Biology subjects

Lindsay, S.

Publications and source records attributed to Lindsay, S..

14 recordsLinked to original sources

bioRxiv2026

Trade-offs between photosynthetic capacity, mesophyll conductance stability and leaf anatomy shape heat and water deficit resilience in Gossypium.

O_LIMesophyll conductance (gm) governs CO2 diffusion to Rubisco and is a key determinant of photosynthetic performance, yet the mechanisms underlying its sensitivity to heat and water stress remain unresolved. C_LIO_LIWe quantified gm temperature responses across diverse Gossypium species and examined anatomical drivers of gm plasticity in cultivated cotton (G. hirsutum) and the wild Australian species G. bickii under elevated temperature and soil water deficit. C_LIO_LISpecies exhibited contrasting gm strategies: G. hirsutum exhibited high gm and carbon assimilation near thermal optima but showed greater sensitivity under combined heat and water deficit, whereas G. bickii maintained comparatively stable gm and photosynthesis across stress conditions. C_LIO_LIUnder water deficit, structural adjustments in G. hirsutum (increased leaf porosity, cell wall thickness and mesophyll surface exposure to intercellular airspaces) were insufficient to sustain gm, suggesting that liquid-phase resistances impose dominant constraints on CO2 diffusion under extreme climatic stress. C_LIO_LIThese results identify gm as a dynamic, multi-component trait and a key physiological vulnerability in cotton, shaped by coordinated anatomical characteristics and potentially cell wall properties and membrane-associated processes, with major implications for mechanistic photosynthesis modelling and improving climate resilience in cotton and other C3 species. C_LI

plant biology↗

bioRxiv2025

Stabilising selection and ecological trade-offs underpin coexistence in a tropical flora

Tropical forests harbour the majority of global plant biodiversity1,2, yet the genomic mechanisms governing the assembly and maintenance of these communities remain poorly understood. Here, we assembled draft genomes for 499 angiosperm species from a lowland rainforest in Singapore, representing 67% of its flora, and integrated these with plant traits and comprehensive forest census data. Across the community, most gene families evolve under stabilising selection, with copy numbers maintained near long-term optima that differ among ecological strategies. These niche-associated genomic attractor states provide a mechanism for convergent adaptation and species coexistence. Modelling stabilising selection also identified a strong trade-off between defence and growth, indicating that pathogen pressure constrains developmental diversification. Consistent with this, species-specific genome space was enriched for resistance genes and transposable elements. In contrast, genomic processes structuring present-day plant community composition differ from those driving deep-time convergence. Genomic comparisons across forest types revealed stronger selection on defence-related pathways in old-growth primary forests and on growth-related processes in regenerating secondary forests, while community-level genomic profiles showed expansions in gene families associated with rapid responses to environmental fluctuations. Stabilising selection therefore links population-level adaptation3,4 with long-term species diversification in the tropics. Niche similarity promotes long-term coexistence, whereas local community structure is shaped by more rapid ecological filtering driven by environmental change. Taken together, these two distinct evolutionary layers provide a genomic framework for understanding how hyperdiverse rainforest floras arise and persist.

genomics↗

bioRxiv2025

A sustained Hox program delineates brainstem neurons essential for breathing

Respiratory neurons in the brainstem must diversify and acquire unique properties during development to enable breathing at birth. Dbx1-expressing progenitors give rise to functionally and molecularly distinct excitatory respiratory populations, including rhythm-generating pre-Botzinger complex (preBotC) neurons and phrenic motor neuron (MN)-projecting rostral Ventral Respiratory Group (rVRG) neurons. These neurons are organized rostrocaudally within the ventral respiratory column (VRC) but, despite their critical functions in breathing, the mechanisms that control their organization and diversification are not well understood. Here, we generate a novel genetic tool to label brainstem neurons within the VRC. We find that rVRG neurons selectively express Hox5 genes through postnatal stages. Selective deletion of all Hox5 paralogs from Dbx1-derived neurons leads to respiratory dysfunction, perinatal death, and changes in the pattern and amplitude of phrenic MN firing. We show that Hox5 inactivation leads to a caudal expansion of putative preBotC neurons, likely at the expense of the rVRG. Collectively, our findings indicate that Hox5 proteins are required for the delineation and functional specialization of excitatory brainstem neurons essential for breathing.

neuroscience↗

bioRxiv2025

Do epidemiologically impactful vector control interventions disrupt mosquito population structure?

Large epidemiological impacts resulting from disease vector control interventions are typically associated with significant disruption of vector populations. While vector density is a frequently measured response, impacts on demography and connectivity are suspected but rarely quantified. We analysed low-coverage whole-genome sequence data of 893 Anopheles gambiae mosquitoes collected between 2014-2015 during a cluster-randomized control trial (cRCT) in Burkina Faso to compare a pyrethroid-only net (ITN) with a pyrethroid-pyriproxyfen (ITN-PPF) net. Despite reductions of clinical malaria by 12%, and vector density by 22% in the ITN-PPF arm, we found no significant changes in An. gambiae population genetic structure or diversity. We found remarkably low population differentiation, and a lack of discernible clustering by treatment, time, or space. Nucleotide diversity and inbreeding coefficient remained stable between treatments, and genome-wide scans showed no putative signatures of selection between trial arms. These results show that ITN-PPF did not alter An. gambiae genetic structure, possibly due to large, vagile populations in West Africa. More widely, this is first evidence that epidemiologically meaningful reductions in vector density may not impact genetic diversity or connectivity, and challenges what constitutes adequate vector control in large populations.

ecology↗

bioRxiv2023

Locus Coeruleus Norepinephrine Neurons Facilitate Orbitofrontal Cortex Remapping and Behavioral Flexibility

To guide behavior, brain regions such as the orbitofrontal cortex (OFC) retain complex information about current tasks and expected outcomes in cellular representations referred to as cognitive maps. When actions produce undesirable results, OFC cognitive maps must update to promote behavioral change. Here, we show that this remapping is driven by the locus coeruleus (LC), a small brainstem nucleus that contains most of the brains norepinephrine (NE)-releasing neurons. In a task that tests behavioral flexibility in rodents, LC-NE activity correlated with task acuity and altered depending on trial outcome. Silencing LC neurons caused perseverative behavior and impeded cognitive remapping in OFC, while enhancing LC activity disrupted the ability of new maps to stabilize. These findings reveal a novel role for bidirectional LC-NE signaling in regulation of OFC cognitive map stability and promotion of flexible behavior that differs from the traditional function of this circuit as a global arousal signal.

neuroscience↗

bioRxiv2022

Long-Range Hopping Conductivity in Proteins

Single molecule measurements show that many proteins, lacking any redox cofactors, nonetheless exhibit electrical conductance on the order of a nanosiemen, implying that electrons can transit an entire protein in less than a nanosecond when subject to a potential difference of less than 1V. In the conventional fast transport scenario where the free energy barrier is zero, the hopping rate is determined by the reorganization energy of approximately 0.8 eV, which sets the time scale of a single hopping event to at least 1s. Furthermore, the Fermi energies of metal electrodes used in experiments are far-removed from the equilibrium redox states of the aromatic residues of the protein, which should additionally slow down the electron transfer. Here, we combine all-atom molecular dynamics (MD) simulations of non-redox active proteins (consensus tetratricopeptide repeats) with an electron transfer theory to demonstrate a molecular mechanism that can account for the unexpectedly fast electron transfer. According to our MD simulations, the reorganization energy produced by the energy shift on charging (the Stokes shift) is close to the conventional value of 0.8 eV. However, the nonergodic sampling of molecular configurations by the protein results in reorganization energies, extracted directly from the distribution of the electrostatic energy fluctuations, that are only ~ 0.2 eV, which is small enough to enable long-range hopping. Using the MD values of the reorganization energies we calculate a current decay with distance that is in agreement with experiment. SignificanceElectron transfer is fundamental to biology, facilitating a range of metabolic processes and efficient energy conversion. Conventionally, electron transfer through proteins is thought to occur via a chain of metal or organic co-factors connecting one side of the protein to another. Recent experiments, however, show that proteins lacking any co-factors can nonetheless transport electrons with high efficiency if properly connected to metal electrodes. This study provides a theoretical model of such cofactor-less transfer, showing that transient occupation of non-equilibrium states of the proteins aromatic residues reduces the barrier to electron hopping, facilitating long range and rapid transport. Our results widen the pool of proteins potentially involved in biological electron transport and provide theoretical underpinning to design of protein molecular electronics.

biophysics↗

bioRxiv2022

Coordinated cadherin functions sculpt respiratory motor circuit connectivity

Breathing, and the motor circuits that control it, are essential for life. At the core of respiratory circuits are Dbx1-derived interneurons, which generate the rhythm and pattern of breathing, and phrenic motor neurons (MNs), which provide the final motor output that drives diaphragm muscle contractions during inspiration. Despite their critical function, the principles that dictate how respiratory circuits assemble are unknown. Here we show that coordinated activity of a type I cadherin (N-cadherin) and type II cadherins (Cadherin-6, -9, and -10) is required in both MNs and Dbx1-derived neurons to generate robust respiratory motor output. Both MN- and Dbx1-specific cadherin inactivation during a critical developmental window results in perinatal lethality due to respiratory failure and a striking reduction in phrenic MN bursting activity. This combinatorial cadherin code is required to establish phrenic MN cell body and dendritic topography; surprisingly, however, cell body position appears to be dispensable for the targeting of phrenic MNs by descending respiratory inputs. Our findings demonstrate that type I and type II cadherins function cooperatively throughout the respiratory circuit to generate a robust breathing output and reveal novel strategies that drive the assembly of motor circuits.

neuroscience↗

bioRxiv2019

Modelling geospatial distributions of the triatomine vectors of Trypanosoma cruzi in Latin America

Approximately 150 triatomine species are known to be infected with the Chagas parasite, Trypanosoma cruzi, but they differ in the risk they pose to human populations. The largest risk comes from species that have a domestic life cycle and these species have been targeted by indoor residual spraying campaigns, which have been successful in many locations. It is now important to consider residual transmission that may be linked to persistent populations of dominant vectors, or to secondary or minor vectors. The aim of this project was to define the geographical distributions of the community of triatomine species in Latin America. Presence-only data with over 12, 000 observations of triatomine vectors were extracted from a public database and target-group background data were generated to account for sampling bias in the presence data. Geostatistical regression was then applied to estimate species distributions and fine-scale distribution maps were generated for thirty triatomine vector species. The results for Panstrongylus geniculatus, P. megistus, Triatoma barberi, T. brasiliensis, and T. pseudomaculata are presented in detail and the model validation results for each of the 30 species are presented in full. The predictive maps for all species are made publicly available so that they can be used to assess the communities of vectors present within different regions of the endemic zone. The maps are presented alongside key indicators for the capacity of each species to transmit T. cruzi to humans. These indicators include infection prevalence, evidence for human blood meals, and colonisation or invasion of homes. A summary of these indicators shows that the majority of the 30 species mapped by this study have the potential to transmit T. cruzi to humans.\n\nAuthor summaryThe Pan American Health Organisations Strategy and Plan of Action for Chagas Disease Prevention, Control and Care highlights the importance of eliminating those triatomine vector species that colonise homes, and has had great success in many locations. Since indoor residual spraying campaigns have targeted these species, their importance relative to other vectors has diminished and their geographical distributions may also have changed. It is now vital to consider the full community of vector species, including previously dominant vectors as well as secondary or minor vector species, in order to target residual transmission to humans. Our aim was to define the geographical distributions of the most commonly reported triatomine species in Latin America. We extracted reports of triatomine vector species observed at specific locations from a public database and we used a geostatistical model to generate fine-scale predictive maps for thirty triatomine vector species. We present these maps alongside a summary of key indicators related to the capacity of each species to transmit the Chagas parasite to humans. We show that most of the 30 species that we have mapped pose a potential threat to human populations.

ecology↗

bioRxiv2019

Engineering an Enzyme for Direct Electrical Monitoring of Activity

Proteins have been shown to be electrically-conductive if tethered to an electrode by means of a specific binding agent, allowing single molecules to be wired into an electrical sensing circuit. This development opens the possibility of exploiting the remarkable chemical versatility of enzymes as sensors, detectors and sequencing devices. We have engineered contact points into a {Phi}29 polymerase by introducing biotinylatable peptide sequences. The modified enzyme was bound to electrodes functionalized with streptavidin. {Phi}29 connected by one biotinylated contact and a second non-specific contact showed rapid small fluctuations in current when activated. Signals were greatly enhanced with two specific contacts. Features in the distributions of DC conductance increased by a factor 2 or more over the open-to closed conformational transition of the polymerase. Polymerase activity is manifested by rapid (millisecond) large (25% of background) current fluctuations imposed on the DC conductance.

bioengineering↗

bioRxiv2019

Decoding the development of the blood and immune systems during human fetal liver haematopoiesis

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs), yet remains poorly defined in humans. Using single cell transcriptome profiling of ~133,000 fetal liver and ~65,000 fetal skin and kidney cells, we identify the repertoire of blood and immune cells in first and early second trimesters of development. From this data, we infer differentiation trajectories from HSC/MPPs, and evaluate the impact of tissue microenvironment on blood and immune cell development. We predict coupling of mast cell differentiation with erythro-megakaryopoiesis and identify physiological erythropoiesis in fetal skin. We demonstrate a shift in fetal liver haematopoietic composition during gestation away from being erythroid-predominant, accompanied by a parallel change in HSC/MPP differentiation potential, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a valuable reference for understanding and harnessing the therapeutic potential of HSC/MPPs.

developmental biology↗

bioRxiv2018

SIR proteins create compact heterochromatin fibers

Heterochromatin is a silenced chromatin region essential for maintaining genomic stability and driving developmental processes. The complicated structure and dynamics of heterochromatin have rendered it difficult to characterize. In budding yeast, heterochromatin assembly requires the SIR proteins -- Sir3, believed to be the primary structural component of SIR heterochromatin, and the Sir2/4 complex, responsible for the targeted recruitment of SIR proteins and the deacetylation of lysine 16 of histone H4. Previously, we found that Sir3 binds but does not compact nucleosomal arrays. Here we reconstitute chromatin fibers with the complete complement of SIR proteins and use sedimentation velocity, molecular modeling, and atomic force microscopy to characterize the stoichiometry and conformation of SIR chromatin fibers. In contrast to previous studies, our results demonstrate that SIR arrays are highly compact. Strikingly, the condensed structure of SIR heterochromatin fibers requires both the integrity of H4K16 and an interaction between Sir3 and Sir4. We propose a model in which two molecules of Sir3 bridge and stabilize two adjacent nucleosomes, while a single Sir2/4 heterodimer binds the intervening linker DNA, driving fiber compaction.

biochemistry↗

bioRxiv2018

Heterogeneous exposure and hotspots for malaria vectors at three study sites in Uganda

Heterogeneity in malaria transmission has household, temporal, and spatial components. These factors are relevant for improving the efficiency of malaria control by targeting heterogeneity. To quantify variation, we analyzed mosquito counts from entomological surveillance conducted at three study sites in Uganda that varied in malaria transmission intensity. Using a Bayesian zero-inflated negative binomial model, validated via a comprehensive simulation study, we quantified household differences in malaria exposure and examined its spatial distribution. We found that housing quality explained large variation among households in mosquito counts. In each site, there was evidence for hot and cold spots, spatial patterns associated with urbanicity, elevation, or other environmental covariates. We also found some differences in the hotspots in rainy vs. dry seasons or before vs. after control. This work identified methods for quantifying heterogeneity in malaria exposure and offered a critical evaluation of spatially targeting interventions at malaria hotspots.

ecology↗

bioRxiv2018

Metagenomic analysis uncovers strong relationship between periodontal pathogens and vascular dysfunction in American Indian population

Periodontal disease (PD) is a well-known risk factor for cardiovascular disease (CVD) but the casual relationship is unclear. American Indians/Alaskan Natives (AI/AN) have high rate of both PD and CVD and a better understanding of how PD might affect heart health would be particularly helpful in this population. In this study, we sequenced the bacterial biofilms of periodontal (gum) pockets and used metagenomic sequencing and vascular health measurements (immune cytokine profiles and vascular flow) to determine the relationship of microbial pathogens and CVD. Twelve subjects were sequenced before and after standard periodontal treatment. Other measures taken before and after treatment included a full dental screening; serum concentration of key immune cytokines from blood samples; lipid profiles from fasting venous blood; and plasma glucose concentrations. The non-invasive Laser Doppler Fluxmetry (LDF) procedure was conducted to measures the microvascular vasodilation. We found highly significant relationships between the total abundance of 4 periodontal pathogens, Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia and Treponema denticola, and the inflammatory cytokine interleukin 1 beta (IL-1{beta}) (r=0.63; p=0.009) as well as with vascular flow post sodium nitroprusside (SNP) treatment (r=p=0.006). Two bacterial species that correlated most with IL-1{beta} were F. nucleatum and P. gingivalis. IL-1{beta} has been strongly implicated as a causal factor in atherosclerosis and in periodontal bone loss. To our knowledge, this is the first direct link between abundance of specific periodontal pathogens and cardiovascular disease in humans, and suggests that these pathogens could be used as warning signs for cardiovascular risk.

microbiology↗

bioRxiv2017

Human iPSC-derived RPE and retinal organoids reveal impaired alternative splicing of genes involved in pre-mRNA splicing in PRPF31 autosomal dominant retinitis pigmentosa

Mutations in pre-mRNA processing factors (PRPFs) cause 40% of autosomal dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed PRPFs cause retinal disease. To understand the molecular basis of this phenotype, we have generated RP type 11 (PRPF31-mutated) patient-specific retinal organoids and retinal pigment epithelium (RPE) from induced pluripotent stem cells (iPSC). Impaired alternative splicing of genes encoding pre-mRNA splicing proteins occurred in patient-specific retinal cells and Prpf31+/- mouse retinae, but not fibroblasts and iPSCs, providing mechanistic insights into retinal-specific phenotypes of PRPFs. RPE was the most affected, characterised by loss of apical-basal polarity, reduced trans-epithelial resistance, phagocytic capacity, microvilli, and cilia length and incidence. Disrupted cilia morphology was observed in patient-derived-photoreceptors that displayed progressive features associated with degeneration and cell stress. In situ gene-editing of a pathogenic mutation rescued key structural and functional phenotypes in RPE and photoreceptors, providing proof-of-concept for future therapeutic strategies.\n\neTOCPRPF31 is a ubiquitously expressed pre-mRNA processing factor that when mutated causes autosomal dominant RP. Using a patient-specific iPSC approach, Buskin and Zhu et al. show that retinal-specific defects result from altered splicing of genes involved in the splicing process itself, leading to impaired splicing, loss of RPE polarity and diminished phagocytic ability as well as reduced cilia incidence and length in both photoreceptors and RPE.\n\nHighlightsO_LISuccessful generation of iPSC-derived RPE and photoreceptors from four RP type 11 patients\nC_LIO_LIRPE cells express the mutant PRPF31 protein and show the lowest expression of wildtype protein\nC_LIO_LIPRPF31 mutations result in altered splicing of genes involved in pre-mRNA splicing in RPE and retinal organoids\nC_LIO_LIPrpf31 haploinsufficiency results in altered splicing of genes involved in pre-mRNA splicing in mouse retina\nC_LIO_LIRPE cells display loss of polarity, reduced barrier function and phagocytosis\nC_LIO_LIPhotoreceptors display shorter and fewer cilia and degenerative features\nC_LIO_LIRPE cells display most abnormalities suggesting they might be the primary site of pathogenesis\nC_LIO_LIIn situ gene editing corrects the mutation and rescues key phenotypes\nC_LI

genetics↗