Biology subjects

Sullivan, C.

Publications and source records attributed to Sullivan, C..

10 recordsLinked to original sources

bioRxiv2026

Multi-factorial regulatory networks of placental antibody transfer by Fc receptors and maternal IgG Fc characteristics are modulated by clinical covariate profiles

Maternal immunoglobulin G (IgG) transferred across the placenta is crucial for newborn immunity. IgG transfer efficiency modulated by Fc characteristics including subclass and glycosylation gives rise to diverse transfer profiles across the population, yet the molecular mechanisms driving this variation are incompletely understood. To disentangle multimodal molecular relationships driving population heterogeneity in maternal-fetal antibody transfer, we characterized placental and serological antibody features in matched human tissues from two geographically distinct cohorts. Unsupervised clustering of maternal clinical covariates in both cohorts revealed a distinct patient profile with reduced plasma C-reactive protein and pregravid BMI and enhanced transfer efficiency of IgG subclasses. Quantification of IgG Fc glycan structures in matched maternal and cord plasma by liquid chromatography-mass spectrometry revealed subclass-specific IgG glycosylation patterns which impacted placental transfer efficiency and correlated with these key clinical features. We profiled expression and colocalization of key Fc {gamma} Receptors (Fc{gamma}Rs) by multiplex immunohistochemistry, revealing cell type-specific expression patterns. Variable Fc{gamma}R expression across gestation was consistent in both cohorts, implicating Fc{gamma}Rs as key drivers of temporal antibody transfer dynamics. While Fc{gamma}Rs were not strongly variable across the clinical profiles, partial correlation analysis of matched samples controlling for gestational age and demographic covariates revealed correlations between Fc{gamma}R expression frequencies and glycan- and subclass-specific transfer efficiency. These data systematically define multi-factorial regulatory networks of antibody transfer by placental Fc receptors and maternal IgG Fc characteristics, which are further modulated by clinical covariates. This study provides a basis for the rational design of prenatal vaccination strategies, administration schedules, and potential lifestyle interventions to improve maternal-fetal immunity.

immunology↗

bioRxiv2026

Molecular determinants of antibody-mediated priming to enhance detection of ctDNA

Liquid biopsies can enable cancer detection and monitoring yet remain limited by low concentrations of ctDNA. To address this limitation, we previously introduced a monoclonal antibody (mAb) "priming agent" that transiently increased the concentration of ctDNA in blood. Here, we investigated the molecular features that drive this effect. In a panel of novel mAbs that bound cfDNA, both those targeting dsDNA and those targeting mononucleosomes increased the concentration of ctDNA. mAbs with high avidity to dsDNA performed best, suggesting dsDNA as the key binding target. One agent preserved short, biologically informative molecules of cfDNA typically depleted at baseline. The Fc domain was dispensable, as F(ab)2 fragments retained priming activity. Leveraging these insights, we engineered single-chain agents using the dsDNA binding domain sso7d, expanding priming strategies beyond immunoglobulins. This study identifies the molecular features and general design principles for mAb-based priming agents to enhance recovery and detection of ctDNA. SignificanceLow concentration of ctDNA limits the sensitivity of liquid biopsies in many applications. This study shows how engineered antibodies and other dsDNA-binding molecules can inhibit clearance of ctDNA from the bloodstream and increase concentration of ctDNA in a blood draw, and identifies the key features that enable this activity. Modulation of cfDNA in the bloodstream using these agents can increase recovery of ctDNA and improve the performance of liquid biopsies for cancer detection.

bioengineering↗

bioRxiv2025

Phosphatase SHP2 pathogenic mutations enhance activity by altering conformational sampling

SH2 domains are critical mediators of cellular signaling, although the molecular mechanisms by which they bind their phosphopeptide ligands remain incompletely understood. We investigate the atomic mechanisms underlying both healthy regulation and dysregulation of the human protein tyrosine phosphatase SHP2, a key regulator of cellular signaling. While most pathogenic mutations cluster near the PTP/N-SH2 interface, the E139D and T42A mutations are located within the regulatory SH2 domains, and their mechanisms of dysregulation remain controversial. The T42A mutation in the N-SH2 domain paradoxically increases phosphotyrosine-peptide binding affinity despite disrupting the hydrogen bond of T42 to the phosphoryl group, a puzzling contradiction that remains unresolved. We find that the T42A mutation shifts the conformational ensemble of peptide-bound N-SH2 toward a zipped {beta}-sheet state and suppresses millisecond conformational exchange, supporting a model in which enhanced stabilization of the zipped conformation contributes to hyperactivation. This conformational shift provides a structural rationale for the increased affinity of T42A and helps reconcile previously conflicting models of peptide-induced SHP2 activation. By integrating X-ray ensemble refinement with NMR relaxation, our work illustrates how complementary structural and dynamic approaches can uncover regulatory mechanisms in SHP2 and may inform broader principles of SH2-mediated phosphopeptide recognition. Significance StatementHere, we characterize how two pathogenic SH2-domain mutations alter SHP2 regulation and lead to hyperactivation. We identify a previously unobserved apo conformation of the N-SH2 domain in which Tyr66 occludes the peptide-binding cleft, indicating that a conformational change is required for full binding of activating phosphopeptides. Our data suggest that the T42A mutation shifts the equilibrium toward a zipped central {beta}-sheet state in the peptide-bound N-SH2 domain as the most likely model underlying the measured 10-fold increased binding affinity. These results help clarify the structural basis for SHP2 regulation and illustrate how conformational dynamics shape SH2-phosphopeptide recognition.

biophysics↗

bioRxiv2025

The dramatic impact of the PER-DBT interaction on circadian timekeeping andtemperature compensation

Circadian timekeeping is orchestrated by multiple clock proteins, but mechanistic understanding is limited. AlphaFold predicts novel interactions between two helical domains of the Drosophila PERIOD (PER) protein and its major kinase Doubletime (DBT). These PER domains, SYQ and LT, are conserved with mammals and are predicted to interact identically with the DBT ortholog casein kinase 1 (CK1). SYQ and LT mutations designed to disrupt this interface result in severe period and temperature-sensitive fly phenotypes, and two LT mutations cause unprecedented free-running periods [≥] 44 hours and temperature-sensitive changes of [~]20 hours. Further characterization of a LT mutant strain shows a severe reduction in both PER phosphorylation and PER degradation. A human PER equivalent of the same LT mutation is a much less efficient in vitro substrate for CK1-mediated phosphorylation. These observations indicate that this conserved PER-DBT interaction is critical for PER phosphorylation, circadian timing and its enigmatic temperature compensation phenomena.

molecular biology↗

bioRxiv2022

The Children's Brain Tumor Network (CBTN) - Accelerating Research in Pediatric Central Nervous System Tumors through Collaboration and Open Science

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Childrens Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTNs 32 member institutions utilize a shared regulatory governance architecture at the Childrens Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4,700 subjects, over 1,500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1,000 tumors and germline material is currently available with data generation for > 5,000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

cancer biology↗

bioRxiv2021

Digital restoration of the pectoral girdles of two Early Cretaceous birds, and implications for early flight evolution

Pectoral girdle morphology is a key determinant of flight capability, but in some respects is poorly known among stem birds. Here, we reconstruct the pectoral girdles of the Early Cretaceous birds Sapeornis and Piscivorenantiornis based on computed tomography and three-dimensional visualization, revealing key morphological details. Enantiornithines such as Piscivorenantiornis have a uniquely localized scapula-coracoid joint, with only one area of articulation. This single articulation contrasts with the double articulation widely present in non-enantiornithine pennaraptoran theropods, including Sapeornis and crown birds, which comprises main and subsidiary articular contacts. A partially closed triosseal canal occurs in non-euornithine birds, representing a transitional stage in flight apparatus evolution. Numerous modifications of the pectoral girdle along the line to crown birds, and lineage-specific pectoral girdle variations, produced diverse pectoral girdle morphologies among Mesozoic birds, which ensured that a commensurate range of capability levels and modes emerged during the early evolution of flight.

evolutionary biology↗

bioRxiv2021

Spatial and temporal dynamics of SAR11 marine bacteria sampled across a nearshore to offshore transect in the tropical Pacific Ocean

Time-series surveys of microbial communities coupled with contextual measures of the environment provide a useful approach to dissect the factors determining distributions of microorganisms across ecological niches. Here, monthly time-series samples of surface seawater along a transect spanning the nearshore coastal environment within K[a]ne ohe Bay on the island of O ahu, Hawai i, and the adjacent offshore environment were collected to investigate the diversity and abundance of SAR11 marine bacteria over a two-year time period. Using 16S ribosomal RNA gene amplicon sequencing, the spatiotemporal distributions of major SAR11 subclades and individual amplicon sequence variants (ASVs) were evaluated. On average, 77% of the SAR11 community was compromised of a small number of ASVs (7 of 106 in total), which were ubiquitously distributed across all samples collected from one or both of the end-member environments sampled in this study (coastal or offshore). SAR11 ASVs were more often restricted spatially to coastal or offshore environments (64 of 106 ASVs) than they were shared among coastal, transition, and offshore environments (39 of 106 ASVs). Overall, offshore SAR11 communities contained a higher diversity of SAR11 ASVs than their nearshore counterparts. This study reveals ecological differentiation of SAR11 marine bacteria across a short physiochemical gradient, further increasing our understanding of how SAR11 genetic diversity partitions into distinct ecological units.

microbiology↗

bioRxiv2019

Mindfulness meditators show enhanced working memory performance concurrent with different brain region engagement patterns during recall

Mindfulness meditation has been shown to improve working memory (WM). However, the altered brain activity underpinning these improvements is underexplored. In non-meditating individuals, modulation of theta and alpha oscillations and 1/f aperiodic activity during WM has been found to be related to WM performance. Resting theta and alpha oscillations have been found to differ in meditators, but WM related oscillation changes and 1/f aperiodic activity have not yet been examined. Additionally, WM event-related-potentials (ERPs) are modulated by attention, which is also enhanced by meditation, so these neural measures are candidates for exploring neural activity underpinning WM improvement in meditators. We recorded EEG from 29 controls and 29 meditators during a modified Sternberg WM task and compared theta, alpha, and 1/f aperiodic activity during the WM delay, and ERPs time-locked to the WM probe. Meditators responded more accurately (p = 0.008, Cohens d = 0.688). Meditators also showed different ERP distributions with earlier left-temporal activation and more frontal distribution of activity (FDR-p = 0.0186, {eta}2 = 0.0903), as well as a reduction in overall neural response strength (FDR-p = 0.0098, {eta}2 = 0.1251). While a higher proportion of meditators showed theta oscillations during the WM delay, no other differences in theta, alpha or 1/f aperiodic activity were present. These results suggest that increased WM performance in meditators might not be the result of higher amplitudes of typical WM activity, but instead due to an alternative neural strategy during WM decision making, which may allow more accurate responses with less neural activation.\n\nHighlights- Long term mindfulness meditators showed improved working memory (WM) accuracy\n- This was concurrent with earlier left temporal activation following probe stimuli\n- As well as a more frontal distribution and reduced overall neural response strength\n- No oscillation differences were present in the working memory delay period\n- Improved WM from altered neural strategy rather than increased neural activity

neuroscience↗

bioRxiv2019

Mindfulness meditation alters neural activity underpinning working memory during tactile distraction

Evidence suggests that mindfulness meditation (MM) improves selective attention and reduces distractibility by enhancing top-down neural modulation. Altered P300 and alpha neural activity from MM have been identified and may reflect the neural changes that underpin these improvements. Given the proposed role of alpha activity in supressing processing of task-irrelevant information, it is theorised that altered alpha activity may underlie increased availability of neural resources in meditators. The present study investigated attentional function in meditators using a cross-modal study design, examining the P300 during working memory (WM) and alpha activity during concurrent distracting tactile stimuli. Thirty-three meditators and 27 healthy controls participated in the study. Meditators showed a more frontal distribution of P300 neural activity following WM stimuli (p = 0.005, {eta}{superscript 2} = 0.060) and more modulation of alpha activity at parietal-occipital regions between single (tactile stimulation only) and dual task demands (tactile stimulation plus WM task) (p < 0.001, {eta}{superscript 2} = 0.065). Additionally, meditators performed more accurately than controls (p = 0.038, {eta}{superscript 2} = 0.067). The altered distribution of neural activity concurrent with improved WM performance suggests greater attentional resources dedicated to task related functions such as WM in meditators. Thus, meditation-related neural changes are likely multi-faceted involving both altered distribution and also amplitudes of brain activity, enhancing attentional processes depending on task requirements.

neuroscience↗

bioRxiv2018

Mindfulness meditators show altered distributions of early and late neural activity markers of attention in a response inhibition task

Attention is a vital executive function, since other executive functions are largely dependent on it. Mindfulness meditation has been shown to enhance attention. However, the components of attention altered by meditation and the related neural activities are underexplored. In particular, the contributions of inhibitory processes and sustained attention are not well understood. Additionally, it is not clear whether improvements in attention are related to increases in the strength of typically activated brain areas, or the recruitment of additional or alternative brain areas. To address these points, 34 meditators were compared to 28 age and gender matched controls during electroencephalography (EEG) recordings of neural activity during a Go/Nogo response inhibition task. This task generates a P3 event related potential, which is related to response inhibition processes in Nogo trials, and attention processes across both trial types. Compared with controls, meditators were more accurate at responding to Go and Nogo trials. Meditators showed a more frontally distributed P3 to both Go and Nogo trials, suggesting more frontal involvement in sustained attention rather than activity specific to response inhibition. Unexpectedly, meditators also showed increased positivity over the right parietal cortex prior to visual information reaching the occipital cortex. Both results were positively related to increased accuracy across both groups. The results suggest that meditators have an increased capacity to modulate a range of neural processes in order to meet task requirements, including higher order processes, and sensory anticipation processes. This increased capacity may underlie the improved attentional function observed in mindfulness meditators.

neuroscience↗