Biology subjects

Mattingly, C.

Publications and source records attributed to Mattingly, C..

4 recordsLinked to original sources

bioRxiv2025

RNA liquid biopsy via nanopore sequencing for novel biomarker discovery and cancer early detection

Liquid biopsies detect disease noninvasively by profiling cell-free nucleic acids that are secreted into the circulation. However, existing methods exhibit low sensitivity for detecting early stages of diseases such as cancer. Here we show that long-read nanopore sequencing of full-length cell-free RNA in plasma from healthy individuals, precancerous Barretts esophagus patients with high-grade dysplasia, or patients with esophageal adenocarcinoma reveals a diverse cell-free RNA transcriptome that can be leveraged for detecting and treating disease. We discovered 270,679 novel, intergenic cell-free RNAs, which we used to build a custom transcriptome reference for quantification, feature selection, and machine learning to accurately classify both precancer and cancer. Moreover, we found potential therapeutic targets, including metabolic, signaling, and immune checkpoint pathways, that are highly upregulated in both precancer and cancer patients. Our findings highlight the utility of our RNA liquid biopsy platform technology for discovering and targeting early stages of disease with molecular precision.

genomics↗

bioRxiv2025

Perinatal Nicotine Exposure Disrupts Hematopoietic Stem Cell Development and Elevates Influenza Susceptibility in Adulthood

Tobacco use during pregnancy has many deleterious health consequences for not only the smoking mother, but also on the unborn fetus. Children of smoking mothers are reported to have higher frequency and severity of respiratory diseases later in life; however, the mechanisms driving this increased vulnerability are not clearly understood. One potential cause of increased disease susceptibility is an altered immune system, originating in epigenetically maladaptive hematopoietic stem cells (HSCs). Here, we show that perinatal nicotine exposure (PNE) alters the establishment of HSCs and fetal-derived non-traditional tissue immune cells, with no alterations in circulating immune cell numbers. Suppression of HSCs and lung immune cells persisted for weeks after PNE had ceased. Strikingly, PNE led to increased disease susceptibility and severity upon challenge with influenza A virus in adulthood. This was associated with significant and highly selective alterations in lung immune cells, emphasizing the importance of cellular mechanisms in resilience to infections. Together, these experiments demonstrate that perinatal exposures that have deleterious consequences on hematopoietic establishment can impair immune function for life and identify the cellular mechanisms by which perinatal nicotine exposure predisposes the offspring to a weakened defense against respiratory pathogens. HIGHLIGHTSO_LIPerinatal nicotine exposure (PNE) causes long-term alterations of hematopoiesis C_LIO_LIPNE perturbs hematopoietic stem cell (HSC) development and maintenance C_LIO_LIPNE diminishes the population of fetal-derived tissue-resident alveolar macrophages C_LIO_LIPNE alters cellular mechanisms, exacerbating disease severity later in life C_LIO_LINicotine suppression of central immunity is manifested mechanistically by altered immune cell output C_LI

developmental biology↗

bioRxiv2019

Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

Considering the impact that Zika virus (ZIKV) infection has on the fetal nervous system and given that the postnatal period is also a time of rapid brain growth, it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Postnatal ZIKV infection in a rhesus macaque (RM) model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant RMs had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection of infants in this model has long lasting neurodevelopmental consequences.

neuroscience↗

bioRxiv2019

Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

To achieve long-term viral remission in HIV-infected children, novel strategies beyond early anti-retroviral therapy (ART) will be necessary. Identifying clinical predictors of time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and potential risks of treatment interruption. To facilitate identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or post-ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we documented that infant and adult macaques have similar SHIV replication and rebound kinetics and equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of time to viral rebound, namely pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to pre-clinically assess novel therapies to achieve a pediatric HIV functional cure.\n\nIMPORTANCENovel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children who currently rely on lifelong ART. Considering the risks and expense associated with ART-interruption trials, identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant non-human primate models of HIV rebound. In this study, we developed an infant RM model of oral Simian/Human Immunodeficiency virus infection expressing clade C HIV Env, and short-term ART followed by ATI, longitudinally characterizing immune responses to viral infection during ART and post-ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of time to viral rebound post-ATI.

immunology↗