Biology subjects

Michael, C.

Publications and source records attributed to Michael, C..

12 recordsLinked to original sources

bioRxiv2026

Longitudinal associations between task-control network functioning, cognition, and the environment in early adolescence

Neural maturation in the "task-control" frontoparietal and dorsal attention networks is thought to support the development of adolescents' cognitive and adaptive functioning. Further, theory suggests that family and neighborhood contexts shape brain network development. Yet, few longitudinal studies have examined the co-development of brain network mechanisms with cognitive and adaptive functioning or with environmental factors that could shape the maturation of these mechanisms. The present study addressed these gaps. We used longitudinal data spanning late childhood (Mage=10 years) to early adolescence (Mage=12) from the Adolescent Brain Cognitive Development (ABCD) Study (n=4862). Stable and construct-valid neural signatures of task-control network functioning were estimated using longitudinal bifactor modeling of neural responses to cognitive demand during the n-back task. Multivariate latent change-score models were used to examine co-development of this signature with cognitive efficiency (drift rate from the diffusion model), teacher-reported attention problems, family conflict, and neighborhood safety. Models accounted for baseline family income. Robust reciprocal relations between task-control activation and cognitive efficiency were identified and the latent change scores for efficiency and task-control activation were positively correlated. Similar reciprocal associations were observed between cognitive efficiency and attention problems. Baseline family income predicted the rate of change in task-control network functioning. This study demonstrates that task-control network functioning co-develops with cognition, which in turn supports attentional functioning development across early adolescence. Further, findings highlight the utility of this neural signature of task-control network functioning for understanding the neural basis of cognitive development and the mechanisms through which environmental experiences shape brain and behavior.

neuroscience↗

bioRxiv2026

Epigenetic and brain age across development: Performance and associations in the MIND consortium

Understanding how biological age measures perform across development lays the groundwork for investigations into lifespan trajectories of healthy aging. We provide the most comprehensive assessment of epigenetic and brain age models across development (birth to 24 years; [≤]20,917 observations across 15 cohorts), evaluating how these models associate with chronological age and with each other, and how these associations change across development. Chronological age-prediction accuracy of epigenetic and brain age models was modest and varied substantially. Accuracy improved with age and stabilized by middle childhood. Few brain and fewer epigenetic clocks performed stably and well across all developmental stages. Performance was better when age range and tissue corresponded between training and testing data. Associations between epigenetic-brain age residuals were small, and changed little across development, tissues or clock generation. Given this developmentally dynamic system of epigenetic-brain age performances and associations, we give key recommendations to improve developmental research in this field.

neuroscience↗

bioRxiv2024

Somatomotor disconnection links sleep duration with socioeconomic context, screen time, cognition, and psychopathology

BackgroundSleep is critical for healthy brain development and emotional wellbeing, especially during adolescence when sleep, behavior, and neurobiology are rapidly evolving. Theoretical reviews and empirical research have historically focused on how sleep influences mental health through its impact on higher-order brain systems. No studies have leveraged data-driven network neuroscience methods to uncover interpretable, brain-wide signatures of sleep duration in adolescence, their socio-environmental origins, or their consequences for cognition and mental health. MethodsHere, we implement graph theory and component-based predictive modeling to examine how a multimodal index of sleep duration is associated with intrinsic brain architecture in 3,173 youth (11-12 years) from the Adolescent Brain Cognitive DevelopmentSM Study. ResultsWe demonstrate that network integration/segregation exhibit a strong, generalizable multivariate association with sleep duration. We next identify a single component of brain architecture centered on a single network as the dominant contributor of this relationship. This component is characterized by increasing disconnection of a lower-order system - the somatomotor network - from other systems, with shorter sleep duration. Finally, greater somatomotor disconnection is associated with lower socioeconomic resources, longer screen times, reduced cognitive/academic performance, and elevated externalizing problems. ConclusionsThese findings reveal a novel neural signature of shorter sleep in adolescence that is intertwined with environmental risk, cognition, and psychopathology. By robustly elucidating the key involvement of an understudied brain system in sleep, cognition, and psychopathology, this study can inform theoretical and translational research directions on sleep to promote neurobehavioral development and mental health during the adolescent transition.

neuroscience↗

bioRxiv2024

Differential reconfiguration of brain networks in children in response to standard versus rewarded go/no-go task demands

Response inhibition and sustained attention are critical for higher-order cognition and rely upon specific patterns of functional brain network organization. This study investigated how functional brain networks reconfigure to execute these cognitive processes during a go/no-go task with and without the presence of rewards in 26 children between the ages of 8 and 12 years. First, we compared task performance between standard and rewarded versions of a go/no-go task. We found that the presence of rewards reduced commission error rate, a measure considered to indicate improved response inhibition. Tau, thought to index sustained attention, did not change across task conditions. Next, changes in functional brain network organization were assessed between the resting state, the standard go/no-go task, and the rewarded go/no-go task. Relative to the resting state, integration decreased and segregation increased during the standard go/no-go task. A further decrease in integration and increase in segregation was observed when rewards were introduced. These patterns of reconfiguration were present globally and across several key brain networks of interest, as well as in individual regions implicated in the processes of response inhibition, attention, and reward processing. These findings align with patterns of brain network organization found to support the cognitive strategy of sustained attention, rather than response inhibition, during go/no-go task performance and suggest that rewards enhance this organization. Overall, this study used large-scale brain network organization and a within-subjects multi-task design to examine different cognitive strategies and the influence of rewards on response inhibition and sustained attention in late childhood.

neuroscience↗

bioRxiv2024

Assessing neurocognitive maturation in early adolescence based on baby and adult functional brain landscapes

Adolescence is a period of growth in cognitive performance and functioning. Recently, data-driven measures of brain-age gap, which can index cognitive decline in older populations, have been utilized in adolescent data with mixed findings. Instead of using a data-driven approach, here we assess the maturation status of the brain functional landscape in early adolescence by directly comparing an individuals resting-state functional connectivity (rsFC) to the canonical early-life and adulthood communities. Specifically, we hypothesized that the degree to which a youths connectome is better captured by adult networks compared to infant/toddler networks is predictive of their cognitive development. To test this hypothesis across individuals and longitudinally, we utilized the Adolescent Brain Cognitive Development (ABCD) Study at baseline (9-10 years; n = 6,489) and 2-year-follow-up (Y2: 11-12 years; n = 5,089). Adjusted for demographic factors, our anchored rsFC score (AFC) was associated with better task performance both across and within participants. AFC was related to age and aging across youth, and change in AFC statistically mediated the age-related change in task performance. In conclusion, we showed that a model-fitting-free index of the brain at rest that is anchored to both adult and baby connectivity landscapes predicts cognitive performance and development in youth.

neuroscience↗

bioRxiv2023

Socioeconomic resources in youth are linked to divergent patterns of network integration and segregation across the brain's transmodal axis

Socioeconomic resources (SER) calibrate the developing brain to the current context, which can confer or attenuate risk for psychopathology across the lifespan. Recent multivariate work indicates that SER levels powerfully influence intrinsic functional connectivity patterns across the entire brain. Nevertheless, the neurobiological meaning of these widespread alterations remains poorly understood, despite its translational promise for early risk identification, targeted intervention, and policy reform. In the present study, we leverage the resources of graph theory to precisely characterize multivariate and univariate associations between household SER and the functional integration and segregation (i.e., participation coefficient, within-module degree) of brain regions across major cognitive, affective, and sensorimotor systems during the resting state in 5,821 youth (ages 9-10 years) from the Adolescent Brain Cognitive Development (ABCD) Study. First, we establish that decomposing the brain into profiles of integration and segregation captures more than half of the multivariate association between SER and functional connectivity with greater parsimony (100-fold reduction in number of features) and interpretability. Second, we show that the topological effects of SER are not uniform across the brain; rather, higher SER levels are related to greater integration of somatomotor and subcortical systems, but greater segregation of default mode, orbitofrontal, and cerebellar systems. Finally, we demonstrate that the effects of SER are spatially patterned along the unimodal-transmodal gradient of brain organization. These findings provide critical interpretive context for the established and widespread effects of SER on brain organization, indicating that SER levels differentially configure the intrinsic functional architecture of developing unimodal and transmodal systems. This study highlights both sensorimotor and higher-order networks that may serve as neural markers of environmental stress and opportunity, and which may guide efforts to scaffold healthy neurobehavioral development among disadvantaged communities of youth.

neuroscience↗

bioRxiv2023

Distinct genetic origins of eumelanin intensity and barring patterns in cichlid fishes

Pigment patterns are incredibly diverse across vertebrates and are shaped by multiple selective pressures from predator avoidance to mate choice. A common pattern across fishes, but for which we know little about the underlying mechanisms, is repeated melanic vertical bars. In order to understand genetic factors that modify the level or pattern of vertical barring, we generated a genetic cross of 322 F2 hybrids between two cichlid species with distinct barring patterns, Aulonocara koningsi and Metriaclima mbenjii. We identify 48 significant quantitative trait loci that underlie a series of seven phenotypes related to the relative pigmentation intensity, and four traits related to patterning of the vertical bars. We find that genomic regions that generate variation in the level of eumelanin produced are largely independent of those that control the spacing of vertical bars. Candidate genes within these intervals include novel genes and those newly-associated with vertical bars, which could affect melanophore survival, fate decisions, pigment biosynthesis, and pigment distribution. Together, this work provides insights into the regulation of pigment diversity, with direct implications for an animals fitness and the speciation process.

evolutionary biology↗

bioRxiv2023

A zebrafish xenotransplant model of anaplastic thyroid cancer to study the tumor microenvironment and innate immune cell interactions in vivo.

Anaplastic thyroid cancer (ATC) is a rare malignant subtype of thyroid cancer. While ATC is rare it accounts for a disproportionately high number of thyroid cancer-related deaths. Here we developed an ATC xenotransplant model in zebrafish larvae, where we can study tumorigenesis and therapeutic response in vivo. Using both mouse (T4888M) and human (C643) derived fluorescently labeled ATC cell lines we show these cell lines display different engraftment rates, mass volume, proliferation, and angiogenic potential. Next, using a PIP-FUCCI reporter to track proliferation in-vivo we observed cells in each phase of the cell cycle. Additionally, we performed long-term non-invasive intravital microscopy over 48 hours to understand cellular dynamics in the tumor microenvironment at the single cell level. Lastly, we tested a well-known mTOR inhibitor to show our model could be used as an effective screening platform for new therapeutic compounds. Altogether, we show that zebrafish xenotransplants make a great model to study thyroid carcinogenesis and the tumor microenvironment, while also being a suitable model to test new therapeutics in vivo. SUMMARY STATEMENTAnaplastic thyroid cancer xenotransplant model in zebrafish larvae to study thyroid cancer tumorigenesis and tumor microenvironment. Using confocal microscopy to understand cell cycle progression, interactions with the innate immune system, and test therapeutic compounds in vivo.

cancer biology↗

bioRxiv2023

Oct4 is a gatekeeper of epithelial identity by regulating cytoskeletal dynamics in skin keratinocytes

Oct4 is a pioneer transcription factor regulating pluripotency. However, it is poorly known whether Oct4 has an impact on epidermal cells. We generated OCT4 knockout clonal cell lines using immortalized human skin keratinocytes to identify a functional role for the protein. Here we report that Oct4-deficient cells transitioned into a mesenchymal-like phenotype with enlarged size and shape, exhibited accelerated migratory behavior, decreased adhesion and appeared arrested at G2/M cell cycle checkpoint. Oct4 absence had a profound impact on cortical actin organization, with loss of microfilaments from cell membrane, increased puncta deposition in the cytoplasm and stress fiber formation. E-cadherin, {beta}-catenin and ZO1 were almost absent from cell-cell contacts while fibronectin deposition was markedly increased in ECM. Mapping of the transcriptional and chromatin profiles of Oct4-deficient cells revealed that Oct4 controls the levels of cytoskeletal, ECM and differentiation related genes, whereas epithelial identity is preserved through transcriptional and non-transcriptional mechanisms.

cell biology↗

bioRxiv2021

Neutrophil reverse migration from liver fuels neutrophilic inflammation to tissue injury in Nonalcoholic Steatohepatitis.

Inflammation is a hallmark in the progression of nonalcoholic-fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Patients with NAFLD are characterized by a chronic low-grade systemic metabolic inflammation (i.e., metainflammation), which contributes to exacerbated however dysfunctional immune response. Neutrophils play an important pathological role in NAFLD progression to NASH; however, how NASH and associated chronic systemic inflammation impact overall the neutrophil response to injury is completely unexplored. Here, we investigated how neutrophil response to tissue injury is altered by the presence of NASH. We used a diet-induced NASH zebrafish model combined with tailfin transection in transgenic zebrafish larvae to study neutrophilic inflammation. Live non-invasive confocal microscopy was used to investigate neutrophil recruitment to tailfin injury through time. Photoconvertion of neutrophils at the liver area followed by time-lapse microscopy was performed to evaluate migration of neutrophils from liver to tailfin injury. Metformin and Pentoxifylline were used to pharmacologically reduce NASH and liver inflammation. We found that larvae with NASH display systemic inflammation and increased myelopoiesis. NASH larvae display a dysfunctional and exacerbated neutrophil response to tailfin injury, characterized by increased neutrophil recruitment, and delayed resolution of inflammation. Interestingly, we showed that neutrophils undergo reverse migration from the NASH liver to the wounded tailfin area. Finally, pharmacological treatment of NASH with Pentoxifylline and Metformin significantly reduced systemic chronic inflammation and the exacerbated recruitment of neutrophils to tissue injury. Taken together, our findings suggest that NASH exacerbates neutrophilic inflammation probably via neutrophil priming at the liver, which can further undergo reverse migration and respond to secondary inflammatory triggers such as tissue injury. Reverse migration of primed neutrophils from the liver might be an important mechanism that fuels the exacerbated neutrophil response observed in NASH conditions and associated metainflammation contributing to poor prognosis and increasing death in patients with metabolic syndrome.

immunology↗

bioRxiv2019

Defining Escherichia coli as a health-promoting microbe against intestinal Pseudomonas aeruginosa

Gut microbiota acts as a barrier against intestinal pathogens, but species-specific protection of the host from infection remains relatively unexplored. Taking a Kochs postulates approach in reverse to define health-promoting microbes we find that Escherichia coli naturally colonizes the gut of healthy mice, but it is depleted from the gut of antibiotic-treated mice, which become susceptible to intestinal colonization by Pseudomonas aeruginosa and concomitant mortality. Reintroduction of fecal bacteria and E. coli establishes a high titer of E. coli in the host intestine and increases defence against P. aeruginosa colonization and mortality. Moreover, diet is relevant in this process because high sugars or dietary fat favours E. coli fermentation to lactic acid and P. aeruginosa growth inhibition. To the contrary, low sugars allow P. aeruginosa to produce the oxidative agent pyocyanin that inhibits E. coli growth. Our results provide an explanation as to why P. aeruginosa doesnt commonly infect the human gut, despite being a formidable microbe in lung and wound infections.\n\nAuthor SummaryHere we interrogate the conundrum as to why Pseudomonas aeruginosa is not a clinical problem in the intestine as opposed to other tissues. P. aeruginosa interacts with Neisseria, Streptococcus, Staphylococcus and Actinomyces species found in the human lung. These are predominantly gram-positive bacteria that induce P. aeruginosa virulence. Moreover, peptidoglycan, which is abundant in gram-positive bacteria, can directly trigger the virulence of P. aeriginosa. We reasoned that P. aeruginosa might be benign in the human gut due to the inhibitory action of benign gram-negative intestinal bacteria, such as Escherichia coli. Therefore, we dissected the antagonism between E. coli and P. aeruginosa and the effect of a conventional, a fat-, a carbohydrate-and a protein-based diet in intestinal dysbiosis. Our findings support the notion that an unbalanced diet or antibiotics induces gut dysbiosis by the elimination of commensal E. coli, in addition to lactic acid bacteria, imposing a gut environment conducive to P. aeruginosa infection. Moreover, commensal E. coli provides an explanation as to why P. aeruginosa doesnt commonly infect the human gut, despite being a formidable microbe in lung and wound infections.

microbiology↗

bioRxiv2018

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F-PY-PICA, 5F-PY-PINACA, and their analogues

The structural diversity of synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) has increased since the first examples were reported a decade ago. 5F-PY-PICA and 5F-PY-PINACA were identified in 2015 as putative SCRA NPS, although nothing is known of their pharmacology. 5F-PY-PICA, 5F-PY-PINACA, and analogues intended to explore structure-activity relationships within this class of SCRAs were synthesized and characterized by nuclear magnetic resonance spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry. Using competitive binding experiments and fluorescence-based plate reader membrane potential assays, the affinities and activities of all analogues at cannabinoid type 1 and type 2 receptors (CB1 and CB2) were evaluated. All ligands showed minimal affinity for CB1 (pKi < 5), although several demonstrated moderate CB2 binding (pKi = 5.45-6.99). At 10 M none of the compounds produced an effect > 50% of CP55,950 at CB1, while several compounds showed a slightly higher relative efficacy at CB2. Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.

pharmacology and toxicology↗