our inference of subaqueous foraging among spinosaurids2 is undermined by selective bone sampling, inadequate statistical procedures, and use of inaccurate ecological categorizations. Myhrvold et al.1 ignore major details of our analyses and results, and instead choose to portray our inferences as if they were based on qualitative interpretations of our plots, without providing additional analyses to support their claims. In this manuscript, we thoroughly discuss all the concerns exposed by Myhrvold et al.1. Additional analyses based on our original datasets2 and novel data presented by Myhrvold et al.1 do not change our original interpretations: while the spinosaurid dinosaurs Spinosaurus and Baryonyx are recovered as subaqueous foragers, Suchomimus is inferred as a non-diving animal.

paleontology↗

bioRxiv2021

Zones of Cellular Damage Around Pulsed-Laser Wounds

After a tissue is wounded, cells surrounding the wound adopt distinct wound-healing behaviors to repair the tissue. Considerable effort has been spent on understanding the signaling pathways that regulate immune and tissue-resident cells as they respond to wounds, but these signals must ultimately originate from the physical damage inflicted by the wound. Tissue wounds comprise several types of cellular damage, and recent work indicates that different types of cellular damage initiate different types of signaling. Hence to understand wound signaling, it is important to identify and localize the types of wound-induced cellular damage. Laser ablation is widely used by researchers to create reproducible, aseptic wounds in a tissue that can be live-imaged. Because laser wounding involves a combination of photochemical, photothermal and photomechanical mechanisms, each with distinct spatial dependencies, cells around a pulsed-laser wound will experience a gradient of damage. Here we exploit this gradient to create a map of wound-induced cellular damage. Using genetically-encoded fluorescent proteins, we monitor damaged cellular and sub-cellular components of epithelial cells in living Drosophila pupae in the seconds to minutes following wounding. We hypothesized that the regions of damage would be predictably arrayed around wounds of varying sizes, and subsequent analysis found that all damage radii are linearly related over a 3-fold range of wound size. Thus, around laser wounds, the distinct regions of damage can be estimated after measuring any one. This report identifies several different types of cellular damage within a wounded epithelial tissue in a living animal. By quantitatively mapping the size and placement of these different types of damage, we set the foundation for tracing wound-induced signaling back to the damage that initiates it.

cell biology↗

bioRxiv2020

A minority of liver-localized CD8 T cells demonstrate difficult-to-detect attraction to Plasmodium-infected hepatocytes

Malaria is a disease caused by Plasmodium parasites, resulting in over 200 million infections and 400,000 deaths every year. A critical step of malaria infection is when sporozoites, injected by mosquitoes, travel to the liver and form liver stages. Malaria vaccine candidates which induce large numbers of malaria-specific CD8 T cells in mice are able to eliminate all liver stages, preventing fulminant malaria. However, how CD8 T cells find all parasites in 48 hours of the liver stage lifespan is not well understood. Using intravital microscopy of murine livers, we generated unique data on T cell search for malaria liver stages within a few hours after infection. To detect attraction of T cells to an infection site, we used the von Mises-Fisher distribution in 3D, similar to the 2D von Mises distribution previously used in ecology. Our results suggest that the vast majority (70-95%) of malaria-specific and non-specific liver-localized CD8 T cells did not display attraction towards the infection site, suggesting that the search for malaria liver stages occurs randomly. However, a small fraction (15-20%) displayed weak but detectable attraction towards parasites which already had been surrounded by several T cells. We found that speeds and turning angles correlated with attraction, suggesting that understanding mechanisms that determine the speed of T cell movement in the liver may improve the efficacy of future T cell-based vaccines. Stochastic simulations suggest that a small movement bias towards the parasite dramatically reduces the number of CD8 T cells needed to eliminate all malaria liver stages, but to detect such attraction by individual cells requires data from long imaging experiments which are not currently feasible. Importantly, as far as we know this is the first demonstration of how activated/memory CD8 T cells might search for the pathogen in nonlymphoid tissues a few hours after infection. We have also established a framework for how attraction of individual T cells towards a location in 3D can be rigorously evaluated.

immunology↗

bioRxiv2020

Environment-imposed constraints make Brownian walkers efficient searchers

Pathogen-specific CD8 T cells face the problem of finding rare cells that present their cognate antigen either in the lymph node or infected tissue. While quantitative details of T cell movement strategies in some tissues such lymph nodes or skin have been relatively well characterized, we still lack quantitative understanding of T cell movement in many other important tissues such as the spleen, lung, liver, and gut. Furthermore, how environmental constraints influence movement patterns of T cells in tissues remains incompletely characterized. Liver is one of the major organs in mice and humans and is the target site for many pathogens such as hepatitis B and C viruses in humans and Plasmodium parasites in multiple mammalian species. We developed a protocol to generate stable numbers of liver-located CD8 T cells, used intravital microscopy to record movement patterns of CD8 T cells in livers of live mice, and analyzed these and previously published data using well-established statistical and computational methods. We show that in most of our experiments Plasmodium-specific liver-localized CD8 T cells perform correlated random walks characterized by transiently superdiffusive displacement with persistence times of 10-15 min that exceed those observed for T cells in lymph nodes. Liver-localized CD8 T cells typically crawl on the lumenal side of liver sinusoids (i.e., are in the blood); simulating T cell movement in digital structures derived from the liver sinusoids illustrates that liver structure alone is sufficient to explain the relatively long superdiffusive displacement of T cells. In experiments when CD8 T cells in the liver poorly attach to the sinusoids (e.g., one week post immunization with radiation-attenuated Plasmodium sporozoites) T cells also undergo Levy flights - large displacements occurring due to cell deattaching from the endothelium, floating with the blood flow, and re-attaching at another location. Our analysis, thus, provides quantitative details of movement patterns of liver-localized CD8 T cells and illustrates how structural and physiological details of the tissue may impact T cell movement patterns.

immunology↗

bioRxiv2020

Reply to Li et al. "Is Oculudentavis a bird or even archosaur?"

We welcome any new interpretation or alternative hypothesis regarding the taxonomic affinity of the enigmatic Oculudentavis khaungraae. However, here we demonstrate that Li et al. have failed to provide conclusive evidence for the reidentification of HPG-15-3 as a squamate. We analyse this specimen in a matrix that includes a broad sample of diapsid reptiles and resolve support for this identification only when no avian taxa are included. Regardless of whether this peculiar skull belongs to a tiny bird or to a bizarre new group of lizards, the holotype of Oculudentavis khaungraae is a very interesting and unusual specimen, the discovery of which represents an important contribution to palaeontology. Its discovery documents a potential new case of convergent evolution in reptiles, while highlighting the importance of amber deposits for documenting taxa not recorded in sedimentary deposits.

paleontology↗

bioRxiv2019

The Biogeography of coelurosaurian theropods and its impact on their evolutionary history

ABSTRACTThe Coelurosauria are a group of mostly feathered theropods that gave rise to birds, the only dinosaurs that survived the Cretaceous-Paleogene extinction event and are still found today. Between their first appearance in the Middle Jurassic up to the end Cretaceous, coelurosaurs were party to dramatic geographic changes on the Earth’s surface, including the breakup of the supercontinent Pangaea, and the formation of the Atlantic Ocean. These plate tectonic events are thought to have caused vicariance or dispersal of coelurosaurian faunas, influencing their evolution. Unfortunately, few coelurosaurian biogeographic hypotheses are supported by quantitative evidence. Here, we report the first, broadly-sampled quantitative analysis of coelurosaurian biogeography using the likelihood-based package BioGeoBEARS. Mesozoic geographic configurations and changes are reconstructed and employed as constraints in this analysis, including their associated uncertainties. We use a comprehensive time-calibrated coelurosaurian evolutionary tree produced from the Theropod Working Group phylogenetic data matrix. Six biogeographic models in the BioGeoBEARS package with different assumptions about the evolution of spatial distribution are tested against the geographic constraints. Our results statistically favour the DIVALIKE+J and DEC+J models, which allow vicariance and founder events, supporting continental vicariance as an important factor in coelurosaurian evolution. Ancestral range estimation indicates frequent dispersal events via the Apulian Route (connecting Europe and Africa during the Early Cretaceous) and the Bering Land Bridge (connecting North America and Asia during the Late Cretaceous). These quantitative results are consistent with commonly inferred Mesozoic dinosaurian dispersals and continental-fragmentation-induced vicariance events. In addition, we recognise the importance of Europe as a dispersal centre and gateway in the Early Cretaceous, as well as other vicariance events like those triggered by the disappearance of land-bridges.View Full Text

paleontology↗

bioRxiv2018

Epigenetic analysis identifies factors driving racial disparity in prostate cancer

Prostate cancer (PCa) is the second most leading cause of death in men worldwide. African American men (AA) represent more aggressive form of PCa as compared to Caucasian (CA) counterparts. Evidence suggests that genetic and other biological factors could account for the observed racial disparity. We analyzed the cancer genome atlas (TCGA) dataset (2015) for existing epigenetic variation in AA and CA prostate cancer patients, and carried out Reduced Representation Bisulphite Sequencing (RRBS) analysis to identify global methylation changes in AA and CA prostate cancer patients. The TCGA dataset analysis revealed that the epigenetic heterogeneity could be categorized into 4 classes, where AA associated primarily to methylation cluster 1 (p value 0.048), and CA associated to methylation cluster 3 (p value 0.000146). We identified enrichment of Wnt signaling genes in both AA and CA, however they were differentially activated in terms of canonical and non-canonical Wnt signaling pathway activation. This was further validated using the GenomeDx expression data. Our RRBS data also suggested distinct methylation patterns in AA compared to CA, and in part validated our TCGA findings. Survival analysis using the RRBS data suggested hypomethylated genes to be significantly associated with recurrence of prostate cancer in CA (p=6.07x10-6) as well as in AA (p=0.0077). Overall, the observed racial disparity in the molecular mechanism involved in the pathogenesis of prostate cancer suggests diverse heterogeneity that potentially could affect survival and should be considered during prognosis and treatment.

cancer biology↗