Biology subjects

Perry, G.

Publications and source records attributed to Perry, G..

12 recordsLinked to original sources

bioRxiv2026

A myosin filament cage drives multiple aspects of mitosis unique to cells dividing within a polarized epithelium

Here we used mouse intestinal organoids expressing endogenously tagged myosin to clarify its roles in those aspects of mitosis unique to division within a polarized epithelium. Super-resolution imaging of rounded metaphase cells revealed a never-before-seen myosin filament cage that only forms in this context, exhibits apical/basal polarity, maintains roundness by resisting surrounding tissue pressure, and repositions laterally to form a contractile ring predetermined to drive planar division and asymmetric cleavage furrow progression. Attenuating cage function inhibited interkinetic nuclear migration and metaphase cell rounding, causing the division plane to shift from planar to orthogonal and resulting in organoids possessing multiple lumens. Following the apical domain marker ZO-1 showed that the new lumens originate at the interface between stacked daughter cells created by orthogonal divisions. We conclude that cells dividing within polarized epithelia create a myosin filament cage designed specifically to drive those aspects of cell division unique to their context.

cell biology↗

bioRxiv2026

No overlap in neurophysiological predictors of moment-to-moment fluctuations of behavioural variability and subjective attentional state

Behaviour fluctuates from moment to moment - often attributed to changes in subjective attentional states (e.g., mind wandering). Yet, it remains unclear how closely behavioural variability and subjective attentional state are related, and whether they share biological mechanisms. Using [~]2 hours of Metronome Response Task data, we combined magnetoencephalography, eye and head tracking, pupillometry, and thought probes to predict trial-to-trial fluctuations in both. Although they covaried weakly, this relationship was largely accounted for by time-on-task. Several markers including blink duration, pupil variability, and head movement predicted both measures. Dissociations also emerged: behavioural variability was linked to broadband functional connectivity and delta power, whereas off-taskness was predicted by theta, alpha, and beta power. Critically, predictive strength of behavioural variability and subjective reports were uncorrelated at the individual level, with substantial individual differences. For both outcomes, multimodal models outperformed univariate analyses. Our findings show that behavioural variability and subjective attentional state are largely dissociable, challenging the assumption that they share underlying process or that one causes the other.

neuroscience↗

bioRxiv2026

Deep nanoparticle protein corona plasma proteomics resolves a stage-specific peripheral signature of Alzheimer's disease

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSAlzheimers disease (AD) progresses over decades, yet plasma biomarkers that resolve disease stage rather than simply detect disease remain scarce. This distinction is clinically consequential because effective AD intervention depends on identifying patients before disease biology has progressed beyond a therapeutically responsive stage. METHODSWe used small-molecule-modulated protein corona proteomics to profile plasma from 90 individuals in the Australian Imaging, Biomarker and Lifestyle cohort, stratified by Centiloid (CL) A{beta}-amyloid burden (30 amyloid- negative, CL < 15; 30 moderate-to-high, CL 26 to 100; 30 very high, CL > 100). We quantified 3,176 proteins and applied differential abundance and actual causality analyses to identify stage-specific and candidate causal proteins. RESULTSDifferential protein abundance was exclusively captured during the moderate-to-high AD transition, revealing a discrete proteomic "switch." The switch was marked by accumulation of the autophagy receptor CALCOCO1, together with coordinated depletion of the S100A8/S100A9 calprotectin complex and core erythroid-cytoskeletal network structural markers (e.g., SPTA1, SPTB, ANK1). Adhesion G protein-coupled receptor G6 (ADGRG6) showed a significant moderate positive monotonic association with absolute CL burden, providing a proportional molecular anchor for cumulative disease burden. Actual causality analysis identified COL6A2, FOXRED2, P3H1, PRR4, and GOLGA5 as candidate upstream drivers linking matrix remodeling, Golgi trafficking, and collagen processing to AD progression. DISCUSSIONThese findings suggest a candidate blood-accessible framework for staging AD by active disease biology, which, if replicated in independent cohorts, may have implications for therapeutic selection and mechanism-guided clinical trials. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/740710v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ead718org.highwire.dtl.DTLVardef@cfa523org.highwire.dtl.DTLVardef@62a367org.highwire.dtl.DTLVardef@1d5c9a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Fine-scale population structure within and among Malagasy societies

The population of Madagascar exhibits a globally unique combination of African and Asian genetic ancestries. Previous studies have described the admixture history of Madagascar at island-wide scales [1,2], but less focus has been paid to fine-scale population structure across the island. We present new genome-wide genetic data from 192 individuals sampled across five regions of Madagascar. We identify population structure at extremely fine spatial scales ([~]10 km) among the Merina of the central highlands. By analysing subpopulations separately, we found one Merina group exhibited similarity to coastal populations in f4 ratios, estimated admixture dates, and pairwise FST distances, while another group was similar to other highland individuals in the same measures. This fine-scale substructure is likely associated with historical coastal-to-highland migration during the 18th and 19th centuries. In contrast, we also observe macro-scale structure in estimated timing of admixture across the island, with southeastern coastal groups exhibiting the earliest estimated admixture timings, and northern groups exhibiting the latest. This pattern corroborates previous results [1,2], and may suggest differing histories of admixture timing among Malagasy populations. Our results emphasise the importance of deep micro-geographic sampling to complement macro-scale analysis when characterising demographic history.

genetics↗

bioRxiv2026

The impact of serial translocations on the genetic diversity of Anegada iguanas (Cyclura pinguis) in the British Virgin Islands

Animal translocations are becoming increasingly popular as a tool for conservationists. Demographic factors can be crucial determinants dictating translocation viability in the short term. Translocated populations pass through artificial bottlenecks and can suffer from founder effects. Reduction in genetic variation relative to their source populations is likely, limiting their adaptive potential. Founder events can increase frequencies of deleterious alleles due to elevated rates of inbreeding and inbreeding depression. Here, we describe the effects of human-driven, serial population translocations on the genetic diversity of critically endangered Anegada iguanas (Cyclura pinguis) in the British Virgin Islands. Though founding populations were extremely small (N=8, N=4), the census sizes of translocated iguana populations increased dramatically over the first twenty years. This implies that these translocations were successful from a demographic perspective despite the small number of animals used, indicating a genetic paradox. To quantify genetic signatures in these bottlenecked populations, blood samples were collected from the source population and two translocated populations and genotyped at 21 microsatellite loci. We found that allele frequencies in translocated populations differed significantly from those of the source, with the translocated populations having less genetic diversity. However, common methods for estimating presence of genetic bottlenecks were non-significant. Estimates of internal relatedness by age class suggest that inbreeding depression may be elevated after translocation, likely reflecting the small initial population sizes associated with these translocation events. Anecdotally, our work shows that translocations may result in subtle genetic erosion that has long-term population viability impacts, even when census size indicates success.

genetics↗

bioRxiv2024

A paleogenomic approach to reconstruct historical responses of coral reefs to anthropogenic change

Coral reefs are declining worldwide due to anthropogenic environmental change. The foundation and health of these ecosystems rely on the harmonious functioning of all members of coral holobionts, i.e., cnidarian host, symbiotic microalgae, and associated microbiome. Coral stress responses often involve shifts in the taxonomic identity of their symbionts and microbiomes. Tracing back changes in coral holobiont composition over prolonged time periods can help us reconstruct health history of reefs and gain a better understanding of coral response to current stressors. Here, we focused on a major Caribbean reef-builder coral, Orbicella faveolata, from Varadero Reef, Colombia. This reef has undergone extensive freshwater sediment discharge and pollution for decades as result of urbanization. We show, for the first time, that paleogenomic and paleoclimatic approaches can be combined to reconstruct historical coral holobiont dynamics potentially associated with anthropogenic disturbances.

molecular biology↗

bioRxiv2024

Parallel phosphoproteomics and metabolomics map the global metabolic tyrosine phosphoproteome

Tyrosine phosphorylation of metabolic enzymes is an evolutionarily conserved post-translational modification that facilitates rapid and reversible modulation of enzyme activity, localization or function. Despite the high abundance of tyrosine phosphorylation events detected on metabolic enzymes in high-throughput mass spectrometry-based studies, functional characterization of tyrosine phosphorylation sites has been limited to a subset of enzymes. Since tyrosine phosphorylation is dysregulated across human diseases, including cancer, understanding the consequences of metabolic enzyme tyrosine phosphorylation events is critical for informing disease biology and therapeutic interventions. To globally identify metabolic enzyme tyrosine phosphorylation events and simultaneously assign functional significance to these sites, we performed parallel phosphoproteomics and polar metabolomics in non-tumorigenic mammary epithelial cells (MCF10A) stimulated with epidermal growth factor (EGF) in the absence or presence of the epidermal growth factor receptor (EGFR) inhibitor erlotinib. We performed an integrated analysis of the phosphoproteomic and metabolomic datasets to identify tyrosine phosphorylation sites on metabolic enzymes with functional consequences. We identified two previously characterized (PKM, PGAM1) and two novel (GSTP1, GLUD1) tyrosine phosphorylation sites on metabolic enzymes with purported functions based on metabolomic analyses. We validated these hits using a doxycycline-inducible CRISPR interference (CRISPRi) system in MCF10A cells, in which target metabolic enzymes were depleted with simultaneous re-expression of wild-type, phosphomutant or phosphomimetic isoforms. Together, these data provide a framework for identification, prioritization and characterization of tyrosine phosphorylation sites on metabolic enzymes with functional significance.

biochemistry↗

bioRxiv2024

Body size is a better predictor of intra- than interspecific variation of animal stoichiometry across realms

Animal stoichiometry affects fundamental processes ranging from organismal physiology to global element cycles. However, it is unknown whether animal stoichiometry follows predictable scaling relationships with body mass and whether adaptation to life on land or water constrains patterns of elemental allocation. To test both interspecific and intraspecific body-size scaling relationships of the nitrogen (N), phosphorus (P), and N:P content of animals, we used a subset of the StoichLife database encompassing 9,933 individual animals (vertebrates and invertebrates) belonging to 1,543 species spanning 10 orders of magnitude of body size from terrestrial, freshwater, and marine realms. Across species, body mass did not explain much variation in %N and %P composition, although the %P of invertebrates decreased with size. The effects of body size on species elemental content were small in comparison to the effects of taxonomy. Body size was a better predictor of intraspecific than interspecific elemental patterns. Between 42 to 45% in intraspecific stoichiometric variation was explained by body size for 27% of vertebrate species and 35% of invertebrate species. Further, differences between organisms inhabiting aquatic and terrestrial realms were observed only in invertebrate interspecific %N, suggesting that the realm does not play an important role in determining elemental allocation of animals. Based on our analysis of the most comprehensive animal stoichiometry database, we conclude that (i) both body size and realm are relatively weak predictors of animal stoichiometry across taxa, and (ii) body size is a good predictor of intraspecific variation in animal elemental content, which is consistent with tissue-scaling relationships that hold broadly across large groups of animals. This research reveals a lack of general scaling patterns in the elemental content across animals and instead points to a large variation in scaling relationships within and among lineages.

ecology↗

bioRxiv2023

Reconstructing colonization dynamics to establish how human activities transformed island biodiversity

AimThe drivers and dynamics of initial human migrations across individual islands and archipelagos are poorly understood, affecting assessments of human-modification of island biodiversity. Here, we describe and test a process-explicit approach for reconstructing human arrival and expansion on islands, which combines archaeological and climate records with high-resolution spatial population models. Using Polynesian colonisation of New Zealand as an example, we show that our new method can generate information crucial for assessing how humans affected biodiversity on islands. InnovationThe transition of islands from prehuman to human dominated ecosystems has typically been assessed by comparing biodiversity before and after time of first arrival, without considering the potential importance of the spatiotemporal dynamics of the human expansion event. Our new approach, which uses pattern-oriented modelling methods to combine inferences of human colonisation dynamics from dated archaeological material with spatially explicit population models, produces validated reconstructions of the pattern and pace of human migration across islands at high spatiotemporal resolutions. From these reconstructions, demographic and environmental drivers of human colonization can be identified, and the role that people had on biodiversity established. Using this technique, we show that closely reconciling inferences of Polynesian colonisation of New Zealand requires there to have been a single founding population of approximately 500 people, arriving between 1233 and 1257 AD, settling multiple areas, and expanding quickly over both North and South islands. The resultant maps of M[a]ori colonisation dynamics provide new opportunities to better determine how human activities transformed biodiversity of New Zealand in space and time. Main conclusionsProcess-explicit models can reconstruct human migration across large islands, producing validated, high resolution spatiotemporal projections of human occupancy and abundance that account for dispersal and population dynamics. This modelling framework should prove effective across any islands and archipelagos where climate and archaeological records are available.

ecology↗

bioRxiv2023

Chemoresistome Mapping in Individual Breast Cancer Patients Unravels Diversity in Dynamic Transcriptional Adaptation

Emerging evidence reinforce the role of non-genetic adaptive resistance to chemotherapy, that involves rewiring of transcriptional programs in surviving tumors. We combined longitudinal transcriptomics with temporal pattern analysis to dissect patient-specific emergence of resistance in breast cancer. Matched triplets of tumor biopsies (pre-treatment, post-treatment and adjacent normal) were collected from breast cancer patients who received neo-adjuvant chemotherapy. Full transcriptome was analyzed by longitudinal pattern classification to follow patient-specific expression modulations. We found that dynamics of gene expression dictates resistance-related modulations. The results unraveled important principles in emergence of adaptive resistance: 1. Genes with resistance patterns are already dysregulated in the primary tumor, supporting a primed drug-tolerant state. 2. In each patient, multiple resistance-related genes are rewired but converge into few dysregulated modules. 3. Rewiring of diverse genes and pathway dysregulation vary among individuals who receive the same treatments. Patient-specific chemoresistome maps disclosed tumors acquired resistance and exposed their vulnerabilities. Mapping the complexity of dysregulated pathways in individual patients revealed important insights on adaptive resistance mechanisms. To survive the toxic drug effect, tumor cells either sustain a drug-tolerant state or intensify it, specifically bypassing the drugs interference. Depicting an individual road map to resistance can offer personalized therapeutic strategies.

cancer biology↗

bioRxiv2022

Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation

Over 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, there remains scope to improve upon the therapeutic window of the current generation of AKT inhibitors. Here we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-driven phenotypes in breast cancer cell lines. A systematic growth inhibition screen across 288 cancer cell lines confirmed a substantially higher potency for INY-05-040 (median GI50adj = 1.1 {micro}M) compared to our first-generation AKT degrader (INY-03-041; median GI50adj = 3.1 {micro}M), with both compounds outperforming catalytic AKT inhibition with GDC-0068 (median GI50adj > 10 {micro}M). Using multi-omic profiling and causal network integration in breast cancer cells, we demonstrate that the enhanced efficacy of INY-05-040 is associated with sustained suppression of AKT signaling, followed by a potent induction of the stress mitogen activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low baseline JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Collectively, our study presents a systematic framework for mapping the network-wide signaling effects of therapeutically relevant compounds, and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling.

cancer biology↗

bioRxiv2019

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

neuroscience↗