Biology subjects

O'Donnell, M.

Publications and source records attributed to O'Donnell, M..

9 recordsLinked to original sources

bioRxiv2026

DINOCT: robust skin surface localization for robotic noncontact dynamic optical coherence elastography

Noncontact dynamic optical coherence elastography (OCE) can measure the elastic properties of anterior soft tissues. However, applying OCE to skin requires tracking mechanical waves propagating in multiple directions to reconstruct mechanical anisotropy. Robotic scanning is well suited to this task but requires accurate probe positioning, alignment to the surface normal, and precise, repeatable rotation. To ensure phase and polarization stability, polarization-maintaining (PM) fibers can be used, although they introduce stripe and ghost artifacts that can destabilize surface detection. We present DINOCT, a DINO-based method to localize the skin surface from optical coherence tomography (OCT) images that combines self-supervised pretraining with DINO (self-DIstillation with NO labels) and iBOT (image BERT pre-training with Online Tokenizer) objectives, low-rank adaptation, and a lightweight curve decoder. Compared with classical and supervised learning baselines, DINOCT achieved competitive localization accuracy on clean test data with a near-zero spike rate. Among the learned methods, DINOCT achieved the lowest average and maximum values of mean absolute error (MAE) for severe synthetic stress conditions and the lowest catastrophic failure rates on a separate recording with strong PM-fiber artifacts.

bioengineering↗

bioRxiv2024

Heparan sulfate modified proteins affect cellular processes central to neurodegeneration and modulate presenilin function

Mutations in presenilin-1 (PSEN1) are the most common cause of familial, early-onset Alzheimers disease (AD), typically producing cognitive deficits in the fourth decade. A variant of APOE, APOE3 Christchurch (APOE3ch), was found associated with protection from both cognitive decline and Tau accumulation in a 70-year-old bearing the disease-causing PSEN1-E280A mutation. The amino acid change in ApoE3ch is within the heparan sulfate (HS) binding domain of APOE, and purified APOEch showed dramatically reduced affinity for heparin, a highly sulfated form of HS. The physiological significance of ApoE3ch is supported by studies of a mouse bearing a knock-in of this human variant and its effects on microglia reactivity and A{beta}-induced Tau deposition. The studies reported here examine the function of heparan sulfate-modified proteoglycans (HSPGs) in cellular and molecular pathways affecting AD-related cell pathology in human cell lines and mouse astrocytes. The mechanisms of HSPG influences on presenilin-dependent cell loss and pathology were evaluated in Drosophila using knockdown of the presenilin homolog, Psn, together with partial loss of function of sulfateless (sfl), a homolog of NDST1, a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in cultured human cell lines, Drosophila, and mouse astrocytes. RNAi of Ndst1 reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of APOE, APOE3, and APOE4. RNA-sequence analysis of human cells deficient in HS synthesis demonstrated effects on the transcriptome governing lipid metabolism, autophagy, and mitochondrial biogenesis and showed significant enrichment in AD susceptibility genes identified by GWAS. Neuron-directed knockdown of Psn in Drosophila produced cell loss in the brain and behavioral phenotypes, both suppressed by simultaneous reductions in sfl mRNA levels. Abnormalities in mitochondria, liposome morphology, and autophagosome-derived structures in animals with Psn knockdown were also rescued by simultaneous reduction of sfl. sfl knockdown reversed Psn-dependent transcript changes in genes affecting lipid transport, metabolism, and monocarboxylate carriers. These findings support the direct involvement of HSPGs in AD pathogenesis.

neuroscience↗

bioRxiv2023

Using Environmental DNA to Reconstruct Amphibian Communities at Sites Infected with Batrachochytrium salamandrivorans in the Netherlands

AO_SCPLOWBSTRACTC_SCPLOWThe recently discovered Batrachochytrium salamandrivorans (Bsal) fungus can cause high mortality rates in some European salamanders and newts (urodelans) and has the potential to expand its currently small invasive range in Europe. Therefore, monitoring its distribution and better understanding both the species threatened and the mechanics of infection are essential in mitigating the damage Bsal may cause. Environmental DNA (eDNA) has emerged as a promising non-invasive method for detecting both this fungal pathogen and the amphibian communities in infected areas. We applied these methods in the province Gelderland, the Netherlands where the pathogen has previously been detected and is expanding its range, with the goal of detecting the natural amphibian community present. We sampled 27 water bodies in the region surrounding the known outbreak sites. We used data from a Bsal-specific qPCR assay to determine its presence-absence and applied an eDNA metabarcoding approach to characterize the amphibian communities using two different primer sets. The 12S vertebrate primer set outperformed the 16S amphibian primer set and detected all the expected amphibians in the study area: Bufo bufo, Lissotriton vulgaris, Pelobates fuscus, Pelophylax spp., Rana temporaria and Triturus cristatus. Bsal was detected at eight of the ponds. A distance-based redundancy analysis found a weak but significant relationship between Bsal presence and the composition of amphibian communities using eDNA. This study provides the foundation for future studies on Bsal and its relationship with amphibian communities in Europe, highlighting the need for further research into the mechanisms of persistence and transmission between water bodies.

ecology↗

bioRxiv2020

A Unique Renal Architecture in Tribolium castaneum Informs the Evolutionary Origins of Systemic Osmoregulation in Beetles

Maintaining internal salt and water balance in response to fluctuating external conditions is essential for animal survival. This is particularly true for insects as their high surface-to-volume ratio makes them highly susceptible to osmotic stress. However, the cellular and hormonal mechanisms that mediate the systemic control of osmotic homeostasis in beetles (Coleoptera), the largest group of insects, remain largely unidentified. Here, we demonstrate that eight neurons in the brain of the red flour beetle Tribolium castaneum respond to internal changes in osmolality by releasing diuretic hormone (DH) 37 and DH47 - homologues of vertebrate corticotropinreleasing factor (CRF) hormones - to control systemic water balance. Knockdown of the gene encoding the two hormones (Urinate, Urn8) reduces renal secretion and restricts organismal fluid loss, whereas injection of DH37 or DH47 reverses these phenotypes. We further identify a novel CRF-like receptor, Urinate Receptor (Urn8R), which is exclusively expressed in a unique secondary cell (SC) in the beetle renal organs, as underlying this response. Activation of Urn8R increases K+ secretion specifically through SCs, creating a lumen-positive transepithelial potential that drives fluid secretion. Together, these data show that beetle renal organs operate by fundamentally different mechanism than those of other insects. Finally, we adopt a fluorescent labelling strategy to identify the evolutionary origin of this unusual renal architecture within the large Order of Coleoptera. Our work thus uncovers an important homeostatic program that is key to maintaining osmotic control in beetles, which evolved in parallel to the radiation of the higher beetle families. Significance StatementBeetles are the most diverse animal group on the planet. Their evolutionary success suggests unique physiological adaptations in overcoming water stress, yet the mechanisms underlying this ability are unknown. Here we use molecular genetic, electrophysiology and behavioral studies to show that a group of brain neurons responds to osmotic disturbances by releasing diuretic hormones that regulate salt and water balance. These hormones bind to their receptor exclusively localized to a unique secondary cell in the renal organs to modulate fluid secretion and organismal water loss. This renal architecture, common to all higher beetle families, is novel within the insects, and provides an important clue to the evolutionary success of the beetles in colonizing an astounding range of habitats on Earth.

physiology↗

bioRxiv2020

Canine cognitive dysfunction (CCD) patients have reduced total hippocampal volumes compared with aging control dogs: a comparative MRI study

Hippocampal atrophy is a key pathologic and MRI feature of human Alzheimers disease (AD). Hippocampal atrophy has not been documented via MRI in canine cognitive dysfunction (CCD), which is considered the dog model of human AD. The purpose of this retrospective comparative volumetric MRI study was to compare total hippocampal volumes between successfully aging (control) dogs and dogs diagnosed with CCD. Mimics(R) software was used to derive total hippocampal volumes and total brain volumes from the MRI studies of 42 aging dogs ([≥] 9 years): 16 dogs diagnosed with CCD and 26 successfully aging controls. Total hippocampal volume normalized to total brain volume was significantly less for CCD patients compared with control dogs (p=0.04). The results of this study suggest that-similar to human AD-hippocampal atrophy is a pathological feature of CCD. This finding has potential importance for both investigating disease mechanisms related to dementia as well as future hippocampal-targeted therapies.

neuroscience↗

bioRxiv2019

Real-time spectroscopic photoacoustic/ultrasound (PAUS) scanning with simultaneous fluence compensation and motion correction for quantitative molecular imaging

For over two decades photoacoustic (PA) imaging has been tested clinically, but successful human trials have been minimal. To enable quantitative clinical spectroscopy, the fundamental issues of wavelength-dependent fluence variations and inter-wavelength motion must be overcome. Here we propose a new real-time, spectroscopic photoacoustic/ultrasound (PAUS) imaging approach using a compact, 1-kHz rate wavelength-tunable laser. Instead of illuminating tissue over a large area, the fiber-optic delivery system surrounding an US array sequentially scans a narrow laser beam, with partial PA image reconstruction for each laser pulse. The final image is then formed by coherently summing partial images at a 50-Hz video rate. This scheme enables (i) automatic laser-fluence compensation in spectroscopic PA imaging and (ii) inter-wavelength motion correction using US speckle tracking, which have never been shown before in real-time systems. The 50-Hz video rate PAUS system is demonstrated in vivo using a murine model of drug delivery monitoring.

bioengineering↗

bioRxiv2019

DNA unwinding mechanism of a eukaryotic replicative CMG helicase

High-resolution structures have not been reported for replicative helicases at a replication fork at atomic resolution, a prerequisite to understand the unwinding mechanism. The eukaryotic replicative CMG helicase contains a Mcm2-7 motor ring, with the N-tier ring in front and the C-tier motor ring behind. The N-tier ring is structurally divided into a zinc finger (ZF) sub-ring followed by the OB fold ring. Here we report the cryo-EM structure of CMG on forked DNA at 3.9 [A], revealing that parental DNA enters the ZF sub-ring and strand separation occurs at the bottom of the ZF sub-ring, where the lagging strand is blocked and diverted sideways by OB hairpin-loops of Mcm3, Mcm4, Mcm6, and Mcm7. Thus, instead of employing a separation pin, unwinding is achieved via a \"dam-and-diversion tunnel\" for steric exclusion unwinding. The C-tier motor ring contains spirally configured PS1 and H2I loops of Mcms 2, 3, 5, 6 that translocate on the spirally-configured leading strand, and thereby pull the preceding DNA segment through the diversion tunnel for strand separation.

biochemistry↗

bioRxiv2018

Nuclease dead Cas9 is a programmable roadblock for DNA replication

DNA replication occurs on chromosomal DNA while processes such as DNA repair, recombination and transcription continue. However, we have limited experimental tools to study the consequences of collisions between DNA-bound molecular machines. Here, we repurpose a catalytically inactivated Cas9 (dCas9) construct fused to the photo-stable dL5 protein fluoromodule as a novel, targetable protein-DNA roadblock for studying replication fork arrest at the single-molecule level in vitro as well as in vivo. We find that the specifically bound dCas9-guideRNA complex arrests viral, bacterial and eukaryotic replication forks in vitro.

biochemistry↗

bioRxiv2017

Rictor/TORC2 mediates gut-to-brain signaling in the regulation of phenotypic plasticity in C. elegans

Animals integrate external cues with information about internal conditions such as metabolic state to execute the appropriate behavioral and developmental decisions. Information about food quality and quantity is assessed by the intestine and transmitted to modulate neuronal functions via mechanisms that are not fully understood. The conserved Target of Rapamycin complex 2 (TORC2) controls multiple processes in response to cellular stressors and growth factors. Here we show that TORC2 coordinates larval development and adult behaviors in response to environmental cues and feeding state in the bacterivorous nematode C. elegans. During development, pheromone, bacterial food, and temperature regulate expression of the daf-7 TGF-{beta} and daf-28 insulin-like peptide in sensory neurons to promote a binary decision between reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which together reflect bacterial-diet dependent feeding status, thus providing a mechanism for integration of food signals with external cues in the regulation of neuroendocrine gene expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated foraging behaviors via the PDFR-1 neuropeptide receptor. We also demonstrate that genetic variation affects food-dependent larval and adult phenotypes, and identify quantitative trait loci (QTL) associated with these traits.Together, these results suggest that TORC2 acts as a hub for communication of feeding state information from the gut to the brain, thereby contributing to modulation of neuronal function by internal state.\n\nAUTHOR SUMMARYDecision-making in all animals, including humans, involves weighing available information about the external environment as well as the animals internal conditions. Information about the environment is obtained via the sensory nervous system, whereas internal state can be assessed via cues such as levels of hormones or nutrients. How multiple external and internal inputs are processed in the nervous system to drive behavior or development is not fully understood. In this study, we examine how the nematode C. elegans integrates dietary information received by the gut with environmental signals to alter nervous system function. We have found that a signaling complex, called TORC2, acts in the gut to relay nutrition signals to alter hormonal signaling by the nervous system in C. elegans. Altered neuronal signaling in turn affects a food-dependent binary developmental decision in larvae, as well as food-dependent foraging behaviors in adults. Our results provide a mechanism by which animals prioritize specific signals such as feeding status to appropriately alter their development and/or behavior.

neuroscience↗