Biology subjects

Martin, J. M.

Publications and source records attributed to Martin, J. M..

13 recordsLinked to original sources

bioRxiv2026

Harnessing FBXO31 with terminal amide-functionalized molecules for targeted protein degradation

Targeted protein degradation (TPD) is a powerful strategy for controlling protein abundance. Here, we establish FBXO31 as a TPD-competent E3 ligase by exploiting its recognition of C-terminal amide-bearing degrons. Using an amidated Ala-Phe motif as a chemical recruiter, multiple small-molecule binders can be transformed into FBXO31-dependent degraders that induce rapid and potent target degradation. Mechanistic studies confirm FBXO31-mediated ternary complex formation and identify key residues in FBXO31 required for recruiter engagement and target degradation. We further show that an FBXO31-based multi-kinase degrader exhibits a distinct and broader degradation profile than a CRBN-based degrader, highlighting a potentially expanded degradable target space beyond CRBN.

biochemistry↗

bioRxiv2025

To preen or not to preen: social predictors of allopreening in a wild parrot

Allogrooming is fundamental to social relationships in many group-living mammals. In primates, allogrooming has been the subject of decades of research, and has been shown to play an essential role in maintaining social affiliations, and often interchanged for social tolerance and support. Yet, while the equivalent behaviour of allopreening occurs in many avian species, most description has been limited to its role in pair formation and maintenance, with little known about non-pair contexts. Here we investigated the decision-making associated with allopreening in wild sulphur-crested cockatoos, conducting detailed observations of 182 allopreening events between 126 individuals while concurrently recording rank, aggressive interactions, and social networks. We found no influence of sex as predicted if allopreening was primarily about pair bonding, but instead a positive correlation between allopreening and aggression (given and received). Within interactions, individuals were influenced by social association strength and rank, with individuals preening for longer and with more turn-taking when interacting with stronger social associates, and individuals investing more in interactions initiated by higher-ranked individuals. Our results are highly suggestive that allopreening may serve a convergent function in wild parrots to primates, both in maintaining social bonds and in negotiating social tolerance.

animal behavior and cognition↗

bioRxiv2025

Thalamic NRXN1-Mediated Input to Human Cortical Progenitors Drives Upper Layer Neurogenesis

According to the protocortex hypothesis, extrinsic thalamic signaling is necessary for refining cortical areas and cell types, but the mechanism by which these inputs shape the development and expansion of the human cortex remains largely unexplored. We fuse cortical and thalamic organoids to study this process. Using single-nuclei RNA-sequencing and cellular imaging, we discover that thalamic signals during a critical period promote human cortical upper-layer neurogenesis. In assembloid models and human primary cortex, we find NRXN1 mediates thalamic axon contact with primate-enriched outer radial glia, driving developmental gene expression changes. Genetic perturbation of NRXN1 in thalamic neurons reduces these contacts and attenuates cortical upper-layer neurogenesis. These findings in human developmental models suggest a novel role for thalamic regulation of primate outer radial glia cell fate.

neuroscience↗

bioRxiv2024

Long-term stability of dominance hierarchies in a wild parrot with fission-fusion dynamics

Dominance hierarchies are a common feature of stable groups, allowing animals to limit the costs of fighting over access to resources. However, while the emergence of dominance is relatively well known from species that form stable groups, less is known about whether hierarchies are maintained in societies with open group membership. One challenge for species that live in an open social environment is that they have the possibility of engaging in dominance interactions with a large number of conspecifics. To better understand how animals navigate the complexities of interacting within a large, open society, we recorded social associations and aggressive interactions in a highly social, communally roosting parrot, the sulphur-crested cockatoo (Cacatua galerita). By following 515 individuals across three neighbouring communities and recording social interactions during foraging, we show that sulphur-crested cockatoos form clear, linear hierarchies. We find males rank higher than females and that adults rank higher than juveniles. Within sex, where individuals may still have to compete with up to 100 individuals from the same age-sex class, body size did not affect dominance rank. Finally, we find that, despite highly dynamic social associations (fission-fusion dynamics) among individuals, hierarchies are stable, with dominance ranks being highly repeatable across at least three years. This study demonstrates that closed group membership is not a pre-requisites for stable dominance hierarchies to emerge.

animal behavior and cognition↗

bioRxiv2024

Developmental convergence and divergence in human stem cell models of autism spectrum disorder

Two decades of genetic studies in autism spectrum disorder (ASD) have identified over a hundred genes harboring rare risk mutations. Despite this substantial heterogeneity, transcriptomic and epigenetic analyses have identified convergent patterns of dysregulation across ASD post-mortem brain tissue. To identify shared and distinct mutational mechanisms, we assembled the largest hiPS cell patient cohort to date, consisting of 70 hiPS cell lines after stringent quality control representing 8 ASD-associated mutations, idiopathic ASD, and 20 lines from non-affected controls. We used these hiPS lines to generate human cortical organoids (hCO), profiling by RNAseq at four distinct timepoints up to 100 days of in vitro differentiation. Early timepoints harbored the largest mutation-specific changes, but different genetic forms converged on shared transcriptional changes as development progressed. We identified a shared RNA and protein interaction network, which was enriched in ASD risk genes and predicted to drive the observed down-stream changes in gene expression. CRISPR-Cas9 screening of these candidate transcriptional regulators in induced human neural progenitors validated their downstream molecular convergent effects. These data illustrate how genetic risk can propagate via transcriptional regulation to impact convergently dysregulated pathways, providing new insight into the convergent impact of ASD genetic risk on human neurodevelopment.

neuroscience↗

bioRxiv2023

Social decision-making in a wild parrot relies on both individual recognition and intrinsic markers

O_LIDominance hierarchies are generally thought to form over time via memory of repeated interactions. However, dominance hierarchies are also occasionally reported in species with fission-fusion social dynamics, where individuals may encounter large numbers of individuals, leading to incomplete social information. It it has been alternatively proposed that the complex decision-making required in these circumstances may lead to increased selection for social cognition and memory, or to the evolution of mixed strategies that rely on memory for interaction with familiars and status signals for strangers. C_LIO_LIHere, test these competing hypotheses by recording social associations and aggressive interactions in a highly social, large-brained parrot, the sulphur-crested cockatoo ( Cacatua galerita). We followed 411 individuals across three neighbouring roost sites, where individuals exhibit stable dominance hierarchies within roosts, alongside a high degree of fission-fusion dynamics within roosts and regular between-roost movements. C_LIO_LIWe found evidence that sulphur-crested cockatoos use a two-fold social strategy when initiating or reacting to an aggression. For familiar individuals, aggressions were initiated or escalated based on rank difference. When facing less familiar individuals, decisions to interact -- or escalate -- were based on the relative weight, with interactions directed towards, and more likely to escalate between, individuals of similar weight. C_LIO_LIOur results suggest that social knowledge remains an important determinant of aggressive interactions in highly fission-fusion systems, but that individuals can dynamically incorporate other potential cues of competitive ability when knowledge is lacking. C_LI

animal behavior and cognition↗

bioRxiv2023

Wild sulphur-crested cockatoos match human activity rhythms to access food in the urban environment

AO_SCPLOWBSTRACTC_SCPLOWUrban areas are growing rapidly across the globe, and wild species are occupying this new environment. Despite offering potential resources, disparities in the urban matrix can lead to specific challenges, with pathways and resources fragmented in space and time. Urban-dwelling species would therefore benefit from learning when and where to exploit human derived food. Here, we investigate whether birds synchronize the exploitation of the most urbanized areas to match food-provisioning patterns, using the example of the popular hand-feeding of sulphur-crested cockatoos (Cacatua galerita) in Sydney, Australia. We monitored the provisioning behaviour of people via a large-scale citizen science program, and tested for synchrony with the spatial behaviour of eight birds equipped with GPS loggers. Our data show that sulphur-crested cockatoos exploited the urban environment, relying on the green areas of the city; importantly, they also visited buildings within more urbanized areas. Sulphur-crested cockatoos used urban space with specific time patterns particularly matching human recreational feeding routines, suggestive of time-place learning. We show that urban environments provide daily temporal foraging resources for which species adjust behaviorally. Thus, our data support the general claim that retaining green spaces in cities is essential to sustainable urban planning, and key to allow species to exploit the urban environment, particularly in areas of high human density. This study builds on the literature investigating human-animal interactions, expanding our understanding of animals exploitation of human behavior. Further research should include the impact of such interactions on urban wildlifes fitness according to their cognitive and behavioral traits.

animal behavior and cognition↗

bioRxiv2023

TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons

Genetic variation in the transcription factor 4 (TCF4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of ASD called Pitt Hopkins Syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models is shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. Here we show that cortical neurons derived from patients with TCF4 mutations have deficits in spontaneous synaptic transmission, network excitability and homeostatic plasticity. Transcriptomic analysis indicates these phenotypes result from altered expression of genes involved in presynaptic neurotransmission and identifies the presynaptic binding protein, RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. Together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.

neuroscience↗

bioRxiv2022

Multi-network analysis reveals context-dependent kin relationships in wild sulphur-crested cockatoos, Cacatua galerita

O_LIA preference to associate with kin facilitates inclusive fitness benefits, and increased tolerance or cooperation between kin may be an added benefit of group living. Many species exhibit preferred associations with kin, however it is often hard to disentangle active preferences from passive overlap, for example caused by limited dispersal or inheritance of social position. C_LIO_LIMany parrots exhibit social systems consisting of pair-bonded individuals foraging in variably sized fission-fusion flocks within larger communal roosts of hundreds of individuals. Previous work has shown that, despite these fission-fusion dynamics, individuals can exhibit long-term preferred foraging associations outside their pair-bonds. Yet the underlying drivers of these social preferences remains largely unknown. C_LIO_LIIn this study, we use a network approach to examine the influence of kinship on social associations and interactions in wild, communally roosting sulphur-crested cockatoos, Cacatua galerita. We recorded roost co-membership, social associations and interactions in 561 individually marked birds across three neighbouring roosts. We then collected genetic samples from 205 cockatoos, and conducted a relationship analysis to construct a kinship network. Finally, we tested correlations between kinship and four social networks: association, affiliative, low-intensity aggression, and high-intensity aggression. C_LIO_LIOur result showed that while roosting groups were clearly defined, they showed little genetic differentiation or kin structuring. Between roost movement was high, with juveniles, especially females, repeatedly moving between roosts. Both within roosting communities, and when visiting different roosts, individuals preferentially associated with kin. Supporting this, individuals were also more likely to allopreen kin. However, contrary to expectation, individuals preferred to direct aggression towards kin, with this effect only observed when individuals shared roost membership. C_LIO_LIBy measuring social networks within and between large roosting groups, we could remove potential effects of passive spatial overlap on kin structuring. Our study reveals that sulphur-crested cockatoos actively prefer to associate with kin, both within and between roosting groups. By examining this across different interaction types, we further demonstrate that sulphur-crested cockatoos exhibit behavioural and context-dependent interaction rules towards kin. Our results help reveal the drivers of social association in this species, while adding to the evidence for social complexity in parrots. C_LI

animal behavior and cognition↗

bioRxiv2020

Genoppi: an open-source software for robust and standardized integration of proteomic and genetic data

Combining genetic and cell-type-specific proteomic datasets can lead to new biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. We used Genoppi to analyze sixteen cell-type-specific protein interaction datasets of four proteins (TDP-43, MDM2, PTEN, and BCL2) involved in cancer and neurological disease. Through systematic quality control of the data and integration with published protein interactions, we show a general pattern of both cell-type-independent and cell-type-specific interactions across three cancer and one human iPSC-derived neuronal type. Furthermore, through the integration of proteomic and genetic datasets in Genoppi, our results suggest that the neuron-specific interactions of these proteins are mediating their genetic involvement in neurodevelopmental and neurodegenerative diseases. Importantly, our analyses indicate that human iPSC-derived neurons are a relevant model system for studying the involvement of TDP-43 and BCL2 in amyotrophic lateral sclerosis.

genetics↗

bioRxiv2020

Structural differences between REM and non-REM dream reports assessed by graph analysis

Dream reports collected after rapid eye movement sleep (REM) awakenings are, on average, longer, more vivid, bizarre, emotional and story-like compared to those collected after non-REM. However, a comparison of the word-to-word structural organization of dream reports is lacking, and traditional measures that distinguish REM and non-REM dreaming may be confounded by report length. This problem is amenable to the analysis of dream reports as non-semantic directed word graphs, which provide a structural assessment of oral reports, while controlling for individual differences in verbosity. Against this background, the present study had two main aims: Firstly, to investigate differences in graph structure between REM and non-REM dream reports, and secondly, to evaluate how non-semantic directed word graph analysis compares to the widely used measure of report length in dream analysis. To do this, we analyzed a set of 125 dream reports obtained from 19 participants in controlled laboratory awakenings from REM and N2 sleep. We found that: (1) graphs from REM sleep possess a larger connectedness compared to those from N2; (2) measures of graph structure can predict ratings of dream complexity, where increases in connectedness and decreases in randomness are observed in relation to increasing dream report complexity; and (3) measures of the Largest Connected Component of a graph can improve a model containing report length in predicting sleep stage and dream complexity. These results indicate that dream reports sampled after REM awakening have on average a larger connectedness compared to those sampled after N2 (i.e. words recur with a longer range), a difference which appears to be related to underlying differences in dream complexity. Altogether, graph analysis represents a promising method for dream research, due to its automated nature and potential to complement report length in dream analysis.

animal behavior and cognition↗

bioRxiv2019

Reduced transfer coefficient of carbon monoxide in pulmonary arterial hypertension implicates rare protein-truncating variants in KDR

BackgroundApproximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. MethodsWe analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. ResultsHeterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. ConclusionsThe Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

genetics↗

bioRxiv2017

Novel causative genes for heritable pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-{beta} pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

genetics↗