Biology subjects

Wallace, M.

Publications and source records attributed to Wallace, M..

30 records · Page 2Linked to original sources

bioRxiv2021

Fast slow folding of an Outer Membrane Porin

In comparison to globular proteins, the spontaneous folding and insertion of {beta}-barrel membrane proteins is surprisingly slow, typically occurring on the order of minutes. Using single-molecule Forster Resonance Energy Transfer to report on the folding of fluorescently-labelled Outer Membrane Protein G we measured the real-time insertion of a {beta}-barrel membrane protein from an unfolded state. Folding events were rare, and fast (<20 ms); occurring immediately upon arrival at the membrane. This combination of infrequent, but rare, folding resolves this apparent dichotomy between slow ensemble kinetics, and the typical timescales of biomolecular folding.

biophysics↗

bioRxiv2021

Biophysical demonstration of co-packaging of glutamate and GABA in individual synaptic vesicles in the central nervous system

Many mammalian neurons release multiple neurotransmitters to activate diverse classes of ionotropic receptors on their postsynaptic targets. Entopeduncular nucleus somatostatin (EP Sst+) neurons that project to the lateral habenula (LHb) release both glutamate and GABA, but it is unclear if these are packaged into the same or segregated pools of synaptic vesicles. Here we describe a novel method combining electrophysiology, spatially-patterned optogenetics, and computational modeling designed to analyze the mechanism of glutamate/GABA corelease. We find that the properties of PSCs elicited in LHb neurons by optogenetic activation of EP Sst+ terminals are only consistent with co-packaging of glutamate and GABA into individual vesicles. Furthermore, serotonin, which acts presynaptically to weaken EP Sst+ to LHb synapses, does so by altering the release probability of vesicles containing both transmitters. Our approach is broadly applicable to the study of multi-transmitter neurons throughout the brain and our results constrain mechanisms of neuromodulation in LHb.

neuroscience↗

bioRxiv2020

Inflexible Updating of the Self-Other Divide During a Social Context in Autism; Psychophysical, Electrophysiological, and Neural Network Modeling Evidence

Autism spectrum disorder (ASD) is a heterogenous disorder predominantly characterized by social and communicative differences, but increasingly recognized to also alter (multi)sensory function. To face the heterogeneity and ubiquity of ASD, researchers have proposed models of statistical inference operating at the level of computations. Here, we attempt to bridge both across domains - from social to sensory - and levels of description - from behavioral computations to neural ensemble activity to a biologically-plausible artificial neural network - in furthering our understanding of autism. We do so by mapping visuo-tactile peri-personal space (PPS), and examining its electroencephalography (EEG) correlates, in individuals with ASD and neurotypical individuals during both a social and non-social context given that (i) the sensory coding of PPS is well understood, (ii) this space is thought to distinguish between self and other, and (iii) PPS is known to remap during social interactions. In contrast to their neurotypical counterparts, psychophysical and EEG evidence suggested that PPS does not remap in ASD during a social context. To account for this observation, we then employed a neural network model of PPS and demonstrate that PPS remapping may be driven by changes in neural gain operating at the level of multisensory neurons. Critically, under the anomalous excitation-inhibition (E/I) regime of ASD, this gain modulation does not result in PPS resizing. Overall, our findings are in line with recent statistical inference accounts suggesting diminished flexibility in ASD, and further these accounts by demonstrating within an example relevant for social cognition that such inflexibility may be due to E/I imbalances.

neuroscience↗

bioRxiv2020

Genomic analysis of Cryaa-R49C and Cryab-R120G knockin mutant mice: 10-year follow-up

ObjectiveTwo experimental samples from a mouse line containing Cryaa or Cryab modifications on a predominantly C57Bl/6 background using 129Sv mouse strain embryonic stem cells were investigated. The objective was to reexamine the precise genetic background of the mice 10 years after they were converted to the C57Bl/6 background. ResultsThe genetic backgrounds of the mice were assessed at the DartMouse Speed Congenic Core Facility at the Geisel School of Medicine at Dartmouth. DartMouse used the Illumina, Inc. Infinium Genotyping Assay to interrogate a custom panel of 5307 SNPs that were spread throughout the genome. The raw SNP data were analyzed using the DartMouse SNaP-Map and Map-Synth software, which allowed for genetic background identification at each SNP location for every mouse. As part of the analysis, 323 SNPs were eliminated from the data prior to generating chromosome maps due to internal quality control protocols. Of the remaining 4984 SNPs, 44.56% were uninformative (not polymorphic between the two relevant genetic backgrounds) and approximately 0.91% gave uninterpretable data. The remaining 54.53% of the returned SNPs were well distributed throughout the genome. The genetic backgrounds were determined to be 98-99% C57Bl/6J, which was the desired background.

genetics↗

bioRxiv2020

Microbiota control of maternal behavior regulates early postnatal growth of offspring

Maternal-offspring bonding and maturation of maternal behavior is necessary during the early postnatal period of an infant to promote optimal development and growth. The regulation of maternal behavior is multifactorial relying both on sensory cues including auditory and olfactory signals emitted by the infant and received by the mother, as well as proper neuroendocrine responses including that of the oxytocin system. The intestinal microbiota has emerged as a critical regulator of growth and development in the early postnatal period of an individual’s life. While, this is best appreciated in the context of direct interactions between the microbiota and the infant, the microbiota can indirectly influence postnatal growth and development by regulating maternal factors. Here, we describe the identification of an intestinal E. coli strain that is pathogenic to the maternal-offspring system during the early postnatal stage of life and results in growth stunting of the offspring. However, rather than having a direct pathogenic effect on the infant, we found that this particular E. coli strain was pathogenic to the dams by interfering with the maturation of maternal behavior. The poor maternal behavior resulted in malnourishment of the pups and impaired IGF-1 signaling leading to the consequential stunted growth. Our work provides a new understanding of how the microbiota regulates postnatal growth and an additional variable that must be considered when studying the regulation of maternal behavior.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2019

Rapid Recalibration of Peri-Personal Space; Psychophysical, Electrophysiological, and Neural Network Modeling Evidence

Interactions between individuals and the environment are mediated by the body and occur within the peri-personal space (PPS) - the space surrounding the body. The multisensory encoding of this space plastically adapts to different bodily constraints and stimuli features. However, these remapping effects have only been demonstrated on the time-scale of days, hours, or minutes. Yet, if PPS mediates human-environment interactions in an adaptive manner, its representation should be altered by sensory history on trial-to-trial timescale. Here we test this idea first via a visuo-tactile reaction time paradigm in augmented reality where participants are asked to respond as fast as possible to touch, as visual object approach them. Results demonstrate that reaction times to touch are facilitated as a function of visual proximity, and the sigmoidal function describing this facilitation shifts closer to the body if the immediately precedent trial had indexed a smaller visuo-tactile disparity (i.e., positive serial dependency). Next, we derive the electroencephalographic correlates of PPS and demonstrate that this measure is equally shaped by recent sensory history. Finally, we demonstrate that a validated neural network model of PPS is able to account for the present results via a simple Hebbian plasticity rule. The present findings suggest that PPS encoding remaps on a very rapid time-scale and is sensitive to recent sensory history.

neuroscience↗

bioRxiv2019

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

Insights into oncogenesis derived from cancer susceptibility loci could facilitate better cancer management and treatment through precision oncology. However, therapeutic applications have thus far been limited by our current lack of understanding regarding both their interactions with somatic cancer driver mutations and their influence on tumorigenesis. Here, by integrating germline datasets relating to cancer susceptibility with tumour data capturing somatically-acquired genetic variation, we provide evidence that single nucleotide polymorphism (SNPs) and somatic mutations in the p53 tumor suppressor pathway can interact to influence cancer development, progression and treatment response. We go on to provide human genetic evidence of a tumor-promoting role for the pro-survival activities of p53, which supports the development of more effective therapy combinations through their inhibition in cancers retaining wild-type p53. SignificanceWe describe significant interactions between heritable and somatic genetic variants in the p53 pathway that affect cancer susceptibility, progression and treatment response. Our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel therapeutic targets.

cancer biology↗

bioRxiv2019

Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits

Inherited genetic variants in tumour suppressors and oncogenes can increase the cancer risk, but little is known about their influence on anthropometric traits. Through the integration of inherited and somatic cancer genetic data, we define functional single nucleotide polymorphisms (SNPs) associated with cancer risk and explore potential pleiotropic associations with anthropometic traits in a cohort of 500,000 individuals. We identify three regulatory SNPs for three important cancer genes that associate with both anthropometric traits and cancer risk. We describe a novel association of a SNP in TP53 (rs78378222) with height, lean body mass measures and basal metabolic rate, as well as validating its known associations with brain and non-melanomatous skin cancer susceptibility. Our results clearly demonstrate that heritable variants in key cancer genes can associate with both differential cancer risk and anthropometric traits in the general population, thereby lending support for a role of genetics in linking these human phenotypes.

genetics↗

bioRxiv2019

Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Adaptation of the islet {beta}-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in {beta}-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurs at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that {beta}-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited similar epigenetic and transcriptional changes. Moreover, genetic variants associated with fasting glucose and type 2 diabetes are enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined. Our findings reveal that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

physiology↗

bioRxiv2019

Leveraging non-human primate multisensory neurons and circuits in assessing consciousness theory

Both the Global Neuronal Workspace (GNW) and Integrated Information Theory (IIT) posit that highly complex and interconnected networks engender perceptual awareness. GNW specifies that activity recruiting fronto-parietal networks will elicit a subjective experience, while IIT is more concerned with the functional architecture of networks than with activity within it. Here, we argue that according to IIT mathematics, circuits converging on integrative vs. convergent yet non-integrative neurons should support a greater degree of consciousness. We test this hypothesis by analyzing a dataset of neuronal responses collected simultaneously from primary somatosensory cortex (S1) and ventral premotor cortex (vPM) in non-human primates presented with auditory, tactile, and audio-tactile stimuli as they are progressively anesthetized with Propofol. We first describe the multisensory (audio-tactile) characteristics of S1 and vPM neurons (mean and dispersion tendencies, as well as noise-correlations), and functionally label these neurons as convergent or integrative according to their spiking responses. Then, we characterize how these different pools of neurons behave as a function of consciousness. At odds with the IIT mathematics, results suggest that convergent neurons more readily exhibit properties of consciousness (neural complexity and noise correlation) and are more impacted during the loss of consciousness than integrative neurons. Lastly, we provide support for the GNW by showing that neural ignition (i.e., same trial co-activation of S1 and vPM) was more frequent in conscious than unconscious states. Overall, we contrast GNW and IIT within the same single-unit activity dataset, and support the GNW.

neuroscience↗

bioRxiv2018

Integrated in vivo quantitative proteomics and nutrient tracing reveals age-related metabolic rewiring of pancreatic β-cell function

Pancreatic {beta}-cell physiology changes substantially throughout life; yet, the mechanisms that drive these changes are poorly understood. Here, we performed comprehensive in vivo quantitative proteomic profiling of pancreatic islets from adolescent and one-year-old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism. We show that these changes in protein abundance are associated with higher activities of glucose metabolic enzymes involved in coupling factor generation as well as increased activity of the coupling factor-dependent amplifying pathway of insulin secretion. Nutrient tracing and targeted metabolomics demonstrated accelerated accumulation of glucose-derived metabolites and coupling factors in islets from one-year-old mice, indicating that age-related changes in glucose metabolism contribute to improved glucose-stimulated insulin secretion with age. Together, our study provides the first in-depth characterization of age-related changes in the islet proteome and establishes metabolic rewiring as an important mechanism for age-associated changes in {beta}-cell function.

physiology↗

bioRxiv2017

Science Game Lab: tool for the unification of biomedical games with a purpose

Games with a purpose and other kinds of citizen science initiatives demonstrate great potential for advancing biomedical science and improving STEM education. Articles documenting the success of projects such as Fold.it and Eyewire in high impact journals have raised wide interest in new applications of the distributed human intelligence that these systems have tapped into. However, the path from a good idea to a successful citizen science game remains highly challenging. Apart from the scientific difficulties of identifying suitable problems and appropriate human-powered solutions, the games still need to be created, need to be fun, and need to reach a large audience that remain engaged for the long-term. Here, we describe Science Game Lab (SGL) (https://sciencegamelab.org), a platform for bootstrapping the production, facilitating the publication, and boosting both the fun and the value of the user experience for scientific games with a purpose.

bioinformatics↗