Biology subjects

Sweeney, A.

Publications and source records attributed to Sweeney, A..

12 recordsLinked to original sources

bioRxiv2026

Ctenophore mesoglea: building a mucus-like body

Ctenophora are one of the earliest, if not the earliest branching animal, making them crucial for insight into the early events of metazoan evolution. Ctenophores are largely composed of an extracellular mesoglea, but they lack homologs for the fibrous collagens that form a typical metazoan extracellular matrix (ECM). Therefore, the nature of this body-dominating material and its physiological role remains unknown. We found that ctenophore mesoglea is dominated by mucin-related proteins and novel sulfated polysaccharides. Mucus-like material that functions as an internal skeleton rather than as an external secretion indicates fundamental differences in epithelial function and ECM physiology between ctenophores and other Metazoa, suggesting an early period of biochemical and biomechanical diversity prior to the innovation of elastic connective tissue.

biochemistry↗

bioRxiv2025

The Cephalopod Reflectin Domain Specifically Chelates Cu(I), Inducing Assembly

Reflectin proteins constitute the reflective layers of cephalopod skin responsible for camouflage and signaling. They are defined by repeated 25 a.a. motifs with conserved MDM tripeptides. The structure-function relations between these motifs and the proteins ability to assemble into a broad set of precisely controlled, optically resonant materials remain elusive. We observe that the MDM motif is also present in the Mets region of the Ctr copper transporter family, where it binds extracellular copper. We tested whether copper may also play an intrinsic role in reflectin protein assembly. Here we show that native reflectin-rich tissue has high concentrations of several transition metal ions, including Cu, and native protein will chelate additional Cu and Ni in the presence of EDTA and strong base. Experiments with two synthetic show reflectin motif peptides bind Cu(I) similar to Mets motif. Peptide-Cu(I) binding induces assembly with a stoichiometry dictated by Cu(I):peptide, resulting in a volume-spanning gel whose properties may inform our understanding of the emergence of optically resonant structures in the living system. We conclude that a core evolved function of reflectin domain is geometrically and thermodynamically specific assembly via Cu(I).

biophysics↗

bioRxiv2024

In vivo Online label-free monitoring of heterogenous oxygen utilization during phototherapy with real-time ultrasound guided photoacoustic imaging

Understanding the tumor microenvironment, particularly the vascular density and the availability of oxygen, is key in individualizing treatment approaches and determining their efficacy. While there are many therapies including radiotherapy that are ineffective in hypoxic tumor microenvironments, here we demonstrate the heterogeneous oxygen consumption during photodynamic therapy (PDT), a non-invasive treatment method using localized light to activate a photosensitive drug in the presence of oxygen that has shown high effectiveness in the treatment of various types of tumors, including those presented in head and neck cancer (HNC) patients. While our previous work has demonstrated that blood oxygen saturation (StO2) mapped before and after treatment with ultrasound-guided photoacoustic imaging (US-PAI) can be used as a surrogate marker for the regionalized long-term efficacy of PDT, real-time monitoring of StO2 during PDT could provide additional insights on oxygen consumption and inform dose design for "on the spot" treatment decisions. Specifically, in this work, we integrated the US-PAI transducer probe with PDT light delivery fibers. We tested the setup on murine tumor models intravenously injected with liposomal benzoporphyrin derivative (BPD) photosensitizer at 0.5 mg/kg dose and photodynamic illumination at 100 and 400 mW/cm2 fluence rate. As expected, we observed with our US-PAI StO2 images that the rate of oxygen utilization increases when using a high fluence rate (HFR) light dose. Particularly in the higher fluence rate group, we observed StO2 reaching a minimum mid-light dose, followed by some degree of re-oxygenation. US-PAI added the advantage of spatial information to StO2 monitoring, which allowed us to match regions of re-oxygenation during therapy to retained vascular function with immunohistochemistry. Overall, our results have demonstrated the potential of US-PAI for applications in online dosimetry for cancer therapies such as PDT, using oxygen changes to detect regionalized physiological vascular response in the tumor microenvironment.

bioengineering↗

bioRxiv2024

Temporal dynamics of fluorescence and photoacoustic signals of a Cetuximab-IRDye800 conjugate in EGFR-overexpressing tumors

Molecular fluorescence-guided surgery has shown promise for tumor margin delineation but is limited by its depth profiling capability. Interestingly, most fluorophores, either clinically approved or in clinical trials, can also be used as photoacoustic contrast agents, yet their use is limited due to the low light fluence permitted for clinical use and the limited sensitivity of current photoacoustic imaging systems. There is therefore an urgent unmet need to establish methods for enhancing contrast in molecular targeted PA imaging which could potentially complement and overcome limitations in molecular fluorescence guided therapies. In this study, we compare the photoacoustic (PA) and fluorescence imaging capabilities of a cetuximab-IRDye800 conjugate in a subcutaneous tumor xenograft model. We demonstrate that while the fluorescence signal increases steadily over time after administration of cetuximab-IRDye800, PA signal peaks early ([~]2 fold higher at 6-hour as compared to pre-injection controls) and then decreases ([~]1.3 fold higher at 24-hour as compared to pre-injection controls). This pattern aligns with previous findings using other antibody-conjugated PA contrast agents. Mechanistically, we demonstrate that the formation of H-aggregates upon antibody conjugation enhances PA contrast of the IRDye800. The disruption of these H-aggregates, as the antibody-dye conjugate is degraded post receptor-mediated endocytosis, decreases PA signal intensity. The timeframe of maximum PA signal and decrease thereafter is consistent with the time frame of receptor-mediated endocytosis of cetuximab-IRDye800. Our data suggests that tumor cell surface binding results in peak PA signal while lysosomal localization and degradation results in a significant drop in PA signal. Our study sheds light on the distinct temporal dynamics of PA and fluorescence signals of Cetuximab-IRDye800 conjugate and we propose that optimizing IRDye800 conjugation to antibodies can further enhance PA signal intensity when timed to precisely to capture IRDye800 in an H-aggregate form.

cancer biology↗

bioRxiv2024

Vascular regional analysis unveils differential responses to anti-angiogenic therapy in pancreatic xenografts through macroscopic photoacoustic imaging

Pancreatic cancer (PC) is a highly lethal malignancy and the third leading cause of cancer deaths in the U.S. Despite major innovations in imaging technologies, there are limited surrogate radiographic indicators to aid in therapy planning and monitoring. Amongst the various imaging techniques Ultrasound-guided photoacoustic imaging (US-PAI) is a promising modality based on endogenous blood (hemoglobin) and blood oxygen saturation (StO2) contrast to monitor response to anti-angiogenic therapies. Adaptation of US-PAI to the clinical realm requires macroscopic configurations for adequate depth visualization, illuminating the need for surrogate radiographic markers, including the tumoral microvessel density (MVD). In this work, subcutaneous xenografts with PC cell lines AsPC-1 and MIA-PaCa-2 were used to investigate the effects of receptor tyrosine kinase inhibitor (sunitinib) treatment on MVD and StO2. Through histological correlation, we have shown that regions of high and low vascular density (HVD and LVD) can be identified through frequency domain filtering of macroscopic PA images which could not be garnered from purely global analysis. We utilized vascular regional analysis (VRA) of treatment-induced StO2 and total hemoglobin (HbT) changes. VRA as a tool to monitor treatment response allowed us to identify potential timepoints of vascular remodeling, highlighting its ability to provide insights into the TME not only for sunitinib treatment but also other anti-angiogenic therapies.

bioengineering↗

bioRxiv2023

Impact of ectopic calcification on vascular oxygenation in placental dysfunction models: Simultaneous in vivo assessment with multi-parametric ultrasound and photoacoustic imaging

Preeclampsia (PE) is a prevalent gestational disorder occurring in 2-10% of all pregnancies. It is associated with placental dysfunction which can result in maternal mortality and preterm birth. Despite scientific advances, the underlying mechanisms of PE and the progression of placental dysfunction remain poorly understood without preventative or curative treatment. Other than blood tests and postdelivery placental diagnostics, there are limited detection methods for monitoring placental health. A major roadblock is the lack of imaging modalities available to monitor placental hemodynamics, as the commonly used clinical imaging systems are either harmful due to ionizing sources, too expensive and inaccessible, or provide insufficient data. We propose the combination of quantitative ultrasound and photoacoustic imaging (QUSPAI) to characterize the material and structural changes of the placenta during pregnancy in normal and disease states. The Slc20a2 murine model of placental dysfunction has previously been characterized by increased ectopic placental vascular calcification, reduced fetal growth, and decreased postnatal bone mineral density. In this study we utilized the Slc20a2 model and imaged knockout (KO) and wildtype (WT) placentae on embryonic day (E)18.5. The dual-wavelength images and radio frequency data were collected in vivo and ex vivo to provide quantitative ultrasound spectral (QUS) parameters and blood oxygen saturation. The photoacoustic images indicated that the WT tissue had statistically higher blood oxygen saturation (StO2) values than the KO tissues while QUS data revealed strain-specific calcification effects. Building upon the E18.5 gestation data collected here, future work will involve monitoring longitudinal changes in these parameters, including early calcification, to support translating this method for early diagnosis of placental vascular diseases.

bioengineering↗

bioRxiv2023

Ultrasound-guided Photoacoustic image Annotation Toolkit in MATLAB (PHANTOM) for preclinical applications

Depth-dependent fluence-compensation in photoacoustic (PA) imaging is paramount for accurate quantification of chromophores from deep tissues. Here we present a user-friendly toolkit named PHANTOM (PHotoacoustic ANnotation TOolkit for MATLAB) that includes a graphical interface and assists in the segmentation of ultrasound-guided PA images. We modelled the light source configuration with Monte Carlo eXtreme and utilized 3D segmented tissues from ultrasound to generate fluence maps to depth compensate PA images. The methodology was used to analyze PA images of phantoms with varying blood oxygenation and results were validated with oxygen electrode measurements. Two preclinical models, a subcutaneous tumor and a calcified placenta, were imaged and fluence-compensated using the PHANTOM toolkit and the results were verified with immunohistochemistry. The PHANTOM toolkit provides scripts and auxiliary functions to enable biomedical researchers not specialized in optical imaging to apply fluence correction to PA images, enhancing accessibility of quantitative PAI for researchers in various fields.

bioengineering↗

bioRxiv2023

ChemEM: flexible docking of small molecules in Cryo-EM structures using difference maps

The rapid advancement of the "resolution revolution" has propelled cryo-electron microscopy (cryo-EM) to the forefront of structure-based drug discovery. However, the majority of cryo-EM structures are solved at medium resolution (3-4[A]), an unexplored territory for small-molecule docking, due to difficulty in positioning ligands and the surrounding side-chains. Therefore, the development of software capable of reliably and automatically docking ligands into cryo-EM maps at such resolutions is of utmost importance. ChemEM is a novel method that employs cryo-EM data, difference mapping, and a physico-chemical scoring function to flexibly dock one or multiple ligands in a protein binding site. To validate its effectiveness, ChemEM was assessed using a highly curated benchmark containing 33 experimental cryo-EM structures, spanning a resolution range of 2.2-5.6 [A]. In all but one case, the method placed the ligands in the density in an accurate conformation, often better than the PDB deposited solutions. Even without the use of cryo-EM density, the ChemEM scoring function outperformed the well-established docking software AutoDock Vina. Furthermore, the study demonstrates that useful information is present in the map even at low resolutions. ChemEM unlocks the potential of medium-resolution cryo-EM structures for drug discovery.

bioinformatics↗

bioRxiv2020

Mutation in position of 32 (G>U) of S2M differentiate human SARS-CoV2 from Bat Coronavirus

The new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a zoonotic pathogen that has rapidly mutated and become transmissible to humans. There is little existing data on the mutations in SARS-CoV-2 and the impact of these polymorphisms on its transmission and viral load. In this study, the SARS-CoV-2 genomic sequence was analyzed to identify variants within the 3UTR region of its cis-regulatory RNA elements. A 43-nucleotide genetic element with a highly conserved stem-loop II-like motif (S2M), was discovered. The research revealed 32 G>U and 16 G>U/A mutations located within the S2M sequence in human SARS-CoV-2 models. These polymorphisms appear to make the S2M secondary and tertiary structures in human SARS-CoV-2 models less stable when compared to the S2M structures of bat/pangolin models. This grants the RNA structures more flexibility, which could be one of its escape mechanisms from host defenses or facilitate its entry into host proteins and enzymes. While this S2M sequence may not be omnipresent across all human SARS-CoV-2 models, when present, its sequence is always highly conserved. It may be used as a potential target for the development of vaccines and therapeutic agents.

microbiology↗

bioRxiv2019

Hyperactive/impulsive and inattention symptoms are associated with reduced ERP activity during different reward processing stages: Evidence from the electrophysiological Monetary Incentive Delay Task in adult ADHD

Hyperactivity/impulsivity and inattention are core symptoms dimensions in attention-deficit/hyperactivity disorder. Some approaches suggest that these symptoms arise from deficits in the ability to anticipate and process rewards. However, evidence is equivocal with regard to ADHD-related differences in brain activity during reward processing. The aim of this study was to investigate when, and how, reward-related ERP activity was associated with hyperactive/impulsive symptoms and inattention symptoms. Adults with ADHD (n=34) and matched comparison participants (n=36) completed an electrophysiological version of the Monetary Incentive Delay task. This task separates reward processing into two stages-namely, an anticipation stage and a delivery stage. During the anticipation stage, visual cues signalled a possible monetary incentive (i.e. a reward or loss). After a brief delay, the delivery stage began, and incentives were delivered contingent on a speeded button-press. Electroencephalogram activity was simultaneously sampled and incentive-related event relate potentials (ERPs) calculated. These data were then analysed by calculating multiple regression models, at each sample point, wherein the correlation between incentive-related ERPs and ADHD symptoms was estimated. Linear and curvilinear associations between ERP activity and ADHD symptoms were tested in each regression mode. Findings suggest that ADHD symptoms were associated ERP activity at different reward processing stages. Hyperactive/impulsive symptoms were associated with reduced ERP activity during the initial anticipation of rewards from 224-329 ms post-reward cue. Inattention symptoms were associated with reduced ERP activity during the initial delivery of rewards from 251-280 ms post-reward onset. Finally, extreme ends of hyperactive/impulsive and inattention symptoms were associated with reduced ERP activity towards the end of the anticipation stage from 500 ms post-reward cue onwards. These results support the idea that reward processing is disrupted in ADHD while also shedding new light on the dynamic relationship between ADHD symptom dimensions and the neurological mechanisms of reward processing.

neuroscience↗

bioRxiv2018

Information content of downwelling skylight for non-imaging visual systems

Light-sensitive proteins (opsins) are expressed in non-imaging tissues like the brain, dermis and reproductive organs of most animals. Such tissues have been shown to sense the intensity and spectrum of light over time. Functional links to circadian and reproductive rhythms have been speculated but remain uncertain. Here we use information theory to quantify the natural scene for non-imaging opsins, i.e., spectral patterns in downwelling skylight. Our approach synthesizes measurements of natural downwelling spectra, atmospheric distortions, and weather, with the biophysical constraints of opsins and biochemical clocks, while minimizing assumptions about how organisms process such information. We find that tissues expressing multiple opsins could use twilight to extract significant information about lunar phase and time of day in many climates. In contrast, information in light intensity is far less robust to atmospheric perturbations. Thus our work quantifies circalunar and circadian regularities in the spectrum of downwelling radiance salient to non-imaging opsins.

biophysics↗

bioRxiv2018

Underlying mechanisms and ecological consequences of variation in exploratory behavior of the Argentine ant, Linepithema humile

Uncovering how and why animals explore their environment is fundamental for understanding population dynamics, the spread of invasive species, species interactions etc. In social animals, individuals within a group can vary in their exploratory behavior and the behavioral composition of the group can determine its collective success. Workers of the invasive Argentine ant (Linepithema humile) exhibit individual variation in exploratory behavior, which affects the colonys collective nest selection behavior. Here we examine the mechanisms underlying this behavioral variation in exploratory behavior and determine its implications for the ecology of this species. We first establish that individual variation in exploratory behavior is repeatable and consistent across situations. We then show a relationship between exploratory behavior and the expression of genes that have been previously linked with other behaviors in social insects. Specifically, we find a negative relationship between exploratory behavior and the expression of the FOR gene. Finally, we determine how colonies allocate exploratory individuals in natural conditions. We find that ants from inside the nest are the least exploratory individuals, while workers on newly formed foraging trails are the most exploratory individuals. Furthermore, workers in the spring, when new resources emerge, are more exploratory than workers in the winter, potentially allowing the colony to find and exploit new resources. These findings reveal the importance of individual variation in behavior for the ecology of social animals and provide mechanistic and functional explanations for how such behavioral variation can emerge.

animal behavior and cognition↗