Biology subjects

Bird, L.

Publications and source records attributed to Bird, L..

6 recordsLinked to original sources

bioRxiv2024

Shaping the developing homunculus: the roles of deprivation and compensatory behaviour in sensory remapping

Some of the most dramatic examples of neuroplasticity in the human brain follow congenital sensory deprivation, though we have limited understanding of the plasticity mechanisms driving such large-scale remapping. Hand loss due to congenital limb differences (CLD) offers a unique temporal dissociation of developmental neuroplasticity mechanisms: While sensory deprivation is congenital, compensatory motor behaviours develop progressively across childhood. Using paediatric neuroimaging and semi-ecological behavioural analysis in children (5-7 years old) and adults (>25 years old) with unilateral upper-limb CLD, we studied deprivation- and use-dependent plasticity in the deprived primary somatosensory cortex and beyond. We reveal that global remapping, encompassing the entire sensory homunculus, is established early and maintained in adulthood. We demonstrate that deprivation-driven homeostatic plasticity can drive this global remapping, with Hebbian-based compensatory learning further contributing to inter-individual differences both in childhood and adulthood. Our findings emphasise the early establishment and stability of cortical maps, despite extensive daily-life behavioural adaptation.

neuroscience↗

bioRxiv2022

Conservation of energetic pathways for electroautotrophy in the uncultivated candidate order Tenderiales

Electromicrobiology can be used to understand extracellular electron uptake in previously undescribed chemolithotrophs. Enrichment and characterization of the uncultivated electroautotroph "Candidatus Tenderia electrophaga" using electromicrobiology led to the designation of the order Tenderiales. Representative Tenderiales metagenome assembled genomes (MAGs) have been identified in a number of environmental surveys, yet a comprehensive characterization of conserved genes for extracellular electron uptake has thus far not been conducted. Using comparative genomics we identified conserved orthologous genes within the Tenderiales and nearest neighbor orders important for extracellular electron uptake based on a previously proposed pathway from "Ca. Tenderia electrophaga". The Tenderiales contained a conserved cluster we designated uetABCDEFGHIJ, which encodes proteins containing features that would enable transport of extracellular electrons to cytoplasmic membrane bound energy transducing complexes such as two conserved cytochrome cbb3 oxidases. For example, UetJ is predicted to be an extracellular undecaheme c-type cytochrome that forms a heme wire. We also identified clusters of genes predicted to facilitate assembly and maturation of electron transport proteins, as well as cellular attachment to surfaces. Autotrophy among the Tenderiales is supported by the presence of carbon fixation and stress response pathways that could allow cellular growth by extracellular electron uptake. Key differences between the Tenderiales and other known neutrophilic iron oxidizers were revealed, including very few Cyc2 genes in the Tenderiales. Our results reveal a possible conserved pathway for extracellular electron uptake and suggests the Tenderiales have an distribution unlimited ecological role coupling metal or mineral redox chemistry and the carbon cycle in marine and brackish sediments. ImportanceElectromicrobiology enables enrichment and identification of chemolithotrophic bacteria capable of extracellular electron uptake to drive energy metabolism and CO2 fixation. The recently described order Tenderiales contains the uncultivated electroautotroph "Candidatus Tenderia electrophaga". The "Ca. Tenderia electrophaga" genome contains genes proposed to make up a previously undescribed extracellular electron uptake pathway. Here we use comparative genomics to show that this pathway is well conserved among Tenderiales spp. recovered by metagenome assembled genomes. This conservation extends to near neighbors of the Tenderiales, but not to other well-studied chemolithotrophs including iron and sulfur oxidizers. Our findings suggest that extracellular electron uptake may be pervasive among the Tenderiales and the geographic location from which metagenome assembled genomes were recovered offers clues to their natural ecological niche.

microbiology↗

bioRxiv2021

Preclinical studies for plant-based oral enzyme replacement therapy (Oral-ERT) in Pompe disease knockout mice with transgenic tobacco seeds expressing human GAA (tobrhGAA)

Genetic deficiency of acid -glucosidase (GAA) results in glycogen storage disease type II (GSDII) or Pompe disease (PD) encompassing at least four clinical subtypes of varying severity (infantile; childhood, juvenile and late onset). Our objective is to develop an innovative and affordable approach for enzyme replacement therapy (ERT) via oral administration (Oral-ERT) to maintain a sustained, therapeutic level of enzyme on a daily basis to improve efficacy of treatment and quality of life for people living with Pompe disease. A consensus at a 2019 US Acid Maltase Deficiency (AMDA) conference suggested that a multi-pronged approach including gene therapy, diet, exercise, etc. must be evaluated for a successful treatment of Pompe disease. Tobacco seeds contain the metabolic machinery that is more compatible with mammalian glycosylation-phosphorylation and processing. Previously, we have shown that a lysate from transgenic tobacco seeds expressing human GAA (tobrhGAA) was enzymatically active and can correct enzyme deficiency in cultured PD cells and in adult lymphocytes of Pompe patients and in vivo in disease-relevant tissues in GAA knockout (KO) mice when administered IP. We have extended these pre-clinical studies in PD knockout (KO) mice with ground tobrhGAA seeds that supports proof-of-concept for Oral-ERT for future clinical trials. Briefly in GAA KO mice, Oral-ERT with ground tobrhGAA seeds showed significant reversal of fore-limb and hind-limb muscle weakness, increased motor coordination/balance/strength and mobility, improved spontaneous learning, increased GAA baseline activity in tissues, reduced glycogen in tissues and negible serum titers to GAA. Pharmacokinetics showed maximum serum GAA concentration (Cs) at 8-10 hr and peak urine excretion at 10-12 hr. The tobrhGAA was taken up in PD fibroblast, lymphoid and myoblast cells. Enzyme kinetics compared favorably or superior to placental hGAA, plus alglucosidase alfa or other rhGAAs for Km, Vmax, pH optima, thermal heat stability and IC50 for inhibitors. The tobrhGAA in seeds was extremely stable stored for 15 years at room temperature. NGS-genome sequencing of the tobrhGAA and wild-type plants and RNA expression profiles was performed and will be posted on our website. Thus, Oral-ERT with ground tobrhGAA seeds is an innovative approach that overcomes some of the challenges of alglucosidase alfa-ERT and provides a more effective, safe and significantly less expensive treatment.

genetics↗

bioRxiv2019

How the dual PDZ domain from Postsynaptic density protein 95 clusters ion channels and receptors.

PSD-95 is a member of Membrane Associated Guanylate Kinase class of proteins which form scaffolding interactions with partner proteins including ion and receptor channels. PSD-95 is directly implicated in modulating the electrical responses of excitable cells. The first two PSD-95/Disks Large/Zona Occludens domains of PSD-95 have been shown to be the key component in the formation of channel clusters. We report crystal structures of the dual domain in both in apo and ligand-bound form; thermodynamic analysis of ligand association and Small Angle X-ray Scattering of the dual domain in the absence and presence of ligands. These experiments reveal that the ligated double domain forms a scaffold in the complete sense of the word. The concentration of the components in this study is comparable to those found in compartments of excitable cells such as the postsynaptic density and juxta-paranodes of Ranvier. The properties of the dual domain explain the basis of the scaffolding function of PSD-95, and provide a more detailed understanding of the integration of key components of neuronal specializations involved in nervous signal transmission.

biophysics↗

bioRxiv2018

Sensory Cue Combination in Children Under 10 Years of Age

Cue combination occurs when two independent noisy perceptual estimates are merged together as a weighted average, creating a unified estimate that is more precise than either single estimate alone. Surprisingly, this effect has not been demonstrated compellingly in children under the age of 10 years, in contrast with the array of other multisensory skills that children show even in infancy. Instead, across a wide variety of studies, precision with both cues is no better than the best single cue - and sometimes worse. Here we provide the first consistent evidence of cue combination in children from 7-10 years old. Across three experiments, participants showed evidence of a bimodal precision advantage (Experiments 1a and 1b) and the majority were best-fit by a combining model (Experiment 2). The task was to localize a target horizontally with a binaural audio cue and a noisy visual cue in immersive virtual reality. Feedback was given as well, which could both (a) help participants judge how reliable each cue is and (b) help correct between-cue biases that might prevent cue combination. A feedback effect was found in Experiment 2, with children who were given single-cue feedback showing the highest rate of cue combination. Given this, we suggest that children at 7-10 years old are capable of cue combination in principle, but must have sufficient representations of reliabilities and biases in their own perceptual estimates as relevant to the task, which can be facilitated through task-specific feedback.

neuroscience↗

bioRxiv2018

The molecular structure of Schistosoma mansoni PNP isoform 2 provides insights into the nucleotide selectivity of PNPs

Purine nucleoside phosphorylases (PNPs) play an important role in the blood fluke parasite Schistosoma mansoni as a key enzyme of the purine salvage pathway. Here we present the structural and kinetic characterization of a new PNP isoform from S. mansoni, named as SmPNP2. Screening of different ligands using a thermofluorescence approach indicated cytidine and cytosine as potential ligands. The binding of cytosine was confirmed by isothermal titration calorimetry, with a KD of 27 M, and kinetic parameters for cytidine catalysis were obtained by ITC resulting in a KM of 76.3 M. SmPNP2 also displays catalytic activity against inosine and adenosine, making it the first described PNP with robust catalytic activity towards both pyrimidines and purines. Crystallographic structures of SmPNP2 with different ligands were obtained and comparison of these structures with the previously described S. mansoni PNP (SmPNP1) provided clues for the unique capability of SmPNP2 to bind pyrimidines. When compared with the structure of SmPNP1, substitutions in the vicinity of SmPNP2 active site alter the architecture of the nucleoside base binding site allowing an alternative binding mode for nucleosides, with a 180{degrees} rotation from the canonical binding mode. The remarkable plasticity of this binding site deepens the understanding of the correlation between structure and nucleotide selectivity, offering new ways to analyses PNP activity.\n\nAuthor SummarySchistosoma mansoni is a human parasite dependent on purine salvage for purine bases supply. Purine nucleoside phosphorylase (PNP) is a key enzyme in this pathway. It carries two PNP isoforms, one previously characterized (SmPNP1) and one unknown (SmPNP2). Here we present the crystallographic structure of SmPNP2 and its complex with cytosine, cytidine, ribose-l-phosphate, adenine, hypoxanthine, and tubercidin. Cytidine and cytosine were identified as ligands of SmPNP2 using a thermofluorescence approach. Binding of cytosine was proven by Isothermal Titration Calorimetry (ITC) and cytidine, inosine, and adenosine kinetic parameters were also obtained. Purine bases showed different binding in the active site, rotated 180{degrees} from the canonical binding mode. Its the first report showing a Low Molecular Mass PNP capable of catalyzing both types of nucleotide bases. The SmPNP2 odd behavior sheds a new light on the Schistosoma mansonis life cycle metabolic adaptation.

biochemistry↗