Biology subjects

Mitchell, M. E.

Publications and source records attributed to Mitchell, M. E..

7 recordsLinked to original sources

bioRxiv2026

A biofilm-derived peptide as an underwater adhesive

Wet adhesives that perform under water have broad applications in industrial and biomedical settings. To date, molecular designs for underwater adhesives have largely been inspired by marine animals including mussels and barnacles. Here, we propose bacterial biofilms as an alternative source of inspiration for underwater adhesives. Specifically, we demonstrate the application potential of a peptide derived from biofilms formed by the notorious pathogen Vibrio cholerae. We characterize the ability of this biofilm-derived peptide to adsorb onto various surfaces and to glue wet surfaces, by using a combination of confocal microscopy, molecular dynamics simulations, atomic force microscopy, lap shear tests, and spectroscopic tools. We further show that the peptide can co-aggregate with microspheres acting as an effective flocculant. Finally, we succeeded in purifying this peptide from E. coli in a functional form, setting the stage for large-scale production. Our results open new design possibilities for underwater adhesives inspired by natural biofilms. TeaserA peptide derived from biofilms adheres to diverse surfaces and shows promising potential as a wet adhesive and flocculant.

bioengineering↗

bioRxiv2025

Task-evoked functional connectivity exhibits novel and strengthened relationships with executive function relative to the resting state

Executive functioning in children has been linked to intrinsic brain network organization assessed during the resting state, as well as to brain network organization during the performance of cognitive tasks. Prior work has established that task-based brain networks are stronger predictors of behavior than resting state networks, yet it is unclear if tasks only strengthen relationships that exist weakly at rest or if tasks also evoke unique relationships. A lack of discernment regarding how tasks and the resting state commonly and uniquely support executive functions precludes a holistic understanding of the neurobiological basis of executive functions. This project investigated differences in brain network organization and relationships with executive function ability between the resting state and two executive function tasks, a stop signal task and an emotional n-back task, using the Adolescent Brain and Cognitive Development (ABCD) Study dataset. Both executive function tasks evoked a more integrated network organization than the resting state, and executive function ability was related to different aspects of brain network organization during the resting state and during the tasks. Further, task-related shifts in brain network organization evoked several new relationships with executive function that were not detectable during the resting state and strengthened a relationship with executive function that existed weakly during the resting state. Overall, this study establishes a distinction between common and unique features of intrinsic and task-evoked brain function that facilitate executive function in children. SignificanceExecutive functions, which encompass goal-directed behaviors critical for life success, emerge from interactions within and between networks of brain regions. Here, we tested how executive functions are linked to functional brain network interactions during the resting state, in which there are no external cognitive demands, and during executive function tasks in late childhood. We found that brain network organization during the performance of executive function tasks evoked a combination of new and strengthened relationships with executive function ability compared to the resting state. This suggests that the brain facilitates executive function performance in children through the recruitment of specific functional interactions during the enactment of executive function.

neuroscience↗

bioRxiv2025

Cognition is associated with task - related brain network reconfiguration in late childhood

In order to transition between a resting state and carrying out cognitively-demanding processes the brain makes a host of subtle changes to its network organization. In adults, less reconfiguration relates to better task performance, suggesting a preconfigured brain organization at rest is beneficial, such that only minute changes are required to execute task demands. Here, we take a developmental lens to this phenomenon, examining reconfiguration in late childhood by leveraging a large sample of 9-11 year olds from the Adolescent Brain and Cognitive Development Study. We find more reconfiguration between the resting state and two executive function tasks is related to better task performance, as well as better crystalized and fluid cognition in some cases. These relationships hold even when accounting for network segregation. These findings suggest a less-preconfigured, and thus more flexible, brain organization that enacts more reconfiguration to move from the resting state into a task state is beneficial in children. This aligns with theories positioning late childhood and the beginning of adolescence as a period of increased brain plasticity where functional brain networks are still undergoing refinement, and thus preconfiguration may be less beneficial and, instead, may place premature constraints on brain organization.

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

Interleukin-6 induces nascent protein synthesis in human DRG nociceptors via MNK-eIF4E signaling

Plasticity of dorsal root ganglion (DRG) nociceptors in the peripheral nervous system requires new protein synthesis. This plasticity is believed to be responsible for the physiological changes seen in DRG nociceptors in animal models of chronic pain. Experiments in human DRG (hDRG) neurons also support this hypothesis, but a direct observation of nascent protein synthesis in response to a pain promoting substance, like interleukin-6 (IL-6), has not been measured in these neurons. To fill this gap in knowledge, we used acutely prepared human DRG explants from organ donors. These explants provide a physiologically relevant microenvironment, closer to in vivo conditions, allowing for the examination of functional alterations in DRG neurons reflective of human neuropathophysiology. Using this newly developed assay, we demonstrate upregulation of the target of the MNK1/2 kinases, phosphorylated eIF4E (p-eIF4E), and nascently synthesized proteins in a substantial subset of hDRG neurons following exposure to IL-6. To pinpoint the specific molecular mechanisms driving this IL-6- driven increase in nascent proteins, we used the specific MNK1/2 inhibitor eFT508. Treatment with eFT508 resulted in the inhibition of IL-6-induced increases in p-eIF4E and nascent proteins. Additionally, using TRPV1 as a marker for nociceptors, we found that these effects occurred in a large number of human nociceptors. Our findings provide clear evidence that IL-6 drives nascent protein synthesis in human TRPV1+ nociceptors via MNK1/2-eIF4E signaling. The work links animal findings to human nociception, creates a framework for additional hDRG signaling experiments, and substantiates the continued development of MNK inhibitors for pain.

neuroscience↗

bioRxiv2020

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.

genetics↗

bioRxiv2018

FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain

The localization and translation of mRNAs is controlled by a diverse array of ribonucleoprotein particles (RNPs), multimolecular complexes containing mRNAs and RNA binding proteins. Fragile X granules (FXGs) are a family of RNPs that exemplify the diversity of RNA granules in the mammalian nervous system. FXGs are found in a conserved subset of neurons, where they localize exclusively to the axonal compartment. Notably, the specific RNA binding proteins and mRNAs found in FXGs depend on brain circuit and neuron type, with all forebrain FXGs containing Fragile X mental retardation protein (FMRP), the protein mutated in the human autism-related disorder Fragile X syndrome. FMRP negatively regulates FXG abundance but is not required for their association with ribosomes or mRNA. To better understand the circuit-dependent mechanisms whereby FMRP associates with and regulates FXGs, we asked how a disease-causing point mutation, I304N, in the KH2 RNA binding domain of FMRP affects these granules in two brain regions - cortex and hippocampus. We found that FMRPI304N had a reduced association with FXGs, as it was absent from approximately half of FXGs in cortex and nearly all FXGs in hippocampus. FXG abundance correlated with the number of FMRP-containing FXGs, suggesting that FMRP regulates FXG abundance by KH2-independent mechanisms that occur locally within the granules. Together, these findings illustrate that cell type-dependent mechanisms guide the assembly of similar RNA granules. Further, point mutations in RNA granule components may lead to cell type-dependent phenotypes that produce atypical forms of disorders that normally arise from more severe mutations.

neuroscience↗