Biology subjects

West, J. A.

Publications and source records attributed to West, J. A..

8 recordsLinked to original sources

bioRxiv2026

Thriving to surviving: light wavelength modulates photoacclimation response in the siphonous green alga Derbesia

Algae require specific acclimation strategies to cope with spectral variability in shallow marine habitats. We investigated how the siphonous green alga Derbesia alters its photosynthetic and metabolic processes under white (WL), blue (BL), green (GL), red (RL), and far-red light (FL) by conducting photobiological and transcriptomic sampling over a 10-day period. Our results show two contrasting photoacclimation strategies: BL and GL promoted metabolic activity associated with growth, whereas FL and RL induced a low-light-like survival strategy characterized by reduced growth and suppression of the core metabolism. Photosynthetic acclimation across all conditions primarily occurs within the light dependent reactions. BL and GL promoted early acclimation marked by the immediate activation of light-harvesting complexes (LHCs) and a key transcriptional regulator MYB, and showed better acclimation marked by the sustained activation of ATPases, ATP transporters, and hormone-signaling components. BL induced a distinct transcriptional shift during the transition to prolonged exposure, including enhanced cyclic electron transport, and key regulators of protein synthesis, DNA replication, and transcriptional regulation. In contrast, FL, and to a lesser extent RL, triggered responses resembling low light acclimation with constrained growth, characterized by inefficient energy utilization, enlarged antenna systems, chloroplast proliferation with aggregations, and reduced growth rates. This study suggests high accumulation of core photopigments and reduction in chlorophyll a/b is an acclimatory response to FL, and consistently higher activation of core metabolic processes under WL likely indicates the evolutionary adaptation of Derbesia to shallow coastal environments where broad-spectrum light predominates. Additionally, our newly sequenced draft genome of the Derbesia strain for this study could serve as a genomic resource for future molecular photobiology research in Bryopsidales algae.

ecology↗

bioRxiv2025

The expanded Bostrychia moritziana genome unveils evolution in the most diverse and complex order of red algae

Red seaweeds form part of an ancient lineage of eukaryotes that were one of the first to evolve multicellularity. Although they share a common evolutionary origin with modern-day plants and display complex multicellular development, we still lack comprehensive genome data from the most highly-evolved groups of red algae. Here, we present a chromosome-level genome assembly of Bostrychia moritziana, a species that is classified into the Rhodomelaceae family of the Ceramiales order, both of which constitute the largest and most diverse family and order of red algae, respectively. Contrary to the commonly held view that red algae generally have small genomes, we report significant genome size expansion in Bostrychia and other Ceramiales species, which we posit as one of at least three independent genome expansion events that occurred during red algal evolution. Our analyses suggest that these expansions do not involve polyploidy or ancient whole genome duplications, but in the case of Bostrychia appear to be largely driven by the dramatic proliferation of a single lineage of giant Plavaka DNA transposons. Consistent with increased genome size, we identify a substantial increase in gene content in Bostrychia that was shaped both by de novo gene emergence and by the amplification of gene families in common with other Ceramiales seaweeds, providing key insight into the genetic adaptations underpinning the evolutionary success of this species-rich order. Finally, our sex-specific assemblies enabled us to resolve the UV sex chromosomes in Bostrychia, which feature expanded gene-rich sex-linked regions. Notably, these sex-linked regions each harbour a distinct TALE-HD transcription factor orthologous to ancient regulators of haploid-diploid transitions in other multicellular lineages. Together, our findings offer a unique perspective of the genomic adaptations driving red algal diversity and demonstrate how this highly successful group of red seaweeds can provide insight into the evolutionary origins and universal principles of complex multicellular plant life.

genomics↗

bioRxiv2023

ATP13A3 Variants Promote Pulmonary Arterial Hypertension by Disrupting Polyamine Transport

AimsPotential loss-of-function variants of ATP13A3, the gene encoding a P5B-type transport ATPase of undefined function, were recently identified in pulmonary arterial hypertension (PAH) patients. ATP13A3 is implicated in polyamine transport but its function has not been fully elucidated. Here, we sought to determine the biological function of ATP13A3 in vascular endothelial cells and how PAH-associated mutations may contribute to disease pathogenesis. We also generated mice harbouring an Atp13a3 variant analogous to a human disease-associated variant to establish whether these mice develop PAH. Methods and ResultsWe studied the impact of ATP13A3 deficiency and overexpression in endothelial cell (EC) models (human pulmonary ECs, blood outgrowth ECs (BOECs) and HMEC-1 cells), including a PAH patient-derived BOEC line harbouring an ATP13A3 variant (LK726X). ATP13A3 localised to the recycling endosomes of human ECs. Knockdown of ATP13A3 in ECs generally reduced the basal polyamine content, consistently reduced putrescine uptake, and altered the expression of enzymes involved in polyamine metabolism. Conversely, overexpression of wild-type ATP13A3 increased polyamine uptake, with an overall preference of putrescine > spermidine > spermine. Functionally, loss of ATP13A3 was associated with reduced EC proliferation, increased apoptosis in serum starvation and increased monolayer permeability to thrombin. Assessment of five PAH-associated missense ATP13A3 variants (L675V, M850I, V855M, R858H, L956P) confirmed loss-of-function phenotypes represented by impaired polyamine transport and dysregulated EC function. Furthermore, mice carrying a heterozygous germ-line Atp13a3 frameshift variant representing a human mutation spontaneously developed a PAH phenotype, with increased pulmonary pressures, right ventricular remodelling and muscularisation of pulmonary vessels. ConclusionWe identify ATP13A3 as a polyamine transporter, deficiency of which leads to EC dysfunction and predisposes to PAH. This suggests a need for targeted therapies to alleviate the imbalances in polyamine homeostasis and EC dysfunction in PAH. Translational perspectiveRare missense ATP13A3 disease-associated variants have been identified in patients with pulmonary arterial hypertension (PAH), though their pathogenicity has not been confirmed as the function of ATP13A3 is not known. We have identified ATP13A3 as a polyamine transporter, showing that ATP13A3 deficiency impaired polyamine homeostasis and uptake, and drove endothelial dysfunction. Conversely, overexpression increased polyamine uptake and rescued the proapoptotic phenotype of cells harbouring a disease-associate variant. Mice heterozygous for a disease-associated Atp13a3 mutation spontaneously develop PAH. These findings support the rationale for exploring dysregulated polyamine homeostasis in PAH and suggest a potential for therapeutic targeting of polyamine pathways in PAH.

cell biology↗

bioRxiv2022

Unifying genomics and transcriptomics in single cells with ResolveOME amplification chemistry to illuminate oncogenic and drug resistance mechanisms

Discovering transcriptional variation in the absence of underlying genomic contributions hinders understanding of molecular mechanisms of disease. To assess this coordination in individual cells, we leveraged a new workflow, ResolveOME, exploiting the attributes of primary template-directed amplification (PTA) to enable accurate, complete-genome assessment of single-nucleotide variation in conjunction with full-transcript RNA-seq. In cultured AML cells resistant to the FLT3 inhibitor quizartinib, we uncovered a FLT3 missense mutation and matched transcript upregulation of AXL signal transduction and enhancer factor modulation driving resistance. In primary breast cancer cells, we detected oncogenic PIK3CA N345K mutations and heterogeneous classes of chromosomal loss and were empowered to interpret these genotypes with the crucial knowledge of cell identity and state derived from the transcriptome. The study reinforces the plasticity of the genome in conjunction with expected transcriptional modulation, leading to combinatorial alterations that affect cellular evolution that can be identified through application of this workflow to individual cells.

genomics↗

bioRxiv2019

Proximal and Distal Gut Mucosa Adapt Differently to Westernized Diet, Promoting an Insulin-Resistant Dysmetabolic State

ObjectiveCombinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. To this end we investigated the metabolic effects of co-administration of previously reported peptide-based GIPR antagonists with the GLP-1 agonist liraglutide. MethodsTwo GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NAc-K10[{gamma}E{gamma}E-C16]-Arg18-hGIP(5-42)), were pharmacologically characterised in vitro in an assay measuring cAMP production in CHO-K1 cells overexpressing the mouse GIPR. These peptides were then characterised in vivo in lean mice for their effect on oral glucose tolerance, as well as their ability to antagonize exogenous GIP action. Finally, a mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of peptide-based GIPR antagonists, alone or in combination with liraglutide. ResultsIn vitro, both GIPR peptides exhibited potent antagonistic properties, with GIPA-2 being the more potent of the two. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and circulated insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels, with offsetting effects on glycemia noted with co-administration with exogenous mouse GIP, suggesting true antagonism via GIPA-2 at the GIP receptor. Chronic administration studies in a DIO mouse model showed expected effects of GLP-1 agonism (via liraglutide), lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy with the GIPR antagonists and GLP-1 showed separation from single intervention arms though augmented insulin sensitizing effects (modestly lowering insulin and HOMA-IR) and lowering plasmas triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. ConclusionWe conclude that, in contrast to the well-documented effects of GLP-1R agonism, systemic administration of peptide-based GIPR antagonists demonstrate minimal benefit on metabolic parameters in DIO mice, exhibiting no major effects on body weight, food intake and glycaemic parameters. However, the co-administration of both a GIPR antagonist together with a GLP1 agonist uncovers interesting synergistic and beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

molecular biology↗

bioRxiv2019

Amitosis confers benefits of sex in the absence of sex to Tetrahymena

Sex appears to be the most successful reproductive strategy in eukaryotes despite its many costs. While a complete explanation for sexs success remains elusive, several evolutionary benefits of sex have been identified. It is predicted that, by forgoing these benefits, asexual lineages are evolutionary dead-ends. Consistent with this prediction, many asexual lineages show signs of accelerated accumulation of deleterious mutations compared to their sexual relatives. Despite these low expectations, some asexual eukaryotic lineages appear to be successful, including the ciliate Tetrahymena. Here, we show that the mechanism of somatic nuclear division in Tetrahymena, known as amitosis, provides benefits similar to sex, allowing for the long-term success of asexual lineages. We found that, when compared to mitosis, amitosis with chromosome copy number control reduces mutation load deterministically, slows the accumulation of deleterious mutations under genetic drift, and accelerates adaptation. These benefits arise because, like sex, amitosis can generate substantial genetic variation in fitness among (asexual) progeny. Our results indicate that the ability of Tetrahymena to persist in the absence of sex may depend on non-sexual genetic mechanisms conferring benefits typically provided by sex, as has been found in other asexual lineages.

evolutionary biology↗

bioRxiv2019

The consequences of lipid remodelling of adipocyte cell membranes being functionally distinct from global lipid storage during obesity

Obesity is a complex disorder where the genome interacts with diet and environmental factors to ultimately influence body mass, composition and shape. Numerous studies have investigated how bulk lipid metabolism of adipose tissue changes with obesity, and in particular how the composition of triglycerides (TGs) changes with increased adipocyte expansion. However, reflecting the analytical challenge posed by examining non-TG lipids in extracts dominated by TGs, the glycerophospholipid (PL) composition of cell membranes has been seldom investigated. PLs contribute to a variety of cellular processes including maintaining organelle functionality, providing an optimised environment for membrane-associated proteins and as pools for metabolites (e.g. choline for one-carbon metabolism and for methylation of DNA). We have conducted a comprehensive lipidomic study of white adipose tissue in mice who become obese either through genetic modification (ob/ob), diet (high fat diet) or a combination of the two using both solid phase extraction and ion mobility to increase coverage of the lipidome. Composition changes in seven classes of lipid (free fatty acids, diglycerides, TGs, phosphatidylcholines, lyso-phosphatidylcholines, phosphatidylethanolamines, and phosphatidylserines) correlated with perturbations in one-carbon metabolism and transcriptional changes in adipose tissue. We demonstrate that changes in TGs that dominate the overall lipid composition of white adipose tissue are distinct from diet-induced alterations of PLs, the predominant components of the cell membranes. PLs correlate better with transcriptional and one-carbon metabolism changes within the cell, suggesting the compositional changes that occur in cell membranes during adipocyte expansion have far-reaching functional consequences.

systems biology↗

bioRxiv2018

Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution

Direct comparisons of human and non-human primate brain tissue have the potential to reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is largely inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. First, we systematically evaluated the fidelity of organoid models to primary human and macaque cortex, finding organoid models preserve gene regulatory networks related to cell types and developmental processes but exhibit increased metabolic stress. Second, we identified 261 genes differentially expressed in human compared to chimpanzee organoids and macaque cortex. Many of these genes overlap with human-specific segmental duplications and a subset suggest increased PI3K/AKT/mTOR activation in human outer radial glia. Together, our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.

developmental biology↗