Biology subjects

White, L.

Publications and source records attributed to White, L..

16 recordsLinked to original sources

bioRxiv2026

Macroalgal fucoidan can activate the biological carbon pump

Macroalgae secrete complex carbohydrate polymers, their extracellular matrix, as protection against microbial degradation. By resisting breakdown, these carbohydrates can contribute to marine carbon sequestration, though mechanisms, extent, and timescales remain unknown. Using ship-based sampling and experiments, we found that brown macroalgae release 1.7-4.2% of carbon fixation as fucoidan, equivalent to 0.32-0.88 mg fucoidan per gram of dry seaweed tissue per day. A Bayesian model trained on our empirical data, coupled with Monte Carlo simulations suggests an annual global release of 13-37 megatons fucoidan carbon. Moreover, degradation resistance combined with surface-activity enabled fucoidan to act as glue that cross-linked allochthonous organic carbon including microbes and proteins into marine snow. Notably, substantial fucoidan exudation was universally conserved across all tested species and regions. Thus, any brown macroalgal species can be used e.g. via aquafarming to enhance the formation of marine snow.

ecology↗

bioRxiv2026

Circular RNA vaccine performance is determined by RNA quality and epitranscriptomic tuning rather than innate activation

Circular RNA (circRNA) is an emerging vaccine modality that is proposed to improve stability, reduce reactogenicity and extend antigen expression compared with linear mRNA. However, the relative contributions to vaccine performance of its covalently closed structure, its purity, and of nucleotide modifications remain poorly described. Here, we systematically dissected these parameters in vivo across two antigen systems. We identified RNA quality as a major determinant of circRNA reactogenicity, with differences in innate immune activation tracking with the presence of residual RNA species in less refined preparations. In contrast, highly purified circRNA exhibited markedly reduced reactogenicity compared with linear mRNA, independent of nucleotide modification. Despite these differences, circRNA and mRNA vaccines elicited comparable antibody titres and T cell responses, indicating that reduced innate activation does not enhance adaptive immune magnitude. Notably, incorporating N6-methyladenosine (m6A) did not affect reactogenicity or antigen expression but selectively enhanced antibody quality, increasing binding affinity and neutralisation capacity. CircRNA vaccination also altered the anatomical distribution of germinal centre responses, reducing splenic antigen-specific germinal centre B cells while preserving lymph node responses. Together, these findings show that circRNA vaccine performance is governed by RNA preparation quality and epitranscriptomic tuning rather than innate activation alone.

immunology↗

bioRxiv2026

BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia

Acute myeloid leukemia (AML) is driven by a combination of genetic alterations and non-mutational mechanisms that disrupt normal hematopoiesis and support leukemic cell survival. While the mutational landscape of AML is well characterized, the non-genetic processes that sustain leukemic maintenance remain comparatively less understood. Using human AML cell lines and murine models of AML, we identify BCL2-associated transcription factor 1 (BCLAF1) as a key regulator of leukemic progression through control of mRNA processing. BCLAF1 physically associates with core spliceosome components and regulates alternative splicing, with a predominant effect on intron retention. We demonstrate that BCLAF1 is required for the productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein expression. Loss of BCLAF1 reduces ATF4 protein levels, leading to downregulation of metabolic target genes and disruption of de novo amino acid biosynthesis. Furthermore, depletion of BCLAF1 sensitizes AML cells to venetoclax, a clinically relevant BCL-2 inhibitor. Together, these findings uncover a previously unrecognized role for BCLAF1 in coordinating mRNA splicing and metabolic adaptation in AML, highlighting its potential as a therapeutic target. Statement of significanceAberrant RNA splicing and metabolic reprogramming are hallmarks of cancer, yet how these processes are mechanistically linked remains unclear. This study identifies BCLAF1 as a key regulator connecting splicing control to amino acid metabolism in acute myeloid leukemia, revealing a previously unrecognized functional vulnerability at the intersection of these pathways.

cancer biology↗

bioRxiv2026

Engineering antigenic breadth against SARS-CoV-2 by pairing divergent RBDs within a single mRNA immunogen

Vaccines capable of eliciting broadly neutralising antibodies (bnAbs) are a major goal for pandemic preparedness. A persistent challenge across vaccine Wields is how to deliberately recruit the rare B cell clones that recognise conserved epitopes shared across diverse viral variants. BnAbs have been known to frequently emerge through extensive somatic hypermutation during afWinity maturation, here we describe an alternative, structure-driven mechanism for bnAb selection. We designed an mRNA vaccine in which two antigenically distinct SARS-CoV-2 variants (Omicron and Delta; O-{Delta}) receptor binding domains (RBDs) are physically fused on a single polypeptide. This design is predicted to favour B cell antigen receptors capable of engaging conserved epitopes on both RBDs with enhanced avidity. A matched non-divergent tandem RBD (Delta-Delta; {Delta}-{Delta}) served as a control. The divergent (O-{Delta}) immunogen was robustly expressed and retained high-afWinity ACE2 binding. In mice, immunisation elicited potent antibody responses and increased the frequency of antigen-speciWic cross-reactive B cells, recognising Delta, Omicron, and the 2002 pandemic strain SARS-CoV RBDs. Using multicolour RBD tetramers and single-cell B cell receptor sequencing, we show that breadth arises via two distinct pathways. The divergent vaccine preferentially enriches clonally distinct cross-reactive B cells (not present within non-cross-reactive B cell pools) with low levels of somatic hypermutation (SHM), consistent with selection of germline-biased precursors. In contrast, the matched control vaccine yields cross-reactivity primarily within existing clonal lineages (clonal overlap between cross-reactive and non-cross-reactive cells) and at higher mutational burdens, consistent with afWinity-maturation-driven acquisition of breadth. Together, these Windings demonstrate that antigen structure can bias B cell selection towards cross-reactive speciWicities without requiring extensive SHM. This work establishes a simple, modular antigen-design principle in which juxtaposing appropriately divergent antigens on a single scaffold promotes the enrichment of bnAb-prone B cells, providing a scalable strategy for vaccine development against rapidly evolving pathogens.

immunology↗

bioRxiv2024

A Label-free Nanowell-based Impedance Sensor for Ten-minute SARS-CoV-2 Detection

This work explores label-free biosensing as an effective method for biomolecular analysis, ensuring the preservation of native conformation and biological activity. The focus is on a novel electronic biosensing platform utilizing micro-fabricated nanowell-based impedance sensors, offering rapid, point-of-care diagnosis for SARS-CoV-2 (COVID-19) detection. The nanowell sensor, constructed on a silica substrate through a series of microfabrication processes including deposition, patterning, and etching, features a 5x5 well array functionalized with antibodies. Real-time impedance changes within the nanowell array enable diagnostic results within ten minutes using small sample volumes (<5 {micro}L). The research includes assays for SARS-CoV-2 spike proteins in Phosphate-buffered saline (PBS) and artificial saliva buffers to mimic real human SARS-CoV-2 samples, covering a wide range of concentrations. The sensor exhibits a detection limit of 0.2 ng/mL (1.5 pM) for spike proteins. Middle East Respiratory Syndrome (MERS-CoV) spike proteins are differentiated from SARS-CoV-2 spike proteins, demonstrating specificity. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/627986v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1a9f2a7org.highwire.dtl.DTLVardef@79d5acorg.highwire.dtl.DTLVardef@bb1bc1org.highwire.dtl.DTLVardef@1b5098_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

A rapid workflow for neuron counting in combined light sheet microscopy and magnetic resonance histology

Information on regional variation in cell numbers and densities in the CNS provides critical insight into structure, function, and the progression of CNS diseases. However, variability can be real or can be a consequence of methods that do not account for technical biases, including morphologic deformations, errors in the application of cell type labels and boundaries of regions, errors of counting rules and sampling sites. We address these issues of by introducing a workflow that consists of the following steps: 1. Magnetic resonance histology (MRH) to establish the size, shape, and regional morphology of the mouse brain in situ. 2. Light-sheet microscopy (LSM) to selectively label all neurons or other cells in the entire brain without sectioning artifacts. 3. Register LSM volumes to MRH volumes to correct for dissection errors and morphological deformations. 4. Implement novel protocol for automated sampling and counting of cells in 3D LSM volumes. This workflow can analyze the cells density of one brain region in less than 1 min and is highly replicable to cortical and subcortical gray matter regions and structures throughout the brain. We report deformation-corrected neuron (NeuN) counts and neuronal density in 13 representative regions in 5 C57B6/6J and 2 BXD strains. The data represent the variability among cases for the same brain region and across regions within case. Our data are consistent with previous studies. We demonstrate the application of our workflow to a mouse model of aging. This workflow improves the accuracy of neuron counting and the assessment of neuronal density on a region-by-region basis, with broad applications in how genetics, environment, and development across the lifespan impact brain structure.

neuroscience↗

bioRxiv2022

A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery, which improve vaccination compliance and demonstrate efficacy against emerging variants. Here we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprised of stabilized, pre-fusion Spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction of lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.

microbiology↗

bioRxiv2021

Multimodal Magnetic Resonance Histology and Light Sheet Imaging for Quantitative Neurogenetics of the Mouse

Paul Lauterbur closed his seminal paper on MRI with the statement that "zeugmatographic (imaging) techniques should find many useful applications in studies of the internal structures, states and composition of microscopic objects" [1]. Magnetic resonance microscopy was subsequently demonstrated in 1986 by three groups [2] [3] [4]. The application of MRI to the study of tissue structure, i.e. magnetic resonance histology (MRH) was suggested in 1993 [5]. MRH, while based on the same physical principals as MRI is something fundamentally different than the clinical exams which are typically limited to voxel dimensions of ~ 1 mm3. Preclinical imaging systems can acquire images with voxels ~ 1000 times smaller. The MR histology images presented here have been acquired at yet another factor of 1000 increase in spatial resolution. Figure S1 in the supplement shows a comparison of a state-of-the-art fractional anisotropy images of a C57 mouse brain in vivo @ 150 m resolution (voxel volume of 3.3 x10-3 mm3) with the atlas we have generated for this work at 15 m spatial resolution (voxel volume of 3.3 x 10-6 mm3). In previous work, we have demonstrated the utility of MR histology in neurogenetics at spatial/angular resolution of 45 m /46 angles [6]. At this spatial/angular resolution it is possible to map whole brain connectivity with high correspondence to retroviral tracers [7]. But the MRH derived connectomes can be derived in less than a day where the retroviral tracer studies require months/years [8]. The resolution index (angular samples/voxel volume) for this previous work was >500,000 [9]. Figure S2 shows a comparison between that previous work and the new atlas presented in this paper with a resolution index of 32 million. Light sheet microscopy (LSM) has undergone similar rapid evolution over the last 20 years. The invention of tissue clearing, advances in immunohistochemistry and development of selective plane illumination microscopy (SPIM) now make it possible to acquire whole mouse brain images at submicron spatial resolution with a vast array of cell specific markers [10] [11] [12] [13]. And these advantages can be realized in scan times of < 6hrs. The major limitation from these studies is the distortion in the tissue from dissection from the cranium, swelling from clearing and staining, and tissue damage from handling. We report here the merger of these two methods: O_LIMRH with the brain in the skull to provide accurate geometry, cytoarchitectural measures using scalar imaging metrics and whole brain connectivity at 15 m isotropic spatial resolution with super resolution track density images @ 5 m isotropic resolution; C_LIO_LIwhole brain multichannel LSM @ 1.8x1.8x4.0 m; C_LIO_LIa big image data infrastructure that enables label mapping from the atlas to the MR image, geometric correction to the light sheet data, label mapping to the light sheet volumes and quantitative extraction of regional cell density. These methods make it possible to generate a comprehensive collection of image derived phenotypes (IDP) of cells and circuits covering the whole mouse brain with throughput that can be scaled for quantitative neurogenetics. C_LI

neuroscience↗

bioRxiv2021

Using mixed-effects modeling to estimate decay kinetics of response to SARS-CoV-2 infection

The duration of natural immunity in response to SARS-CoV-2 is a matter of some debate in the literature at present. For example, in a recent publication characterizing SARS-CoV-2 immunity over time, the authors fit pooled longitudinal data, using fitted slopes to infer the duration of SARS-CoV-2 immunity. In fact, such approaches can lead to misleading conclusions as a result of statistical model-fitting artifacts. To exemplify this phenomenon, we reanalyzed one of the markers (pseudovirus neutralizing titer) in the publication, using mixed-effects modeling, a methodology better suited to longitudinal datasets like these. Our findings showed that the half-life was both longer and more variable than reported by the authors. The example selected by us here illustrates the utility of mixed-effects modeling in provide more accurate estimates of the duration and heterogeneity of half-lives of molecular and cellular biomarkers of SARS-CoV-2 immunity.

immunology↗

bioRxiv2020

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naive adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. We conclude that the DENV2 component in the vaccine is immunodominant because of the high levels of serum neutralizing antibodies targeting type-specific epitopes. We also conclude that DENV1, 3 and 4 vaccine components are less immunogenic because most study subjects did not develop type-specific serum neutralizing antibodies to these serotypes. While DENV vaccine development has been guided by the presence of neutralizing antibodies to each serotype as a benchmark, our results indicate that the presence of neutralizing antibodies alone are not a reliable indicator of the immunogenicity of each vaccine component. Author summaryThe development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a correlate of safe and effective vaccine induced immunity. However, the absolute levels of neutralizing antibodies to each serotype has proven to be an unreliable correlate of protection. Levels of antibodies to epitopes that are unique to each serotype, which are measures of immunity independently stimulated by each vaccine component, rather than total quantity of neutralizing antibodies, are likely to be better correlates of protection. Here, we mapped the specificity of antibodies induced by the Takeda tetravalent dengue vaccine TAK-003 in monkeys and humans with no prior immunity to dengue. The TAK-003 vaccine induces high levels of serotype 2 specific neutralizing antibodies that map to known protective epitopes. In contrast, the serotype 1, 3 and 4 neutralizing antibody responses are lower and mainly consist of cross-reactive antibodies binding to epitopes conserved between serotypes. These heterotypic antibodies, which are most likely derived from the serotype 2 component, may not provide long term protection in vivo.

immunology↗

bioRxiv2020

Development of a Coronavirus Disease 2019 Nonhuman Primate Model Using Airborne Exposure

Airborne transmission is predicted to be a prevalent route of human exposure with SARS-CoV-2. Aside from African green monkeys, nonhuman primate models that replicate airborne transmission of SARS-CoV-2 have not been investigated. A comprehensive and comparative evaluation of COVID-19 in African green monkeys, rhesus macaques, and cynomolgus macaques following airborne exposure to SARS-CoV-2 was performed to define parameters critical to disease progression and the extent to which they correlate with human COVID-19. Respiratory abnormalities and viral shedding were noted for all animals, indicating successful infection. Cynomolgus macaques developed fever, and thrombocytopenia was measured for African green monkeys and rhesus macaques. Type II pneumocyte hyperplasia and alveolar fibrosis were more frequently observed in lung tissue from cynomolgus macaques and African green monkeys. The data indicate that, in addition to African green monkeys, macaques can be successfully infected by airborne SARS-CoV-2, providing viable macaque natural transmission models for medical countermeasure evaluation. One Sentence SummaryNonhuman primates develop COVID-19 following airborne virus exposure.

microbiology↗

bioRxiv2019

Robotic microscopy for everyone: the OpenFlexure Microscope

Optical microscopes are an essential tool for both the detection of disease in clinics, and for scientific analysis. However, in much of the world access to high-performance microscopy is limited by both the upfront cost and maintenance cost of the equipment. Here we present an open-source, 3D-printed, and fully-automated laboratory microscope, with motorised sample positioning and focus control. The microscope is highly customisable, with a number of options readily available including trans- and epi-illumination, polarisation contrast imaging, and epi-florescence imaging. The OpenFlexure Microscope has been designed to enable low-volume manufacturing and maintenance by local personnel, vastly increasing accessibility. We have produced over 100 microscopes in Tanzania and Kenya for educational, scientific, and clinical applications, demonstrating that local manufacturing can be a viable alternative to international supply chains that can often be costly, slow, and unreliable.

microbiology↗

bioRxiv2019

Not all MDAs should be created equal-determinants of MDA impact and designing MDAs towards malaria elimination

Malaria remains at the forefront of scientific research and global political and funding agendas. Previous malaria models of mass-interventions have consistently oversimplified how mass interventions are implemented. We present an individual based, spatially explicit model of malaria transmission that includes all the programmatic implementation details of mass drug administration (MDA) campaigns. We uncover how the impact of MDA campaigns is determined by the interaction between implementation logistics, patterns of human mobility and how transmission risk is distributed over space. This translates into a higher likelihood of malaria elimination for areas with true prevalence under 3% with a faster implementation, in highly mobile populations. If populations are more static, deploying less interventions teams would be cost optimal and predicted to be as impactful. We conclude that mass drug interventions can be an invaluable tool towards malaria elimination in the right context, specifically when paired with effective vector control.

physiology↗

bioRxiv2019

Population-Level Disease Dynamics Reflect Individual Heterogeneities in Transmission

Host heterogeneity in disease transmission is widespread and presents a major hurdle to predicting and minimizing pathogen spread. Using the Drosophila melanogaster model system infected with Drosophila C virus, we integrate experimental measurements of individual host heterogeneity in social aggregation, virus shedding, and disease-induced mortality into an epidemiological framework that simulates outbreaks of infectious disease. We use these simulations to calculate individual variation in disease transmission and apportion this variation to specific components of transmission: social network degree distribution, infectiousness, and infection duration. The experimentally-observed variation produces substantial differences in individual transmission potential, providing evidence for genetic and sex-specific effects on disease dynamics at a population level. Manipulating variation in social network connectivity, infectiousness, and infection duration in simulated populations reveals that these components affect disease transmission in clear and distinct ways. We consider the implications of this genetic and sex-specific variation in disease transmission and discuss implications for appropriate control methods given the relative contributions made by social aggregation, virus shedding, and infection duration to transmission in other host-pathogen systems.

ecology↗

bioRxiv2018

Herd protection against Plasmodium falciparum infections conferred by mass antimalarial drug administrations and the implications for malaria elimination

IntroductionAll nations of the Greater Mekong Subregion have committed to elimination of malaria by the year 2030. Elimination efforts rely on increasing access to diagnosis and treatment. However, asymptomatic infections pose a major challenge for these efforts. One approach towards eliminating asymptomatic reservoirs is targeted mass antimalarial drug administration (MDA). Here we present a fine scale spatiotemporal analysis of malaria incidence and prevalence in villages undergoing MDA.\n\nMethodsFour villages along the Myanmar-Thailand border were selected for a MDA pilot study based on clinical records and prevalence surveys. Passive detection of clinical episodes was facilitated through community based malaria clinics in each village. All villagers were screened using venous blood and ultra-sensitive qPCR (uPCR) for detection of parasites at baseline and every subsequent 3 months until month 18 (M18). A final screening was done at M24. MDAs were conducted on M0, M1 and M2 in two villages and on M9, M10, M11 in the remaining two villages. Which villages received early or deferred MDA was decided using restricted randomization. MDA participation, clinical episodes and uPCR detected infections were mapped to participant houses. Scan statistics were used to test for clusters of malaria episodes, malaria infections and non-adherence to MDA. Mixed effects regressions were used to test for risk factors for clinical episodes after MDA.\n\nResultsNeighborhood level MDA adherence was a major predictor for clinical episodes of malaria post-MDA, suggesting a strong herd effect. Each village had a cluster of P. falciparum infections at M0. After M0, there were no clusters of uPCR detectable P. falciparum infections. Clinical episodes of P. falciparum occurred in one village only which had a cluster of non-adherence to MDA and a high mosquito vector human biting rate. Individuals with subclinical P.falciparum infections were more likely to have subsequent clinical episodes than individuals who had no subclinical infections. Individuals who lived in a house with someone who had a clinical episode were more likely to also have a clinical episode subsequently than individuals residing in a house free of P.falciparum infections.\n\nConclusionTo our knowledge this is the first study to show a herd effect from MDA for malaria. These data and results have significance for spatial targeting of interventions for malaria elimination. Clusters of non-adherence to MDA participation can lead to failed elimination if they occur among individuals with asymptomatic infections and given sufficient mosquito vector exposure. Community participation, which can be facilitated through community engagement, is key to MDA success.

epidemiology↗

bioRxiv2018

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk

Late onset Alzheimers disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

genetics↗